Substance Evaluation Conclusion document EC No 202-049-5
SUBSTANCE EVALUATION CONCLUSION
as required by REACH Article 48
and
EVALUATION REPORT
for
Naphthalene
EC No 202-049-5
CAS No 91-20-3
Evaluating Member State(s): United Kingdom
Dated: December 2018
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA Page 2 of 100 December 2018
Evaluating Member State Competent Authority
HSE
CRD, Redgrave Court
Merton Road, Bootle
Merseyside, L20 7HS
Email: UKREACHCA@hse.gov.uk
Year of evaluation in CoRAP: 2016
Member State concluded the evaluation without any further need to ask more information from
the registrants under Article 46(1) decision.
Further information on registered substances here:
http://echa.europa.eu/web/guest/information-on-chemicals/registered-substances
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA Page 3 of 100 December 2018
DISCLAIMER
This document has been prepared by the evaluating Member State as a part of the substance
evaluation process under the REACH Regulation (EC) No 1907/2006. The information and views
set out in this document are those of the author and do not necessarily reflect the position or
opinion of the European Chemicals Agency or other Member States. The Agency does not
guarantee the accuracy of the information included in the document. Neither the Agency nor the
evaluating Member State nor any person acting on either of their behalves may be held liable
for the use which may be made of the information contained therein. Statements made or
information contained in the document are without prejudice to any further regulatory work that
the Agency or Member States may initiate at a later stage.
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA Page 4 of 100 December 2018
Foreword
Substance evaluation is an evaluation process under REACH Regulation (EC) No.
1907/2006. Under this process the Member States perform the evaluation and ECHA
secretariat coordinates the work. The Community rolling action plan (CoRAP) of substances
subject to evaluation, is updated and published annually on the ECHA web site
1
.
Substance evaluation is a concern driven process, which aims to clarify whether a
substance constitutes a risk to human health or the environment. Member States evaluate
assigned substances in the CoRAP with the objective to clarify the potential concern and,
if necessary, to request further information from the registrant(s) concerning the
substance. If the evaluating Member State concludes that no further information needs to
be requested, the substance evaluation is completed. If additional information is required,
this is sought by the evaluating Member State. The evaluating Member State then draws
conclusions on how to use the existing and obtained information for the safe use of the
substance.
This Conclusion document, as required by Article 48 of the REACH Regulation, provides the
final outcome of the Substance Evaluation carried out by the evaluating Member State.
The document consists of two parts i.e. A) the conclusion and B) the evaluation report. In
the conclusion part A, the evaluating Member State considers how the information on the
substance can be used for the purposes of regulatory risk management such as
identification of substances of very high concern (SVHC), restriction and/or classification
and labelling. In the evaluation report part B the document provides explanation how the
evaluating Member State assessed and drew the conclusions from the information
available.
With this Conclusion document the substance evaluation process is finished and the
Commission, the Registrant(s) of the substance and the Competent Authorities of the other
Member States are informed of the considerations of the evaluating Member State. In case
the evaluating Member State proposes further regulatory risk management measures, this
document shall not be considered initiating those other measures or processes. Further
analyses may need to be performed which may change the proposed regulatory measures
in this document. Since this document only reflects the views of the evaluating Member
State, it does not preclude other Member States or the European Commission from
initiating regulatory risk management measures which they deem appropriate.
1
http://echa.europa.eu/regulations/reach/evaluation/substance-evaluation/community-rolling-action-plan
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 5 December 2018
Contents
Part A. Conclusion .............................................................................................. 7
1. CONCERN(S) SUBJECT TO EVALUATION ......................................................... 7
2. OVERVIEW OF OTHER PROCESSES / EU LEGISLATION ................................... 7
3. CONCLUSION OF SUBSTANCE EVALUATION .................................................... 9
4. FOLLOW-UP AT EU LEVEL ................................................................................ 9
4.1. Need for follow-up regulatory action at EU level ................................................................. 9
4.1.1. Harmonised Classification and Labelling ......................................................................... 9
4.1.2. Identification as a substance of very high concern, SVHC (first step towards authorisation) .. 9
4.1.3. Restriction ................................................................................................................. 9
4.1.4. Other EU-wide regulatory risk management measures ................................................... 10
5. CURRENTLY NO FOLLOW-UP FORESEEN AT EU LEVEL ................................... 15
5.1. No need for regulatory follow-up at EU level .................................................................... 15
5.2. Other actions .............................................................................................................. 15
6. TENTATIVE PLAN FOR FOLLOW-UP ACTIONS (IF NECESSARY) ..................... 15
Part B. Substance evaluation ............................................................................ 16
7. EVALUATION REPORT ................................................................................... 16
7.1. Overview of the substance evaluation performed ............................................................. 16
7.2. Procedure ................................................................................................................... 18
7.3. Identity of the substance .............................................................................................. 18
7.4. Physico-chemical properties .......................................................................................... 20
7.5. Manufacture and uses .................................................................................................. 20
7.5.1. Quantities ................................................................................................................ 20
7.5.2. Overview of uses ...................................................................................................... 20
7.6. Classification and Labelling ........................................................................................... 27
7.6.1. Harmonised Classification (Annex VI of CLP) ................................................................ 27
7.6.2. Self-classification ...................................................................................................... 28
7.7. Environmental fate properties ....................................................................................... 28
7.8. Environmental hazard assessment ................................................................................. 28
7.9. Human Health hazard assessment ................................................................................. 28
7.9.1. Toxicokinetics ........................................................................................................... 29
7.9.2. Acute toxicity and Corrosion/Irritation ......................................................................... 30
7.9.3. Sensitisation............................................................................................................. 39
7.9.4. Repeated dose toxicity ............................................................................................... 39
7.9.5. Germ cell Mutagenicity .............................................................................................. 51
7.9.6. Carcinogenicity ......................................................................................................... 51
7.9.7. Toxicity to reproduction (effects on fertility and developmental toxicity) .......................... 66
7.9.8. Hazard assessment of physico-chemical properties ........................................................ 66
7.9.9. Selection of the critical DNEL(s)/DMEL(s) and/or qualitative/semi-quantitative descriptors for
critical health effects ............................................................................................. 66
7.9.10. Conclusions of the human health hazard assessment and related classification and
labelling ............................................................................................................... 69
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 6 December 2018
7.10. Assessment of endocrine disrupting (ED) properties ....................................................... 70
7.11. PBT and VPVB assessment .......................................................................................... 70
7.12. Exposure assessment ................................................................................................. 70
7.12.1. Human health ......................................................................................................... 72
7.12.2. Environment ........................................................................................................... 86
7.12.3. Combined exposure assessment ................................................................................ 86
7.13. Risk characterisation .................................................................................................. 87
7.14. Additional information ................................................................................................ 91
7.15. References ................................................................................................................ 93
7.16. Abbreviations ............................................................................................................ 97
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 7 December 2018
Part A. Conclusion
1. CONCERN(S) SUBJECT TO EVALUATION
Naphthalene was placed on the CoRAP because the worker inhalation DNEL of 25 mg/m
3
(8-hour Time Weighted Average (8-hr TWA)) used in the registration dossiers is
substantially higher than the national occupational exposure limits (OELs) of 0.5 mg/m
3
,
8-hr TWA and short term limit established in Germany in 2011
2
. Exposure data obtained
at the time of the Existing Subtances Regulation (ESR) review suggests workers may be
exposed to levels significantly above the new German OEL. It is important to determine
how the use profile and exposure situation has changed since the previous review. Also,
there is evidence that substitutes may now be available for some uses.
The DNEL value in question relates to inflammatory reactions in the olfactory epithelium,
where tumours have been observed in rats. Therefore irritation to the respiratory tract,
repeated dose inhalation toxicity and carcinogenicity were all included within the scope of
the human health hazard evaluation. In addition, an assessment of haemolytic anaemia
was made since this effect is a lead health concern for naphthalene.
2. OVERVIEW OF OTHER PROCESSES / EU
LEGISLATION
The following EU wide legislation includes specific provisions for naphthalene:
Biocidal Products Directive (98/8/EC): Napthalene is listed in Annex I “Active
substances identified as existing” and Annex II “Active substances to be examined under
the review programme” as product type 19 (“Repellant and attractants”). No satisfactory
application was submitted within the permitted timeframe therefore a non-inclusion
decision was taken and from 29 July 2008 naphthalene has not been permitted to be used
in mothballs supplied to the EU market.
Cosmetics Regulation (Regulation (EC) No. 1223/2009): Napthalene is listed as
entry no. 1167 in Annex II “List of substances prohibited in cosmetic products” meaning it
must not be used as an ingredient in cosmetic products.
Water Framework Directive (2008/105/EC): Naphthalene is listed as a priority
substance. Environmental quality standards have been established for naphthalene. There
are an annual average EQS for inland and other surface waters of 2 µg/l and maximum
allowable concentration for inland and other surface waters of 130 µg/l.
Pollutant Release and Transfer Register (Regulation (EC) No. 166/2006):
Naphthalene is listed as entry no 68 in Annex II of this regulation and is therefore one the
pollutants for which information on releases must be submitted to a central European
register providing certain conditions are met. The capacity thresholds triggering reporting
are:
Threshold for release to air: 100 kg/year
Threshold for release to water: 10 kg/year
Threshold for release to land: 10 kg/year
2
A list of OELs worldwide for naphthalene can be found at:
http://limitvalue.ifa.dguv.de/WebForm_ueliste2.aspx (accessed June 2018). In 2018, the German
OEL was revised again to 2 mg/m
3
(8-hr TWA) accompanied by a skin notation (see:
https://www.baua.de/DE/Angebote/Rechtstexte-und-Technische-
Regeln/Regelwerk/TRGS/pdf/TRGS-900.pdf?__blob=publicationFile) (accessed October 2018) .
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 8 December 2018
Threshold for off-site transfer of pollutants: 100 kg/year
Manufacture, process or use threshold: 10,000 kg/year
Inland Transport of Dangerous Goods Directive (2008/68/EC): Napthalene is listed
with UN no.1334 and is subject to the rules for transporting dangerous goods established
by this directive.
First IOELV directive (2000/39/EC): This directive brought the limit value for
naphthalene of 50 mg/m
3
(8-hr TWA) that was established under the 1
st
ILV directive into
scope of the Chemical Agents Directive.
Previous assessments covering the human health effects and use patterns of naphthalene
include:
Existing Substances Regulation (Regulation (EEC) No. 793/93): Naphthalene was
included in the first priority list of substances. The risk assessment report was
published in 2003 with an addendum covering a risk assessment for the
environment published in 2007
3
.
US Department of Health and Human Services, Agency for Toxic Substance and
Disease Registry (2005)
4
. Toxicological Profile for naphthalene, 1-
mehtylnaphthalene and 2-methylnaphthalene.
UK Health Protection Agency (2007)
5
. Naphthalene health effect, incident
management and toxicology. Information on naphthalene (also called naphthene or
naphthalin), for responding to chemical incidents.
IARC (2002)
6
. Some Traditional Herbal Medicines, Some Mycotoxins, Naphthalene
and Styrene.
SCOEL (2010). Recommendation from the Scientific Committee on Occupational
Exposure Limits for naphthalene. SCOEL/SUM/90 (European Commission, 2010)
IPCS (2000)
7
. International Programme on Chemical Safety, Poisons Information
Monograph 363.
DECOS (2012)
8
. Naphthalene. Evaluation of the genotoxicity and carcinogenicity.
Subcommittee on the Classification of Carcinogenic Substances of the Dutch Expert
Committee on Occupational Safety (DECOS), a Committee of the Health Council of
the Netherlands
Danish EPA (2015)
9
. Survey of naphthalene (CAS 91-20-3). Environmental project
No. 1721, 2015. ISBN no. 978-87-93352-34-6.
WHO (2010)
10
. WHO Guidelines for Indoor Air Quality: Selected Pollutants. ISBN-
13: 978-92-890-0213-4
AGS, Ausschuss für Gefahrstoffe (2018). AGW - Begründung zu Naphthalin in TRGS
900
11
3
https://echa.europa.eu/information-on-chemicals/information-from-existing-substances-regulation/-
/substance-rev/2491/term (accessed November 2016)
4
http://www.atsdr.cdc.gov/ToxProfiles/tp67.pdf (accessed November 2016)
5
https://www.gov.uk/government/publications/naphthalene-properties-incident-management-and-toxicology
(accessed November 2016)
6
http://monographs.iarc.fr/ENG/Monographs/vol82/ (accessed November 2016)
7
http://www.inchem.org/documents/pims/chemical/pim363.htm (accessed November 2016)
8
https://www.gezondheidsraad.nl/sites/default/files/Naftaleen201230.pdf (accessed November 2016)
9
http://mst.dk/service/publikationer/publikationsarkiv/2015/jul/survey-of-naphthalene/ (downloaded
November 2016)
10
https://www.ncbi.nlm.nih.gov/books/NBK138704/ (accessed November 2016)
11
http://www.baua.de/de/Themen-von-A-Z/Gefahrstoffe/TRGS/Arbeitsplatzgrenzwerte.html__nnn=true
(accessed October 2018)
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 9 December 2018
3. CONCLUSION OF SUBSTANCE EVALUATION
The evaluation of the available information on the substance has led the evaluating Member
State to the following conclusions, as summarised in Table 1 below.
Table 1
CONCLUSION OF SUBSTANCE EVALUATION
Conclusions
Tick box
Need for follow-up regulatory action at EU level
Harmonised Classification and Labelling
Identification as SVHC (authorisation)
Restrictions
Other EU-wide measures (update EU-wide OEL)
No need for regulatory follow-up action at EU level
4. FOLLOW-UP AT EU LEVEL
4.1. Need for follow-up regulatory action at EU level
4.1.1. Harmonised Classification and Labelling
Not applicable.
4.1.2. Identification as a substance of very high concern, SVHC (first
step towards authorisation)
Naphthalene does not meet the criteria outlined in Article 57 for identification as a
substance of very high concern.
4.1.3. Restriction
Although the eMSCA considers that the registrants’ DNEL is too high, there is no evidence
that any registered use of naphthalene is creating unacceptable risks to workers. No
restrictions are currently foreseen. Instead, the eMSCA proposes that the EU-wide OEL
value of 50 mg/m
3
should be revised (see section 4.1.4).
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UK MSCA 10 December 2018
4.1.4. Other EU-wide regulatory risk management measures
The eMSCA concludes that for naphthalene, setting an OEL under workplace legislation
provides the best framework to determine an appropriate level for worker exposure and
the corresponding risk management measures.
The lead health concerns for naphthalene are haemolytic anaemia and carcinogenicity. Now
and in the future, (potential) exposures in the workplace are the principal exposure
scenarios of concern.
Evidence from humans drives the concern for haemolytic anaemia since the main
experimental species (rats, mice and rabbits) do not appear to be a suitable model for this
effect. In humans, the occurrence of haemolytic anaemia has been reported in at least 30
individuals, typically following single or repeated oral intake of naphthalene mothballs but
also following inhalation and dermal exposure to naphthalene from clothing. Individuals
who are deficient in the enzyme glucose-6-phosphate dehydrogenase (G6PD) may be more
susceptible to the haemolytic effects of naphthalene than others in the general population.
Owing to the circumstances surrounding the poisoning incidents, it is not possible to
determine the doses involved and the nature of the dose-response relationship cannot be
identified. It is therefore not possible to calculate a derived no effect level (DNEL) for this
effect and perform a quantitative risk characterisation. At the time of the ESR review, an
investigation was performed into the feasibility of conducting a workplace survey to look
for signs of haemolytic anaemia. However, it was determined that the only suitable
population for such a study (the workforce of a mothball manufacturing plant was identified
because they were exposed to high levels of naphthalene without confounding exposures)
was too small to draw meaningful conclusions. No further information was therefore
requested and it was concluded in the ESR Risk Assessment Report (RAR) that body
burdens in the mg/kg range may be of concern for haemolytic anaemia.
Very little new information has emerged since the ESR review to shed further light on a
no-effect level for haemolytic anaemia in humans. In the light of this continuing
uncertainty, the conclusion remains that body burdens in the mg/kg range may be of
concern. It is also the case that there is no evidence to clarify whether or not naphthalene
exposed workers currently experience haemolytic anaemia; if they do, then one can infer
from the absence of reports that the degree of effect is not sufficient to prevent them from
attending work.
The concern for carcinogenicity is driven by experimental evidence, particularly from
studies in rats. In long-term repeated exposure studies, nasal tumours have been observed
at levels that also caused non-neoplastic inflammatory changes and it appears likely that
inflammation is a necessary precursor for the tumours. The ESR review concluded that the
tumours observed in animal studies are likely to have arisen via a non-genotoxic
mechanism and this conclusion has been upheld by the mode of action (MoA) analysis
performed during this evaluation.
The postulated mode of action (MoA) for the nasal tumours in rats proposes that
naphthalene is metabolised to cytotoxic metabolites by a CYP enzyme (CYP2F) in tumour-
forming tissues. Those metabolites are responsible for the inflammation and regenerative
hyperplasia which precede carcinogenesis. The presence of a CYP2F enzyme in humans
indicates that there is a potential for similar naphthalene metabolism in humans. The
anatomical, physiological and metabolic differences between rats and humans, including
breathing route, anatomy of the nasal cavity and (based on findings from in vitro studies)
the likely lower rate of naphthalene metabolism in humans are noted. On the basis of these
differences, it is possible that the consequences of naphthalene inhalation in humans will
vary from those observed in the rat.
There is no evidence of nasal tumours resulting from naphthalene exposure in humans.
However, the absence of case reports or other forms of epidemiological study of this issue
cannot be considered to represent convincing evidence that the tumours observed in rats
are not relevant to humans.
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 11 December 2018
In mice receiving inhalation exposure to naphthalene, tumours were not observed in nasal
tissue. However, it is not known whether the mouse or rat is a better model for the effects
of naphthalene inhalation exposure.
Therefore the total information available is not sufficient to conclude that the finding of
nasal tumours in rats exposed to naphthalene by inhalation is not relevant for humans
(albeit that humans might well be at least quantitiatively less sensitive to such an effect).
The current Carc Cat. 2 classification is based on this perspective.
In setting their long-term inhalation DNEL of 25 mg/m
3
(8-hr TWA), the registrants chose
to rely on information obtained from an unpublished survey of workers at 12 European
abrasives producers, conducted in 2010. Few details from this survey were provided in the
registration. Company doctors are reported to have never observed blood anomalies or
haemolytic anaemia or other occupational health effects in workers, some of whom had
been employed for up to 40 years. However, the registrants have not provided sufficient
information about the endpoints that were assessed in medical examinations of these
workers, nor the frequency of examinations, to understand how comprehensive these
assessments were. It is claimed that workers were regularly exposed to levels approaching
25 mg/m
3
(8-hr TWA). However, no information has been provided to confirm the levels
of exposure these workers were subjected to in their daily work and a more recent study
in this sector (Sucker et al, 2016) reported a maximum personal 8-hr TWA value of 11.58
mg/m
3
(see table 31). The registrants have therefore not provided sufficient evidence to
demonstrate that their DNEL will be protective of worker’s health and the eMSCA
considered alternative routes by which an appropriate and robust DNEL can be derived.
If the conventional DNEL setting approach is followed, in the absence of reliable dose
response data from humans, a suitable starting point should be selected from studies in
animals. The no-observed adverse effect concentration (NOAEC) from the 90-day
inhalation study by Dodd et al (2012) of 0.52 mg/m
3
provides such a starting point. At the
next dose administered to rats in this study, 5.24 mg/m
3
, only minimal hyperplasia was
observed in the respiratory/transitional epithelium suggesting the true no-effect
concentration might lie somewhere between 0.52 and 5.24 mg/m
3
. Since no further
information is available to identify a more accurate no-effect concentration, it would be
necessary to use the value of 0.52 mg/m
3
as the starting point which, if the conventional
assessment factors are applied, leads to a worker, long-term inhalation DNEL of 0.053
mg/m
3
.
However, a recent workplace study (Sucker et al, 2016) found no consistent evidence for
nasal inflammation in workers occupationally exposed to levels up to 10 mg/m
3
(8-hour
time weighted average (TWA)) naphthalene. In this study, a battery of tests were
performed to look for signs of nasal inflammation and adverse effects on olfactory function.
Endoscopic examinations of nasal tissues revealed that slight to moderate inflammation
was present in participants from the high exposed, moderately exposed and reference
groups (which had daily naphthalene exposures of 6.97±3.10 mg/m
3
(8 hr TWA)
(arithmetic mean±standard deviation), 0.66±0.27 mg/m
3
(8-hr TWA) and 0.15±0.10
mg/m
3
(8-hr TWA) respectively). A comparison of readings taken on Monday and Thursday
revealed an increase in endoscopy examination scores (suggesting more severe
inflammation) in some individuals from each group and a decrease in scores (suggesting
less severe inflammation) from other individuals, with a greater tendency (statistically
significant) for scores to increase (Monday – Thursday) in moderately and high exposed
workers compared with the reference group. However, there were no differences between
the moderate and high exposed groups, despite the 10-fold higher naphthalene exposure
in the high exposed group. No consistent changes were observed in biomarkers for
inflammation in nasal lavage or sputum samples from the exposed and reference groups.
Also, where statistical differences were observed between the exposed and reference
groups, there was often a high degree of overlap in the range of results (for example, for
total endoscope scores, the Thursday readings ranged from 0-13 in the high exposed
group, from 3-13 in the moderately exposed group and from 0-9 in the reference group).
Complicating the analysis is the fact that both exposure groups were also exposed to
inhalable and respirable dusts including ceramic grain and silica which could have
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 12 December 2018
contributed to the observed nasal inflammation. It is therefore difficult to determine what
role naphthalene might have played in any nasal effects observed in these workers.
Overall, there was no indication of a substantial effect of naphthalene inhalation on nasal
irritation, with exposures up to about 7 mg/m
3
(8-hr TWA). On this basis, a DNEL of 0.053
mg/m
3
(8-hr TWA) will be a very precautionary value given the lack of consistent evidence
for inflammatory changes associated with naphthalene in workers with daily exposure to
levels of naphthalene over 100 times higher than this DNEL.
It is also worth noting that the DNEL is at the low end of the range of exposures recorded
for office workers that are spatially separated from areas where naphthalene is in use
(exposures for these office workers ranged from 0.05 – 1.05 mg/m
3
(8-hr TWA) (see table
31)). This suggests that if exposures are to be maintained below this DNEL, it is likely that
there would need to be a major redesign of the sites where the data for Sucker et al were
collected and potentially other sites using naphthalene. Requiring the downstream use
chain for naphthalene registrants to adopt this DNEL would also set higher standards of
control for these sites compared with sites where exposure to naphthalene arises because
it is a component in a substance of unknown or variable composition (UVCB) or generated
as a process by-product. For example, Price and Jaycock (2008) suggested exposure to
naphthalene can be expected to be in the range 0.01 – 0.3 mg/m
3
(8-hr TWA) for refining
and petroleum industries, asphalt (paving and roofing) and industries using pitch to
manufacture refractory materials or graphite electrodes. For these reasons the eMSCA does
not think that a DNEL of 0.053 mg/m
3
provides a workable reference point from which to
derive a control strategy for naphthalene.
Due to the lack of understanding of the most appropriate experimental models for the
effects of naphthalene in humans, the eMSCA does not consider that requiring further
experimental studies is an appropriate course of action. Instead, the eMSCA proposes that
an EU-wide OEL will be the most appropriate way to manage risks. Setting an EU-wide
limit value would not only target the sectors of use that have been covered by this
evaluation, but would also target other sectors where exposure to naphthalene arises
because it is a component in a substance of unknown or variable composition (UVCB) or
because it is generated as a process by-product. It would ensure that consistent standards
of control are adopted wherever there is occupational exposure to naphthalene and that
these standards apply across all EU-territories.
The current EU-wide Indicative Occupational Exposure Limit Value (IOELV) of 50 mg/m
3
(8-hr TWA) was introduced via the first Indicative Limit Value Directive (91/322/EEC) and
was directly transposed into the current system via the second IOELV Directive
(2006/15/EC). Although the IOELV has been reviewed by the Scientific Committee on
Occupational Exposure Limits (SCOEL, 2010), the review took place at a time when
potentially relevant experimental studies were ongoing. SCOEL therefore declined to
recommend a limit value pending publication of this data.
The studies SCOEL were waiting for have now been published along with a new workplace
study (Sucker et al, 2016) and all of the new evidence has been considered in this
evaluation. Since the IOELV is twice as high as the registrants’ DNEL of 25 mg/m
3
(8-hr
TWA) and five times higher than the levels in air measured by Sucker et al, (2016) for
directly exposed workers (up to around 10 mg/m
3
) the eMSCA concludes that the IOELV is
not providing any incentive for employers to improve workplace control. The current IOELV
should therefore be revised.
In considering what number should be adopted for the OEL, it will be useful to understand
the levels in air that are achievable with the currently applied controls and working
practices. REACH registrations only describe the registrants’ recommended risk
management measures but do not provide clarity about the measures currently
implemented by downstream users and the associated levels of exposure.
A key piece of information to take into account in setting the OEL is the biological
monitoring data obtained by Sucker et al, summarised in table 12. This showed that the
majority of non-smoking workers carrying out tasks involving direct exposure to
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 13 December 2018
naphthalene at levels of up to 10 mg/m
3
(8-hr TWA) do not appear to clear the body burden
of naphthalene accrued during the working week over the weekend. The 95
th
percentile
levels of unriary 1- and 2-napthol in directly exposed workers in pre-shift samples on
Monday was 958 µg/L compared with 85 µg/L in workers with indirect exposure and 18
µg/L in workers with no or rare exposure. Although Sucker et al did not measure body
burdens, the potential body burden corresponding to the exposures estimated for the
grinding wheel scenario can be calculated. If it is assumed that an average worker weighs
70 kg and inhales 10 m
3
air per shift, and that there is 100% absorption by the inhalation
route, the body burden accrued by the end of the week may be around 2.8 mg/kg (this
value is based on an estimated elimination constant (k
el
) of 0.5/d derived by the registrants
from the biomonitoring data presented by Sucker et al and does not take a possible
additional contribution from dermal exposure into account). . This value should be
considered commensurate with the “low mg/kg” range identified in the ESR RAR as
potentially of concern for the possibility of producing haemolytic anaemia. There was no
evidence in this study that maintaining an elevated body burden of naphthalene was
evidently detrimental to the health of the workers studied. However, significant
uncertainties apply: the study focussed on examinations of the nasal passages, markers
for haemolytic anaemia and G6PD deficiency were not investigated; there is uncertainty
surrounding the dose-response relationship for haemolytic anaemia, particularly taking
into account that around 4% of the European population may have the G6PD deficiency
making them more susceptible to naphthalene induced haemolytic anaemia, and; there is
uncertainty surrounding the dose-response relationship for nasal inflammation, with the
possibility that such inflammation could have the potential to progress to nasal tumour
development in humans. The eMSCA argues that, with all these uncertainties, it seems
sensible to aim to limit exposure to levels that do not cause workers to retain a residual
body burden of naphthalene from one week to the next.
The high urinary 1- and 2-napthol levels measured by Sucker et al (2016) could potentially
have arisen as a result of either inhalation or dermal exposure or a combination of the two.
The eMSCA has been informed that it is standard practice for these workers to wear gloves
if there is the potential for direct skin contact with naphthalene. Assuming that appropriate
gloves are being worn and suitable management systems are in place to ensure the gloves
are used correctly, this directs attention towards inhalation as being the main route of
exposure.
The conclusion is therefore reached that airborne exposures to naphthalene should be kept
below 10 mg/m
3
(8-hr TWA).
To ensure body burdens are kept within acceptable levels, it is not clear how far below 10
mg/m
3
it is necessary to reduce airborne exposure. Ideally this decision should be informed
by additional information linking measured airborne exposures with biological levels across
a range of sectors where there is the potential for exposure to naphthalene. Such an
extensive survey will require the voluntary participation of a wide range of companies and
workers and it seems unrealistic to place this as a requirement on the REACH registrants
of naphthalene. This is therefore identified as a recommendation from this evaluation.
It also seems appropriate to reflect on the potential exposures associated with the current
operating conditions and risk management measures identified in the naphthalene REACH
exposure scenarios.
For the manufacture of naphthalene and the use of naphthalene as a feedstock/
intermediate, worst case modelled estimates for PROCs 4, 8a, 8b and 9 suggest airborne
exposure may exceed 10 mg/m
3
if a worker performs these tasks exclusively for the entire
shift. It is possible that worker exposure has been overestimated, for example a higher
level of containment may be implemented than has been assumed in the exposure
calculations and the time workers spend working directly with naphthalene may be much
less than has been assumed. Unless more details are provided in registrations about the
way processes are currently operated it will not be possible to refine these worst case
estimates.
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 14 December 2018
The information provided in registrations and from Sucker et al about exposure to
naphthalene during the manufacture of abrasives suggests that additional control
measures should be implemented to further limit the release of naphthalene to air during
activities involving direct handling of naphthalene i.e. weighing, mixing, sieving, pressing
and moulding (see section 7.12.1.1.4 for details).
Very little information is available about the formulation, military use and service life of
naphthalene containing smoke bombs/grenades. This is another sector where naphthalene
exposures may be sufficiently high that workers retain a residual body burden from one
week to the next. Further information should be obtained to clarify working practices in
this sector. Decisions can then be taken about the need (or not) to implement additional
control measures e.g. containment or LEV to limit the release of naphthalene particulate
and vapour to air.
In summary, in addition to the conclusion that the existing EU-wide OEL for naphthalene
should be revised, the following recommendations are made:
To ensure that it is transparent in the exposure scenario how all relevant work
activities are covered, either a specific contributing scenario for routine cleaning
and maintenance activities should be provided or registrants should indicate which
of the already chosen contributing scenarios apply to these activities. Registrants
should update registrations with this information without undue delay.
To allow authorities to better understand the current operating conditions and any
risk management measures that are used, and to put the exposure estimates into
context, all registrants should provide additional descriptions of the the
tasks/activities that are performed and the risk management measures that are
applied for all uses covered in their CSRs. Registrants are recommended to update
registrations with this information without undue delay.
All sectors of industry where there is a potential for exposure to levels of
naphthalene that could approach or exceed 10 mg/m
3
(8-hr TWA) should consider
gathering information on levels in air and corresponding biological levels under
current working conditions. Where there is evidence that body burdens in workers
regularly exceed background levels at the start of the working week, operating
conditions and risk management measures should be re-examined. The Biologischer
Arbeitsstoffreferenzwert (BAR) of 35 µg total urinary 1- and 2-naphthol/L urine
established by the German Research Foundation (Deutsche
Forschungsgemeinschaft, DFG) may be a useful benchmark to use for this
assessment. If it appears necessary to reduce worker exposure, additional controls
should be implemented in accordance with the hierarchy of control described in the
Chemical Agents Directive (98/24/EC). In addition to the sectors covered in this
evaluation, it may also be useful to investigate exposure to naphthalene in other
sectors such as those where UVCB mixtures are used which contain naphthalene as
an impurity and sectors where naphthalene is emitted as a process by-product.
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 15 December 2018
5. CURRENTLY NO FOLLOW-UP FORESEEN AT EU LEVEL
5.1. No need for regulatory follow-up at EU level
Not applicable.
5.2. Other actions
Not applicable
6. TENTATIVE PLAN FOR FOLLOW-UP ACTIONS (IF
NECESSARY)
New data has become available since SCOEL published its recommendation in March 2010.
SCOEL and DG Employment are therefore recommended to prioritise this substance for
setting of a new OEL-value.
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 16 December 2018
Part B. Substance evaluation
7. EVALUATION REPORT
7.1. Overview of the substance evaluation performed
Naphthalene was included in the first Priority List of substances to be assessed under the
Existing Substances Regulation (EEC/793/93). Sections of the Risk Assessment Report
(RAR) covering risks to human health were finalised in 2003, and the environmental risk
assessment was finalised in 2007. The RAR identified a need for reducing the risks to
human health for a number of uses of naphthalene, namely:
All occupational exposure scenarios, except the professional use of coal tar soaps
and shampoos;
Consumer use of mothballs and
Consumer exposure following the laying of damp proofing.
A Risk Reduction Strategy (RRS) document was therefore prepared to examine options to
address these risks. This was finalised in 2007 and covered the following uses:
Manufacture of naphthalene;
Use in phthalic anhydride manufacture and other chemical synthesis;
Blending and use of creosote;
Manufacture of mothballs;
Manufacture and use of coal tar paints and waterproof membranes;
Professional use of consumer products e.g. creosote products and coal tar pitch
based damp proof laying;
Manufacture of grinding wheels;
Consumer use of mothballs and creosote;
Consumer exposure following damp proofing.
This evaluation aimed to confirm that the measures identified in the ESR RRS have been
taken into account by the Registrants in their CSRs.
After the ESR RRS was completed, the IOELV for naphthalene that is listed in the 1
st
IOELV
directive (50 mg/m
3
, 8-hr TWA) was reviewed by DG Employment’s Scientific Committee
on Occupational Exposure Limits (SCOEL). In 2010, SCOEL concluded that it was “not
feasible to derive a health-based limit” but that their conclusion should be reassessed when
further data about the carcinogenic potential of naphthalene became available. The
German authorities have also reviewed the MAK value for naphthalene and a new limit of
0.5 mg/m
3
(8-hr TWA) was established in 2011
12
. Given the uncertainties about the
sustainability of an IOELV of 50 mg/m
3
, the evaluation examined the available toxicological
data for naphthalene to see if the Registrant’s DNELs were appropriate.
12
http://limitvalue.ifa.dguv.de/WebForm_ueliste2.aspx (accessed November 2016). This limit was
revised to 2 mg/m
3
in 2018 (see: https://www.baua.de/DE/Angebote/Rechtstexte-und-Technische-
Regeln/Regelwerk/TRGS/pdf/900/900-naphthalin.pdf?__blob=publicationFile&v=3 , accessed
October 2018)
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 17 December 2018
There was also evidence that substitutes for naphthalene may be available for some uses.
The evaluation therefore looked at the use pattern for naphthalene to see how this has
changed since the ESR work was completed.
Table 2 shows a list of evaluated endpoints with corresponding outcomes. More details can
be found in the relevant sections below.
Table 2: Summary of endpoints evaluated
EVALUATED ENDPOINTS
Endpoint evaluated
Outcome/conclusion
Acute Toxicity (Haemolytic anaemia)
Haemolytic anaemia confirmed. Insufficient
information was available for DNEL
derivation.
Irritation to the respiratory tract
Effects on olfactory and respiratory epithelia
of the nasal cavity have been observed in rats
after acute exposure to naphthalene. NOAELs
could not be identified from these studies.
However, the DNEL derived for repeated dose
toxicity is considered to be protective for this
endpoint.
Repeated dose toxicity
A DNEL was derived for non-neoplastic
lesions caused by exposure to naphthalene by
inhalation.
Carcinogenicity
The nasal tumours in rats cannot be
dismissed as being irrelevant to humans. The
DNEL derived for repeated dose toxicity is
also considered to be protective for
carcinogenicity.
Exposure (human health)
There is evidence that the use pattern has
changed since the ESR review owing mainly
to changes in use as a biocide and in personal
care products. It is not possible to tell how
widely the recommendations made in the ESR
RRS have been implemented based on the
information provided in REACH registrations
and it is recommended that additional
descriptive information is provided on the
current operating conditions and risk
management measures that are applied at
sites manufacturing and using naphthalene
since this will help to put quantitative
exposure estimates into context. It is also
recommended that registrants update their
dossiers with scenarios to cover routine
cleaning and maintenance. There is a concern
that the current risk management approach
that is adopted in some sectors may result in
directly exposed workers maintaining a
residual body burden of naphthalene from
one week to the next . Further attention
needs to be paid in particular to limiting
airborne exposure since this seems to be the
dominant route.
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UK MSCA 18 December 2018
7.2. Procedure
The evaluation was targeted to the human health hazard and exposure concerns outlined
above. No evaluation of the environmental fate, hazard or risk assessment was
undertaken.
On the basis of an opinion of the ECHA Member State Committee and because of initial
grounds for concern relating to the numerical value of the DNEL adopted by the registrants
and about the potential exposure levels associated with certain uses, naphthalene CAS No
91-20-3 (EC No 202-049-5) was included in the Community rolling action plan (CoRAP) for
substance evaluation to be evaluated in 2016. The updated CoRAP was published on the
ECHA website on 17 March 2016. The Competent Authority of the United Kingdom
(hereafter called the evaluating MSCA / eMSCA) was appointed to carry out the evaluation.
The initial assessment started on 27 May 2016.
Analytical information provided in the dossiers was assessed to confirm substance identity
and composition.
The information assessed in the evaluation included that in the registration dossiers,
publically available information (see references in section 7.14) and information provided
to the eMSCA by the registrants and representatives of industry sectors using naphthalene.
The eMSCA held a teleconference with the registrants on 26 July 2016 to discuss the
evaluation process. A first draft of the use and exposure assessment was sent to the
registrants on 12 December 2016 to confirm that the information being presented in the
evaluation report was factually correct and that no confidential exposure and use
information had been included in the non-confidential sections of the report. This prompted
interactions between the eMSCA and representatives of the abrasive manufacturing sector
who agreed to provide further information to the eMSCA about the way naphthalene is
used in the manufacture of abrasives.
The new information was provided on 13 February 2017 and was taken into account by the
eMSCA along with information provided at a teleconference with the registrants and
representatives of the abrasive manufacturers on 7 March 2017.
Since the information available to the eMSCA in March 2017 was not sufficient to reach a
conclusion about risk and the adequacy of the recommended RMMs for each of the
exposure scenarions covered in REACH registrations, a draft decision document was
prepared. This asked for information to justify the approach taken to derive the long-term
inhalation DNEL. Requests were also made for more information about the methods used
to control naphthalene in air and the working practices that are used to limit worker contact
with naphthalene during specific activities.
During the commenting period, the registrants provided further information about the
approach taken to set their long-term inhalation DNEL. At this point the eMSCA took the
decision to terminate the decicion making process and conclude the evaluation with a
recommendation for the EU-wide OEL to be revised. Although the requested information
about controls and working practices had not been received and may be useful for the
limits setting process, the REACH decision making process does not seem to be the most
efficient way to obtain this requested information and it is desireable to avoid delay.
7.3. Identity of the substance
Table 3 displays the identity of the substance according to the ECHA dissemination website.
Table 3
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 19 December 2018
SUBSTANCE IDENTITY
Public name:
naphthalene
EC number:
202-049-5
CAS number:
91-20-3
Index number in Annex VI of the CLP
Regulation:
601-052-00-2
Molecular formula:
C
10
H
8
Molecular weight range:
128.17 g/mol
Synonyms:
Albocarbon
Dezodorator
Moth flakes
Naphthaline
Tar camphor
White tar
NSC 37565
Naphthene
Type of substance ☒Mono-constituent ☐ Multi-constituent ☐ UVCB
Structural formula:
Very limited information was provided by most of the registrants to confirm the identity of
the registered substance. It is recommended that registrants consider the requirements of
Annex VI 2.3.5 to ensure that they are compliant and have data specific to their
registration.
Most registrants provided some analytical information to support the composition reported
in section 1.2 of their dossiers, but registrants are reminded that they should include
sufficient information for the analysis to be reproduced. Table 4 gives the typical non-
confidential composition.
Table 4
Constituent
Constituents
Typical
concentration
Concentration range
Remarks
naphthalene
>80%
Exact concentration
confidential
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UK MSCA 20 December 2018
7.4. Physico-chemical properties
Table 5 lists the physicochemical properties for naphthalene from the ECHA dissemination
website. All of the information is taken from published articles or handbooks.
Table 5
OVERVIEW OF PHYSICOCHEMICAL PROPERTIES
Property
Value
Physical state at 20°C and 101.3 kPa
Solid white flakes/granules with aromatic odour
Melting/freezing point
79°C
Boiling point
218°C
Vapour pressure
10.5 Pa at 25 °C
Water solubility
31.7 mg/L at 25°C
Partition coefficient n-octanol/water (Log
Kow)
3.7 at 25°C
Flammability
Flammable
Flash Point
78.5°C
Explosive properties
The explosive limits by volume of fuel at 25 °C
and 760 mm Hg for naphthalene have been
quoted at 0.9 to 5.9 in Lange's Handbook (1992)
and Kirk-Othmer (1991) where the original
reference is to data obtained by the US Bureau
of Mines (Jones and Scott, 1946)
Granulometry
Supplied in molten mass, granules or flakes
Dissociation constant
Waived
Relative density
1.085 at 20°C (naphthalene pure)
7.5. Manufacture and uses
7.5.1. Quantities
Table 6 gives the tonnage information from the ECHA dissemination website.
Table 6
AGGREGATED TONNAGE (PER YEAR)
☐ 1 – 10 t
☐ 10 – 100 t
☐ 100 – 1000 t
☐ 1000- 10,000 t
☐ 10,000 – 100,000 t
☒ 100,000 –
1,000,000 t
☐ > 1000,000 t
☐ Confidential
7.5.2. Overview of uses
7.5.2.1 Manufacture
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UK MSCA 21 December 2018
Naphthalene may be produced from coal tar or petroleum with coal tar being the most
common source. A document published by the Danish EPA in 2015 suggests that over 92%
of world production in 2012 was produced from coal tar (Danish EPA, 2015). At the time
of this evaluation, 13 active registrants were listed on ECHA’s dissemination site located in
the UK (1), Czech Republic (2), Spain (3), Belgium (2), Germany (3), Denmark (1), Italy
(1)
13
. One inactive Registrant located in the Netherlands was also listed. This is a slight
change to the situation that was reported in the ESR review (ECB, 2003). When information
was gathered for the ESR review, companies producing naphthalene were located in the
UK, Belgium, France, Italy, Netherlands, Denmark, Germany, Austria and Spain. The
Austrian tar distillation plant closed around 1999 and the plant in France closed in 2005.
At the time of the ESR review, one company used both coal tar and petroleum as sources
for naphthalene, the remaining companies used coal tar as their only source. Production
figures from individual producers ranged from 4,000 to 70,000 tonnes per annum. The
total EU production was estimated at 200,000 tonnes per annum of which 60,000 tonnes
was exported and 152,000 tonnes used in EU. The total amount currently used in the EU,
including imports, is slightly higher than the total EU production estimated for the ESR
review.
Modern sites producing naphthalene generally do so under controlled conditions and in
contained systems with several sites operating under strictly controlled conditions (SCC).
Since naphthalene is processed at temperatures of around 90°C, pipelines are sealed and
insulated to maintain the necessary temperatures and workers operate the plant remotely
from control rooms. Naphthalene is supplied either in the molten state or as solid
granules/flakes. Where naphthalene is supplied in the molten state, it is possible to
maintain SCC throughout the production process. This is not possible where naphthalene
is supplied as granules/flakes.
The following manufacturing process information is based on descriptions provided in the
ESR report.
7.5.2.1.1 Production from coal tar
Naphthalene is produced from coal tar fractions by crystallisation and distillation.
Distillation of coal tar produces several fractions including the middle fraction (naphthalene
oil) which is the most abundant source of naphthalene and contains about 50% of the
naphthalene available from coal tar. The middle fraction is allowed to cool in shallow pans
and the naphthalene crystallises. The crude naphthalene produced may then be distilled
further. The yield of crude naphthalene is 4.8 kg/100 litres of coal tar. The naphthalene oil
fraction is then further processed to produce naphthalene. This processing can involve the
distillation of the naphthalene oil to produce a crude grade with a crystallisation point of
74°C to 78°C. This crude grade is suitable for applications such as the manufacture of
phthalic anhydride. A purer grade can be produced by treating the naphthalene oil fraction
with sulphuric acid followed by neutralisation and redistillation to give a product with a
crystallising point of over 79°C. However, this method does not completely remove
thionaphthalene which is the main impurity in the crude naphthalene. Alternatively, the
more commonly adopted method is to carry out a crystallisation of the naphthalene oil to
produce a pure grade that does not contain thionaphthalene and other impurities. The pure
grades produced by these methods can be used for applications such as insecticides.
Drained oils remaining from this purification of the naphthalene oil may be blended for use
in creosote oils or if not suitable they can be used in the manufacture of carbon black.
As well as the naphthalene oil, various other fractions are also produced which can contain
naphthalene. These oil fractions are further processed to separate commercially viable
chemicals such as anthracene from anthracene oil. Alternatively they are used in blends,
13
https://echa.europa.eu/registration-dossier/-/registered-dossier/15924 (accessed 17 January
2017)
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 22 December 2018
for example in base oil for road tar production. At the time of the ESR review, it was noted
that drained oils remaining from this further processing could be blended to produce
creosote, which may contain up to 25% naphthalene. Information provided informally to
the eMSCA during the evaluation suggests that modern creosote formulations do not
contain such high levels of naphthalene. A personal communication from Koppers Denmark
to the authors of the Danish EPA report stated the usual naphthalene content in creosote
is now around 5% (Danish EPA, 2015). Any remaining oils (these may contain about 4%
naphthalene) may be sold for the manufacture of carbon black. At the time of the ESR
review it was understood that some producers may supply heating oils containing up to
10% naphthalene. The eMSCA does not know if this is still the case.
7.5.2.1.2 Production from petroleum
Naphthalene may also be produced from petroleum fractions high in methylnaphthalenes.
Dealkylation is carried out at high temperature and pressure in the presence of hydrogen
to produce naphthalene that is 99% pure and low in sulphur. The ESR review indicated
that this method was only used by one European producer. Precise details of the process
were not reported. The literature details several methods that involve two principal steps.
The first is the production of an aromatic oil in the naphthalene - alkylnaphthalene boiling
range by hydroaromatization or cyclisation. The second step is the dealkylation of such oils
either thermally or catalytically. The naphthalene that is produced, usually by
crystallisation, is recovered as a high quality product, usually by fractional distillation.
Naphthalene is also recovered from the stream of methyl naphthalenes formed in cracking
of heavy liquids (naphthas and gas oils) for ethylene production.
7.5.2.2 Use
Since the ESR review, the range of uses for naphthalene in the EU has narrowed and
several uses resulting in exposure to professionals and consumers have ceased. Table 7
provides a comparison of uses covered by current registrations with the uses identified in
the ESR report.
Table 7: Identified uses for naphthalene
USES
Registered use(s)
Uses identified in the ESR review*
Uses as
intermediate
Use as a feedstock in the
manufacture of other substances
under SCC
Use as an intermediate
Use as a feedstock in the manufacture
of other substances
Use as an intermediate
Formulation
Formulation of smoke
bombs/grenades (military use)
Formulation into pyrotechnics
Formulation of mothballs
Formulation of coal tar paints and
waterproofing membranes
Formulation of creosote
Uses at
industrial sites
Distribution
Use of naphthalene in the abrasive
industry
Distribution
Use of naphthalene in the abrasive
industry
Uses by
professional
workers
Military use of smoke
bombs/grenades (including reloading)
Use of pyrotechnics
Use of creosote
Use of coal tar paints and
waterproofing membranes
Use of coal tar shampoos/soaps
Use of mothballs
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UK MSCA 23 December 2018
Uses by
consumers
Use of creosote
Use of coal tar paints and
waterproofing membranes
Use of coal tar shampoos/soaps
Use of mothballs
Article service
life
Service life of smoke bombs/grenades
Service life of pyrotechnics
Service life of mothballs
Service life of coal tar paints and
waterproofing membranes
* Uses in grey are not reported in REACH registrations for naphthalene
7.5.2.2.1 Use as an intermediate
The majority of naphthalene produced and imported into the EU is used as an intermediate
in the manufacture of phthalic anhydride, azo dyes, naphthalene sulphonic acids, alkylated
naphthalene solvents, 2-naphthol, pharmaceuticals and insecticides. Table 8 lists the
tonnages directed to different manufacturing processes reported in the ESR review. This
level of detail is not provided in registration dossiers so it is not possible to update the
tonnages directed to specific chemical manufacturing processes. However, aggregated
information indicates that currently over 200,000 tpa naphthalene is used as an
intermediate including use under SCC.
Table 8: Best estimates from the ESR review for naphthalene tonnages used in
production streams using naphthalene as feedstock (ECB, 2003)
Use
Tonnage (from
ESR report)
Manufacture of phthalic anhydride
40,000 tpa
Manufacture of azo dyes
46,000 tpa
Manufacture of naphthalene sulphonic acids
24,000 tpa
Manufacture of alkylated naphthalene solvents
15,000 tpa
Manufacture of 2-naphthol
12,000 tpa
Manufacture of pharmaceuticals
4,000 tpa
Total
141,000 tpa
One major use for naphthalene is as an intermediate in the manufacture of phthalic
anhydride. The ESR review reported that this process was carried out at 3 sites (ECB,
2003). ECHA’s dissemination site now lists 29 active registrants and 3 inactive registrants
across many EU countries (site accessed on 11 October 2016). The aggregated tonnage of
these registrations is 100,000 to 1,000,000 tpa. Ortho-xylene is an alternative feedstock
and the amount of naphthalene that is used depends on the relative prices of these two
substances (Griego et al, 2008, Danish EPA, 2015).
Naphthalene is used in the production of azo dyes via the intermediates 2-naphthol and
naphthalene sulphonic acids. Historically this was a major use accounting for 46,000 tpa
in 1986 (BUA, 1989). The eMSCA does not have information on whether and how this has
changed in the in the intervening 30 years.
Naphthalene is used to produce naphthalene sulphonic acids by reaction with formaldehyde
and sulphuric acid and subsequent neutralisation with sodium hydroxide and ammonia.
The principal use for naphthalene sulphonic acids is for the manufacture of plasticisers for
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 24 December 2018
concrete. Naphthalene sulphonic acids are also used in the manufacture of an ingredient
for plasterboard (wallboard or drywall), as dispersants in synthetic and natural rubbers, in
tanning agents (syntans) for the leather industry, as dispersants in pesticide formulations
and in lead-acid battery plates. Naphthalene sulfonic acids are also used in the synthesis
of 1-naphthol and 2-naphthol, precursors for various dyestuffs, pigments, rubber
processing chemicals and other chemicals and pharmaceuticals. There is understood to be
only negligible residual naphthalene remaining in the naphthalene sulphonic acids after
reaction. The tonnage information reported in the ESR review dates from 1986. More recent
information obtained for the Danish EPA report suggests that around 50% of global
naphthalene demand and 70% of China’s demand is now used to manufacture naphthalene
sulphonic acids (Danish EPA, 2015). The eMSCA does not know if the EU has a similarly
high demand.
At the time of the ESR review, one company used naphthalene to manufacture alkyl
naphthalene sulfonates. These surfactants are used in many industrial applications as
nondetergent wetting agents that effectively disperse colloidal systems in aqueous media.
The major commercial applications are in the agricultural chemical industry, which uses
alkyl naphthalene sulfonates for wettable powder and wettable granular (dry-flowable)
formulations, and the textile and fabric industry, which utilizes the wetting and defoaming
properties for bleaching and dyeing operations.
The ESR review identified one company using naphthalene to manufacture 2-naphthol. The
assumption in the ESR review that about 12,000 tonnes of naphthalene per annum is used
in this process may be inaccurate since this intermediate is used in the manufacture of azo
dyes and there may have been some double counting in assigning tonnages to these uses.
The 1989 BUA report estimated that 4,000 tonnes of naphthalene were used as a feedstock
in various “miscellaneous” applications in 1986. No details are provided, but one of these
may have been the manufacture of the insecticide 1-naphthyl-N-methylcarbamate (trade
names Carbaryl, or Sevin, although this substance is not believed to be produced in
significant quantities within the EU). The eMSCA does not have any more recent
information.
7.5.2.2.2 Smoke bombs
Naphthalene is used in pyrotechnics to simulate explosions or create black smokes. The
REACH registrations limit this use to smoke bombs and grenades for military use.
Previously it was also used to create special effects in the film industry. Although this use
is not covered in registrations, it cannot be excluded that some special effects companies
may import small quantities of naphthalene containing pyrotechnics. The ESR review states
that around 15 tpa of naphthalene were being used to manufacture pyrotechnics across
eight sites; four in the UK, two in Germany, and one each in France and Italy. It is not
known if all of the sites identified at the time of the ESR review are still operating.
7.5.2.2.3 Abrasives
Naphthalene is used as an artificial pore former in the manufacture of grinding wheels to
give a high porosity product. At the time of the ESR review, there were at least 3 companies
in the EU using a total of 350 tpa naphthalene to produce grinding wheels. Further
information was gathered for the risk reduction strategy from companies involved in the
manufacture of grinding wheels in the UK, in other EU Member States, through trade
associations representing abrasives manufacturers in Member States and also with
manufacturers themselves. Several consultees reported using increased quantities of
naphthalene and thought that this trend would continue over the next few years. Only two
companies reported decreasing consumption figures. As a result of this new information,
it became apparent that at least 12 sites were making grinding wheels in the EU (one
consultee suggested that there may be 12 producers in Germany alone). It was estimated
that around 900 – 1,000 tpa naphthalene was being used for this purpose.
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 25 December 2018
Currently it is estimated that around 20-25 companies across Europe use naphthalene to
manufacture abrasives (Sucker et al, 2016). Information from REACH registrations
suggests the total tonnage currently used for this purpose lies between the tonnages
reported in the ESR review and the risk reduction strategy.
Options to substitute naphthalene with other substances were considered in the ESR RRS.
These include 1,4-dichlorobenzene (CAS No. 106-46-7), bubbled alumina and glass
spheres, butyl carbamate, plastics and plant-derived pore formers such as crushed nuts
and nut shells, wood chippings, rice and olive stones. Although some companies submitting
information for the RRS indicated substitution was an option for them, others identified
barriers relating to product quality and safety problems for certain products. Recently work
has been carried out to investigate the suitability of oxalic acid as a pore forming agent
14
.
In principle, the material may be suitable. However, it was found necessary to coat oxalic
acid granules with a water repellent coating to prevent its rehydration during processing.
The coating agent that was used in this study (30% stearic acid) produced cracks in the
grinding wheels and it was not possible to develop a suitable granulation process within
the time frame of the project. It is not clear what other efforts companies have made to
find substitutes for naphthalene since the risk reduction strategy document was finalised.
However, the eMSCA has been told informally that the abrasives sector is actively looking
for alternatives and some companies have already achieved complete substitution. No
further details about these substitutions were available.
7.5.2.2.4 Uses identified in the ESR report but not covered in registrations
Mothballs
At the time of the ESR review, about 1000 tpa naphthalene was being used to manufacture
moth repellants with most production being located at one site in Belgium. It was noted
that around 90% of the production at this site was exported out of the EU. Although
naphthalene was listed in Annex I of the Biocidal Products Directive (98/8/EC) as an
existing active ingredient, no application was submitted within the required timeframe so
a non-inclusion decision was taken. Since 29 July 2008, it has not been permitted to supply
mothballs containing naphthalene to the EU market although there may be some remaing
use in museums to protect articles preserved in storage drawers/cupboards from attack by
pests (Danish EPA, 2015).
Creosote
The ESR review reported that around 10,000 tpa naphthalene was being used to produce
creosote (ECB, 2003). Creosote and coal tar creosote are complex mixtures of coal tar
derivatives which may include naphthalene. They are commonly used as wood
preservatives for use against wood-destroying insects and wood-rotting fungi. When the
ESR review was conducted, creosote was approved for both amateur and professional use
and could contain up to 25% naphthalene according to specifications described in EN
13991:2003. Of the three grades described in this European Standard, only Grades B and
C are now produced. Grade B may contain up to 2% naphthalene. This is recommended
for pressure impregnation of poles for overhead power and telecommunication lines and
for structural timbers. Grade C is a higher boiling point grade and does not contain
naphthalene.
In 2003, creosote was typically used for outdoor in situ painting of wooden articles where
long service was required such as fences, telegraph poles and railway sleepers. Creosote
was not allowed for use inside residential property. In 2003, prohibitions on amateur use
introduced via Directive 2001/90/EC came into force, halting consumer use for outdoor
treatment of e.g. fences. Approvals for professional and industrial creosote/coal tar
creosote products were allowed to continue, subject to restrictions on the specification of
14
https://www.dbu.de/OPAC/ab/DBU-Abschlussbericht-AZ-29452.pdf (site accessed 22 November
2016, document in German)
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 26 December 2018
the products and restrictions on situations where wood that has been treated with
creosote/coal tar creosote could be used. These restrictions are now detailed in Annex
XVII, entry 31, of the REACH Regulation. The purpose of the restriction was to limit
exposure to benzo[a]pyrene and water extractable phenols and not specifically
naphthalene.
Subsequent to this, the use of creosote as a wood preservative has been reviewed under
the Biocidal Products Directive. As a result of the review, creosote has been included in
Annex 1 of Directive 98/8/EC subject to the conditions described in Directive 2011/71/EU
15
.
From 01 May 2013 wood preservatives containing creosote need to be authorised for use
in the EU and approvals have now been granted.
Coal tar paints and waterproofing membranes
At the time of the ESR review, tar containing naphthalene was used in some specialist
paints and waterproof membranes. This use accounted for around 26 tpa naphthalene. The
ESR RAR reported that waterproofing membranes contained about 1% naphthalene. Coal
tar paints contained about 1-2%, coal tar epoxy paints contained less than 0.1% and coal
tar polyurethane sealers less than 1%. These paints and membranes were generally used
by the building trade. Waterproof membranes were supplied in 2.5 litre containers up to
200 litre drums. These were generally used to retrospectively waterproof floors and walls,
and could be applied to wet surfaces. These systems were estimated to account for about
10% of the waterproofing market. One producer reported that about 600,000 litres of
waterproof membrane were used each year in the UK. The ESR RAR stated that tar paints
were not used in Germany and that the Scandinavian countries were moving away from
them. Information provided from trade associations for the ESR RRS document suggested
that naphthalene containing products were no-longer used and the eMSCA has not found
evidence to contradict this information. However, if such products are manufactured
outside the EU, it would be possible for companies and consumers to import small
quantities of naphthalene containing products via internet sales.
Coal tar shampoos and soaps
Shampoos and soaps are regulated under the Cosmetics Regulation (Regulation (EC) No.
1223/2009). Napthalene is listed as entry no. 1167 in Annex II “ list of substances
prohibited in cosmetic products” meaning it must not be used as an ingredient in cosmetic
products. If coal tar shampoos and soaps containing naphthalene are still produced outside
the EU, consumers could obtain these shampoos and soaps via internet sales or purchases
made while visiting non-EU countries.
7.5.2.2.5 Other substances that may contain naphthalene as a constituent
C
10
-C
12
aromatic hydrocarbon solvents
For the purposes of REACH registration, hydrocarbon solvents have been grouped into 9
categories based on the principle constituents
16
and this convention was also used for
submissions to the OECD high production volume (HPV) programme (McKee et al, 2015).
Naphthalene is an identified constituent of solvents falling into category 2, C
10
-C
12
aromatics (CAS No. 64742-94-5). This category was redesignated as C
10
-C
13
aromatic
hydrocarbon solvents for the OECD HPV programme (OECD 2012).
15
http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2011:195:0046:0051:EN:PDF.
16
Further information about the naming convention adopted for REACH registrations of
hydrocarbon solvents is available at: http://www.reachcentrum.eu/Consortia%20Documents/P-
I163/Other/P-I163_HSPA_Naming_convention_2011.03.pdf (accessed on 17
January 2017).
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 27 December 2018
Solvents covered by this category are UVCBs. McKee et al (2015) identifies 4 compositions
covered by this category. These are referred to as C
10
aromatics which cover the carbon
number range C
9
-C
11
(composition >99% aromatics with either < or > 1% naphthalene)
and C
10
-C
13
aromatics which cover the carbon number range C
10
-C
13
(composition >99%
aromatics with either < or > 1% naphthalene). The upper limit for naphthalene in any
composition is 10% (OECD, 2012). These solvent mixtures are registered for a wide range
of uses, including use in coatings, cleaning agents, lubricants, oil and gas production, metal
working fluids/rolling oils, binders and release agents, agrochemicals, road and
construction applications, use in laboratories, use in water treatment chemicals, use as a
fuel and use in functional fluids. Several of these uses may be performed by consumers
including use in coatings, use in cleaning agents, use in lubricants, use in agrochemicals,
use as a fuel and use in functional fluids.
Jet fuels
Napthalene may be present in certain aviation fuels. JP-5, JP-8, and Jet A fuels are
kerosene-based jet fuels. Kerosene-based hydrocarbon fuels are complex mixtures of up
to 260+ aliphatic and aromatic hydrocarbon compounds in the C
6
- C
17+
range, possibly
encompassing 2000+ isomeric forms. This includes varying concentrations of substances
such as benzene, n-hexane, toluene, xylenes, trimethylpentane, methoxyethanol,
naphthalenes (including polycyclic aromatic hydrocarbons [PAHs]), and certain other C
9
-
C
12
fractions (i.e., n-propylbenzene, trimethylbenzene isomers) (Ritchie, 2003).
Naphthalene has been used as a marker in studies examining the exposure of military
personnel to JP 8 fuel (Chao et al, 2005, Chao et al, 2006).
Other petroleum/coal tar distillates
The Danish EPA report indicated that naphthalene may be present in tars used to make
asphalt. It may also be present in the PAH mixtures that are found in extender oils and
associated with carbon black and in fuels including heating oil (Danish EPA, 2015). The
Danish EPA report presents a list of products where naphthalene has been measured in
levels ranging from 0.2 to 2800 mg/kg. The highest levels were reported for tattoo inks,
wood tar and printed matter. Some toothbrushes were also reported to contain high levels.
7.6. Classification and Labelling
7.6.1. Harmonised Classification (Annex VI of CLP)
HARMONISED CLASSIFICATION ACCORDING TO ANNEX VI OF CLP
REGULATION (REGULATION (EC) 1272/2008)
Index No
International
Chemical
Identification
EC No
CAS No
Classification
Spec.
Conc.
Limits,
M-
factors
Notes
Hazard Class
and Category
Code(s)
Hazard
statem
ent
code(s
)
601-052-00-2
Naphthalene
202-049-5
91-20-3
Acute Tox. 4*
H302
Carc. 2
H351
Aquatic Acute 1
H400
Aquatic Chronic 1
H410
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 28 December 2018
7.6.2. Self-classification
• In the registration(s):
Registrants apply the harmonised classification and additionally one Registrant self-
classifies as; Flam. Solid 2; H228
• Additionally the following hazard classes are notified among the aggregated
self-classifications in the C&L Inventory:
Flam. Sol. 2 H228 – Flammable solid
Flam. Sol. 1 H228 – Flammable solid
Asp. Tox. 1 H304 – May be fatal if swallowed and enters airways
STOT RE 1 H373 (eyes, blood) – May cause damage to organs (eyes, blood) through
prolonged or repeated exposure
Aquatic Chronic 3 H412 – Harmful to aquatic life with long leasting effects
Aquatic Chronic 2 H411 – Toxic to aquatic life with long lasting effects
7.7. Environmental fate properties
Not evaluated.
7.8. Environmental hazard assessment
Not evaluated.
7.9. Human Health hazard assessment
The human health hazards of naphthalene have been assessed under the Existing
Substances Regulation (ESR) (EC 2003). Currently, naphthalene is classified for the
following endpoints in Annex VI of the CLP Regulation - Acute Tox. 4* (oral), Carc. 2,
Aquatic Acute 1 and Aquatic Chronic 1. Classification for carcinogenicity was based on
observations of rare nasal tumours (respiratory epithelial adenomas and olfactory epithelial
neuroblastomas) in rats following exposure to naphthalene by inhalation.
Haemolytic anaemia and inflammatory reactions in the olfactory epithelium are the areas
of concern. These effects have been considered in detail in order to calculate Derived No
Effect Levels (DNELs) and to address the issue of human relevance.
Information in the registration dossier that was published after the ESR Review was
considered. A literature search for information published post 1 January 2008 was
performed by the eMSCA and revealed a number of case reports of haemolytic anaemia
together with several pieces of literature relevant to the discussion about the effects on
the olfactory epithelium following exposure to naphthalene. Since the publication of the
ESR Review, a number of short term studies, in which rats were exposed to naphthalene
by inhalation, have been conducted. In addition, there have been reports considering the
relevance of the findings in rats to humans. The new information has been presented in
section 7.9. The findings support and expand upon the data presented in the ESR Review.
Concentrations have been converted from ppm to mg/m
3
using a conversion factor of 5.24
as calculated by the International Agency for Research on Cancer (IARC Monographs
Volume 82).
For completeness, relevant information from the EU ESR Review has also been included.
The remaining sections under human health have been left blank.
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 29 December 2018
7.9.1. Toxicokinetics
The information in italics below has been taken from the ESR Review (2003).
The limited information available in humans indicates that naphthalene is readily absorbed
by all routes of exposure and animal data shows that almost complete and rapid absorption
occurs following ingestion.
Information on dermal absorption of naphthalene is scarce. Available data show that after
radioactively labelled naphthalene was applied to the skin of 5-8 male Sprague Dawley rats
(over a surface area of 13cm
2
), half of the naphthalene was absorbed within 2.1 hours
(Turkall et al. 1994).
Metabolism in rodents is chiefly by P450 oxidation, with subsequent glutathione
conjugation, as well as epoxide hydroxylation to naphthalene 1,2-dihydrodiol. There is
some evidence that significant enterohepatic recirculation of naphthalene metabolites
occurs in rodents.
In humans, naphthalene is metabolised to 1-naphthol, 2-naphthol and 1,2- and
1,4-naphthoquinone. In vitro studies in human liver microsomes and human lung
preparations indicate that epoxide hydrolase is involved in the metabolic pathway by which
naphthalene is metabolised to naphthalene 1,2-dihydrodiol.
After a single dose of labelled naphthalene (20mg/kg in in olive oil) was administered to
54 male Wistar rats by intraperitoneal injection, plasma levels of the radioactive label
declined in a biphasic fashion, with half-lives of 0.8 and 99 hours in phases I and II,
respectively (Kilanowicz et al. 1999).
The proposed metabolic pathway is illustrated in figure 7.9.1.
Individuals who are deficient in G-6-PD (glucose-6-phosphate dehydrogenase) are
particularly sensitive to haemolytic anaemia produced by naphthalene (Gosselin et al.,
1984). This deficiency is genetically determined and occurs more often in males. The defect
results in an inability by the red blood cell to maintain a balance between reduced and
oxidised glutathione which in turn results in an increased susceptibility to oxidative attack
by exogenous chemicals. It seems probable that the oxidative attack, following exposure
to naphthalene, can occur following redox cycling of the naphthalene metabolites 1-
naphthol and the quinone.
Nkhoma et al. (2009) conducted a scientific review and meta-analysis to ascertain the
global prevalence of G-6-PD deficiency and estimated the prevalence of this deficiency to
be 3.9% in Europe.
The urine is the main route of rapid excretion in humans and animals.
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 30 December 2018
Figure 7.9.1 Naphthalene metabolism (Agency for Toxic Substances and Disease Registry;
ATSDR (2005))
7.9.2. Acute toxicity and Corrosion/Irritation
An assessment of the acute oral, dermal and inhalation toxicity of naphthalene is provided
in this section. This includes a consideration of both systemic and site of contact effects
(i.e. irritation to the respiratory tract).
7.9.2.1. Acute toxicity
Oral
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 31 December 2018
The existing acute toxicity classification of naphthalene has not been reconsidered as part
of this evaluation. However, an assessment of the haemolytic anaemia observed in animals
and in humans after acute exposure has been made. The information in italics below has
been taken from the ESR Review (EC 2003).
ESR Review of naphthalene (2003)
Acute toxicity studies in rats and mice are available. However, since these studies gave no
information about haemolytic anaemia, they have not been included here. Studies in dogs
are described below.
In an early poorly conducted study a single oral dose of 400 mg/kg or 1,500 mg/kg
naphthalene was administered in the diet to two dogs (Zuelzer and Apt, 1949). On the
eighth day there was a reduction of the haemoglobin to 6.6 gm/100 ml and 10.2 gm/100
ml (from 9.3 and 14.4 gm/100 ml) for the low and high dose, respectively. Both animals
showed an increase in the number of Heinz bodies in erythrocytes, and reticulocytosis
began on the 7th day reaching a maximum on the 10th day. Lethargy, vomiting and
diarrhoea were also noted in the dog treated with the higher dose. Complete recovery was
achieved 1-2 weeks after administration.
Information from the ESR Review about the acute toxicity of naphthalene in humans is as
described in the following paragraphs.
There are a great many case reports in the literature of acute haemolytic anaemia produced
by naphthalene. The signs and symptoms of haemolytic anaemia associated with
naphthalene exposure are well described (e.g. Gosselin et al., 1984, Mack, 1989).
The first signs and symptoms of toxicity are usually dark urine, pallor, abdominal pain,
fever, nausea, vomiting and diarrhoea. On clinical examination the liver and spleen were
enlarged. Haematological effects are fragmentation of red blood cells with anisocytosis and
poikilocytosis, jaundice, anaemia with a reduction in haemoglobin levels and haematocrit
values and resulting reticulocytosis and leucocytosis. More severe reactions also include
Heinz body formation, haemoglobinuria and mild methaemoglobinaemia. In young children
deaths have occurred due to kernicterus (a severe neural condition associated with high
levels of bilirubin in the blood). In older children and adults renal failure may occur. Liver
damage has also been described, but as a rare occurrence.
Naphthalene was used in the past as an antihelminithic (antiparasitic) agent. It has not
been possible to obtain any details of this use, although some sources (e.g. ACGIH, 1991)
indicate that the dose levels used were in the range 0.1-0.5 g three times daily,
approximately equivalent to 4-20 mg/kg/day. However no other details are given,
particularly with respect to whether or not there were any side effects at these dose levels.
Twelve cases of oral ingestion by young children of naphthalene-containing mothballs have
been reported (Melzer-Lange and Walsh-Kelly, 1989; Todisco, 1991; Zuelzer and Apt,
1949; Shannon and Buchannon, 1982; Zinkham and Childs, 1958; Mackell et al., 1951).
The majority of the children were aged between 1-3 years. Seven were male and 2 female
(the sex of the remaining three cases was not specified). The first signs of toxicity were
usually seen within hours to up to 2 days after exposure. Haemolytic anaemia was
diagnosed in all cases and signs and symptoms were similar to those described above, with
haemoglobin levels falling to 2-6 g/100 ml in 10 cases (average haemoglobin concentration
in children aged one year is 12.5 g/100 ml; Wright, 1971). No deaths occurred. In one
case haemolysis was reported to have begun 24 to 72 hours after exposure (Shannon and
Buchannon, 1982). G-6-PD deficiency was reported in all of the cases (8) in which it was
investigated. The amount of naphthalene ingested was not known for any of these cases
although consumption apparently ranged from between having sucked one mothball to
approximately half its size to swallowing whole two to three mothballs. According to one
review naphthalene mothballs usually weigh between 500 and 3,600 mg and contain 100%
naphthalene (Mack, 1989). It should, however, be noted that further consumption, and
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 32 December 2018
perhaps repeated exposure may have occurred without the knowledge of the parents. Thus
no firm conclusions regarding any dose-response relationship can be drawn.
Quantitative details of intake levels of naphthalene producing effects in children are
available in the secondary literature. However such data on doses received are old and are
difficult to substantiate and therefore should be used with caution. For example, Sollmann
(1957) mentions a very early report which apparently stated that 2 g naphthalene taken
over a 2-day period killed a 2 year old child (Prochownik, 1911), but it has been impossible
to obtain a copy of the original report.
A few cases of haemolytic anaemia following ingestion of naphthalene have also been
reported in teenagers or adults. An early report described a case study of a 16 year old
female who had deliberately consumed approximately 6 g of naphthalene, although it is
not stated how this estimation was made (Gidron and Leurer, 1956). Within 12-hours she
was suffering from abdominal pain and vertigo. On day 2 after the ingestion her erythrocyte
count had approximately halved, her urine had darkened in colour and she complained of
pain in the kidneys. Despite a blood transfusion on day 2 she had become jaundiced on
day 3. Treatment, including another blood transfusion continued. By day 7 the jaundice
had subsided. On day 8 her erythrocyte count began to rise and the urine returned to a
normal colour. Pain in the kidneys was reported to have continued for "some days". G-6-
PD status was not assessed. Based on the requirement for two blood transfusions it seems
possible that the estimated 6 g of naphthalene ingested represents a lethal dose to
humans.
Haemolytic anaemia (with no red blood cells being seen on blood microscopy) was reported
in a female who had drunk approximately 50 ml of an oil which was reported to contain a
"high concentration" of naphthalene (Ostlere et al., 1988). The female was apparently not
G-6-PD deficient. Her sister also drank the oil and did not show any signs of toxicity.
A secondary literature source cited an incident occurring in 1902 in which severe pain in
the bladder and a severe impairment in vision were reported within nine hours of a man
taking 5 g unpurified naphthalene over a 13-hour period (Grant, 1974). Vision apparently
remained severely impaired 1 year after the incident. Due to the age of the report, the
unpurified nature of the naphthalene and the lack of other similar reports, despite its past
use as a medicine, no conclusions should be drawn from this report.
Information found subsequent to the ESR Review
A literature search (covering the period from January 2008 - present) carried out by the
eMSCA in August 2016 revealed no additional animal studies with naphthalene for this
endpoint but seven case reports of individuals reporting a single exposure to naphthalene
mothballs were found (Kapoor et al. 2014, Annamalai et al. 2012, Kundra et al. 2015, Lim
et al. 2009, Roumieu et al. 2015, Chauhan et al. 2014, Deo et al. 2016).
In one of the reports, a 15 year old boy had accidentally consumed a single mothball (Deo
et al. 2016). His symptoms were more severe than those in the other case studies, with a
methaemoglobin level of 25.3%. However it is not clear when this measurement was taken
in relation to mothball consumption. Medical staff found that he was glucose-6-phosphate
dehydrogenase (G-6-PD)-deficient. This case study shows that consumption of a single
mothball can result in severe acquired methaemoglobinaemia in a G-6-PD-deficient
individual. The actual dose consumed by the individual is unknown.
The second report described a 33 year old female who had been complaining of fatigue
(Roumieu et al. 2015). A marabout gave the female a potion containing seeds, pigeon and
a mothball in an attempt to cure her fatigue, but the woman was taken to hospital three
days later with a number of symptoms including fatigue, confusion and jaundice. She was
diagnosed with regenerative normochromic, normocytic anaemia and haemolysis. G-6-PD
and methaemoglobin levels were normal in this patient. Her symptoms improved following
a transfusion of packed red blood cells and intravenous hydration.
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 33 December 2018
The remaining 5 cases confirmed that naphthalene exposure can result in haemolytic
anaemia in humans. The patients described in the case studies were between 2 and 29
years of age and had consumed mothballs (some accidentally; some deliberately). In the
cases where the number of mothballs consumed was ascertained, the patients consumed
between 3 and 12 mothballs. The symptoms presented were similar to those described
above. No deaths were reported in these case studies. In one case, G-6-PD levels could
not be measured due to patient refusal. In the four remaining cases, G-6-PD levels were
normal.
NOAEL identification for acute oral toxicity
In contrast to the consistent reports describing cases of haemolytic anaemia in humans
following oral exposure to naphthalene, haemolytic anaemia was not observed in
experimental animals (rats and mice). Although evidence of haematotoxicity was found in
dogs, the study was conducted poorly. Therefore there does not appear to be a suitable
animal model. In March 2010, the Scientific Committee on Occupational Exposure Limits
(SCOEL) produced a report on naphthalene. Regarding haemolytic anaemia, the SCOEL
also concluded that, ‘there are no useful experimental data from which to extrapolate to
humans for this endpoint.’
Due to the lack of a suitable animal model, the uncertainty about the doses consumed by
humans in cases of poisonings and the lack of exposure-response information, establishing
a NOAEL or a LOAEL for systemic effects following acute exposure to naphthalene is not
possible. On this basis and using the estimation of 6g of naphthalene as a lethal dose to
humans, the eMSCA concurs with the conclusion in the ESR Review that values in the
mg/kg range are considered to give rise to concern for acute haemolytic anaemia.
Assuming a body weight of 60kg for a typical adult female, 6g of naphthalene (Gidron and
Leurer, 1956) would equate to a lethal dose of 100 mg/kg bw.
Dermal
ESR Review of naphthalene (2003)
No information was available to inform specifically about the acute toxicity of naphthalene
following dermal exposure.
Information found subsequent to the ESR Review
No new information is available.
Therefore the possibility of a systemic effect following exposure to naphthalene via the
dermal route cannot be excluded.
Inhalation
ESR Review of naphthalene (2003)
No information was available to inform specifically about the acute toxicity of naphthalene
following inhalation exposure.
Information found subsequent to the ESR Review
No new information is available.
Therefore the possibility of a systemic effect following exposure to naphthalene via the
inhalation route cannot be excluded.
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 34 December 2018
7.9.2.2. Corrosion/Irritation
The potential for naphthalene to cause skin and/or eye irritation has not been evaluated.
The local effects of this substance on the respiratory tract following single or short term
exposure have been considered below.
Irritation to the respiratory tract
ESR Review of naphthalene (2003)
No information on the respiratory tract irritation potential of naphthalene was presented in
the ESR Review.
Information found subsequent to the ESR Review
Two studies have been conducted to provide information relevant to a consideration of the
carcinogenic mechanism of action in rats.
Study in rats – 1 and 5 day(s) exposure, 6 hour duration
Dodd et al. (2010) administered naphthalene vapour to F344 and Sprague Dawley (SD)
rats for either 1 day (6 hours) or 5 days (6 hours/day). Animals were sacrificed by
intraperitoneal injection of phenobarbital and subsequent exsanguation on the day after
the last exposure to naphthalene. Animals in recovery groups were sacrificed fourteen days
after the last exposure to the test substance. In both the 1 day and 5 day studies, the
nasal tissues underwent histopathological examination.
No clinical observations attributable to naphthalene exposure were reported during or
following treatment for the 1-day and 5-day studies. Similarly, there were no significant
exposure-related effects on bodyweight and no gross pathological lesions attributable to
naphthalene exposure were observed.
(i) Five rats/sex/strain were exposed to naphthalene (99.9% pure) at 0, 0.1, 0.3, 1, 10
and 30ppm (equivalent to 0, 0.52, 1.57, 5.24, 52.4 and 157mg/m
3
) for 6 hours (whole
body exposure). Necrotic lesions were reported in both the olfactory and the respiratory
epithelia.
Nasal olfactory epithelium necrosis was observed in a concentration-dependent manner
from 0.52 mg/m
3
in SD rats and from 5.24 mg/m
3
in F344 rats, with severity grades
ranging from minimal to moderately severe. The extent and severity of the lesions
increased with dose according to the study author. However, quantitative data to
substantiate this description are not available. The incidences of this effect are provided in
the table below. The necrosis reported at 0.52 and 1.57 mg/m
3
was described as minimal
and was also observed in one SD female control. At ≤ 1.57 mg/m
3
, the lesions were not
observed in every transverse section that was examined.
Table 9: Incidence of nasal olfactory epithelium lesions in rats following naphthalene
exposure (Dodd et al. 2010)
Exposure concentration,
mg/m
3
F344
Males
F344
Females
SD Males
SD
Females
0
0/5
0/5
0/5
1/5
0.52
0/5
0/5
2/5
1/5
1.57
0/5
0/5
3/5
2/5
5.24
5/5
4/5
4/5
4/5
52.4
5/5
5/5
5/5
5/5
157
5/5
5/5
5/5
5/5
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 35 December 2018
Nasal respiratory epithelium necrosis was first observed at 5.24 mg/m
3
in 1 male SD rat
only and was described as minimal. At 52.4 mg/m
3
, this effect was observed in all treated
animals (both strains), as tabulated below. No quantitative information on the severity of
these lesions is available.
Table 10: Incidence of nasal respiratory epithelium necrosis in rats following naphthalene
exposure (Dodd et al. 2010)
Exposure concentration,
mg/m
3
F344
Males
F344
Females
SD
Males
SD
Females
0
0/5
0/5
0/5
0/5
0.52
0/5
0/5
0/5
0/5
1.57
0/5
0/5
0/5
0/5
5.24
0/5
0/5
1/5
0/5
52.4
5/5
5/5
5/5
5/5
157
5/5
5/5
5/5
5/5
In conclusion, this study showed that the olfactory epithelium was a more sensitive target
for naphthalene toxicity than the respiratory epithelium, and that the SD was a more
sensitive strain than F344. Necrotic lesions in the olfactory epithelium were noted at all
exposure levels in male and female SD rats following a single exposure to naphthalene.
Additionally, olfactory epithelium necrosis was observed in one control female SD rat.
Information on the severity of these lesions at different exposure levels was limited; no
quantitative data were provided. It is possible that the effects observed at the lowest test
concentration of naphthalene and in the control rat were all of minimal severity. However,
from the data provided in this study, it is not possible to identify reliably a NOAEC. The
lowest test concentration of 0.52 mg/m
3
is therefore considered conservatively to be a
LOAEC under the conditions of this study.
(ii) Ten rats/sex/strain were similarly exposed to 0.1, 1 and 10ppm (equivalent to 0.52,
5.24 and 52.4 mg/m
3
) naphthalene (99.9% pure) for 5 days (6 hours/day, whole body
exposure). Five rats sex/strain were in the control group. Additionally, there were 5
rats/sex/strain and 10 rats/sex/strain in the 0 mg/m
3
and 52.4 mg/m
3
recovery groups,
respectively.
Among these animals, effects on the nasal respiratory epithelium were not reported.
However, nasal olfactory epithelium degeneration was characterised together with its
relative position in the nasal cavity:
Level III - ethmoid recess near anterior end of pharyngeal duct;
Level IV - centre of ethmoid recess;
Level V - posterior end of ethmoid recess and pharyngeal duct.
Lesions observed on the olfactory epithelium in this study were described as degenerative.
Additionally, evidence of prior and ongoing necrosis was reported.
In SD rats at the lowest concentration (0.52 mg/m
3
), nasal olfactory epithelium
degeneration was observed in 2/10 test females and 0/10 males. No lesions were seen in
controls. Necrotic lesions were seen in 10/10 females and 9/10 males at 5.24 mg/m
3
and
in all animals at the top concentration (52.4 mg/m
3
). The region of the nasal cavity
characterised as level III was more sensitive than levels IV and V. Level III was closer to
the front of the nasal cavity. The degenerative lesions were graded from minimal to
moderately severe. Full details are provided in the table below.
At the lowest concentration (0.52 mg/m
3
), nasal olfactory epithelium degeneration was not
observed in F344 rats. However, this effect was observed at Level III of the nasal cavity in
8/10 male and 10/10 female F344 rats at 5.24 mg/m
3
. At the top concentration (52.4
mg/m
3
), nasal olfactory epithelium degeneration was more severe and more widespread
than at the mid concentration, covering Levels III, IV and V as shown in the table below.
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 36 December 2018
Table 11: Incidence and Severity of nasal Olfactory Epithelium Degeneration (Dodd et al.
2010)
F344 Males
F344 Females
SD Males
SD Females
Location
0 mg/m
3
Level III
0/5
0/5
0/5
0/5
Level IV
0/5
0/5
0/5
0/5
Level V
0/5
1/5 (0.2)**
0/5
0/5
0.52 mg/m
3
Level III
0/10
0/10
0/10
2/10 (0.2)
Level IV
0/10
0/10
0/10
0/10
Level V
0/10
0/10
0/10
0/10
5.24 mg/m
3
Level III
8/10 (0.8)
10/10 (1.0)
9/10 (0.9)
10/10 (1.0)
Level IV
0/10
0/10
0/10
0/10
Level V
0/10
0/10
0/10
0/10
52.4 mg/m
3
Level III
10/10 (2.7)
10/10 (2.9)
10/10 (2.8)
10/10 (2.7)
Level IV
10/10 (3.0)
10/10 (3.0)
10/10 (2.9)
10/10 (2.8)
Level V
4/10 (0.5)
7/10 (1.5)
9/10 (2.5)
7/10 (1.8)
** Values in parentheses denote the mean group severity score, where 0 = not remarkable, 1 =
minimal, 2 = slight/mild, 3 = moderate, 4 = moderately severe and 5 = severe/high
Following a recovery period of 14 days, the incidence of nasal olfactory epithelium
degeneration did not change in SD rats exposed to 52.4 mg/m
3
naphthalene for 5 days, or
in Levels III and IV in F344 rats. A reduced incidence of this effect was observed in Level
5 of F344 rats only. However, the severity of the observed lesions did reduce in both strains
of rat and was only minimal by the end of the recovery period as shown in table below.
Table 12: Nasal Olfactory Epithelium Degeneration in recovery groups (Dodd et al. 2010)
F344 Males
F344 Females
SD Males
SD Females
Location
0 mg/m
3
+ Recovery
Level III
0/5
0/5
0/5
0/5
Level IV
0/5
0/5
0/5
0/5
Level V
2/5 (0.4)**
0/5
0/5
0/5
52.4 mg/m
3
+ Recovery
Level III
10/10 (1.0)
10/10 (1.1)
10/10 (1.0)
10/10 (1.1)
Level IV
10/10 (1.1)
10/10 (1.1)
10/10 (1.0)
10/10 (1.2)
Level V
1/10 (0.1)
3/10 (0.3)
9/10 (0.9)
8/10 (0.8)
** Values in parentheses denote the mean group severity score, where 0 = not remarkable, 1 =
minimal, 2 = slight/mild, 3 = moderate, 4 = moderately severe and 5 = severe/high
In SD rats, nasopharyngeal goblet cell hyperplasia/hypertrophy was observed in both sexes
at the top dose only.
In F344 rats, goblet cell hyperplasia/hypertrophy was observed in 1/10 males and 1/10
females at the lowest concentration (minimal severity), in 2/10 males and 1/10 females at
the next concentration (minimal severity) and in all animals at the highest concentration
(minimal to mild severity), as tabulated below.
Table 13: Incidence and severity of nasopharyngeal goblet cell hyperplasia/hypertrophy
(Dodd et al. 2010)
F344 Males
F344 Females
SD Males
SD Females
Location
0 mg/m
3
Level IV
0/5
0/5
0/5
0/5
Level V
0/5
0/5
0/5
0/5
0.52 mg/m
3
Level IV
0/10
0/10
0/10
0/10
Level V
1/10 (0.1)**
1/10 (0.1)
0/10
0/10
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 37 December 2018
5.24 mg/m
3
Level IV
2/10 (0.2)
1/10 (0.1)
0/10
0/10
Level V
1/10 (0.1)
1/10 (0.1)
0/10
0/10
52.4 mg/m
3
Level IV
10/10 (1.6)
7/10 (1.2)
1/10 (0.1)
3/10 (0.3)
Level V
10/10 (2.0)
10/10 (2.0)
5/10 (0.6)
8/10 (0.8)
** Values in parentheses denote the mean group severity score, where 0 = not remarkable, 1 =
minimal, 2 = slight/mild, 3 = moderate, 4 = moderately severe and 5 = severe/high
Nasopharyngeal goblet cell hyperplasia/hypertrophy was observed in 2 F344 rats (1 male
and 1 female) at 0.52 mg/m
3
. However the mean group severity score of this lesion was
only 0.1 in both sexes. Furthermore, although this lesion was not observed in control
animals in the main phase of the study, it was observed at the end of the recovery period
in 1/5 male F344 control rat and therefore the effect observed at 0.52 mg/m
3
is not
considered to be treatment-related.
Following a 14 day recovery period, complete recovery from nasopharyngeal goblet cell
hyperplasia/hypertrophy was observed in SD rats (both sexes) exposed to 52.4 mg/m
3
naphthalene. In F344 rats, recovery from these effects was not complete after 14 days but
there were reductions in incidence and severity of this lesion as shown in the table below.
Table 14: Incidence and severity of nasopharyngeal goblet cell hyperplasia/hypertrophy
in recovery groups (Dodd et al. 2010)
F344 Males
F344 Females
SD Males
SD Females
Location
0 mg/m
3
+ Recovery
Level IV
1/5 (0.2)**
0/5
0/5
0/5
Level V
1/5 (0.2)
0/5
0/5
0/5
52.4 mg/m
3
+ Recovery
Level IV
7/10 (0.8)
6/10 (0.8)
0/10
0/10
Level V
5/10 (0.7)
10/10 (1.5)
0/10
0/10
** Values in parentheses denote the mean group severity score, where 0 = not remarkable, 1 =
minimal, 2 = slight/mild, 3 = moderate, 4 = moderately severe and 5 = severe/high
In conclusion, nasal olfactory epithelium degeneration was observed in 2/10 SD females
at the lowest concentration (0.52 mg/m
3
) and therefore a NOAEC cannot be identified from
this study. The effects observed at 0.52 mg/m
3
occurred at a low incidence and severity
and therefore 0.52 mg/m
3
is considered to be a conservative LOAEC.
4 hour exposure
In order to assess whether the route of exposure affected the pattern of non-neoplastic
nasal lesions in rats, Lee et al. (2005) exposed male SD rats to naphthalene by inhalation
(described here) and by intraperitoneal injection (described in section 7.9.2.2.2). In order
to characterise the lesions and allow a comparison between the routes of exposure, higher
concentrations of naphthalene were administered in this study compared to in the previous
studies.
Male rats (6 /group) were exposed to filtered air (controls) and naphthalene (dissolved in
acetonitrile) at concentrations of 3.4±0.5 ppm or 23.8±1.7 ppm (equivalent to 17.8±2.6
mg/m
3
and 125±8.9 mg/m
3
) for 4 hours. All rats were sacrificed using sodium
phenobarbital and exsanguination 24 hours after exposure to naphthalene. The anterior
and posterior parts of the nasal cavity were examined histopathologically and the
observations are provided in the table below.
Effects on the olfactory epithelium were not observed in rats exposed to filtered air.
24 hours after exposure to 17.8 mg/m
3
naphthalene, observations of severe cellular lesions
were confined to the olfactory mucosa only. A correlation between injuries and the pattern
Substance Evaluation Conclusion document EC No 202-049-5
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of airflow in the nasal cavity was established, with more severe injuries being observed in
the anterior part of the nasal passage in comparison to the posterior part.
Table 15: Lesions of the olfactory epithelium in rats following a 4 hour exposure to
naphthalene via inhalation, Lee et al. (2005)
Anterior part of nasal passage
Posterior part of nasal passage
Controls
none
none
17.8
mg/m
3
Continuity of the olfactory mucosa
was broken by areas of necrotic
olfactory receptor cells
Reduced volume of cytoplasm
from sustentacular cells above the
nuclei
Vacuoles in the olfactory
epithelium
Patches of exfoliated cells
Injury was confined around the
dorsal medial meatus
Continuity of the olfactory mucosa
was broken by areas of necrotic
olfactory receptor cells
Reduced volume of cytoplasm
from sustentacular cells above the
nuclei
Vacuoles in the olfactory
epithelium
Injury was confined around the
dorsal medial meatus
125
mg/m
3
Numerous exfoliated cells and cell
debris trapped in the nasal
passage
Numerous exfoliated cells and cell
debris trapped in the nasal
passage
Numerous intraepithelial vacuoles
Reduced volume of cytoplasm
from sustentacular cells of the
dorsal medial meatus
Injury at this dose was not evenly
distributed across the posterior part of the
nasal passage. Lesions extended ventrally
along the medial meatus.
Since lesions were observed at both concentrations, the results of this study do not allow
a NOAEC to be identified. However, the study demonstrates that following inhalation
exposure to naphthalene, the extent of lesions on the olfactory epithelium of rats correlates
with the pattern of airflow.
NOAEC identification for irritation to the respiratory tract following inhalation exposure
The available information does not allow a NOAEC to be identified because lesions were
observed at all concentrations in the short term inhalation studies. However, since lesions
at the lowest concentration level occurred at a low incidence and appear to have been of
low severity (Dodd et al. 2010), 0.52 mg/m
3
has been identified as a conservative LOAEC.
Additional information: intraperitoneal route
To analyse the effects of systemic exposure, naphthalene (in corn oil) was administered to
rats (3/group) at doses of 0, 25, 50, 100 or 200 mg/kg bw by intraperitoneal injection (Lee
et al. 2005). All rats were sacrificed using sodium phenobarbital and exsanguination 24
hours after exposure to naphthalene. The anterior and posterior parts of the nasal cavity
were examined histopathologically.
Adverse effects on the olfactory epithelium were observed at 100 and 200 mg/kg bw only.
The injuries at this dose level were more widespread than those occurring after inhalation.
A greater degree of injury was observed in the posterior region compared to the anterior
region as shown in the table below.
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 39 December 2018
Table 16: Lesions of the olfactory epithelium in rats following exposure to naphthalene via
intraperitoneal injection, Lee et al. (2005)
Anterior part of nasal passage
Posterior part of nasal passage
0, 25, 50
mg/kg bw
none
none
100 mg/kg
bw
Although widespread injury was
reported in this region, no further
details were provided.
Dorsal medial meatus
Occasional degeneration of
sustentacular cell cytoplasm
Intraepithelial vacuoles
Rest of olfactory epithelium
Extensive exfoliation
Large vacuoles and loss of cilia in
ciliated columnar cells
200 mg/kg
bw
Although widespread injury was
reported in this region, no further
details were provided.
Severe cellular exfoliation across
this region (including basal cells)
Large vacuoles and loss of cilia in
ciliated columnar cells
Since similar effects were observed in rats following exposure to naphthalene by inhalation
and intraperitoneal exposure, the results suggest that the lesions may be attributable to
local metabolism and are not necessarily site-of-contact effects.
In this study, values of 50 mg/kg bw and 100 mg/kg bw can be identified for the NOAEL
and LOAEL, respectively.
7.9.3. Sensitisation
Not evaluated.
7.9.4. Repeated dose toxicity
Studies evaluated as part of the ESR Review have not been re-evaluated. The descriptions
of the findings reported in the ESR Review have been copied and included in italics below
for information.
7.9.4.1. Summary and discussion of repeated-dose toxicity
Oral
ESR Review of naphthalene (2003)
Studies in rats, mice and rabbits are available. However, these do not provide any
information on haemolytic anaemia or non-neoplastic nasal lesions and have therefore not
been included in this evaluation. Rodents do not appear to be a suitable model for
naphthalene-induced haemolytic anaemia in humans.
Studies in dogs
7 day study
In a poorly conducted study with no controls, an average daily dose of 220 mg/kg/day was
administered in the diet to a single dog over 7 days (Zuelzer and Apt, 1949). During an
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 40 December 2018
observation period of 36 days, lethargy, ataxia and diarrhoea were observed beginning on
the fifth day of treatment. Also on the fifth day of treatment the white blood cell count rose
from 14,400 to 25,500 and Heinz bodies appeared in the majority of erythrocytes. On the
ninth day there was a reduction of the haemoglobin to 2.4 gm/100 ml, red blood cell count
to 1.3.106 and haematocrit to 7.5 volumes % (from 13.1 gm/100 ml, 6.78.106 and 41.5,
respectively). The clinical signs and reductions in haematological parameters resolved over
36 days. An optical examination was not conducted.
Haemolytic anaemia was observed in a 15 year old male who was reported to have
developed a liking for sucking naphthalene mothballs and a 19 year old female who
"intermittently sucked and chewed" naphthalene mothballs during her pregnancy (Zinkham
and Childs, 1958). Signs and symptoms were the same as those described for acute
ingestion of naphthalene. Both individuals were G-6-PD deficient. There was no indication
of level or duration of exposure in either case.
Information found subsequent to the ESR Review
No new information is available.
Dermal
ESR Review of naphthalene (2003)
No information specifically on dermal exposure is available, although dermal exposure to
naphthalene solid and vapour may have occurred in the studies summarised in the
inhalation section.
Information found subsequent to the ESR Review
No new information is available.
Inhalation
ESR Review of naphthalene (2003)
Studies in rats
13 week study
In a well conducted unpublished study, groups of 10 male and 10 female rats were exposed
nose only for 6 hours/day, 5 days a week for 13 weeks to 0, 2, 10 or 58 ppm (approximately
0, 10, 50 or 300 mg/m
3
) vapourised naphthalene (Huntingdon Research Centre, 1993a).
A gross pathological examination was carried out on a wide range of tissues and a
microscopic examination was carried out on a range of tissues including the lungs, liver,
kidneys, adrenals, testes, eyes and optic nerve. Prior to terminal sacrifice, samples of blood
were taken from all rats for haematological and clinical chemistry evaluation. In high dose
animals body weight gain was reduced by 43% and 34% in males and females, respectively
and was associated with reduced food consumption. There were no toxicologically
significant haematological or clinical chemistry findings observed. Similarly, no significant
changes were noted in organ weight or gross pathology.
Microscopic analysis of the nasal epithelium revealed treatment-related effects at all dose
levels. The severity of the effects was dose-related. At the highest exposure level (300
mg/m
3
) changes included erosion of the olfactory epithelium, hyperplasia of basal cells in
the olfactory epithelium and loss of Bowmans' glands. At the lowest exposure level (10
mg/m
3
) changes in olfactory epithelium were less marked but included slight
disorganisation, mild erosion (in one rat), minimal atrophy, rosette formation (an attempt
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 41 December 2018
at proliferative repair by the olfactory neuroepithelium), occasional degenerate cells, loss
of Bowmans' glands and minimal hyperplasia. There were no treatment related effects
observed in the lungs or nasal respiratory epithelium at this dose. There were no observed
changes in the nasal passages of control animals. In one low dose rat there was evidence
of squamous metaplasia of the respiratory epithelium, however as this lesion was not seen
in the other rats at higher doses this lesion was not considered toxicologically significant.
The effects at 10 mg/m
3
were generally minimal in severity and seen in only small numbers
of animals, and therefore appear to represent the low end of the dose-response curve for
nasal effects. Overall, signs of damage to the olfactory epithelium were seen at all doses
down to 10 mg/m
3
(2 ppm), and a NOAEL cannot be identified for local effects.
4 week study
In a well conducted unpublished study, groups of 5 male and 5 female rats were exposed
nose only for 6 hours/day, 5 days a week for 4 weeks to 0, 1, 3, 10, 29 or 71 ppm
(approximately 0, 5, 15, 50, 150 or 370 mg/m
3
) vapourised naphthalene (Huntingdon
Research Centre, 1993b).
Investigations were similar to the 13-week study performed in the same laboratory. Results
were similar to those observed in the 13-week study. High dose animals showed
approximately a 50% reduction in body weight gain associated with reduced food
consumption. There was no evidence of systemic toxicity. Local effects were observed with
signs of proliferative repair in the nasal olfactory epithelium changes observed at all doses
down to 5 mg/m
3
(1 ppm), and therefore a NOAEL for local effects cannot be identified.
For both the 4 and 13-week studies the mechanism by which the observed effects in the
olfactory nasal epithelium arise is unclear, although the effects may be mediated by locally
produced metabolite(s) of naphthalene. The relevance of these effects to human health is
uncertain, as there may be significant species differences in local metabolism. However,
there is no evidence to indicate that these effects are not relevant to human health.
105 week toxicity/ carcinogenicity study (US NTP study)
Groups of 49 male and 49 female F344/N rats were exposed to 0, 10, 30 or 60 ppm
naphthalene vapour (>99% pure) (approximately equivalent to 0, 50, 150 or 300 mg/m
3
)
in inhalation chambers for 6 hours/day, 5 days/week for 105 weeks (NTP, draft report
2000
17
). Additional groups of 9 male and 9 female rats were exposed to 10, 30 or 60 ppm
naphthalene for 18 months for evaluation of toxicokinetic parameters.
In this study, the vapour generator was comprised of a heated mantle surrounding a glass
reaction flask. Heated nitrogen was metered into the flask to carry the vapourised
naphthalene out of the generator. The temperature of the bulk chemical was maintained
below the melting point and the temperature of the vapour above the bulk naphthalene
was maintained between 66° and 71°C. The vapour was carried into the exposure room
via a heated Teflon line.
All animals were observed twice daily with clinical findings and body weights recorded
every 4 weeks beginning at week 4 and every 2 weeks beginning at week 92. Complete
necropsy and microscopic examinations were performed on all core study animals.
Survival rates of all exposed groups were similar to those of chamber controls. Survival
rates at the end of the study in control, low, medium and high dose males were 24/49,
22/49, 23/49 and 21/49, respectively. The corresponding rates in the females were 28/49,
21/49, 28/49 and 24/49, respectively. At termination, mean body weights of all exposed
17
Only the draft report was available at the time of the ESR Review the eMSCA has checked the final
version of the report and made a couple of minor changes to the ESR Review text included in this
document.
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 42 December 2018
groups of male rats were 4-11% lower than those of controls. No significant differences
were noted in mean body weights of the treated females compared to control animals.
There were no treatment-related clinical signs of toxicity in any of the treatment groups.
The incidences of a variety of non-neoplastic lesions of the nasal tract in both sexes were
statistically significantly greater in naphthalene exposed animals than controls. These
lesions included, in the olfactory epithelium: atypical (basal cell) hyperplasia, atrophy,
chronic inflammation, and hyaline degeneration; in the respiratory epithelium: hyperplasia,
squamous metaplasia, hyaline degeneration, and goblet cell hyperplasia; and glandular
hyperplasia and squamous metaplasia. In general, the severity of the olfactory and
glandular lesions increased with increasing exposure concentrations.
Since lesions were observed at all concentration levels in this study, it is not possible to
identify a NOAEC.
Further to the summary above, the eMSCA considers the following data from the NTP study
relevant for the evaluation of naphthalene-induced carcinogenicity. The incidences and
severity of the observed non-neoplastic effects are provided in the three following tables.
Table 17: Incidence and severity of non-neoplastic effects in the olfactory epithelium (NTP,
2000)
Sex
Males
Females
Dose/ mg/m
3
0
52.4**
157
314
0
52.4
157
314
Atypical
hyperplasia
0/49
48/49
(2.1)*
45/48
(2.5)
46/48
(3.0)
0/49
48/49
(2.0)
48/49
(2.4)
43/49
(2.9)
Atrophy
3/49
(1.3)
49/49
(2.1)
48/48
(2.8)
47/48
(3.5)
0/49
49/49
(1.9)
49/49
(2.7)
47/49
(3.2)
Chronic
inflammation
0/49
49/49
(2.0)
48/48
(2.2)
48/48
(3.0)
0/49
47/49
(1.9)
47/49
(2.6)
45/49
(3.4)
Hyaline
degeneration
3/49
(1.3)
46/49
(1.7)
40/48
(1.7)
38/48
(1.5)
13/49
(1.1)
46/49
(1.8)
49/49
(2.1)
45/49
(2.1)
Neuroblastoma
0/49
0/49
4/48
3/48
0/49
2/49
3/49
12/49
* The values in parentheses denote the average severity of the effect in affected animals where 1 =
minimal, 2 = mild, 3 = moderate, 4 = marked
( ) The average severity of the lesions was calculated by dividing the total severity score for a
particular exposure by the total number of animals examined.
** The exposure concentrations in this table differ very slightly from the values provided in the text
from the ESR Review. The values in the table above were converted from ppm to mg/m
3
using a
conversion factor of 5.24 (IARC Monographs Volume 82) whereas a conversion factor of 5 was used
in the ESR Review.
Table 18: Incidence and severity of non-neoplastic effects in the respiratory epithelium
(NTP, 2000)
Sex
Males
Females
Dose/ mg/m
3
0
52.4**
157
314
0
52.4
157
314
Hyperplasia
3/49
(1.0)*
21/49
(2.2)
29/48
(2.0)
29/48
(2.2)
0/49
18/49
(1.6)
22/49
(1.9)
23/49
(1.7)
Squamous
metaplasia
0/49
15/49
(2.1)
23/48
(2.0)
18/48
(1.8)
0/49
21/49
(1.6)
17/49
(1.5)
15/49
(1.8)
Hyaline
0/49
20/49
19/48
19/48
8/49
33/49
34/49
28/49
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 43 December 2018
degeneration
(1.2)
(1.4)
(1.2)
(1.0)
(1.2)
(1.4)
(1.2)
Goblet cell
hyperplasia
0/49
25/49
(1.3)
29/48
(1.2)
26/48
(1.2)
0/49
16/49
(1.0)
29/49
(1.2)
20/49
(1.0)
Adenoma
0/49
6/49
8/48
15/48
0/49
0/49
4/49
2/49
* The values in parentheses denote the average severity of the effect in affected animals where 1
= minimal, 2 = mild, 3 = moderate, 4 = marked
Table 19: Incidence and severity of non-neoplastic effects in the nasal cavity (NTP,
2000)
Sex
Males
Females
Dose/ mg/m
3
0
52.4
157
314
0
52.4
157
314
Glandular
hyperplasia
1/49
(1.0)*
49/49
(2.2)
48/48
(2.9)
48/48
(3.5)
0/49
48/49
(1.9)
48/49
(3.1)
42/49
(3.3)
Glandular
squamous
metaplasia
0/49
3/49
(3.0)
14/48
(2.1)
26/48
(2.5)
0/49
2/49
(2.0)
20/49
(2.5)
20/49
(2.8)
* The values in parentheses denote the average severity of the effect in affected animals where 1
= minimal, 2 = mild, 3 = moderate, 4 = marked
Neoplastic effects are reported in Section 7.9.6.
Studies in mice
14 day study
Groups of between 4 and 10 male and female B6C3F1 mice were exposed to 0, 10 or 30
ppm naphthalene by inhalation for 6 hours daily, 5 days a week for 14 days (NTP, 1992).
It was stated that no biologically significant changes in haemolytic parameters were
observed at any dose level. Other signs of toxicity were not assessed and a general NOAEL
cannot be identified from this limited study.
104 week carcinogenicity study (US NTP study)
In a carcinogenicity study by the same group of workers, groups of 140/dose B6C3F1 mice
were exposed to 0 or 10 ppm/day (0, 50 mg/m
3
/day) and groups of 270/dose to 30
ppm/day (150 mg/m
3
/day) naphthalene vapour for 6-hours/day, 5 days/week for up to
104 weeks (NTP, 1992). All animals were observed daily and body weights recorded at
least monthly. Necropsy was performed on all animals. Complete histopathological
examinations were performed on control and high exposure concentration animals and on
all animals found dead or killed moribund prior to the end of the study. Histopathology of
the lungs and nasal cavities was also performed on low exposure concentration mice. Serial
slit-lamp biomicroscopy and indirect ophthalmoscopic examinations were performed on 5
animals of each sex from all groups at 6-month intervals.
Survival rates were generally good, particularly in the exposed groups. Survival of control
males was significantly lower than exposed males. Survival rates at the end of the study
in control, low and high dose males were 26/70, 52/69 and 118/133, respectively. The
corresponding rates in the females were 59/69, 57/65 and 102/135, respectively. (The low
survival in the control males was reported to be due to “wound trauma” and secondary
infection resulting from increased fighting in the group). No significant differences were
noted in mean body weights of the treated animals compared to control animals. There
were no treatment-related clinical signs of toxicity in any of the treatment groups and there
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 44 December 2018
were no treatment-related ocular changes in any of the selected animals throughout the
study.
Non-neoplastic changes were only seen in the lungs and nose. A dose-related increase in
alveolar and bronchial inflammation (3/139 (2%); 34/134 (25%); 108/270 (40%)
18
in 0,
10 and 30 ppm groups) with macrophage accumulation, lymphocyte infiltration and
alveolar epithelial hyperplasia was noted in all groups. The severity of the lung effects was
described as minimal to mild but was reported to be more pronounced in exposed animals
than controls. Virtually all of the exposed animals, and none of the controls, showed nasal
epithelium inflammation with olfactory epithelium metaplasia and respiratory epithelium
hyperplasia in the nose. These effects mainly occurred in the posterior nasal cavity and
were described as minimal to mild.
Since lesions were observed in all exposure groups, a NOAEC cannot be identified from this
study.
Further to the summary above, the eMSCA considers that the following data are relevant,
summarising the incidences of non-neoplastic lesions in the nasal cavity of mice (NTP,
1992).
Table 20: Incidence and severity of non-neoplastic findings in the nasal cavity in mice
exposed to naphthalene for 2 years (NTP, 1992)
Sex
Males
Females
Dose (mg/m
3
)
0
52.4**
157
0
52.4
157
Chronic inflammation
0/70
67/69
(2.2)*
133/135
(2.6)
1/69
(2.0)
65/65
(2.3)
135/135
(2.4)
Metaplasia of the
olfactory epithelium
0/70
66/69
(2.5)
134/135
(2.6)
0/69
65/65
(2.5)
135/135
(2.4)
Hyperplasia of the
respiratory epithelium
0/70
66/69
(2.6)
134/135
(2.8)
0/69
65/65
(2.5)
135/135
(2.7)
* Denotes average severity grade, where 1 = minimal, 2 = mild, 3 = moderate, 4 = marked
** The exposure concentrations in this table differ very slightly from the values provided in the text
from the ESR Review. The values in the table above were converted from ppm to mg/m
3
using a
conversion factor of 5.24 (IARC Monographs Volume 82) whereas a conversion factor of 5 was used
in the ESR Review.
Neoplastic findings are described in Section 7.9.6.
Human information
Several cases of adverse health effects have been reported following repeated exposure to
naphthalene. The principal route of exposure appears to be inhalation although dermal
exposure to the vapour may also have occurred and the possibility of additional oral
exposure cannot be discounted.
Eighteen cases of haemolytic anaemia, following exposure to naphthalene vapours, have
been reported (Shannon and Buchannon, 1982; Valaes et al., 1963; Dawson et al., 1958;
Cock, 1957; Grigor et al., 1966). The majority of the cases were neonates. Fourteen were
male and 4 female. Exposure to naphthalene vapour was via clothing and blanketing which
had been stored with naphthalene mothballs. The signs and symptoms of anaemia were
18
Value changed from that reported in ESR Report (108/170, 63%) as that appears to have been
an error.
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 45 December 2018
as described above in Section 7.9.2.1. Two cases of neonatal kernicterus were reported
and death occurred in one of the neonates. G-6-PD deficiency was reported in 11/17 cases
where it was investigated. One study, which included 6 neonates who were G-6-PD
deficient and another 7 who were not, stated that the haemolysis was more severe in those
who were deficient (Valaes et al., 1963). The level and duration of exposure was not known
in any of these cases, although hospital admissions were commonly made within two weeks
of birth. Dermal exposure to solid naphthalene may have occurred in one case for which it
was stated that the clothing was "impregnated" with naphthalene mothballs (Dawson et
al., 1958).
No conclusions can be drawn, with respect to the role of naphthalene exposure, from a
single case report of aplastic anaemia in a 68-year old woman, who had been employed in
a clothing resale shop for 39 years, where she was exposed to paradichlorobenzene and
naphthalene (Harden and Baetjer, 1978).
A poorly reported paper described eye effects in a group of 21 workers who were involved
in manual processes where they came into contact with solid, molten and presumably
vaporised naphthalene (Ghetti and Mariani, 1956). The exposure duration is unclear from
the report but appears to vary from 1-5 years. Optical lens opacities were noted in 8
workers. However "almost all" of the lesions were pin-point peripheral opacities of the
nucleus of the lens, which "largely unaffected" the vision of the individuals. These opacities
were described as "slight" (could only be detected by slit lamp). Also, the individuals
themselves were reported to be unaware of any damage. However details of two of the
cases were presented, and in these two cases cataracts and more marked diffuse opacities
were reported. Overall it is not clear from the information provided, whether the effects
reported were in excess of that expected in the general population.
A secondary literature source (Grant, 1974) reported three cases of decreased visual
acuity, chorioretinitis or lens cataract formation in men occupationally exposed to
naphthalene during the early 1900s (Van der Hoeve, 1906; Gottstein et al., 1926). Other
signs of naphthalene toxicity did not occur and naphthalene exposure levels (to the solid
and/or vapour) were not known. Similarly Gosselin (1984) cited another early reference
which apparently claimed that corneal ulceration and cataracts were noted in a worker who
had been exposed to naphthalene vapour and dust (Adams and Henderson, 1930). No
conclusions as to the potential of naphthalene to cause eye damage can be drawn from
these early case reports in view of the lack of information on exposure to other chemical
or physical agents which may act as confounders.
Information found subsequent to the ESR Review
Studies in rats
90 day inhalation study
Since the publication of the ESR Review, one key repeated dose inhalation toxicity study
has been conducted in rats.
F344 rats (10/sex/group) were exposed to naphthalene vapour (99.9% pure) at
concentrations of 0, 0.1, 1, 10 and 30 ppm (equivalent to 0, 0.52, 5.24, 52.4 and 157
mg/m
3
) for 90 days (6h/day, 5 days/week, whole body exposure). Animals were sacrificed
on the day after the last exposure to naphthalene (Dodd et al. 2012).
Additional groups of animals were retained for a recovery period of 4 weeks. There are
some inconsistencies in the report relating to the recovery groups, but there appears to
have been a recovery group for all exposure levels (10 rats/ sex/ exposure group).
According to the study authors, the results were similar in both sexes. However, data were
presented for males only, therefore statements on ‘both sexes’ relate to the study authors’
conclusions.
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 46 December 2018
Nasal tip and Level I of the nasal cavity (transitional/respiratory epithelium)
Low grade inflammation was observed at the nasal tip and Level I of the nasal cavity
(transitional/respiratory epithelium) in controls and all exposure groups. The study authors
considered that these findings were not treatment-related. The eMSCA concurs with this
view and thus on this basis it is considered that there were no treatment-related nasal
lesions observed in rats exposed to 0.52 mg/m
3
in this study.
Olfactory epithelium
No effects on the olfactory epithelium were observed in either sex exposed to 5.24 mg/m
3
naphthalene, as shown the table below. At 52.4 and 157 mg/m
3
, lesions of the olfactory
epithelium including necrosis and degeneration were observed in both sexes. A ‘prominent’
basal cell hyperplasia was described as occurring in association with the degeneration of
the olfactory epithelium. Effects reported in this study occurred in a concentration-related
manner.
Table 21: Incidence and severity of lesions of the olfactory epithelium in male rats
following exposure to naphthalene by inhalation for 90 days
Exposure (mg/m
3
)
0
0.52
5.24
52.4
157
Level II
Basal cell hyperplasia
-
-
-
7/10 (1.0)
10/10 (1.7)
Degeneration/necrosis
-
-
-
8/10 (1.5)
10/10 (1.7)
Level III
Basal cell hyperplasia
-
-
-
8/10 (0.8)
10/10 (1.9)
Degeneration/necrosis
-
-
-
10/10 (1.4)
10/10 (2.3)
Level IV
Basal cell hyperplasia
-
-
-
9/10 (1.0)
10/10 (2.1)
Degeneration/necrosis
-
-
-
10/10 (2.0)
10/10 (2.7)
Level V
Basal cell hyperplasia
-
-
-
6/10 (0.6)
10/10 (2.0)
Degeneration/necrosis
-
-
-
9/10 (1.1)
10/10 (1.8)
Residual olfactory epithelial degeneration and basal cell hyperplasia were observed in the
recovery groups although there were small reductions in the severity and incidence of
these lesions at the end of the recovery period, as tabulated below.
Table 22: Incidence and severity of lesions of the olfactory epithelium in the recovery
groups of male rats following exposure to naphthalene by inhalation for 90 days and 4
subsequent weeks of recovery
Exposure (mg/m
3
)
0
0.52
5.24
52.4
157
Level II
Basal cell hyperplasia
-
-
-
8/9 (0.89)
8/10 (1.9)
Degeneration/necrosis
-
-
-
6/9 (0.89)
8/10 (1.3)
Level III
Basal cell hyperplasia
-
-
-
7/9 (0.78)
10/10 (1.9)
Degeneration/necrosis
-
-
-
9/9 (1.0)
10/10 (1.7)
Level IV
Basal cell hyperplasia
-
-
-
6/9 (0.67)
10/10 (1.8)
Degeneration/necrosis
-
-
-
8/9 (0.89)
10/10 (1.4)
Level V
Basal cell hyperplasia
-
-
-
2/9 (0.22)
9/10 (1.4)
Degeneration/necrosis
-
-
-
-
6/10 (0.6)
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UK MSCA 47 December 2018
Transitional/respiratory epithelium
In animals exposed to 5.24 mg/m
3
naphthalene vapour, there was minimal hyperplasia in
the transitional/ respiratory epithelium, as shown in the table below. At 52.4 and 157
mg/m
3
, mild hyperplasia and minimal squamous metaplasia were observed in the
respiratory epithelium.
Table 23: Incidence and severity of lesions of the transitional/respiratory epithelium in
rats following exposure to naphthalene by inhalation for 90 days
Exposure
(mg/m
3
)
0
0.52
5.24
52.4
157
Level I
Inflammation
6/10
(0.8)
6/10
(0.9)
5/10 (0.8)
5/10 (0.6)
4/10 (0.4)
Level II
Squamous
metaplasia
-
-
-
8/10 (0.9)
8/10 (0.8)
Hyperplasia
-
-
10/10 (1.0)
10/10 (1.4)
10/10 (1.4)
At the end of the 4 week recovery period, there was complete recovery from squamous
metaplasia and hyperplasia in the transitional/ respiratory epithelium with the exception
of a single observation of hyperplasia in a male who had been exposed to 52.4 mg/m
3
naphthalene, as shown in the table below.
Table 24: Incidence and severity of lesions of the transitional/ respiratory epithelium in
the recovery groups of rats following exposure to naphthalene by inhalation for 90 days
and 4 subsequent weeks of recovery
Exposure (mg/m
3
)
0
0.52
5.24
52.4
157
Level I
Inflammation
5/10 (0.6)
6/10
(0.7)
6/10 (0.7)
8/9 (1.0)
8/10 (0.9)
Level II
Squamous
metaplasia
-
-
-
-
-
Hyperplasia
-
-
-
1/9 (0.11)
-
In addition to the observations tabulated above, goblet cell hyperplasia was observed in
the nasopharyngeal ducts of a small number of rats exposed to 5.24, 52.4 and 157 mg/m
3
naphthalene. After 4 weeks of recovery, this lesion was observed in a single male at 52.4
mg/m
3
only.
Conclusion
Since no treatment-related effects were reported at the lowest level of exposure, a NOAEC
of 0.52 mg/m
3
has been identified from this study.
13 week Inhalation study
In addition, the same group of scientists exposed F344 rats (5/sex/group) to 0, 0.1, 1, 10
and 30 ppm naphthalene (equivalent to 0, 0.52, 5.24, 52.4 and 157 mg/m
3
) for 6 hours
per day 5 days per week for 13 weeks (Meng et al. 2011). Limited information about the
observed effects on the respiratory and olfactory epithelia is available because the primary
aim of this study was to investigate whether naphthalene increased mutations in the p53
tumour suppressor gene in the nasal tissues of rats. However, the observed effects appear
to be consistent with those observed in the new key study described above (Dodd et al.
2012). At 5.24 mg/m
3
, minimal hyperplasia was observed in the transitional/ respiratory
epithelium. From 52.4 mg/m
3
, adverse effects were observed in both the olfactory and
respiratory epithelia.
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 48 December 2018
This study supports a NOAEC of 0.52 mg/m
3
in rats for non-neoplastic lesions in the nasal
cavity following exposure to naphthalene.
Information found subsequent to the ESR Review
Human information
Bio-monitoring study
Recently, a biomonitoring study of workers exposed to naphthalene in the abrasives
industry has been conducted (Sucker et al. 2016). This cross-sectional study (dated
28/10/16) was conducted by the IPA (Institut für Prävention und Arbeitsmedizin der
Deutschen Gesetzlichen Unfallversicherung). Three production plants in Germany and two
in Austria were included in the study. As detailed in Section 7.12.1.1.5 of this Evaluation
Report, a variety of short-term (15-min TWA) and full-shift (8-hour TWA) inhalation
exposures were measured in different work areas in these factories. Exposures for the
highest exposure group were in the ranges 3.47-69.6 mg/m
3
(15-min TWA) and 3.62-
11.58 (mg/m
3
(8-hour TWA). Some exposures therefore exceeded national workplace
limits. The study aimed to identify any clinical signs of toxicity related to naphthalene
exposure over a 3-month period in 2014. In particular, there was a focus on signs of
irritation and/or inflammation of the nasal mucosa. The study was not designed to provide
information on whether any observed nasal lesions might have potential to progress to
nasal tumours.
The potential effect of naphthalene exposure on the blood system was not investigated in
this study.
The study was conducted from 20
th
July to 23
rd
October 2014. This period included the
least favourable exposure conditions (i.e. seasonally high naphthalene exposure levels due
to high exterior temperatures) and avoided the possibility of seasonal effects such as those
that might arise from environmental allergens (especially pollen in the spring) or seasonal
respiratory tract infections (mainly in winter).
Effects potentially related to naphthalene exposure were identified via a combination of
questionnaires (filled in by study participants) and medical examinations. Medical
examinations took place before workers started their shift on Mondays and after the
workers finished their shift on Thursdays. The examinations were conducted by a
healthcare professional and comprised of the following:
otorhinolaryngological examinations to identify clinical signs of
irritation/inflammation and damage to the nasal mucosa, including endoscopy
of the nasopharyngeal cavity and acoustic rhinometry, and investigation of the
sensitivity of the nasal mucosa;
investigation of the olfactory response to identify clinical signs of an impaired
sense of smell;
investigation of biomarkers in the nasal lavage, sputum and blood to assess
possible subclinical signs of irritation/inflammation and damage to the upper
respiratory tract due to reactive metabolic products and oxidative stress;
investigation of naphthalene odour perception to identify habituation effects;
recording the subjective perception of naphthalene exposure in terms of the
intensity of olfactory (odour intensity, nuisance level, nausea) and trigeminal
sensations (e.g. stinging, burning, sharp) in the region of the eyes and nose,
and in terms of specific stimulating symptoms (e.g. nasal irritation) and non-
specific symptoms (e.g. headaches, nausea) by means of a questionnaire.
In addition, a blood sample was used to verify the allergy status and a urine
sample to verify the smoking status through cotinine.
Urinary levels of the naphthalene metabolites 1-naphthol and 2-naphthol were measured
before and after shift as biological markers of exposure. The obtained values were used,
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 49 December 2018
together with work history and the results of air monitoring, to divide the subjects into 3
groups: highly exposed; moderately exposed and the reference group. Exposure levels for
those workers who volunteered for further assessment were as follows:
Table 25: Naphthalene exposure levels in the biomonitoring study (Sucker et al. 2016)
Exposure Group
Air monitoring (mg/m
3
) 8-hour
TWA
Biomonitoring (µg/g creatinine)
Median
Mean
Range
Median
Mean
Range
Reference (n=22)
(no or rare
naphthalene
exposure)
0.13
0.15±0.10
0.05 - 0.36
19
18±11
6 - 40
Moderate (n=17)
(indirect
naphthalene
exposure)
0.59
0.66±0.27
0.20 - 1.22
108
108±49
43 - 210
High (n=22)
(direct naphthalene
exposure)
6.30
6.97±3.10
2.46 - 11.58
1256
1489±999
293 - 4352
The numbers of workers in each exposure group differ slightly from the numbers provided
in Table 11 section 7.12.1.1.5. This is because a number of employees were subsequently
re-allocated to a different exposure group based on the activities they carried out.
It was noted that the workers included in the study may also have been exposed to ceramic
grain, silica or other inhalable dusts.
Thirty two male workers volunteered to be included in the study alongside 31 reference
subjects who had not worked with naphthalene for 10 years or more. Employees who had
smoked in the last 12 months were not eligible to take part in the study. Raised levels of
cotinine, indicative of smoking, were observed in two employees, who were subsequently
excluded from the study.
Workers were excluded from the study if they had a previous or current medical condition
of the upper respiratory tract or a significant medical condition associated with the
impairment of the sense of smell.
There were 22, 17 and 22 participants in the reference, moderately exposed and highly
exposed groups, respectively. The average age of workers in the highly exposed group was
10 years younger than those in other groups.
The questionnaires revealed that complaints of eye-related effects were significantly more
likely to be reported by the highly-exposed workers than the reference group. Significantly
more nasal complaints were reported by employees in both exposed groups compared to
reference subjects. These effects were generally stronger on Thursdays than those
reported on Mondays. Employees reported that these effects were clearly noticeable only
when handling naphthalene directly. After the end of the shift, virtually no complaints were
present any longer.
Following endoscopic examination, ENT (ear, nose and throat) specialists reported slight
to moderate nasal inflammation. Although a significant difference between the moderate
and high exposure groups was not identified at the end of shift on Thursdays, there were
significant differences between the reference and exposed groups.
Acoustic rhinometry did not provide evidence of nasal swelling related to naphthalene
exposure. Trigeminal sensitivity of the nasal mucosa tended to increase with increased
exposure. However, differences between exposure groups were not statistically significant.
Nasal septum perforations, which occur with a prevalence rate of approximately 1% in the
general population, were observed in 2/22 workers in the high exposure group. However,
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 50 December 2018
one of these employees had previously had surgery of the nasal septum and was therefore
considered to be inherently at increased risk of the observed effect. The second employee
had undergone surgery for nasal polyps in the past. It is unclear whether the surgery could
have led to the nasal septum perforations. It is uncertain whether these observations are
related to naphthalene exposure.
Samples of nasal lavage fluid and induced sputum were obtained from participants pre-
and post-shift in order to measure levels of biomarkers indicative of inflammation in the
upper and lower respiratory tract, respectively.
Nasal lavage: Quantification of neutrophil granulocytes did not provide any evidence of
acute inflammation. Measured levels of 8-isoprostane (indicator of oxidative stress) and
leukotriene B
4
(indicator of inflammation) decreased over the course of the working week
in reference subjects but increased over this period in the exposed groups. However,
variation of these values over time or between groups was not significant and therefore
these markers do not provide strong evidence of oxidative stress or inflammation in this
study.
High levels of another potential indicator of chronic inflammation (C-reactive protein) were
observed in both the reference and moderately exposed groups only. Likewise, no
difference was noted in levels of Substance P (another potential indicator of inflammation)
over time or between groups. Attempts to quantify levels of interleukin 6 (IL-6) were
unsuccessful because the concentration was below the level of the detection in 91% of the
samples. No effect of group or time was identified for levels of IL-8 in the nasal lavage.
Matrix metalloproteinase-9 (MMP-9) is a mediator known to play a role in inflammatory
processes. An increase in MMP-9 levels from Monday to Friday was observed in the exposed
groups only. Tissue inhibitor of metalloproteinase-1 (TIMP-1) is an inhibitor of MMP-9 and
levels of this marker were lower in exposed subjects than in reference subjects on both
Mondays and Thursdays. As noted by the study authors, an increased concentration of
MMP-9 could suggest that there was inflammation in the nasal region. The MMP-9/TIMP-1
ratio was higher at the end of the shift in the high exposure groups than in the reference
or moderate exposure groups. However, the differences between groups for both these
markers were not statistically significant.
There was a significant correlation between the exposure index and the levels of two
biomarkers measured before the shift on Mondays: total protein and IL-8.
Overall, a clear, consistent pattern of changes to the key biomarkers in nasal lavage was
not apparent; the data provide only limited evidence of inflammation in the upper
respiratory tract of exposed subjects.
Induced sputum: There was a significant correlation between naphthalene exposure
(internal and external indices) and the levels of neutrophil granulocytes and substance P
measured after the shift on Thursdays. These markers are both considered to indicate a
possible inflammatory response in the lower respiratory tract. In contrast, the MMP-
9/TIMP-1 ratio did not differ between groups. However, the patterns observed for other
markers were very similar to those seen in the nasal lavage and do not provide a clear
picture. Therefore the results provide only limited evidence of inflammation in the lower
respiratory tract.
Blood: Two markers of inflammation were also assayed in blood samples.
Levels of IL-6 were below the detection limit in approximately two thirds of the samples
and therefore this marker was excluded from the investigation.
Club cell protein 16 (CC16) is protective against inflammatory processes in the lung. Levels
of CC16 in the blood were quantified because a low concentration of this protein may
indicate tissue damage. The levels of CC16 were lower in exposed subjects than in
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 51 December 2018
reference subjects, both on Monday (before shift) and Thursday (after shift). A significant
decrease in CC16 levels from Monday to Thursday was noted in all groups, although the
decrease in the high exposure groups was slightly greater than in other groups. There was
a statistically significant association between the levels of CC16 protein measured at the
end of the week and internal exposure, and also between blood serum CC16 levels and
external exposure. However, as noted by the study author, there was a large degree of
overlap of the confidence intervals for each group.
Overall, in this study, clinical and subclinical signs of slight acute inflammation in the nasal
mucosa of both exposed groups were reported. Clear exposure-response relationships
were not observed, but measurements of some parameters differed between reference
subjects and exposed subjects. However, as concluded by the study authors themselves,
there was a large degree of overlap in the observations derived for each study group.
Furthermore, it cannot be dismissed that co-exposure of workers to other chemicals may
have confounded this study. For these reasons, the data do not allow any firm conclusions
to be made about the toxicity of naphthalene. The data are considered at most to provide
only limited evidence that exposure to naphthalene in this work place may be causing nasal
irritation and inflammation in humans. The study did not provide any information on
naphthalene’s potential to induce haemolytic anaemia in humans.
The authors summarised the results of the study as follows:
“In summary, no consistent pattern of (inflammatory) effects was seen, either in the
moderately or in the highly exposed group. For some parameters (e.g. nasal
endoscopic score) minor but statistically significant differences between the exposed
group and the reference group have been observed which are compatible with mild
acute inflammatory effects. On the other hand, in a great part of parameters, particular
regarding biomarkers, there was no consistent difference between the moderately and
highly exposed groups and also no adversity developed over time within the working
week covered in this study. In parameters that showed (statistically significant)
differences between the reference group and the exposed groups there was often a
considerable overlapping of values between the groups. In view of the broad range of
the naphthalene exposure by more than one order of magnitude it seems questionable
that the described differences are only due to naphthalene itself. The overall exposure
situation including inhalable and respirable dust, especially from ceramic grain or silica,
has to be taken into consideration.”
7.9.5. Germ cell Mutagenicity
This endpoint was not evaluated.
7.9.6. Carcinogenicity
Naphthalene is classified as a Category 2 Carcinogen in Annex VI of the CLP Regulation
(EC 2008/1272). Treatment-related increases in the incidence of neuroblastoma in the
olfactory epithelium and adenoma in the respiratory epithelium were observed in rats
following inhalation exposure to naphthalene (NTP 2000). Additionally, lung tumours were
observed in mice following chronic exposure to naphthalene by inhalation (NTP, 1992).
However the findings is mice were not considered to be of relevance to humans. Therefore
the harmonised classification of naphthalene for carcinogenicity was based on the nasal
tumours observed in rats.
7.9.6.1. Summary and discussion of carcinogenicity
Inhalation
ESR Review of naphthalene (2003)
Substance Evaluation Conclusion document EC No 202-049-5
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Study in rats
Groups of 49 male and 49 female F344/N rats were exposed to 0, 10, 30 or 60 ppm
naphthalene vapour (>99% pure) (approximately equivalent to 0, 50, 150 or 300 mg/m
3
)
in inhalation chambers for 6 hours/day, 5 days/week for 105 weeks.
Neuroblastoma of the nasal olfactory epithelium was observed in males from the 30 and
60 ppm groups (4/48 and 3/48, respectively) and in all exposed groups of female rats
(2/49, 3/49 and 12/49 at 10, 30 and 60 ppm, respectively). This neoplasm did not occur
in chamber control rats or male rats exposed to 10 ppm. In addition, this tumour has not
been observed in the historical chamber control rats in NTP 2-year inhalation studies.
Increases were also observed in adenomas of the respiratory epithelium in males from all
exposure groups (control: 0/49, 10 ppm: 6/49, 30 ppm: 8/48 and 60 ppm: 15/48) and
females from the 30 and 60 ppm exposure groups (control: 0/49, 30 ppm: 4/49 and 60
ppm: 2/49). Compared to concurrent chamber controls the increases in respiratory
epithelium adenomas were statistically significant in males but not females. The draft
report states that nasal adenomas have not been observed in NTP historical chamber
control rats. No lung tumours were observed.
In addition to the nasal neoplasms, the incidences of a variety of non-neoplastic lesions of
the nasal tract in both sexes were statistically significantly greater in naphthalene exposed
animals than controls. These lesions included, in the olfactory epithelium: atypical (basal
cell) hyperplasia, atrophy, chronic inflammation, and hyaline degeneration; in the
respiratory epithelium: hyperplasia, squamous metaplasia, hyaline degeneration, and
goblet cell hyperplasia; and glandular hyperplasia and squamous metaplasia. In general,
the severity of the olfactory and glandular lesions increased with increasing exposure
concentrations.
Overall this study demonstrated an increase in the incidence of respiratory epithelial
adenomas in naphthalene exposed males from 10 ppm and females from 30 ppm and
olfactory epithelial neuroblastomas (a very rare tumour type) in males from 30 ppm and
females from 10 ppm. These tumours occurred at sites where non-neoplastic inflammatory
changes also occurred and are considered to be treatment-related.
Studies in mice
104 week study (NTP, 1992)
Groups of 70 male and 70 female B6C3F1 mice were exposed to 0 or 10 ppm naphthalene
vapour and groups of 135 males and 135 females to 30 ppm naphthalene vapour (>99%
pure) (equivalent to 0, 50 and 150 mg/m
3
/day) in inhalation chambers for 6 hours/day, 5
days/week for 104 weeks (NTP, 1992).
A statistically significant increase occurred in the incidence of alveolar/bronchiolar
adenomas in high-exposure females (controls: 5/69, 7%; 10 ppm: 2/65, 3%; 30 ppm:
28/135, 21%; historical incidence and range in NTP inhalation studies in female mice:
5.8%, 0-10%). One alveolar/bronchiolar carcinoma was also noted in a high-dose female
(1%) but as the historical control incidence is 2.8% (range 0-6%) no significance can be
placed on this finding. Exposed males also showed an increased incidence in
alveolar/bronchiolar adenomas and carcinomas. However these increases were not
statistically significant and/or were within historical control values (adenomas: 7/70
(10%); 15/69 (22%); 27/135 (20%); 69/478 (14.4%), carcinomas: 0/70; 3/69 (4%);
7/135 (5%); 30/478 (6.3%), in control, low and high exposure and NTP historical controls,
respectively).
Overall this study demonstrated an increase in the incidence of benign adenomas in female
mice at a site where non-neoplastic inflammatory changes also occurred. There was no
increase in malignant tumours. Other than the non-neoplastic changes in the lungs and
nose no other signs of general toxicity were noted and it is possible that the study could
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have included a higher concentration of naphthalene. That is, the study could have been
more rigorous but is none the less, adequate.
6 month study
In a limited and briefly reported inhalation study groups of 30 male and female Strain A/J
mice were exposed to 0, 10 or 30 ppm naphthalene (equivalent to 0, 50 and 150
mg/m
3
/day) for 6 hours/day, 5 days/week for 6 months (Adkins et al., 1986). Survival was
unaffected by treatment. Body weight and signs of toxicity were not reported. Macro- and
microscopic examinations were only conducted on the lungs. There was an increase in the
incidence of lung adenomas, although it is not clear if this increase was statistically
significant (Controls: 21%, 10 ppm: 29%, 30 ppm: 30%). No other details were given.
Overall due to the high incidence of lung adenomas in controls, the small numbers of
animals used and the limited study length, no meaningful conclusions can be drawn from
these findings.
Dermal
There is no information available.
Human information
Two brief reports are available of four cases of laryngeal cancer which occurred in workers
engaged in the purification of naphthalene (Wolf, 1976; 1978). It is difficult to define from
the reports whether the author identified these four cases independently or whether they
were brought to his attention by an external source. However, it is clear from the reports
that all the cases were smokers and were exposed to other substances including coal tar
volatiles. Overall, no conclusion can be drawn from these reports regarding the role, if any,
of naphthalene in the production of these cancers.
Information found subsequent to the ESR Review
No further carcinogenicity studies have been conducted since the ESR Review
7.9.6.2. Conclusion on carcinogenicity - Mode of Action (MoA)
The text in italics, below, has been taken from the ESR Review (EC 2003) and included for
information.
In view of the negative results obtained in the in vivo genotoxicity studies, naphthalene is
considered to be non-genotoxic. Given this, the tumours in the animal studies are
considered to arise via a non-genotoxic mechanism and consideration must therefore be
given to other potential mechanisms underlying the carcinogenic response.
An in vivo Unscheduled DNA Synthesis (UDS) study (stae tissues sampled) and an in vivo
bone marrow micronucleus assay gave negative results, as described in the ESR Review.
The eMSCA considers that there is no information available to change the weight-of-
evidence-based approach presented in the ESR Review which concluded that naphthalene-
induced tumours are likely to have resulted from a non-genotoxic mechanism.
Cytotoxicity
In relation to the rat nasal tumours, the tumours develop only at the sites where non-
neoplastic inflammatory changes also occur (changes such as atrophy, hyperplasia and
metaplasia). Thus, it is considered that the development of the nasal tumours in the rat is
a consequence of chronic tissue injury, for which an identifiable threshold of effect will
exist, although currently not identified. However, the available data do not allow the
identification of a threshold for chronic tissue damage, nor is there any clear information
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on whether or not local tissue metabolism is involved in the toxicity of naphthalene to the
nasal epithelium.
There are anatomical differences in the nasal passages between rats and humans, and
differences in breathing pattern (rats are obligate nasal breathers) which may affect airflow
and deposition patterns of naphthalene. Thus, there is some uncertainty concerning the
relevance of the rat nasal effects to human health. However, overall, it is not possible to
dismiss the rat nasal olfactory data as being of no relevance for humans.
The development of naphthalene-induced mouse lung adenomas is unlikely to be of
relevance to human health due to species differences in pulmonary metabolism. In vitro
studies with lung microsomal preparations clearly showed that mouse lung preparations
metabolised naphthalene at substantially greater rates (up to 100-fold) than those from
hamster, rat or monkey. Furthermore, intra-peritoneal dosing of 50 mg/kg naphthalene
led to specific toxicity to Clara cells in the lungs of mice, but no such toxicity was observed
in rats even at 1,600 mg/kg. In addition, no lung tumours were seen in rats. Hence, the
pattern of toxicological evidence indicates that the mouse is more susceptible to the
pulmonary toxicity of naphthalene than other species, and therefore the observed
pulmonary adenomas seen in mice at 30 ppm (150 mg/m
3
) are not considered to be of
relevance to human health.
Based on the information presented in the ESR Review, the eMSCA concurs with the
conclusion that lung adenomas observed in mice are not relevant to human health and
that the nasal tumours (neuroblastoma and adenoma) may be relevant for human health.
On this basis, the eMSCA’s analysis of naphthalene-induced carcinogenesis has focussed
on the nasal tumours observed in rats.
7.9.6.3. Additional evaluation (2016/2017)
At the Naphthalene State of the Science Symposium (NS3) held in 2006, the panel noted
that the maximum tolerated dose (MTD) had been exceeded in both rats and mice and that
the available data were strongly supportive of cytotoxicity having a role in the formation
of the observed tumours. The panel considered that naphthalene is not a classical
genotoxic carcinogen (North et al. 2008). Although it was concluded that focal cellular
proliferation enhanced (and possibly enabled) the occurrence of nasal tumours, the panel
could not rule out the possibility of genotoxicity being involved on the basis of evidence of
irritation, but not tumours, occurring in the mouse nose (Bogen et al. 2008).
Additionally, the panel postulated that if one were to use the results of the rodent bioassays
to estimate tumour rates in humans, the resultant predicted incidence would considerably
exceed the observed rate in humans (North et al. 2008) and therefore meaningful
predictions of tumour incidences in humans cannot be obtained via a simple linear
extrapolation from data on rats exposed to cytotoxic concentrations of naphthalene (Bogen
et al. 2008).
Magee et al. (2010) carried out a retrospective population risk assessment by extrapolating
the data from rats (NTP, 2000) to estimate the incidence of respiratory epithelial adenomas
and olfactory epithelial neuroblastomas one would expect to observe in the US population.
The estimation was based on naphthalene Unit Risk Factors proposed by the US
Environmental Protection Agency (EPA) based on the tumours observed in rats. The study
authors found that cancer potency estimates based on the rat NTP bioassay significantly
overestimated the total number of nasal tumours actually observed in the US population
and therefore considered that the rat may be an inappropriate model for estimating the
risk of naphthalene-induced nasal tumours in humans.
The panel at the Naphthalene State of the Science Symposium also noted that the toxicity
is caused by metabolites of naphthalene rather than naphthalene itself (Bogen et al.
(2008).
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Since the Symposium, a number of authors have further considered the potential of
naphthalene to induce nasal tumours. The following information is considered to be of
relevance to the assessment of the carcinogenic mode of action of naphthalene.
Metabolism
Naphthalene is understood to be metabolised by CYP2F (and/or other CYPs) to the reactive
epoxide, which in turn is conjugated with glutathione. Cytotoxicity is associated with GSH
depletion in cells, chronic inflammation, and regenerative hyperplasia have been reported
to follow naphthalene metabolism (Rhomberg et al. 2010).
Although collocation of CYP2F activity and cytotoxicity could indicate causality, it is possible
that collocation could just be coincidental (Rhomberg et al. 2010) and the possibility that
other CYP enzymes are involved cannot be excluded. However, the low concentration of
CYP2F in the rat lung together with the absence of tumours in this location supports the
postulation that CYP2F does have some involvement in the primary metabolism of
naphthalene.
Morris and Buckpitt (2009) measured the uptake of naphthalene in the upper respiratory
tract of F344 rats (6-12 males/ group and 7-8 females/group) with a focus on the olfactory
epithelium. Naphthalene (1, 4, 10 or 30 ppm; equivalent to 5.24, 21, 52.4 and 157 mg/m
3
)
was administered to rats (nose-only) at inspiratory flow rates of 150 or 300 ml/min. An
inhibitor of cytochrome P450 (CYP450), namely 5-phenyl-1-pentyne (PP), was
administered to additional groups of rats (7-8/sex/group) prior to naphthalene exposure.
In rats not pre-treated with PP, the efficiency of naphthalene uptake decreased with
increasing concentration of naphthalene. In addition, it was noted that flow rate
significantly affected uptake: naphthalene uptake was lower at a flow rate of 300 ml/min
than at 150 ml/min. The findings were similar in both sexes although the uptake efficiency
was higher in males than in females.
In rats pre-treated with PP (both sexes), the efficiency of naphthalene uptake did not vary
significantly with concentration and was lower than animals not exposed to PP. The activity
of metabolites in the olfactory mucosa was approximately 80% lower in pre-treated rats.
Since PP inhibits CYP450, the lower naphthalene uptake efficiency in the presence of PP
supports the assertion that naphthalene is metabolised by CYP enzymes in the nasal
olfactory mucosa.
These findings do not rule out a role for CYP2E1 in naphthalene metabolism because this
CYP isozyme is also inhibited by PP. Data comparing the activity of CYP2F to CYP2E1 is
lacking but some reported evidence suggests that CYP2F is more efficient and could
therefore be the primary CYP enzyme in naphthalene metabolism (Rhomberg et al. 2010).
This assertion is supported by meaurements of the efficiency of naphthalene oxide
generation using recombinant CYP2F4 from rats (Baldwin et al. 2005 as cited by Rhomberg
et al. 2010) and recombinant CYP2F2 from mice (Schultz et al. 1999 as cited by Rhomberg
et al. 2010). The efficiency of epoxide generation by recombinant CYP2F4 and CYP2F2 from
rodents was similar (V
max
of 107 min
-1
and 104 min
-1
, respectively). Metabolism of
naphthalene to 1-naphtol via recombinant CYP2E1 from humans was less efficient (V
max
of
8.4 min
-1
) (Cho et al. 2006 as cited by Rhomberg et al. 2010).
In summary, the evidence is considered to support a role for CYP enzymes (CYP2F and/ or
other isozymes) in the initial metabolism of naphthalene.
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7.9.6.3.1. MoA Analysis
The eMSCA has additionally assessed the MoA of the nasal tumours using the IPCS
(International Programme on Chemical Safety) conceptual framework (Sonich-Millin et al.,
2001).
7.9.6.3.1.1. Postulated Mode of Action
The postulated mode of action (MoA) proposes that naphthalene is metabolised to cytotoxic
metabolites by a CYP enzyme (CYP2F) in tumour-forming tissues. Those metabolites are
responsible for the inflammation and regenerative hyperplasia which precede
carcinogenesis.
7.9.6.3.1.2. Key events
The key events in the proposed mode of action are the initial metabolism of naphthalene
by a CYP enzyme to reactive intermediates (eg expoxides) which lead to GSH depletion,
cytotoxicity , inflammation, hyperplasia and eventually tumours in the target tissues.
Evidence of cytotoxicity (atypical hyperplasia, atrophy, chronic inflammation and hyaline
degeneration in the olfactory epithelium and hyperplasia, squamous metaplasia, hyaline
degeneration and goblet cell hyperplasia in the respiratory epithelium) was measured in
the NTP study in which the nasal tumours were observed, and also in the NTP study in
mice, in which tumours were observed in the lung only. The studies did not examine GSH
depletion or the initial metabolism of naphthalene to the epoxide.
In addition, the nasal tissue was examined histopathologically in recently conducted
inhalation studies in rats (Dodd et al. 2010, 2012).
7.9.6.3.1.3. Exposure-response relationship (data provided in section 7.9.4.)
2 year NTP inhalation study in rats
Olfactory epithelium
In controls, no incidences of neuroblastoma were reported and the key events in the
olfactory epithelium (atypical hyperplasia, atrophy, chronic inflammation, hyaline
degeneration) were of minimal severity or non-existent in this group. The key events were
observed in almost all of treated animals in all dose groups, whilst tumours were observed
at all doses in females and at the mid and high doses in males.
The severity of atypical hyperplasia, atrophy and chronic inflammation increased with dose
in both sexes. However, the severity of hyaline degeneration did not increase in an
exposure-dependent manner in either sex. In females, the increased severity of the non-
neoplastic findings in the nasal tissue was consistent with the exposure-related increased
incidence of neuroblastoma.
Generally, the results indicate that neuroblastoma occurred at doses at which the key
events were observed. However, there were no reports of neuroblastoma in low dose males
despite the incidences and severities of non-neoplastic lesions being similar in both sexes.
The reason for the sex difference in the incidence of tumours in the olfactory epithelium is
unclear.
Respiratory epithelium
Similarly, no incidences of adenoma were reported in controls and the key events in the
respiratory epithelium (hyperplasia, squamous metaplasia, hyaline degeneration, goblet
cell hyperplasia) were of minimal severity or non-existent in this group. The key events
were observed in approximately half of treated animals in all dose groups, whilst tumours
were observed at all doses in males and at the mid and high doses in females.
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The severity of the lesions in the respiratory epithelium did not increase with dose in either
sex. This appears to be inconsistent with the exposure-related increased incidence of
adenoma in males.
Despite evidence of the key events in low dose females, there were no reports of adenoma
in these animals. The reason for the sex difference in the incidence of adenoma in the
respiratory epithelium is unknown. However, in general, the results indicate that adenoma
occurred at doses at which the key events were observed irrespective of the severity of
the non-neoplastic lesions.
18 month NTP study in mice
Unlike in rats, nasal tumours were not reported in mice. The absence of nasal tumours
could be considered inconsistent with the findings in rats. However, the non-neoplastic
lesions reported in mice do not include all of the key events described in rat nasal tissue.
In the 18 month study histopathological examinations were performed on the nasal cavities
of all mice. Therefore the lack of reports of some of the key events in mice (e.g. atrophy,
hyaline degeneration and atypical hyperplasia in the olfactory epithelium) indicates that
these effects were absent in mice rather than overlooked due to a limited study design.
Therefore the data in mice support the assertion that the key events, listed in the tables
in Section 7.9.4. are necessary precursors for tumorigenesis in nasal tissue. However, the
reason for the absence of the key events in mice following exposure to naphthalene is
unclear.
Short term inhalation studies in rats
The NTP does not appear to have conducted a 90 day study in rats (as they frequently do
in their program) that would allow for a comparison between different durations of
exposure in the same lab. Treatment-related non-neoplastic nasal lesions were observed
at the lowest exposure level (2 ppm, equivalent to 10.5 mg/m
3
) in a 90 day study in rats
(Huntingdon Research Centre, 1993a). Similarly, non-neoplastic lesions were observed in
the noses of rats at concentrations below 1 ppm (5.24 mg/m
3
) in acute and subchronic
studies (Dodd et al. 2010, Dodd et al. 2012). The NOAEC in the recent 90 day study was
0.52 mg/m
3
. However, due to the short duration of these studies, the data do not inform
on whether the non-neoplastic lesions would have progressed to tumours over time.
After short term exposure of rats to naphthalene by both inhalation and intraperitoneal
injection, the incidence of the observed lesions correlated with formation of naphthalene-
1,2-epoxide (Lee et al. 2005). This information supports the assertion that metabolism of
naphthalene is involved in the carcinogenic MoA.
Antioxidant/Antielectrophilic response to metabolites
Cichocki et al. (2014) exposed F344 rats (both sexes) nose-only to 0, 1, 3, 10 or 30 ppm
naphthalene vapour (equivalent to 0, 5.24, 15.7, 52.4 or 157 mg/m
3
) for 4 or 6 hours. It
is not clear how many animals were used. The study aimed to characterise the initial
biochemical events in the olfactory and respiratory mucosa following exposure to
naphthalene and to identify any sex-specific responses to the formation of electrophilic
metabolites in the nasal passages that could explain the sex differences in the observed
tumour incidences. Due to the nature of this study, the tissues were not examined
histopathologically.
GSH levels in the respiratory/transitional and olfactory mucosa were significantly lower in
all dose groups (both sexes) than in controls after both 4 and 6 hours of exposure to
naphthalene. The decrease in GSH levels in comparison to controls was approximately 70%
and 40% in the respiratory and olfactory epithelia, respectively and did not show any
consistent difference between sexes.
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Induction of genes indicative of oxidative stress was observed in the respiratory/
transitional and olfactory mucosa. In the olfactory mucosa, induction of the measured
antioxidant genes (glutamyl cysteine ligase (catalytic subunit), NADPH quinone oxidase 1
and heme oxygenase 1) was greater in males than in females. The greater antioxidant
response in males may contribute to the observed differences in tumour incidences in the
olfactory mucosa. No such differences were reported in the respiratory/ transitional mucosa
and therefore the results do not help to explain the sex differences in the tumour incidences
observed in the respiratory epithelium.
7.9.6.3.1.4. Temporal association
Since there was no interim sacrifice in the 2 year NTP study in rats, it is not possible to
evaluate whether the postulated key events preceded tumorigenesis in this particular
study.
However, the acute (1 day), subacute (5 days) and subchronic (90 days) inhalation studies
conducted by Dodd et al. (2010, 2012) and Lee et al. (2005) are useful in the examination
of the temporal association between the key events and the tumours.
Olfactory epithelium
In rats, there is consistent evidence showing that adverse effects on the olfactory
epithelium occur shortly after exposure to naphthalene. For example, necrosis of the
olfactory epithelium was observed in F344 and Sprague Dawley rats exposed to a single 6
hour dose of naphthalene. Likewise, effects on the olfactory epithelium were reported after
4 hours of exposure to naphthalene (Lee et al. 2005). Exposure-dependent degeneration
of the olfactory epithelium was also reported in both strains of rat in the 5 day study (Dodd
et al. 2010).
In the 90 day study (Dodd et al. 2012), lesions of the olfactory epithelium including
necrosis and degeneration of the olfactory epithelium in association with a prominent basal
cell hyperplasia, were observed in F344 rats (both sexes) at 52.4 and 157 mg/m
3
.
Respiratory epithelium
Similarly, effects on the respiratory epithelium were observed in rats after short exposures
to naphthalene. Dodd et al. (2010) reported necrosis of the nasal respiratory epithelium in
F344 and Sprague Dawley rats following an acute exposure (6 hours) to naphthalene. Mild
hyperplasia and minimal squamous metaplasia in the respiratory epithelium were observed
in rats exposed to naphthalene for 90 days (Dodd et al. 2012).
No tumours were reported in these short term studies. Therefore clear evidence is available
to show that adverse effects including necrosis of the olfactory epithelium and hyperplasia
of the respiratory epithelium occur prior to the formation of tumours in these tissues.
7.9.6.3.1.5. Strength, consistency, and specificity of association of tumour
response with key events
Strength
In rats, the data show that nasal tumours occurred at sites at which cytotoxicity was
observed, where there are high concentrations of naphthalene metabolising enzymes and
GSH depletion, providing support for the postulated mode of action (Rhomberg et al.
2010).
The presence of tumours in the rat nose, where all of the key events were observed, is
consistent with the absence of tumours in the mouse nose, where only some of the key
events were reported.
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More recent inhalation studies by Dodd et al. (2010, 2012) showed that non-neoplastic
lesions occur at a lower dose (0.52 and 5.24 mg/m
3
) and after a shorter duration (1 day,
5 days, 90 days) than tested in the NTP carcinogenicity studies. However, it is unknown
whether exposure to naphthalene at this level would lead to carcinogenicity, given a longer
duration of exposure.
Since there was no interim sacrifice in the NTP study, it is not possible to ascertain whether
the non-neoplastic lesions occurred prior to the formation of tumours. However, the
findings in the shorter duration studies support the assertion that the cytotoxicity does
precede carcinogenicity.
Consistency
Treatment-related increases in the incidence of neuroblastoma in the olfactory epithelium
and adenoma in the respiratory epithelium following inhalation exposure to naphthalene
have been observed in both sexes of a single species (rats). Treatment-related tumours in
the nasal tissue were not observed in mice.
In humans, there are reports of laryngeal cancer in four workers involved in the purification
of naphthalene, as described in the ESR Review. However, since these workers were
smokers and were co-exposed to coal tar volatiles, no reliable conclusions could be drawn
from this information. Therefore no conclusive evidence is available to show that
naphthalene causes such tumours in humans. The lack of case reports detailing the
occurrence of tumours in the nasal tissue of humans exposed to naphthalene may suggest
that the tumour types observed in rats are species-specific. However, the lack of reports
could be due to the low number of workers exposed to naphthalene, the long latency period
for tumorigenesis, or the possibility that naphthalene exposure does lead to these tumours
in humans, but the cause of the tumours has not been not identified correctly, if at all.
Therefore the absence of evidence of nasal tumours in humans exposed to naphthalene is
not considered to negate the findings in rodents.
Cytotoxic non-neoplastic lesions have been observed consistently in rats and mice following
inhalation exposure to naphthalene in studies ranging from 1 day to 2 years in duration
(Dodd et al. 2010, 2012; Lee et al. 2005; NTP; 1992, 2000). The results of the
biomonitoring study (Sucker et al. 2016) provide limited information about naphthalene’s
potential to irritate human nasal tissue.
Specificity
The tumours in the olfactory and respiratory epithelium occurred at sites where key
cytotoxic events were observed and therefore there appears to be a large degree of
specificity. However, some non-neoplastic lesions do not progress to carcinogenicity, for
example tumours were not observed in the mouse nasal tissue despite observations of
chronic inflammation, metaplasia of the olfactory epithelium and hyperplasia of the
respiratory epithelium. The reason for the species difference is unclear.
7.9.6.3.1.6. Biological plausibility and coherence
Biological plausibility
Naphthalene is not considered to be mutagenic. The postulated MoA is consistent with the
biologically plausible explanation that chronic inflammation (Vineis et al. 2010) and
regenerative cell hyperplasia can result in carcinogenesis through a non-genotoxic MoA.
Coherence
Non-neoplastic nasal lesions have been reported in rats in numerous studies, showing that
short- and long-term exposure to naphthalene by inhalation results in irritation to the
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respiratory tract. The location of these lesions is consistent with the postulation that they
are necessary precursors to naphthalene-induced tumours.
7.9.6.3.1.7. Other modes of action
A MoA involving genotoxicity caused by naphthalene metabolites (namely naphthalene-
1,2-dioxide, 1,2-naphthoquinone and 1,4-naphthoquinone) has been proposed. However,
in view of the negative results obtained in the in vivo genotoxicity studies, naphthalene
was considered to be non-genotoxic by the authors of the ESR Review. The eMSCA agrees
that the tumours observed in rodents are most likely to have arisen via a non-genotoxic
mechanism.
7.9.6.3.1.8. Assessment of postulated mode of action
Naphthalene is not genotoxic. On consideration of the consistent evidence of non-
neoplastic lesions occurring in the nasal tissue at low doses and only shortly after exposure
to naphthalene, together with the fact that tumours in rodents were only observed at sites
where cytotoxicity was observed, the eMSCA has a high level of confidence in the
postulated cytotoxic mode of action. In the published literature, it is widely considered that
the weight of evidence supports a mode of action involving cytotoxicity and regenerative
hyperplasia (Bailey et al. 2015; Dodd et al. 2012; Rhomberg et al. 2010; SCOEL, 2010).
There is also support for a dual mode of action, involving both cytotoxicity and genotoxicity
(Bogen, 2008).
7.9.6.3.1.9. Uncertainties, inconsistencies, and data gaps
Tumour incidences
In the NTP study, adenomas were observed in 6, 8 and 15 rats at 52.4, 157 and 314
mg/m
3
. However, degeneration, hyperplasia and metaplasia of the respiratory epithelium
were not reported in 2/6, 2/8 and 3/15 (at 52.4, 157 and 314 mg/m
3
, respectively) of the
animals in which adenoma was observed. It has been postulated that non-neoplastic
lesions may have been present in exposed rats, but these lesions may subsequently have
been obliterated by the tumours (Bailey et al. 2015). The available data do not allow a firm
conclusion on this postulation to be made. However, when taking all of the evidence into
consideration, this inconsistency is not considered to reduce the confidence in the
postulated MoA.
Despite observations of the key events in low dose male and female rats, neuroblastoma
was not observed in low dose males and adenoma was not observed in low dose females.
The study authors commented that the severity of the effects of the olfactory epithelium
tended to increase with increased dose. Therefore, it is possible that the olfactory epithelial
lesions at the low dose were not severe enough to progress neuroblastoma in males.
However, the severity of the effects at the low dose was very similar in both sexes and
therefore the reason for the absence of neuroblastoma and adenoma in low dose males
and females, respectively, remains unclear.
In addition, it is unclear why only some of the key events were observed in the nasal tissue
of mice following exposure to naphthalene. The species differences may indicate a greater
inherent sensitivity of rats to the toxic effects of naphthalene on the nasal tissue.
Mode of Action/ Metabolism
Since there are similar levels of CYP2F in the nasal tissue of rats and mice, the reason for
the absence of tumours in the mouse nose is uncertain. It has been suggested that tumour
formation may require further metabolism of naphthalene (beyond the formation of the
epoxide by CYP2F), and that this happens in the nasal passages of rats but not mice
(Rhomberg et al. 2010). The same group postulated that fewer initiated cells may have
progressed to tumours in mice compared to rats due to greater cytotoxicity in the nasal
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cavity of mice. However, the group conceded that the results of the NTP study do not allow
an assessment of this theory because almost 100% cytotoxicity was observed at all doses
(Bailey et al. 2015). Cytotoxicity was indeed observed in a greater proportion of mice than
in rats in the NTP studies (NTP 1992, 2000). However, at the top dose, cytotoxicity was
observed in the olfactory epithelium of almost all rats and the lesions were more severe
than in the nasal cavity of mice. Since these non-neoplastic lesions progressed to tumours
in rats but not in mice, the eMSCA does not consider the postulation put forward by Bailey
et al. (2015) to be plausible.
Another inconsistency is that CYP2F is present in the liver of both rats and mice, yet
tumours, inflammation and regenerative hyperplasia have not been observed here. It was
suggested that detoxification of naphthalene in the liver prevents GSH depletion and
subsequent cytotoxicity (Rhomberg et al. 2010). However, following in vitro exposure of
hepatocytes from rats and mice to naphthalene for 3 hours (Kedderis et al. 2014), a
statistically significant and dose-dependent decrease in GSH levels was noted at ≥500µM
naphthalene. After 24 hours in monoculture there was some recovery of GSH levels,
although recovery was not complete. Although this study was conducted in vitro, it shows
that naphthalene exposure can decrease GSH levels in rat hepatocytes. It is possible that
although GSH levels decreased in hepatocytes in vitro, sufficient levels of GSH remain in
vivo to preclude cytotoxicity. However, it is not possible to draw this conclusion with
certainty based on the information available.
It has been proposed that the amounts and efficiencies of enzymes (CYP2F, GSH
transferase, EH, DD and DNA repair enzymes) are different in different tissues in each
species and that a disrupted balance of these enzymes could explain the species differences
and site specific observations (Rhomberg et al. 2010).
7.9.6.3.1.10. Conclusion:
The eMSCA concurs with the conclusion in the ESR Review that the tumours observed in
animal studies are likely to have arisen via a non-genotoxic mechanism. The available data
are considered to be highly supportive of a cytotoxic MoA for naphthalene-induced
carcinogenesis in the rat nasal cavity. Whilst there are some uncertainties, these are not
considered to place doubt on the postulated MoA.
7.9.6.4. Human relevance
Having established the Mode of Action of naphthalene carcinogenesis in animals, the
relevance of tumours to humans requires further consideration.
7.9.6.4.1. Physiology and Anatomy
Zhang and Kleinstreuer (2011) modelled the deposition of naphthalene in the human
respiratory system using a computational fluid-particle dynamics (CFPD) simulation.
The simulations showed that the deposition fraction (DF) of naphthalene in the upper
airways is approximately 25%. However this value can vary considerably depending on
how absorbing the airways walls are. According to the study authors, a DF of 67% could
arise if the walls of the airway perfectly absorbed naphthalene. Vapours that are not
deposited in the upper airways travel deeper down the respiratory tract.
Notably, the authors reported a decrease in DF in the upper respiratory tract from 24%
when exclusively breathing nasally, to 16% when exclusively breathing orally. This could
be of particular importance when considering the relevance of the rodent data to humans.
Since rats are obligate nasal breathers, the pattern of injury may not be a reflective of the
situation in humans. It could reasonably be assumed that the DF in the upper respiratory
tract would be higher in rats than in humans.
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7.9.6.4.2. Route of exposure
In a combined inhalation/ intraperitoneal study (Lee et al. 2005), 6 male SD rats/ group
were exposed to naphthalene by inhalation (17.8±2.6 mg/m
3
and 125±8.9 mg/m
3
for 4
hours). Three male SD rats/ group were exposed to naphthalene via intraperitoneal
injection (0, 25, 50, 100 or 200 mg/kg). Olfactory epithelium lesions were noted following
administration of naphthalene by both inhalation (at both concentrations) and
intraperitoneal injection (from 100 mg/kg). This shows that the effects can arise following
inhalation and systemic administration. However, the route of exposure was found to affect
the pattern of adverse effects on the nasal passages of treated rats. After inhalation, the
degree of injury correlated with the amount of airflow passing over a particular region of
the nasal cavity. In contrast, the degree of injury was consistent throughout the nasal
mucosa following systemic administration.
7.9.6.4.3. Kinetics
Buckpitt et al. (2013) investigated the metabolism of naphthalene and its metabolites in
male rodents and rhesus monkeys (13 females and 6 males) using microsomal
preparations from the respiratory tract. In this study, the maximum rate of naphthalene
metabolism (V
max
) in the rat olfactory epithelium was described as very high at 54
nmol/mg/min, which was four times greater than the V
max
in microsomes from the rat
respiratory nasal epithelium. Due to poor yields of microsomal proteins from non-human
primates, the results from this species were more variable. However, in comparison to the
rat, naphthalene was metabolised at a lower rate in non-human primates (approximately
5% of that observed in the rat nasal olfactory epithelium).
7.9.6.4.4. Metabolism – enzyme expression
At the Naphthalene State of the Science Symposium (NS3), the panel acknowledged that
human enzyme CYP2F1 (which metabolises naphthalene to the epoxide) has been
identified in human respiratory tissue (Bogen et al. 2008). CYP2F1 is 82% homologous to
the mouse enzyme CYP2F2, but appears to be present in human respiratory tissue at much
lower levels than the levels of CYP2F4 found in rat nasal tissue (Bailey et al. 2015).
The panel also noted that in rhesus macaques, CYP2F was found only in the nasal
ethmoturbinates, and at levels 10-20 times lower than found in rodents (Bogen et al.
2008).
7.9.6.4.5. Rate of metabolism
It was noted by the panel, however, that the rate of metabolism by the human CYP2F1 is
low (Bogen et al. 2008). This was supported by Rhomberg et al. (2010), who noted that
in vitro data suggest that naphthalene metabolism occurs at a much lower rate in humans
than in rodents.
7.9.6.4.6. Extent of metabolism
The results of a physiological-based pharmacokinetic model showed that naphthalene
metabolism is approximately five times higher in the rat nose than in humans and therefore
some doubts have been cast on the relevance of the rodent data for humans at typical
human exposure concentrations (Bailey et al. 2015).
The dose-response relationship of naphthalene on GSH levels, ATP levels and cytotoxicity
has been investigated in vitro (Kedderis et al. 2014). Cells from the lung, nasal respiratory
epithelium and liver were isolated from male B6C3F1 mice, male F344 rats and human
donors. Of particular interest are the results from the nasal epithelium in rats and humans.
The respiratory epithelium was chosen because cells from the olfactory epithelium are
difficult to isolate from humans.
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Nasal respiratory epithelial cells were extracted from 2 men and 1 woman. It is unclear
how many rodents were used in the study. Cell preparations from the nasal respiratory
epithelium in humans (single cell suspension) and rodents (tissue explants) were exposed
to naphthalene (0, 500, 1000 and 2000 µM) for 3 hours before aliquots were removed to
measure ATP, LDH, GSH and protein levels. Cells were placed in monolayer cultures for 24
hours before the same parameters were measured again.
After 3 hours, significant decreases in GSH and ATP levels were observed in the rat
respiratory epithelium at 2000 µM only. Levels recovered after 24 hours.
Statistically significant decreases in cell viability were not observed in rodent nasal
respiratory epithelial cells following exposure to naphthalene.
After 3 hours, concentration-dependent decreases in cell viability, GSH levels and ATP
levels were observed in human nasal respiratory epithelial cells. Some recovery from
cytotoxicity was observed after 24 hours. At 500 µM, one of the three samples recovered
completely after 24 hours in culture. In the remaining two samples, GSH and ATP levels
recovered but cell viability did not. At 1000 µM, some recovery of ATP and GSH levels was
noted in one sample after 24 hours. At 2000 µM, ATP and GSH levels remained low in all
3 samples.
Under the conditions of this study, naphthalene had a greater effect on cell viability, GSH
levels and ATP levels in human cells in vitro than in rodent cells. This evidence suggests
that the cytotoxicity observed in vivo in rats may be of relevance to humans.
7.9.6.4.8. Protein adducts
Although the available evidence suggests that initial metabolism of naphthalene is lower
in monkeys and humans than in rats, DeStefano-Shields et al. (2009) found that covalently
bound metabolites are formed at similar rates in the nasal epithelium of rhesus macaques
and male SD rats.
Saeed et al. (2009) administered naphthalene (1200 or 500 nmol) and its metabolites (500
nmol of 1-naphthol, 1,2-dihydrodiolnaphthalene (1,2-DDN), 1,2-dihydroxynaphthalene
(1,2-DHN) and 1,2-naphthoquinone) dermally to mice (4-5/group). In this study, 2
depurinating adducts (1,2-DHN-1-N3Ade and 1,2-DHN-1-N7Gua) were formed when 1,2-
naphthoquinone and enzymically activated naphthalene, 1-naphthol, 1,2-DDN and 1,2-
DHN reacted with DNA. In addition, the major stable adducts were formed by 1,2-
naphthoquinone. Saeed et al. considered that the formation of these adducts is involved
in the initiation of carcinogenesis. It is noted that this study applied naphthalene dermally
and used mice rather than rats. However, combined with the information regarding the
rate of formation of protein adducts in humans, the relevance of this mechanism to humans
cannot be dismissed.
7.9.6.4.9. Metabolites
Kedderis et al. (2014) measured the levels of metabolites formed in nasal respiratory
epithelial cells from rats, mice and humans following in vitro exposure to 500 µM
naphthalene. The results are shown below.
Table 26: Levels of metabolites in the nasal respiratory epithelial cells following exposure
to naphthalene; an extract from Kedderis et al. 2014
Rats
Mice
Humans
Naphthalene
metabolite
(pmol)
Naphthalene dihydrodiol
6.6/28.8/5.4
23.1/18.8/0
0
1,2-naphthoquinone GSH conjugate
0/0/95.6
0
0
1,4-naphthoquinone GSH conjugate
0/9.3/20.6
11.2/0.5/0.4
0
Naphthalene diolepoxide GSH conjugates
0
7.7/6.5/0
0
Naphthalene diepoxide diGSH conjugate
0
0
0
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The results appear to contrast the finding that naphthalene had a greater effect on cell
viability, GSH levels and ATP levels in human cells than in rodent cells in this study.
However, cell preparations from each species were also exposed to 1000 and 2000 µM
naphthalene. At these concentrations, the decreases in GSH and ATP levels were more
dramatic than at 500 µM but unfortunately, measurements of metabolites at these
concentrations are not available. Therefore no firm conclusions can be drawn from this
information.
7.9.6.4.10. Computational Fluid Dynamics Model
Campbell et al. (2014) investigated cross species dosimetry using a computational fluid
dynamics-physiologically based pharmacokinetic (CFD-PBPK) model. The aim of the study
was to extrapolate the (non-cancer) NOAELs from rats to humans and derive a human
equivalent concentration (HEC). The HEC was defined in the report as ‘the continuous
exposure concentration in the human that would produce a tissue exposure at the site of
toxicity equivalent to that at the NOAEL or LOAEL in the animal.’ The study authors used
a NOAEL of 0.1ppm (0.524 mg/m
3
) from the 90 day rat study (Dodd et al. 2012).
The authors developed the model by extrapolating metabolic rates from rats and monkeys
in vitro to in vivo. The model predicted a HEC of 0.12 ppm (0.63 mg/m
3
) in the dorsal
olfactory region. The study authors commented that, ‘the metabolic capacity in the human
is insufficient to produce the higher rates of metabolite production estimated for the rat.’
7.9.6.4.11. Conclusions by others on the human relevance of tumours
The relevance of the animal data to humans has been addressed by a number of authors.
In the absence of clarity regarding the relevance of positive animal bioassays to human
health, the panel at the Naphthalene State of the Science Symposium (NS3) held in 2006
questioned the value of the available data for making regulatory decisions (North et al.
2008).
Rhomberg et al. (2010) were cautious about extrapolating the results observed at very
high doses in animal bioassays to humans and commented that the lack of case reports of
nasal tumours in humans suggested that naphthalene was not a causal factor.
The carcinogenic and genotoxic potential of naphthalene were evaluated by the Health
Council of the Netherlands in 2012. The Health Council concurred with the assessment
made by Rhomberg et al. (2010) and considered that carcinogenesis in rodents following
naphthalene exposure is not relevant to humans.
Lewis (2012) reported on the human relevancy of animal carcinogenicity. After reviewing
the available data, Lewis noted that no epidemiological data of workers exposed only to
naphthalene are available. However, on the basis of differences in anatomy and
metabolism in the upper respiratory tract of rats and humans, Lewis considered that the
relevancy of the rat data to human health was somewhat questionable.
Bailey et al. (2015) considered that the data indicate that at typical human exposure levels,
the low rate of naphthalene metabolism in humans would not deplete GSH to levels that
would cause toxicity and tumours.
The anatomical and physiological differences alone were not considered sufficient by the
ASTDR to eliminate concern for the possible human relevance of naphthalene-induced
nasal lesions in rodents.
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7.9.6.5. eMSCA Assessment of human relevance
7.9.6.5.1. Are the key events in the animal MoA plausible in humans?
For the MoA to be relevant to humans, a cytochrome P450 enzyme must be present in
human nasal tissue in order for naphthalene to be metabolised. A CYP2F enzyme, with
82% homology to that found in mice, has been reported in humans (Bogen et al. 2008).
Therefore, there is potential for initial metabolism of naphthalene to the epoxide in
humans.
7.9.6.5.2. Taking into account kinetic and dynamic factors, are key events in the
animal MoA plausible in humans?
Metabolism
The level of the CYP2F enzyme is 10-20 times lower in rhesus macaques than the levels of
CYP2F in rodents. Furthermore, the human CYP2F is thought to metabolise naphthalene at
a lower rate than the CYP2F isozyme expressed in rodents (Bogen et al. 2008, Bailey et al.
2015). In microsomal preparations, naphthalene and its metabolites were metabolised at
a greater rate in rodents than in non-human primates (Buckpitt et al. 2013).
Although the available evidence suggests that initial metabolism of naphthalene is lower
in monkeys and humans than in rats, DeStefano-Shields et al. (2009) found that covalently
bound metabolites are formed at similar rates in the nasal epithelium of rhesus macaques
and male SD rats.
In vitro, naphthalene has been shown to reduce cell viability and deplete GSH and ATP
levels to a greater extent in human cells than in cells from rats and mice (Kedderis et al.
2014).
Physiology and Anatomy
Physiological differences between rats and humans may affect the relevance of the rat
data. A computational fluid-particle dynamics simulation showed that the fraction of
naphthalene deposited in the human upper respiratory tract decreased from 24% when
exclusively breathing nasally, to 16% when exclusively breathing orally (Zhang and
Kleinstreuer, 2011). Since rats are obligate nasal breathers, the output of this
computational model could suggest that more naphthalene would be deposited in the upper
airways of rats than in humans.
The pattern of airflow has been shown to affect the pattern of injury in the nasal cavity
following exposure of rats to naphthalene by inhalation (Lee et al. 2005). Due to anatomical
differences between the nasal cavities of humans and rodents, this finding could indicate
that the pattern of injury in humans may differ from that observed in rats.
7.9.6.5.3. Conclusion
The presence of a CYP2F enzyme in humans indicates that there is a potential for
naphthalene metabolism in humans. The anatomical, physiological and metabolic
differences between rats and humans, including breathing route, anatomy of the nasal
cavity and the likely lower rate of naphthalene metabolism in humans are noted. On the
basis of these differences, it is possible that the consequences of naphthalene inhalation
in humans will vary from those observed in the rat.
It is acknowledged that there is no evidence of nasal tumours resulting from naphthalene
exposure in humans. However, the absence of case reports or other forms of
epidemiological study of this issue cannot be considered to represent convincing evidence
that the tumours observed in rats are not relevant to humans.
In mice receiving inhalation exposure to naphthalene, tumours were not observed in nasal
tissue. However, it is not known whether the mouse or rat is a better model for the effects
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 66 December 2018
of naphthalene inhalation exposure. Therefore the information available is not sufficient to
conclude that the finding of nasal tumours in rats exposed to naphthalene by inhalation is
not relevant for humans (albeit that humans might well be at least quantitatively less
sensitive to such an effect).
7.9.7. Toxicity to reproduction (effects on fertility and developmental
toxicity)
This endpoint was not evaluated.
7.9.8. Hazard assessment of physico-chemical properties
Naphthalene is a solid with a relatively low vapour pressure but sublimes slowly at room
temperature and has a characteristic odour. Naphthalene is not classified as flammable or
explosive however it can be considered as capable of forming explosive mixtures with air
in particulate or vapour form. Although not an oxidising agent itself naphthalene can be
readily oxidised by other oxidising agents and undergoes a violent reaction with chromic
oxide, CrO
3
.
7.9.9. Selection of the critical DNEL(s)/DMEL(s) and/or
qualitative/semi-quantitative descriptors for critical health effects
In the LOUS (List of Undesirable Substances) Review (2014), the Danish Ministry of the
Environment reviewed naphthalene. Denmark noted that the available data indicate the
occupational levels of naphthalene are considerably below the current OEL of 50 mg/m
3
.
However, reference was made to Preuss et al. (2003), who suggested that the occupational
threshold limit value for naphthalene should be set at 1.5 mg/m
3
. Denmark considered
that 1.5 mg/m
3
is an exposure level that can be realistically obtained and provided support
to the conclusion of Preuss et al. (2003) on the basis that an increased incidence of nasal
tumours were observed in the NTP study in rats at 50 mg/m
3
(the current OEL).
eMSCA DNEL Derivation
There is no information to suggest that short term peak exposures are relevant for nasal
effects. Therefore, the eMSCA has derived a DNEL for long term inhalation exposure only.
Table 27: NOAEL and LOAEL values in rats after exposure to naphthalene by inhalation
Study
duration
Strain of
rat
Concentrations
(mg/m
3
)
NOAEL
(mg/m
3
)
LOAEL
(mg/m
3
)
Effects at LOAEL
Remarks
4 hour
exposure,
SD rats
Lee et al.
(2005)
17.8±2.6 and
125±8.9
None
17.8±2.6
Continuity of the
olfactory mucosa
was broken by areas
of necrotic olfactory
receptor cells
Reduced volume of
cytoplasm from
sustentacular cells
above the nuclei
Vacuoles in the
olfactory epithelium
Patches of exfoliated
The
concentrations
in this study
were much
higher than
those
administered
in other
studies and
therefore this
study provides
minimal
information
relevant to
DNEL
derivation.
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cells in the anterior
part of the nasal
passage
6 hour
exposure,
F344 and
SD rats
Dodd et al.
(2010)
0, 0.52, 1.57,
5.24, 52.4 and
157
None
0.52
Nasal olfactory
epithelium necrosis
in 2/5 SD males and
1/5 SD females.
Nasal
olfactory
epithelium
necrosis was
also observed
in 1/5 SD
female
control.
0.52mg/m
3
is
considered to
be a
conservative
LOAEC.
5 day
exposure
(6h/d), F344
and SD rats
Dodd et al.
(2010)
0.52, 5.24 and
52.
None
0.52
Nasal olfactory
epithelium
degeneration in 2/10
SD females
Nasopharyngeal
goblet cell
hyperplasia/hypertro
phy in 1/10 F344
male and 1/10 F344
female
Nasal
olfactory
epithelium
degeneration
was also
reported in
1/5 F344
female
control.
0.52mg/m
3
is
considered to
be a
conservative
LOAEC.
90 days
exposure
(6h/d,
5d/week),
F344 rats
Dodd et al.
(2012)
0, 0.52, 5.24,
52.4 and 157
0.52
5.24
Hyperplasia of the
respiratory
epithelium in 10/10
rats (graded as
minimal)
90 days
exposure,
(6h/d,
5d/week),
F344 rats
Meng et al.
(2011)
0, 0.52, 5.24,
52.4 and 157
0.52
5.24
Minimal hyperplasia
in the transitional/
respiratory
epithelium.
Limited
information
about effects
on the
respiratory
and olfactory
epithelia is
available due
to the nature
of the study.
2 year
carcinogenic
ity study,
F344 rats
NTP (2000)
0, 50, 150 or 300
None
50
Olfactory
epithelium: atypical
hyperplasia,
atrophy, chronic
inflammation and
hyaline degeneration
in almost all animals
(both sexes) and
neuroblastoma in
2/49 females
Respiratory
epithelium:
The
concentrations
in this study
were much
higher than
those
administered
in subsequent
studies of
shorter
duration and
therefore this
study provides
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hyperplasia,
squamous
metaplasia, hyaline
degeneration and
goblet cell
hyperplasia in 30-
67% of animals
(both sexes) and
adenoma in 6/49
males
Glandular
hyperplasia in
almost all animals
(both sexes)
Glandular squamous
metaplasia in 3/49
males and 2/49
females
minimal
information
relevant to
DNEL
derivation
The NOAEC from the 90 day study was 0.52 mg/m
3
(Dodd et al. 2012). However, the next
dose administered to rats in this study was 5.24 mg/m
3
, where minimal hyperplasia was
observed in the respiratory/transitional epithelium. Therefore, the true NOAEC may lie
between 0.52 and 5.24 mg/m
3
. However no further information is available to identity a
more accurate NOAEC, and therefore a value of 0.52 mg/m
3
will be taken forward to
calculate the DNEL.
Workers
NOAEC = 0.524 mg/m
3
The NOAEC was identified from a study where rats were exposed to naphthalene for
6h/day. The following calculation has been done to adjusting the NOAEC to account for
exposures of 8h/day:
Inh 8h NOAEC = Inh 6h NOAEC x 6/8 x 0.67
= 0.524 x 6/8 x 0.67
= 0.26331 mg/m
3
As described in the section on ‘relevance to humans’, the rat is considered to be the most
sensitive species for this effect and therefore a value of 1 has been assigned for the
interspecies differences.
A standard assessment factor of 5 for workers has been used.
The eMSCA considers that the duration of exposure did not affect the NOAEC and therefore
a value of one will be used for the extrapolation of a subchronic exposure to a chronic
exposure.
On the whole, the quality of the database is good and therefore an assessment value of 1
is warranted.
Assessment factors: 1 for remaining interspecies differences
5 for workers
1 for subchronic to chronic
1 for quality of whole database
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So DNEL = 0.26331 = 0.053 mg/m
3
1 x 5 x 1 x 1
Table 28
CRITICAL DNELS/DMELS
Endpoint of
concern
Type of
effect
Critical
study(ies)
Corrected
dose
descriptor(s)
(e.g. NOAEL,
NOAEC)
DNEL/
DMEL
Justification/
Remarks
Repeated
dose toxicity
(inhalation)
Inflammatio
n of the
respiratory/
olfactory
epithelium
Dodd et al.
(2012)
NOAEC =
0.524mg/m
3
DNEL =
0.053
mg/m
3
Since the carcinogenicity is
considered to arise as a
consequence of the
cytotoxicity, this DNEL is
considered to be
protective against both
repeated dose toxicity and
carcinogenicity.
It is recognised that the DNEL derived from experimental animal data is considerably lower
than current levels of exposure in the workplace. Given the lack of consistent evidence for
inflammatory changes in nasal lavage and sputum samples taken from workers with daily
exposure to levels of naphthalene over 100 times higher than this DNEL (Sucker et al.,
2016) the eMSCA considers this is a very precautionary DNEL. Whilst it is possible to use
the existing IOEL (50 mg/m
3
) to derive a DNEL for workers (Appendix R8-13 of ECHA’s
Guidance on Information Requirements and Chemical Safety Assessment) because of the
uncertainties about the sustainability of the current IOELV this approach was not
considered by the eMSCA.
7.9.10. Conclusions of the human health hazard assessment and related
classification and labelling
Haemolytic anaemia
Case reports of haemolytic anaemia in humans confirm that naphthalene presents a hazard
to human health. However, there does not appear to be a suitable animal model that would
allow a dose-response assessment to be made. The available data do not allow a NOAEL
to be derived or a DNEL to be calculated. On the basis of the information available and
using the estimation of 6 g of naphthalene as a lethal dose to humans, the eMSCA concurs
with the conclusion in the ESR Review that values in the mg/kg range are considered to
give rise to concern for acute haemolytic anaemia.
Inflammatory effects on the olfactory epithelium and Carcinogenicity
The eMSCA considered that the available data are highly supportive of a cytotoxic mode of
action for naphthalene-induced carcinogenesis in the rat nasal cavity, whereby
naphthalene is metabolised to cytotoxic (non-genotoxic) metabolites by a CYP enzyme in
tumour-forming tissues including in the olfactory epithelium. Those metabolites are
thought to be responsible for the inflammation and regenerative hyperplasia which precede
carcinogenesis.
A DNEL of 0.053 mg/m
3
has been derived for the non-neoplastic lesions. Since this value
is considered to be protective for the non-neoplastic precursor lesions, it is also considered
to be protective against carcinogenesis. Although no consistent effects on the nasal cavity
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were observed in a recent bio-monitoring study, the relevance of nasal tumours to humans
cannot be dismissed based on the available data. However, physiological, anatomical and
metabolic differences between rodents and humans suggest that the rat is a conservative
model.
On the basis of the current information the eMSCA does not consider additional
classification is needed and agrees with the existing harmonised classification.
7.10. Assessment of endocrine disrupting (ED) properties
Not evaluated. Endocrine disruption was not in the scope of this evaluation.
7.11. PBT and VPVB assessment
Not evaluated.
7.12. Exposure assessment
Overview of sources of exposure to naphthalene
Naphthalene is a naturally occurring substance. It is ubiquitous in the environment, but at
very low levels in pristine air. Price and Jaycock (2008) suggest levels of between 1 x 10
-
7
and 3 x 10
-6
mg/m
3
(2 x 10
-8
– 6 x 10
-7
ppm based on the conversion factor of 1 ppm =
5.24 mg/m
3
reported in the ESR review).
Naphthalene occurs in pristine air because it is a product of the incomplete combustion of
biomass. It has also been found to be produced naturally by certain species. There are
reports that trace amounts of naphthalene are produced by magnolias (Azuma et al, 1996).
The Formosan subterranean termite has been found to produce naphthalene, possibly as
a repellant against predator species such as ants, poisonous fungi and nematode worms
(Chen et al, 1998). Some strains of the endophytic fungus Muscodor albus also appear to
produce naphthalene among a range of volatile organic compounds, and Muscodor
vitigenus produces naphthalene almost exclusively (Daisy et al, 2002).
Higher levels are found in suburban and urban air due mainly to traffic pollution and there
appears to be high spatial and temporal variability. Price and Jaycock (2008) suggest levels
between 1 x 10
-6
and 0.001 mg/m
3
(2 x 10
-7
–1.9 x 10
-4
ppm) would be typical for the
United States of America (US) and there is no reason to think that levels would be
substantially different in suburban and urban areas across Europe.
Other sources contributing to naphthalene levels in ambient air include emissions arising
from the processing of coal, crude oil and natural gas, aluminium, iron and steel production,
foundries and power plants as well as industrial processes that manufacture or use
naphthalene as a raw ingredient (ECB, 2003). Indeed, naphthalene will be present
anywhere that process generating PAHs as a result of combustion are in operation. In
combustion processes that emit PAHs, it has been observed that naphthalene is the most
abundant PAH. For example, it accounted for 58% of the total PAH emissions from a Danish
asphalt factory (Danish EPA, 2015). Emissions also arise from the use of products made
from petroleum refining streams such as asphalt, jet fuels and lubricants where
naphthalene may be present as a minor component in these UVCB mixtures. Information
cited by Price and Jaycock (2008) suggests that in fuels it may be present at between
0.0021 – 1.1% by weight with the highest level reported for jet fuel (JP-8) and in
lubricating and motor oils at between 0.00005 and 0.25%. Automotive products containing
naphthalene as a minor component include products available for consumers. Other
products that may contain naphthalene as an impurity include carbon black. Levels of
between 2.3 and 8.68 mg/kg naphthalene have been reported (Danish EPA, 2015).
Price and Jaycock (2008) separate industries where there is a potential for exposure to
naphthalene into two categories. The low exposure category includes the refining and
petroleum industries, asphalt (paving and roofing) and industries using pitch to
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UK MSCA 71 December 2018
manufacture refractory materials or graphite electrodes. Here it is claimed, daily airborne
exposure can be expected to be in the range 0.01 – 0.3 mg/m
3
(8-hr TWA). The high
exposure category includes creosote production and use, workers exposed to jet fuels, coal
tar and coke industries, production of naphthalene from coal tar and chemical industries
using naphthalene as a raw material. Daily airborne exposures are estimated to be in the
range of 0.1 – 3 mg/m
3
(8-hr TWA). Naphthalene was used as a biomarker to study
inhalation and dermal exposure to JP-8 in air force maintenance personnel (Chao et al,
2006). Levels of naphthalene measured in the workers breathing zone over a 4-hour
sampling period ranged from 0.0007 – 3.910 mg/m
3
(n= 83, geometric mean 0.61
mg/m
3
). Dermal naphthalene levels, measured using a tape stripping process sampling
pre-defined regions of the body, ranged from 0.0001 – 5.09 mg/m
2
(n= 85, geometric
mean 0.0042 mg/m
3
).
Naphthalene is found in indoor air. Price and Jaycock (2008) suggest typical levels are of
the order of 0.0001 – 0.01 mg/m
3
(0.000019 – 0.0019 ppm) in US homes. Preuss et al
(2003) quoted levels of 0.0007 – 0.014 mg/m
3
for German homes. To put these values
into context, the odour threshold reported under additional physicochemical information
on ECHA’s dissemination site is 0.08 ppm
19
. Smoking, use of kerosene space heaters, wood
stoves, vehicle emissions and stored petroleum products from attached garages, cooking
and use of consumer products containing naphthalene (e.g. mothballs) all contribute.
Although naphthalene containing mothballs are no longer used in the EU, many of the other
sources are applicable to European homes. Cigarette smoke in particular has been
identified as significant source with indoor naphthalene levels estimated to be
approximately 10 times higher in the homes of smokers (average concentrations ranged
from 0.0018 to 0.0095 mg/m
3
) compared with non-smokers (average concentrations
ranged from 0.00018 to 0.0017 mg/m
3
) (Jia and Batterman, 2010). There is also
information suggesting that low levels of naphthalene may be emitted from compact
fluorescent light bulbs (Danish EPA, 2015). The Danish report cites tests performed by a
German laboratory which found 12 of 14 light bulbs emitted naphthalene at a rate of 0.001
– 0.008 µg/bulb/hr. One outlier emitted naphthalene at a rate of 0.205 µg/bulb/hour.
In most of these situations, naphthalene is found as a vapour, but may also be present in
the particuate phase (e.g. in cigarette smoke where naphthalene can be found bound to
other particulate material). In indoor environments, naphthalene tends to partition to
surfaces which prolongs the duration of exposure.
In addition to airborne and dermal exposure, there is a potential for dietary exposure. The
ESR review reported low levels in a range of biota and foodstuffs (ECB, 2003). Cooking
processes such as grilling, charbroiling and smoking have the potential to add to the
naphthalene content in food (Price and Jaycock, 2008). In 2002, the US EPA estimated
that the average daily intake of naphthalene for an adult was 0.041 - 0.237 µg/kd/day
(Preuss et al, 2003).
Of these possible sources of exposure, the REACH registrations focus on the manufacture
of naphthalene and identified uses for naphthalene itself. UVCB substances which may
contain naphthalene as a component are covered by separate registrations and are not
discussed in this evaluation. However, when deciding on the significance of the exposures
estimated for naphthalene in REACH registrations it is important to take account of the
existence of a wide range of additional possible sources all of which will contribute to the
daily body burden received by an individual.
19
https://echa.europa.eu/registration-dossier/-/registered-dossier/15924/4/24 (site accessed 11
October 2016)
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UK MSCA 72 December 2018
7.12.1. Human health
The exposure assessments submitted by the registrants cover manufacture (including
manufacture under strictly controlled conditions (SCC)), industrial use an intermediate
(including use under SCC as a feedstock in the manufacture of other chemicals), industrial
use to manufacture grinding wheels and its use to formulate smoke bombs/grenades for
military use. Scenarios have also been provided covering military use of smoke
bombs/grenades and service life of smoke bombs/grenades. No consumer uses have been
identified and none of the registered uses are expected to lead to service life exposure for
consumers.
7.12.1.1 Worker
The worker exposure assessments primarily rely on modelling calculations to estimate full
shift exposure (mainly ECETOC TRA version 3 but ECETOC TRA version 2 has been used to
assess exposure to naphthalene during use in the manufacture of grinding wheels). Short-
term peak exposures have not been modelled and the eMSCA agrees with the registrants
that this is not required for naphthalene.
Naphthalene is a subliming solid. In certain processes it is handled at elevated temperature
90°C or above to prevent the material solidifying in pipelines and vessels. Exposure will
therefore predominantly be to vapour/fume. In order to generate exposure esimates using
the TRA tool, the registrants have assumed that naphthalene will behave as a medium or
high dustiness solid. Although this approach has not been formally implemented within the
TRA tool, the tool developers reviewed the approach as part of the improvements
introduced with version 3 (ECETOC, 2012). The tool developers concluded that this
approach is likely to provide very precautionary estimates (ECETOC Technical Report 114,
Appendix E). The eMSCA is therefore satisfied that the TRA tool has been used within its
applicability domain.
7.12.1.1.1 Published measured data
There is very little information in the public domain on current worker exposure to
naphthalene during REACH registered uses. Preuss et al (2003) published a collation of
exposure measurements and biological monitoring results obtained from literature
published in the preceeding 25 years. Although this paper includes some information
relating to naphthalene distillation and the manufacture of phthalic anhydride, the original
reports were published in the late 1990s. As such, the information may not be relevant to
current working conditions and has not been taken into account in this evaluation. The
paper does give an indication of industries where naphthalene may be generated as a
process by-product. Recently, a study has been performed to measure exposure to
naphthalene during the manufacture of abrasives (Sucker et al, 2016). This study is
discussed below under the relevant scenario heading.
7.12.1.1.2 Manufacture including manufacture under SCC
Naphthalene is manufactured in predominantly closed processes. According to information
provided in 2007 for the risk reduction strategy document, sites are often highly automated
with machines and robots undertaking jobs such as packaging naphthalene granules/flakes
into bags. Although much of the manufacturing process takes place under strictly controlled
conditions (SCC), the registrants state that the process to solidify naphthalene to produce
flake/granules does not meet the requirements for SCC. The following discussion relates
to manufacturing processes that are not performed under SCC at all stages of the process.
The PROCs selected by registrants to describe manufacture include PROCs 1, 2, 3, 8a, 8b
and 15. The greatest potential for worker exposure occurs during sampling, tanker filling,
granulation, packaging and maintenance activities. Sampling and tanker loading tasks may
occur up to eight times per day. Exposure will therefore arise as a series of short, but
potentially high, peaks and will be to both particulate and vapour, although the latter is
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 73 December 2018
likely to be the greatest contributor to exposure. High peak exposures may also arise
during the manual handling which may occur during granulation and packaging.
When the ESR RRS was prepared, the majority of EU production sites appeared to rely
more on personal protective equipment (PPE) than containment to limit worker exposure
during activities such as sampling. The PPE described in the risk reduction strategy included
overalls, safety shoes, safety goggles and CAT II tested chemical resistant disposable
gloves (nitrile-rubber) or leather gloves. CAT II gloves are designed to protect against
intermediate risks in accordance with the Personal Protective Equipment Directive
(89/686/EEC). Where respiratory protective equipment (RPE) was used this took the form
of safety goggles fitted with a dust respirator (particle filter FFP3) or masks fitted with
organic filters. Protection factors were not reported. Only one site had implemented
containment (closed boxes with LEV) around sampling points. At this site, breathing
apparatus with multi filter was required during vaccum cleaning, with maintenance at the
flaker drum requiring air-fed breathing apparatus.
From the information provided in REACH registrations it is not clear if this information is
still applicable. The eMSCA has been told informally that Cat III gloves are now used in
many cases. Cat III gloves are designed to be used for irreversible or mortal risks. In
addition to the indepentent testing and certification necessary for the gloves to carry a CE
mark which must be performed for Cat II gloves, the quality assurance system must be
independently checked
20
.
In relation to other risk management measures, one registrant reported a need to use RPE
(confirming to EN 140 fitted with type A filter, protection factor not reported) during
sampling from production equipment located outdoors. Gloves, overalls and eye protection
were also required. This registrant also reported a need to use RPE (described as before),
gloves and eye protection as a secondary measure for material transfers covered by PROC
8b where containment or LEV is fitted at fill points. Other registrants did not provide this
level of detail in their CSRs. The exposure calculations did not take account of the use of
LEV or RPE, even for transfers covered by PROC 8a where a high potential for exposure
may be expected. The only risk management measures identified were gloves for activities
covered by PROCs 8a and 8b and some requirements for general ventilation for transfers
taking place indoors. This does not mean that a higher level of control has not been
implemented in practice. It could simply reflect the case that the registrants have identified
the minimum RMMs required to maintain 8-hr TWA exposure below their DNEL.
A specific assessment has not been provided in REACH registrations for routine cleaning
and maintenance. These activities have the potential to produce high exposures and may
require different risk management measures to those required for other activities
associated with naphthalene manufacture. In this situation, it may be appropriate to
consider cleaning and maintenance as a separate contributing scenario. According to
version 3.0 of the Information Requirements and Chemical Safety Assessment Guidance
(IR & CSA) Guidance, Chapter R.14, section R14.5.1, exposure assessments should include
a contributing scenario describing conditions for periodic cleaning and maintenance if such
activities are not already covered in one or more of the other contributing scenarios.
Note to registrants: To ensure that it is transparent in the exposure scenario how all
relevant work activities are covered, it is helpful to either include a specific contributing
scenario for routine cleaning and maintenance activities or indicate which of the already
chosen contributing scenarios apply to these activities.
20
http://www.ansell.eu/industrial/pdf/en-guide/EN%20Guide_EN.pdf. From 21 April 2018,
Directive 89/686/EEC will be repealed by the new Regulation (EU) 2016/425 of the European
Parliament and of the Council of 9 March 2016 on personal protective equipment.
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 74 December 2018
Inhalation
To provide context to the exposure information provided in registrations, it is helpful to
look back at the information provided for the ESR review and risk reduction strategy and
this will be done for each exposure scenario. The exposure data for manufacture that was
submitted for the ESR review came from various tar distillation plants operated by one EU
producer.
Table 29: Occupational exposure to naphthalene during tar distillation (various
plants throughout Europe) as reported in the ESR review (ECB, 2003)
Plant area
Range (mg/m
3
)*
Crystallisation
0.1 to 0.8
Laboratory
0.40
Tank car loading with coal tar products
0.76 to 4.8
Coal tar distillation
0.16
* The number of samples was not reported
These results were stated to be representative, to derive from personal sampling and
reflect 8-hour TWA exposure. A further value of 6.3 mg/m
3
(assumed to represent an 8-hr
TWA) was reported as the highest value recorded. This was taken forward to the risk
characterisation. For the ESR RRS, a small number of additional measurements (collected
between 2003 and 2007) were provided from 3 of the seven manufacturing sites in
operation in the EU at that time. The new measurements appear to be consistent with the
data reported in the ESR RAR. However, the contextual information accompanying the new
data was incomplete so the original exposure estimate from the ESR RAR was used for the
risk reduction strategy.
Moving forward to the REACH registrations, although early versions of CSRs included
measured data, most registrants have updated and now rely solely on modelled estimates
to characterise exposure during manufacture (ECETOC TRA V3). The measured data was
collected between 2007 and 2010 and is stated to represent a typical European
manufacturing operation. The samples were taken during normal operating conditions and
included a mixture of personal and static, vapour and dust measurements. Unfortunately
sampling duration was not reported so it is not possible to obtain time weighted averages
from the most recent measured data and it cannot be used for the risk characterisation.
The risk characterisation provided by the registrants is based on modelled data and the
eMSCA will also use modelled data for its assessment.
Dermal
Dermal exposure can occur during the production of naphthalene, when operators come
into contact with surfaces contaminated from splashing or condensed vapour, or as a result
of direct contact onto the skin. As processing predominantly takes place in closed systems,
dermal exposure will primarily occur during activities such as sampling and the uncoupling
of pipes or cleaning of occasional spills. This was characterised in the ESR RAR as “direct
handling with incidental contact” and it was assumed that operators wore gloves. Dermal
exposure was predicted to be within the range 0 – 0.1 mg/cm
2
/day but thought likely to
be at the lower end for most activities. The upper end of the range was thought to reflect
exposure during maintenance activities. This assessment was not changed when the risk
reduction strategy was prepared.
The modelled dermal exposure estimates reported in registrations suggest dermal
exposure may be an order of magnitude higher. Not all calculations assumed the use of
gloves (glove use was taken into consideration for PROCs 8a and 8b) and this is one
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UK MSCA 75 December 2018
possible source of overprediction since the use of gloves may be more widespread than
has been assumed for the purposes of REACH exposure calculations. There is also the
possibility that the use of estimates for a medium/high dustiness solid results in
overprediction.
Recommendations from the risk reduction strategy
The ESR RRS concluded that containment should be implemented where possible and that
the PPE being used, in particular the use of CAT II gloves was not suitable for naphthalene
since this is regarded as a high hazard substance whereas CAT II gloves are tested for
medium hazard substances. It was also recommended that an industry code of good
practice should be drawn up. It appears that Cat III gloves are now used. The PROC codes
selected to describe manufacture suggest that this takes place in predominantly closed
systems. It is not known if there is scope for further containment around the transfers
described by PROC 8a. The eMSCA has no information about whether or not a code of good
practice has been developed.
Conclusions about exposure during manufacture
Several sources of uncertainty have been identified in relation to the inhalation and dermal
exposure estimates presented in registrations. The eMSCA does not expect that the
modelled estimates which are being used for the risk characterisation underestimate
potential exposure. However, it is not possible to determine if there is any substantial
overestimation given the uncertainty. It is also not clear if the recommendation for greater
use of containment has been implemented to the fullest extent possible. The eMSCA will
therefore assume that the modelled estimates are representative of the exposures likely
to arise where naphthalene is not manufactured under SCC and that the parameters chosen
to calculate these estimates reflect current operating conditions and risk management
measures.
7.12.1.1.3 Use as an intermediate including use as feedstock in the manufacture
of other substances under SCC
Two scenarios have been submitted to cover the use of naphthalene to manufacture other
substances. These are use as a feedstock in the manufacture of other substances under
SCC and use as an intermediate.
Use as a feedstock in the manufacture of other substance under SCC is described with
PROCs 2, 3, 8b and 15. No exposure estimates have been provided for this scenario but
registrants have provided a description of the SCC that are applied. Since no exposure
assessment has been provided, this scenario will not be discussed further. The following
discussion relates to use as an intermediate where SCC are not implemented at all stages
of the process.
The PROCs selected by the registrants to describe this use include PROCs 1, 2, 3, 4, 8a,
8b, 9 and 15.
Most of the information available for the ESR RAR and RRS came from a UK site using
naphthalene to manufacture phthalic anhydride and it was assumed that the working
conditions would be similar for other intermediate uses since these also take place in closed
plant. For the ESR RRS, additional sites provided information about the controls that were
in use. As is the case for manufacture, the main opportunities for exposure arise during
sampling and maintenance. Exposure may also occur during delivery where a small amount
of naphthalene is run off (to remove possible contaminants) prior to connecting to the
storage tank. The pattern of exposure is therefore likely to be to a series of short but
potentially high peaks.
The risk management measures that were used for these tasks included gloves (where
reported these were described as “Cat II tested ABCD” – the letters denote the chemical
classes which the gloves have been tested with), safety helmets, goggles, respirators
(where reported the type was described as A1P1 representing a low capacity/efficiency
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UK MSCA 76 December 2018
filter suitable for organic vapours and particulates) and safety boots. Two sites also referred
to the use of LEV but did not give information on the processes where it was applied. Where
periodic maintenance is performed and workers need to enter vessels to scrape out
solidified naphthalene, air line breathing apparatus and gloves are worn.
It is not possible to see if the situation has changed since REACH entered into force based
on the information provided in REACH registrations. The exposure calculations do not take
account of the use of RPE or LEV. There are requirements for gloves to be worn for activities
covered by PROCs 4, 8a, 8b and 9 and general ventilation for PROCs 4, 8a and 8b where
these processes take place indoors. As noted previously, this may reflect the case that the
registrants have identified the minimum RMMs required to maintain 8-hr TWA exposure
below their DNEL rather than present an accurate picture of current operating conditions
and risk management practices.
Inhalation
The exposure data that was submitted for the ESR RAR (see table 30) came from a personal
air sampling exercise undertaken in 1994. It was considered that occupational exposure
during the manufacture of other substances would be similar to these data for phthalic
anhydride.
Table 30: Occupational exposure to naphthalene during its use in the
manufacture of phthalic anhydride as reported in the ESR RAR (ECB, 2003)
Task
Result (mg/m
3
)*
8-hour TWA (mg/m
3
)
Process operator
0.38
0.57
Charge hand
0.22
0.33
Process operator
0.62
0.93
Charge hand
1.30
2.00
* Results represent single data points for a 12-hour shift
For the ESR review, the maximum value of 2 mg/m
3
was used as the basis for the risk
characterisation. For the ESR RRS, a small number of additional measurements (collected
between 2003 and 2007) were provided none of which exceeded the value used for the
risk characterisation in the ESR RAR. No new measured data have been submitted in
REACH registrations, hence the risk characterisation will rely on modelled data. The
modelled estimates (generated using ECETOC V3) imply that exposures to naphthalene
during its use as an intermediate will be very similar to exposures during manufacture and
the parameters used to generate modelled estimates are the same. Given that this use of
naphthalene is performed under very similar conditions to manufacture, the eMSCA
identifies the same uncertainties in relation to these modelled estimates.
Dermal
Dermal exposure can occur as a result of contact with contaminated surfaces due to
splashing or condensed vapour or as a result of direct skin contact during sampling and
the uncoupling of pipes. As for manufacture, this was characterised in the ESR RAR as
“direct handling with incidental contact” and it was assumed that operators wore gloves.
Dermal exposure was predicted to be within the range 0 – 0.1 mg/cm
2
/day but thought
likely to be at the lower end for most activities. The upper end of the range may reflect
exposure during maintenance activities. This assessment was not changed when the risk
reduction strategy was prepared.
The modelled dermal exposure estimates reported in registrations suggest dermal
exposure may be an order of magnitude higher. Not all calculations assumed the use of
gloves (glove use is taken into account for PROCs 4, 8a, 8b and 9) and this is one possible
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 77 December 2018
source of overprediction since the use of gloves may be more widespread than has been
assumed for the purposes of risk characterisation calculations. There is also the possibility
that the use of estimates for a medium/high dustiness solid results in overprediction.
Recommendations made in the risk reduction strategy
The recommendations made in the ESR RRS document are very similar to those for
manufacture. These include greater use of enclosures around sampling points and greater
use of LEV to capture releases at source. Questions were raised about the suitability of
CAT II gloves and there was a recommendation for industry to develop good practice
guidance. It is not clear how widely these recommendations have been implemented based
on the information presented in the CSRs.
Conclusions about exposure during use as an intermediate
The conclusions for use as an intermediate are the same as those for manufacture. Several
sources of uncertainty have been identified in relation to the inhalation and dermal
exposure estimates presented in registrations. The eMSCA does not expect that the
modelled estimates which are being used for the risk characterisation underestimate
potential exposure. However, it is not possible to determine if there is any substantial
overestimation given the uncertainty. It is also not clear if the recommendations from the
risk reduction strategy for greater use of engineering controls such as containment and
LEV have been implemented. The eMSCA will therefore assume that the modelled
estimates are representative of the exposures likey to arise during use as an intermediate
where SCC are not applied at all stages of the process and that the parameters chosen to
calculate these estimates reflect current operating conditions and risk management
measures.
7.12.1.1.4 Use of naphthalene in the abrasive industry
Napthalene is used as a pore forming agent in the production of inorganic bonded abrasive
tools (grinding wheels). The registrants have described this process using PROCs 5 and 14.
Sized granules of crystalline naphthalene are blended with other components such as grit
and binders. The proportion of naphthalene in these blends ranges from 5 – 40% by
volume. The blends are then cold pressed to give the required shape/density and dried to
remove excess moisture. Pressing typically takes 1-2 minutes and involves pressures of
up to 14 – 35 MPa (2,000 – 5,000 pounds per square inch (psi)). The grinding wheels are
then stored on drying racks (in chamber dryers or vacuum driers) at temperatures of 50 –
150°C for several hours (up to 45 hours may be needed in some cases to ensure crack
free drying) to allow the naphthalene to volatilise out of the wheel leaving behind pores.
Naphthalene removal may also be carried out using steam recovery where the wheels are
placed inside an oven and steam injected. In this process, the driven off naphthalene is
carried on the steam and recovered from the subsequent condensate. Finally, the wheels
are placed inside a kiln at around 1,200°C (range 850 – 1,300°C) to “cure” in a process
that can take between 40 and 120 hours depending on the size of the grinding wheel. The
curing process means that finished grinding wheels do not contain any residual
naphthalene.
Information provided in early versions of CSRs suggested that typically LEV is applied
where dust generation or vapour release is expected. However, assessments were also
provided to cover situations where LEV is not in use. Air conditioning may also be in
operation to limit the build up of volatilised naphthalene in work areas. No RPE is worn for
routine tasks but may be required for maintenance activities where there is the potential
for exposure to excessive levels of dust/vapour. Gloves are worn, the registrants identify
the glove materials and thicknesses that are required depending on the duration of
activities. Organisational measures that are in place include training, regular cleaning, the
use of dedicated storage areas and it is reported that periodic medical surveys are
undertaken.
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Inhalation
A recent report by Sucker et al (2016) provides comprehensive information about exposure
to naphthalene in abrasives manufacture including a description of the operational
conditions and risk management measures that were in place at the time the samples were
collected (between July and October 2014 from 5 abrasive manufacturing sites located in
Germany and Austria). It is assumed that these sites are representative for other abrasive
manufacturing sites across the EU. At each site, sampling took place on Thursday of the
week that health investigations were also performed (see section 7.9.8 for details). Both
personal and static measurements were made. Personal monitoring included 15-minute
samples collected onto Tenax
®
TA tubes (these detect substances in the vapour phase)
and 4 - 5.5 hour samples collected via the GGP-Mini sampling head (designed to
simultaneously sample vapour and particulate fractions). Static monitoring was performed
in areas where naphthalene exposure was expected to occur. Sampling devices were
located at a height of approximately 1.5 m and included up to 8 hour sampling using the
GGP-Mini sampling head to record the vapour and particulate phase and silica gel tubes
which will record only the vapour phase. The limits of detection/quantification were not
reported.
Exposures during the production of grinding wheels will be to both naphthalene particulate
and naphthalene vapour. During early stages of the process, sieving, weighing, blending
and pressing particulate exposure is likely to dominate as the naphthalene blends are
transferred to and from storage / transfer containers and scooped in smaller quantities to
weigh scales and moulds. Typically the components of the grinding wheels are prepared
and mixed in the same working hall as the moulding and pressing operations. Typically
materials are weighed manually, only one site used automated filling of blending machines
from storage tanks. Prior to blending, grinding wheel components are sieved either through
an automated vibrating screen or manually. Typically LEV is used to limit emissions during
sieving and it is stated that most sites have fitted LEV to the blending machines to capture
emissions during filling. Where blending involves the addition of binders that result in
wetting of the blend, this will help to reduce dust formation. Lids on blending machines are
closed during blending, though in some cases may be opened to add ingredients during
the blending process. On completion of the blending process, the mixture is collected in a
container. It is not clear what controls are in use to limit the release of naphthalene during
this transfer. A magazine article published in 2014, includes photographs illustrating the
blending and sieving stages (Sawodny, 2014). These show an apparently open transfer of
powder from the blender to the sieve without LEV. The worker is wearing a close fitting
half mask designed to capture particulates but not vapours, cotton overalls, eye protection
and gloves. These illustrations are stated by the registrants to be representative for these
activities.
After each batch has been mixed, blenders are cleaned with a hand brush or by “blowing
out”. Quantities of up to 150 kg may be blended at a time. Preparation of batches, blending
and emptying and cleaning the blender typically takes 15 minutes and 6 – 12 blending
operations may be performed in each blender per shift. In addition to the use of LEV,
mechanically enhanced room ventilation was fitted in the production hall at one site. Others
relied on natural ventilation in working areas via opening of gates and ridge turrets.
Blended formulations are typically weighed manually into the moulding and pressing
machines but some use of automated feeding was reported. Sometimes blended
formulations may be sieved again. The report stated that LEV was sometimes available at
weighing stations and some moulding and pressing machines had LEV fitted, but in many
cases no LEV was installed.
After the pressing process is completed, residual formulation is swept off the machines
with hand brushes. Moulds are cleaned out using hand brushes or by “blowing out”. The
quantities used per abrasive item range from a few grams to around 15 kg and pressing
cycles vary from 2-3 minutes up to around 15 minutes per cycle. Between 15 and 100
abrasive items are produced each shift.
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Final processing of the abrasives includes the use of grinding and polishing machines.
Sometimes water is used as a dust suppressant but dry processing also occurs. Most
machines incorporate LEV. Occasionally closed systems with cooling lubricants are used.
Although there should be no exposure to naphthalene from the abrasives at this stage,
workstations were sometimes located in areas where naphthalene was handled.
Workers wear respiratory protective equipment (RPE) during mixing and sieving of dusty
blends. Sawodny (2014) shows a worker wearing a close fitting but not sealed half mask
of a type that is designed to capture particulates but not vapours. This type of RPE does
not seem to be consistent with the RPE recommended by the registrants in their guidance
for safe use. The worker is also wearing cotton overalls, eye protection and gloves. The
emMSCA has been informed that gloves are typically worn when blends containing
naphthalene are handled.
Exposure measurements were aggregated across all sites and were stratified according to
task and potential for direct exposure to naphthalene. Personal exposure measurements
are summarised in table 31.
Table 31: Personal short-term and full-shift exposure*
Working area
Short-term mg/m
3
(15-
minute TWA)**
Full shift mg/m
3
(8-hour
TWA)
Arithmetic
Mean ± SD
Median
(range)
Arithmetic
Mean ± SD
Median
(range)
Direct exposure
Mixing/sieving (n=11)
15.92 ± 18.41
11.64
(3.47 – 69.6)
8.05 ± 2.96
7.48
(3.62 – 11.58)
Pressing/moulding
(n= 14)
6.17 ± 4.39
6.41
(0.23 –
12.83)
4.89 ± 3.68
4.72
(0.36 – 11.16)
Indirect exposure
Post-
processing/finishing
(n=12)
0.8 ± 0.75
0.60
(0.2 – 3.05)
0.57 ± 0.23
0.52
(0.2 – 0.96)
No or rare exposure
Finshing/packing
(n=13)
(spatially separated)
0.12 ± 0.05
0.12
(0.04 – 0.2)
0.17 ± 0.1
0.13
(0.06 – 0.36)
Office (n=10)
(spatially separated)
0.05 ± 0.04
0.05
(0.01 – 0.13)
0.33 ± 0.39
0.14
(0.05 – 1.05)
* The LOD for the sampling and analysis procedure was not reported and no information was provided on the
procedure to deal with non-detects in the statistical analysis. The eMSCA also noted some discrepancies between
the tabulated exposure data and the data that was presented in scatter plots by Sucker et al. This table is based
on the tabulated data.
**The device used to collect short-term samples is designed to sample the vapour phase and hence these values
may underestimate short-term worker exposure in situations such as sieving and mixing where particulate
aerosols may be generated in addition to vapour. However, no differences were observed between static sampling
devices designed to collect vapour only or vapour and particulate suggesting that any underestimation may be
small.
For areas where direct exposure to naphthalene may occur, no distinction was made
between measurements taken where LEV was and was not in operation.
The highest short-term naphthalene concentrations for directly exposed workers were
obtained for sieving of pure naphthalene. The data set included 4 short-term
measurements that exceeded 50 mg/m
3
demonstrating that high peak exposures can occur
during this activity. Sucker et al (2016) also commented that the lowest naphthalene
concentrations measured for mixing and for moulding/pressing were for workstations
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UK MSCA 80 December 2018
located close to an open window. The mean full shift exposure for workers engaged in
mixing where the workstation was adjacent to an open window (3.62 mg/m
3
, 8-hr TWA)
was approximately half of the value for workers situated at mixing stations elsewhere (7.75
mg/m
3
, 8-hr TWA). The maximum short term exposure in the “window” group (4.93
mg/m
3
, 15-minute TWA) was almost ten times lower than mixers located away from
windows (41.83 mg/m
3
, 15-minute TWA). The high short term exposures observed during
sieving and observation that working next to an open window is associated with
significantly lower exposures suggests that where LEV was used, it may not have been
working effectively. Use of dry hand brushing and “blowing out” (which implies the use of
compressed air or similar to blow away contaminants) mixing vessels and moulds, if this
is done, could also have contributed to the high transient peaks and higher concentrations
away from windows. Dry hand brushing and use of compressed air are not consistent with
good occupational hygiene practice for a hazardous substance and alternative ways of
cleaning equipment should be considered.
Working areas with potential bystander exposure included e.g. the turning shop, the post-
and final processing where this was located in the same area as other production stages,
the firing kilns and storage silos.
The remaining two groups include workers engaged in finishing/packing activities where
this is physically separated from other production stages and office staff. At some sites,
office and planning areas were situated within the production areas and managers and
quality control staff spent some of their time in areas with naphthalene exposure.
Elsewhere, offices were located separately and employees would only rarely enter
production areas (less than 30 minutes per day or 3 hours per week). It is assumed that
the office measurements do not include data from sites where the office is located within
the production area. The exposures measured for bystanders and office workers suggest
airborne exposures for these groups will rarely exceed 1 mg/m
3
. This is still in the same
region as the high industry exposure category reported by Price and Jaycock (2010).
The measurements reported by Sucker et al (2016) appear to be consistent with the
measurements reported in registrations and the information made available for the ESR
RAR. For the ESR RAR, measured data were provided for one EU site manufacturing
grinding wheels. The data set consisted of two personal vapour measurements collected
on separate occasions. Exposures were 2.9 and 5.4 mg/m
3
8-hour TWA. This plant had
fitted LEV to the mixers, although mainly to control dust evolving during mixing and not
during material transfer to and from vessels. Due to the limitations (e.g. unidentified
exposure location, sample period, low number of samples, exposure period etc) in the
industry data set, modelled (using EASE) data was used to generate exposure estimates
for the risk characterisation. The following estimates were used for the risk
characterisation:
Inhalation (with LEV): 1.4 – 3.1 mg/m
3
(0.27 – 0.59 ppm)
Inhalation (without LEV): 6.9 – 20 mg/m
3
(1.32 – 3.81 ppm)
Early versions of CSRs report measured data collected from 3 EU sites. The data were split
into the following activities:
Weighing, sieving and mixing (n = 9)
Forming and pressing (n = 10)
Storage, drying and firing (n = 10)
The measurements apparently included both personal and static measurements. Workers
wore gloves, eye protection and protective overalls. In some cases mechanically assisted
ventilation or LEV was in place, but most samples were taken in areas where LEV was not
in use.
Taking all of the available information together, it is the eMSCA’s opinion that 10 mg/m
3
(8hr TWA) can be taken as a reasonable worst case exposure for airborne exposure to
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 81 December 2018
naphthalene during abrasive manufacture. This is the number that the eMSCA will use in
its risk characterisation. The eMSCA has noted evidence that current working practices and
ineffective LEV may have contributed to the high expsoures reported for workers engaged
in activities with potential direct contact with naphthalene. It is also noted that the samples
were collected during the summer and early autumn when ambient temperatures were
high and this could have increased volatilisation of naphthalene from powdered blends
compared with the levels of volatilisation that could occur during periods of lower ambient
temperature. These factors will be taken into consideration in the risk characterisation.
As an observation, in addition to the measured data provided in early versions of CSRs,
modelled exposure estimates (ECETOC TRA V2) were submitted to complement the
measured data. It was assumed that naphthalene behaved as a medium dustiness solid
and calculations were performed both with and without LEV. Interestingly, the modelled
estimates are below the “average” values obtained from the measured data provided in
early versions of CSRs and are below the lower end of the ranges estimated using the EASE
tool in the ESR RAR suggesting that the assumption that naphthalene behaves as a medium
dustiness solid may be inaccurate for this scenario. The previous EASE estimates
correspond more closely with the measured data.
Dermal
Dermal exposure to naphthalene is likely during the manufacture of grinding wheels from
handling the blends and from contaminated surfaces. This work involves considerable
dermal contact with the dry blends and unfinished wheels. For the ESR RAR, this was
characterised as “direct handling with extensive contact, where extensive refers to greater
than ten significant contacts in a shift”. This results in a prediction of 1 to 5 mg/cm
2
/day.
Since operators will for most of the time be in contact with blends containing only 30%
naphthalene the prediction was reduced to to 0.3 to 1.5 mg/cm
2
/day.
Estimates generated using the ECETOC TRA tool version 2 suggested potential dermal
exposures to be an order of magnitude higher than the range identified in the ESR RAR.
The registrants applied a linear reduction to the initial estimates to take account of the
assumption that blends may contain up to 40% naphthalene. Even with this reduction, the
registrants are using values 3-4 times higher than those used in the ESR RAR. The values
that are being used by the registrants may overestimate dermal exposure given that
information provided to the eMSCA by abrasive manufacturers indicates that blends
typically contain only 10-13% naphthalene.
The eMSCA used the ECETOC TRA tool version 3 to generate dermal exposure estimates.
The model prediction is not affected by the degree of dustiness assumed. It is assumed
that workers wear gloves with 80% effectiveness. For a mixture containing >25%
naphthalene and for the situation where LEV is not in use, the following exposures are
estimated:
PROC 5 2.74 mg/kg/day
PROC 14 0.69 mg/kg/day
The eMSCA will take these values forward to the risk characterisation.
If it is assumed that LEV is in operation and this is taken into account for dermal exposure,
these estimates are reduced by a factor of 10. This reduction is not considered relevant for
naphthalene since the tasks likely to give rise to the greatest dermal exposure (manual
sieving and brushing out mixing vessels and moulds) involve direct dermal contact.
Biological monitoring data
Sucker et al (2016) performed analyses of urine samples for 1-naphthol and 2-naphthol as
biological markers of exposure. Pre- and post-shift urine spot samples were collected from
exposed workers each day of the week that the health investigations took place. In
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UK MSCA 82 December 2018
addition, post-shift samples were collected from reference subjects (those expected to
have no or rare naphthalene exposure) on Monday and Thursday. Samples were analysed
according to the method published by the MAK Commission (see table 32). The limit of
quantification for the method was stated to be 1 µg/L. Since smoking may contribute to
naphthalene metabolite levels, smoking status was objectively verified by quantifying
urinary cotinine levels using a value of 100 µg/L to distinguish between smokers and non-
smokers.
Table 32: Biomonitoring results
Pre shift µg/L
Post shift µg/L
Mean
(range)
Median
(25-
75%ile)
95%
Number
> BAR
Mean
(range)
Median
(25-
75%ile)
95%
Number
> BAR
Direct naphthalene exposure (n=27)
Monday
239
(6-1543)
156
(35-259)
958
20
1228
(38-
4715)
767
(222-
1886)
3540
27
Thursday
968
(33-
6139)
612
(179-
1317)
2512
26
1909
(37-
7438)
1569
(765-
2650)
4869
27
Indirect naphthalene exposure (n=26)*
Monday
25
(1-102)
16
(17-30)
85
6
36
(10-58)
36
(27-47)
55
3
Thursday
35
(10–55)
41
(18-52)
54
3
70
(4-199)
51
(19-121)
162
16
No or rare naphthalene exposure (n=10)
Monday
9 (2-18)
7 (3-14)
18
0
n/a
Thursday
n/a
15 (0-
65)
10 (4-17)
46
1
* Samples were collected from 26 workers, pre-shift on Monday and post-shift on Thursday. Initially
20 in this group were assessed as having no or rare exposure and so samples were only taken on
Monday morning and Thursday evening. Six workers from this group were sampled throughout the
week.
When interpreting biological monitoring data it is helpful to establish some points of
reference. A Biologischer Arbeitsstoffreferenzwert (BAR) of 35 µg total urinary 1- and 2-
naphthol/L urine has been established by the German Research Foundation (Deutsche
Forschubgsgemeinschaft, DFG). This is the 95
th
percentile of levels from people who do not
smoke and are not occupationally exposed to naphthalene. Results at or below this level
in people with potential occupational exposure suggest that their exposure at work is not
making a significant contribution to exposure from other sources. Other biomonitoring
studies quoted by Preuss et al (2003) reported urinary 1-naphthol levels ranging from <1
– 30.5 µg/L and 2-naphthol levels ranging from <0.5 – 12.9 µg/L in non-smokers. Sucker
et al (2016) calculated a total urinary 1- and 2- naphthol level corresponding to exposure
at the recently established German AGW value of 0.5 mg/m
3
. Based on the data they
collected from this group of workers they estimated this would be around 97 µg/L or 86
µg/g creatinine. They also estimated that the urinary concentration corresponding to the
IOELV value of 50 mg/m
3
would be 22000 µg/L or 12500 µg/g creatinine.
Very few samples were below the LOD. In workers with no or rare exposure at work, levels
generally remain below the BAR throughout the week. In workers with indirect exposure,
although there was a trend for levels to increase through the week, levels remained close
to or below the BAR in pre-shift samples. It was only in post-shift samples collected later
in the week that levels started to rise above levels deemed to correspond to exposure at
the German AGW value.
A different picture was found for workers with direct exposure. In this group, most workers
had levels of urinary 1- and 2-naphthols in excess of the BAR at the start of the working
week and in many cases the levels at the start of the week were also higher than levels
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 83 December 2018
deemed to correspond to exposure at the AGW value. Workers with the highest levels
exceeded this value by 10 – 15 fold indicating that several workers from this group are
maintaining a raised body burden of naphthalene from one week to the next. Across the
shift and through the week, urinary levels showed clear increases from the levels recorded
at the start of the week. In end of shift samples, urinary levels for the majority of directly
workers exceeded levels deemed to correspond to exposure at the AGW value. The highest
urinary 1- and 2-naphthol level of 10127 µg/L was reported for a post-shift sample
collected from a directly exposed worker on Tuesday (mid-week results were reported in
Sucker et al (2016) but have not been presented in table 32 above).
These biological monitoring results show that under current working practices at these
sites, there is a potential for significant exposure to naphthalene for directly exposed
workers (i.e. those engaged in mixing/sieving and pressing/moulding). The observation
that several of the directly exposed workers start the week with body burdens well above
levels deemed to correspond to exposure at the AGW value is a concern. Additional controls
and improvements in working practices should be implemented to reduce the body burdens
that workers are receiving. Given that the photographs in Sawodny (2014) apparently
show representative working conditions, it may be useful to consider if exposure to
naphthalene in the vapour phase is making a greater contribution to worker exposure than
has been assumed. It may be useful to reconsider the way inhalation exposures are
managed.
Recommendations made in the risk reduction strategy
Concerns were raised in the risk reduction strategy that even if LEV was implemented
across the sector, this might not be sufficient to reduce exposures to levels that would be
considered acceptable. It was recommended that new exposure information should be
generated and this has been done. Companies were also advised to pursue substitution as
far as possible. Although the tonnages of naphthalene that are currently reported to go to
this use are of the order of several hundred tonnes per annum, information provided
informally by the abrasive industry during the evaluation indicates that some companies
have successfully replaced naphthalene.
Conclusions about use to manufacture abrasives
Allthough improvements have been made in response to the ESR RRS, the new exposure
data and accompanying contextual information suggests that additional improvements
may be required.
It is evident from the biological monitoring data that the body burdens attained during the
working week are sufficiently high that they cannot be cleared over the weekend. Assuming
gloves are worn when blends containing naphthalene are handled, the high body burdens
will have occurred as a result of inhalation exposure. The activities contributing the greatest
to airborne naphthalene levels are sieving and mixing. For these activities, short-term (15-
minute TWA) peaks of around 70 mg/m
3
have been reported with full shift (8-hr TWA)
values averaging 8.05 ± 2.96 mg/m
3
. Practices which could contribute to high transient
peaks include manual weighing and sieving of dry particulate material with ineffective or
no LEV, inadequate enclosures around filling points, briefly opening lids on blending
machines during mixing to add ingredients and the use of dry hand brushing and “blowing
out” (which the eMSCA assumes refers to the use of compressed air to blow particulate out
of moulds). It is also possible that dermal exposure may be contributing to total body
burdens if suitable procedures are not in place to manage glove use.
Naphthalene is a hazardous substance and it is a concern that the body burdens attained
during the working week by directly exposed workers cannot be cleared from the body
over the weekend.
The eMSCA therefore recommends that working practices in this sector should be reviewed.
Clear information needs to be provided in the exposure scenario about the correct risk
management measures that should be used, including information about appropriate
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 84 December 2018
methods for routine cleaning. Downstream users need to ensure that they fully comply
with the exposure scenario.
Note to registrants: In the light of the new information about the exposures and body
burdens that can be attained under current working practices, registrants are advised to
work with the abrasives sector to develop good practice guidelines for the use of
naphthalene. Exposure scenarios should be updated so that safe working practices are
documented unambiguously. Particular attention should be paid to the methods specified
for routine cleaning of mixing vessels and moulds during production. It may also be useful
to consider developing additional communication tools e.g. posters/videos which can be
used by downstream users in worker training programmes.
7.12.1.1.5 Formulation of smoke bombs/grenades (military use), military use
(including reloading) and service life.
Although the ESR RAR reported use of naphthalene in pyrotechnics which included
pyrotechnics used for special effects in the film industry, this source of exposure was not
specifically discussed in either the ESR RAR orrisk reduction strategy. The only exposure
information about this use therefore derives from modelled data (ECETOC TRA V3)
submitted in registrations and the scenario has been specifically limited to military use.
The life cycle for smoke bombs/grenades containing naphthalene has been divided into
three scenarios. The PROCs selected for these scenarios include:
Formulation: PROCs 4, 5, 8a, 9, 14, 15 and 19 (activities may take place indoors
or outdoors).
Military use (including reloading): PROCs 5, 8a and 9 (activities may take place
indoors or outdoors).
Service life: PROC 21 (outdoors only).
For formulation it is assumed that naphthalene may be handled as the substance itself and
it is characterised as a high dustiness solid. For the scenarios covering military use and
service life it is assumed that naphthalene is present at up to 25% in a solid in solid
mixture. For military use it is assumed the mixture has a high dustiness, for service life it
is assumed the mixture has a low dustiness. Gloves are required for all activities with the
exception of service life where no gloves are required. No other risk management measures
have been identified. Since the eMSCA does not have any further information about these
uses, it will assume that the exposure estimates reported in CSRs are representative of
the exposures likey to arise during formulation, military use and service life of smoke
bombs/grenades. The eMSCA notes that in the case of PROCs 4, 5 and 8a, the registrants
found it necessary to limit the duration of exposure, in some cases to less than 1 hour per
day, in order to achieve RCRs < 1. The exposure value calculated by the ECETOC TRA tool
is based on the assumption that there is no further exposure to naphthalene during the
working day. If this pattern of work is not typical for the downstream user it may be
necessary to apply additional controls to ensure adequate control.
Notes to registrants: To ensure that companies receiving exposure scenarios including
tasks assessed on a reduced duration basis implement sufficient measures to protect their
workers, clarification should be provided with the scenario that the RMMs identified apply
where the worker does not have further exposure to naphthalene during the shift.
In the light of the new information about the exposures and body burdens that can be
attained under working practices adopted during the manufacture of abrasives, registrants
are advised to reconsider the measures that are recommended for formulation and for
reloading of smoke bombs/grenades. Based on the PROC codes selected for this scenario,
the eMSCA identifies similarities with the activities performed during the manufacture of
abrasives and is concerned that no measures have been identified in the exposure
scenarios for formulation and for reloading of smoke bombs that will limit the release of
naphthalene into the workroom air. Workers experiencing daily exposure at the levels of
naphthalene estimated for this scenario are likely to accrue body burdens that will carry
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 85 December 2018
across to the next working week. It is recommended that working practices are reviewed
and the exposure scenario is updated to include controls that will limit the release of
naphthalene to air. Attention should be paid to the methods specified for routine cleaning
during production to avoid the use of methods that allow dust to become airborne which
will unnecessarily raise airborne levels of contamination throughout the workroom. It may
also be useful to consider developing additional communication tools which can be used by
downstream users in worker training programmes.
7.12.1.1.6 Overall conclusions for worker exposure
This evaluation focusses on the manufacture and uses of naphthalene covered by
naphthalene registrations. This does not cover all potential sources of exposure to
naphthalene from REACH registered substances since exposure to naphthalene may occur
where this substance is a constituent of UVCB mixtures covered by other registrations.
Workplace exposure will also arise where there is combustion of carbonaceous material
and from activities such as tar and asphalt laying e.g. roofing and road repair. Workers
performing activities covered in REACH registrations for naphthalene and other substances
containing naphthalene will also be exposed to naphthalene from non-work related
sources. Table 33 provides a summary of the exposure information discussed in this
evaluation.
Table 33: Summary of exposure to naphthalene.
Source
Inhalation
Dermal
(mg/kg/day)
Low end of
range
(mg/m
3
)
High end of
range (mg/m
3
)
Sources not covered in naphthalene registrations
Pristine air
1X10-7
3X 10-6
n/a
Suburban air
1X10-6
0.001
n/a
Indoor air (non –smoker)
0.0001
0.0017
n/a
Indoor air (smoker)
0.0018
0.01
n/a
Industrial exposure (lower
exposure industries)
0.01
0.3
n/a
Odour threshold
0.42
n/a
Industrial exposure (higher
exposure industries)
0.1
3
n/a
Exposure conclusions for uses covered in REACH registrations
Manufacture
eMSCA relying on
modelled data
from registration
eMSCA relying on
modelled data
from registration
Use as an intermediate
eMSCA relying on
modelled data
from registration
eMSCA relying on
modelled data
from registration
Manufacture of abrasives
10 (8-hr TWA)
PROC 5 2.74
PROC 14 0.69
Formulation and use of
smoke bombs/grenades
eMSCA relying on
modelled data
from registration
eMSCA relying on
modelled data
from registration
n/a not available
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 86 December 2018
Based on information obtained during the evaluation, it can be concluded that
improvements have been implemented in response to the ESR RRS. However, the new
exposure data for abrasive manufacture indicates that the current working practices are
not reducing worker exposure sufficiently to enable in workers carrying out tasks with
direct exposure to naphthalene to clear the body burden of naphthalene accrued during
the working week before starting work the next week. Additional improvements should be
made, in particular to the methods used to limit inhalation exposure. It would be useful to
check working practices and corresponding exposure levels at sites formulating and
reloading smoke bombs. The lack of measures to limit the release of naphthalene to the
workroom air during these acivities may result in these workers maintaining a residual
body burden of naphthalene from one week to the next if they work with naphthalene on
a daily basis.
For its risk characterisation, the eMSCA will use the modelled estimates generated by the
registrants for scenarios covering manufacture, use as an intermediate and formulation of
smoke bombs/grenades. For manufacture of abrasives, the eMSCA will take 10 mg/m
3
(8-
hr TWA) as a reasonable worst case for inhalation exposure and will use its own modelled
exposure estimates for dermal exposure (see table 33). Since a DNEL has not been derived
for biological monitoring data this data will not be used to perform a quantitative risk
characterisation. However, the findings will be taken into consideration.
7.12.1.2 Consumer
No consumer uses have been identified for naphthalene in REACH registrations and it
seems likely that the consumer uses that were identified in the ESR review have largely
ceased with the possible exception of cases where consumers purchase products directly
from non-EU suppliers.
Consumer exposure to naphthalene is still possible if consumers use products containing
naphthalene that are covered by other REACH registrations e.g. substances covered by the
C
10
-C
12
aromatic hydrocarbon solvents category. Additional background exposure for the
general population will also occur from a wide range of possible sources and this may
exceed consumer exposure from substances that are covered by REACH registrations.
These sources of exposure have not been quantified as part of this evaluation.
7.12.2. Environment
Not evaluated.
7.12.3. Combined exposure assessment
Registrants either refer to the combined exposure assessments published in the ESR report
or provide an assessment that only addresses combined exposure to emissions to the
environment arising from the exposure scenairos covered in REACH registrations. These
environmental emissions are minor and do not make a significant additional contribution
to daily exposure from other sources. The Registrants are not required to quantify
exposures arising from other potential sources of background exposure or exposure arising
from uses of other substances and products that may contain naphthalene but are not
covered in REACH registrations for naphthalene.
Given the ubiquitous nature of these sources it is likely that the exposure predictions
arrived at in REACH registrations will underestimate total daily exposure for workers and
the general population. The eMSCA does not have enough information on the potential
scale of these additional sources to characterise risks in a meaningful way. However, this
is identified as a source of uncertainty for the risk characterisation.
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 87 December 2018
7.13. Risk characterisation
Human Health
The lead health concerns for naphthalene are haemolytic anaemia and carcinogenicity. Now
and in the future, (potential) exposures in the workplace are the principal exposure
scenarios of concern.
Evidence from humans drives the concern for haemolytic anaemia since the main
experimental species (rats, mice and rabbits) do not appear to be a suitable model for this
effect. In humans, the occurrence of haemolytic anaemia has been reported in at least 30
individuals, typically following single or repeated oral intake of naphthalene mothballs but
also following inhalation and dermal exposure to naphthalene from clothing. Individuals
who are deficient in the enzyme glucose-6-phosphate dehydrogenase (G6PD) may be more
susceptible to the haemolytic effects of naphthalene than others in the general population.
Owing to the circumstances surrounding the poisoning incidents, it is not possible to
determine the doses involved and the nature of the dose-response relationship cannot be
identified. It is therefore not possible to calculate a derived no effect level (DNEL) for this
effect and perform a quantitiative risk characterisation. At the time of the ESR review, an
investigation was performed into the feasibility of conducting a workplace survey to look
for signs of haemolytic anaemia. However, it was determined that the only suitable
population for such a study (the workforce of a mothball manufacturing plant was identified
because they were exposed to high levels of naphthalene without confounding exposures)
was too small to draw meaningful conclusions. No further information was therefore
requested and it was concluded in the ESR RAR that body burdens in the mg/kg range may
be of concern for haemolytic anaemia.
Very little new information has emerged since the ESR review to shed further light on a
no-effect level for haemolytic anaemia in humans. In the light of this continuing
uncertainty, the conclusion that body burdens in the mg/kg range may be of concern
remains. It is also the case that there is no evidence to clarify whether or not naphthalene
exposed workers currently experience haemolytic anaemia; if they do, then one can infer
from the absence of reports that the degree of effect is not sufficient to prevent them from
attending work.
The concern for carcinogenicity is driven by experimental evidence, particularly from
studies in rats. In long-term repeated exposure studies, nasal tumours have been observed
at levels that also caused non-neoplastic inflammatory changes and it appears likely that
inflammation is a necessary precursor for the tumours. The ESR review concluded that the
tumours observed in animal studies are likely to have arisen via a non-genotoxic
mechanism and this conclusion has been upheld by the mode of action (MoA) analysis
performed during this evaluation (see section 7.9.6.3.1).
The postulated mode of action (MoA) for the nasal tumours in rats proposes that
naphthalene is metabolised to cytotoxic metabolites by a CYP (CYP2F) enzyme in tumour-
forming tissues. Those metabolites are responsible for the inflammation and regenerative
hyperplasia which precede carcinogenesis. The presence of a CYP2F enzyme in humans
indicates that there is a potential for naphthalene metabolism in humans. The anatomical,
physiological and metabolic differences between rats and humans, including breathing
route, anatomy of the nasal cavity and (based on findings from in vitro studies) the likely
lower rate of naphthalene metabolism in humans are noted. On the basis of these
differences, it is possible that the pattern of effects observed in humans will vary from
those observed in the rat.
There is no evidence of nasal tumours resulting from naphthalene exposure in humans.
However, the absence of case reports or other forms of epidemiological study of this issue
cannot be considered to represent convincing evidence that the tumours observed in rats
are not relevant to humans.
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 88 December 2018
In mice receiving inhalation exposure to naphthalene, tumours were not observed in nasal
tissue. However, it is not known whether the mouse or rat is a better model for effects of
naphthalene inhalation exposure. Therefore, the total information available is not sufficient
to conclude that the finding of nadal tumours in rats exposed to naphthalene by inhalation
is not relevant for humans (albeit that humans might well be at least quantitatively less
sensitive to such an effect). The current Carc Cat. 2 classification is based on this
perspective.
In setting their long-term inhalation DNEL of 25 mg/m
3
(8-hr TWA), the registrants chose
to rely on information obtained from an unpublished survey of workers at 12 European
abrasives producers, conducted in 2010. Few details from this survey were provided in the
registration. Company doctors are reported to have never observed blood anomalies or
haemolytic anaemia or other occupational health effects in workers, some of whom had
been employed for up to 40 years. However, the registrants have not provided sufficient
information about the endpoints that were assessed in medical examinations of these
workers, nor the frequency of examinations, to understand how comprehensive these
assessments were. It is claimed that workers were regularly exposed to levels approaching
25 mg/m
3
(8-hr TWA). However, no information has been provided to confirm the levels
of exposure these workers were subjected to in their daily work and a more recent study
in this sector (Sucker et al, 2016) reported a maximum personal 8-hr TWA value of 11.58
mg/m
3
(see table 31). The registrants have therefore not provided sufficient evidence to
demonstrate that their DNEL will be protective of worker’s health and the eMSCA
considered alternative routes by which an appropriate and robust DNEL can be derived.
If the conventional DNEL setting approach is followed, in the absence of reliable dose
response data from humans, a suitable starting point should be selected from studies in
animals. The no-observed adverse effect concentration (NOAEC) from the 90-day
inhalation study by Dodd et al (2012) of 0.52 mg/m
3
provides such a starting point. At the
next dose administered to rats in this study, 5.24 mg/m
3
, only minimal hyperplasia was
observed in the respiratory/transitional epithelium suggesting the true no-effect
concentration might lie somewhere between 0.52 and 5.24 mg/m
3
. However, since no
further information is available to identify a more accurate no-effect concentration, it would
be necessary use the value of 0.52 mg/m
3
as the starting point which, if the conventional
assessment factors are applied, leads to a worker, long-term inhalation DNEL of 0.053
mg/m
3
.
However, a recent workplace study (Sucker et al, 2016) found no consistent evidence for
nasal inflammation in workers occupationally exposed to levels up to 10 mg/m
3
(8-hour
time weighted average (TWA)) naphthalene. In this study, a battery of tests were
performed to look for signs of nasal inflammation and adverse effects on olfactory function.
Endoscopic examinations of nasal tissues revealed that slight to moderate inflammation
was present in participants from the high exposed, moderately exposed and reference
groups (which had daily naphthalene exposures of 6.97±3.10 mg/m
3
(arithmetic
mean±standard deviation), 0.66±0.27 mg/m
3
and 0.15±0.10 mg/m
3
respectively). A
comparison of readings taken on Monday and Thursday revealed an increase in endoscopy
examination scores (suggesting more severe inflammation) in some individuals from each
group and a decrease in scores (suggesting less severe inflammation) from other
individuals, with a greater tendency (statistically significant) for scores to increase (Monday
– Thursday) in moderately and high exposed workers compared with the reference group.
However, there were no differences between the moderate and high exposed groups,
despite the 10-fold higher naphthalene exposure in the high exposed group. No consistent
changes were observed in biomarkers for inflammation in nasal lavage or sputum samples
from the exposed and reference groups. Also, where statistical differences were observed
between the exposed and reference groups, there was often a high degree of overlap in
the range of results (for example, for total endoscope scores, the Thursday readings ranged
from 0-13 in the high exposed group, from 3-13 in the moderately exposed group and
from 0-9 in the reference group). Complicating the analysis is the fact that both exposure
groups were also exposed to inhalable and respirable dusts including ceramic grain and
silica which could have contributed to the observed nasal inflammation. It is therefore
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 89 December 2018
difficult to determine what role naphthalene might have played in any nasal effects
observed in these workers. Overall, there was no indication of a substantial effect of
naphthalene inhalation on nasal irritation, with exposures up to about 7 mg/m
3
. On this
basis, a DNEL of 0.053 mg/m
3
will be a very precautionary value given the lack of
consistent evidence for inflammatory changes associated with naphthalene in workers with
daily exposure to levels of naphthalene over 100 times higher than this DNEL.
It is also worth noting that the DNEL is at the low end of the range of exposures recorded
for office workers that are spatially separated from areas where naphthalene is in use
(exposures for these office workers ranged from 0.05 – 1.05 mg/m
3
(8-hr TWA) (see table
31)). This suggests that if exposures are to be maintained below this DNEL, it is likely that
there would need to be a major redesign of the sites where the data for Sucker et al were
collected and potentially other sites using naphthalene. Requiring the downstream use
chain for naphthalene registrants to adopt this DNEL would also set higher standards of
control for these sites compared with sites where exposure to naphthalene arises because
it is a component in a substance of unknown or variable composition (UVCB) or generated
as a process by-product. For example, Price and Jaycock (2008) suggested exposure to
naphthalene can be expected to be in the range 0.01 – 0.3 mg/m
3
(8-hr TWA) for refining
and petroleum industries, asphalt (paving and roofing) and industries using pitch to
manufacture refractory materials or graphite electrodes. For these reasons the eMSCA does
not think that a DNEL of 0.053 mg/m
3
provides a workable reference point from which to
derive a control strategy for naphthalene.
Due to the lack of understanding of the most appropriate experimental models for the
effects of naphthalene in humans, the eMSCA does not consider that requiring further
experimental studies is an appropriate course of action. Instead, the eMSCA proposes that
an EU-wide OEL will be the most appropriate way to manage risks. Setting an EU-wide
limit value would not only target the sectors of use that have been covered by this
evaluation, but would also target other sectors where exposure to naphthalene arises
because it is a component in a UVCB or because it is generated as a process by-product.
It would ensure that consistent standards of control are adopted wherever there is
occupational exposure to naphthalene and that these standards apply across all EU-
territories.
The current EU-wide Indicative Occupational Exposure Limit Value (IOELV) of 50 mg/m
3
(8-hr TWA) was introduced via the first Indicative Limit Value Directive (91/322/EEC) and
was directly transposed into the current system via the second IOELV Directive
(2006/15/EC). Although the IOELV has been reviewed by the Scientific Committee on
Occupational Exposure Limits (SCOEL, 2010), the review took place at a time when
potentially relevant experimental studies were ongoing. SCOEL therefore declined to
recommend a limit value pending publication of this data.
The studies SCOEL were waiting for have now been published along with a new workplace
study (Sucker et al, 2016) and all of the new evidence has been considered in this
evaluation. Since the IOELV is twice as high as the registrants’ DNEL of 25 mg/m
3
(8-hr
TWA) and five times higher than the levels in air measured by Sucker et al, (2016) for
directly exposed workers (up to around 10 mg/m
3
) the eMSCA concludes that the IOELV is
not providing any incentive for employers to improve workplace control. The current IOELV
should therefore be revised.
In considering what number should be adopted for the OEL, it will be useful to understand
the levels in air that are achievable with the currently applied controls and working
practices. REACH registrations only describe the registrants’ recommended risk
management measures but do not provide clarity about the measures currently
implemented by downstream users and the associated levels of exposure.
A key piece of information to take into account in setting the OEL is the biological
monitoring data obtained by Sucker et al, summarised in table 12. This showed that the
majority of non-smoking workers carrying out tasks involving direct exposure to
naphthalene at levels of up to 10 mg/m
3
(8-hr TWA) do not appear to clear the body burden
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 90 December 2018
of naphthalene accrued during the working week over the weekend. The 95
th
percentile
levels of unriary 1- and 2-napthol in directly exposed workers in pre-shift samples on
Monday was 958 µg/L compared with 85 µg/L in workers with indirect exposure and 18
µg/L in workers with no or rare exposure. Although Sucker et al did not measure body
burdens, the potential body burden corresponding to the exposures estimated for the
grinding wheel scenario can be calculated. If it is assumed that an average worker weighs
70 kg and inhales 10 m
3
air per shift, and that there is 100% absorption by the inhalation
route, the body burden accrued by the end of the week may be around 2.8 mg/kg (this
value is based on an estimated elimination constant (k
el
) of 0.5/day derived by the
regsitrants from the biomonitoring data presented by Sucker et al and does not take a
possible contribution from dermal exposure into account). This value should be considered
commensurate with the “low mg/kg” range identified in the ESR RAR as potentially of
concern for the possibility of producing haemolytic anaemia. There was no evidence in this
study that maintaining an elevated body burden of naphthalene was evidently detrimental
to the health of the workers studied. However, significant uncertainties apply: the study
focussed on examinations of the nasal passages, markers for haemolytic anaemia and
G6PD deficiency were not investigated; there is uncertainty surrounding the dose-response
relationship for haemolytic anaemia, particularly taking into account that around 4% of the
European population may have the G6PD deficiency making them more susceptible to
naphthalene induced haemolytic anaemia; and there is uncertainty surrounding the dose-
response relationship for nasal inflammation, with the possibility that such inflammation
could have the potential to progress to nasal tumour development in humans. The eMSCA
argues that, with all these uncertainties, it seems sensible to aim to limit exposure to levels
that do not cause workers to retain a residual body burden of naphthalene from one week
to the next.
The high urinary 1- and 2-napthol levels measured by Sucker et al (2016) could potentially
have arisen as a result of either inhalation or dermal exposure or a combination of the two.
The eMSCA has been informed that it is standard practice for these workers to wear gloves
if there is the potential for direct skin contact with naphthalene. Assuming that appropriate
gloves are being worn and suitable management systems are in place to ensure the gloves
are used correctly, this directs attention towards inhalation as being the main route of
exposure.
The conclusion is therefore reached that airborne exposures to naphthalene should be kept
below 10 mg/m
3
(8-hr TWA).
To ensure body burdens are kept within acceptable levels, it is not clear how far below 10
mg/m
3
it is necessary to reduce airborne exposure. Ideally this decision should be informed
by additional information linking measured airborne exposures with biological levels across
a range of sectors where there is the potential for exposure to naphthalene. Such an
extensive survey will require the voluntary participation of a wide range of companies and
workers and it seems unrealistic to place this as a requirement on the REACH registrants
of naphthalene. This is therefore identified as a recommendation from this evaluation.
It also seems appropriate to reflect on the potential exposures associated with the current
operating conditions and risk management measures identified in the naphthalene REACH
exposure scenarios.
For the manufacture of naphthalene and the use of naphthalene as a feedstock/
intermediate, worst case modelled estimates for PROCs 4, 8a, 8b and 9 suggest airborne
exposure may exceed 10 mg/m
3
if a worker performs these tasks exclusively for the entire
shift. It is possible that worker exposure has been overestimated, for example a higher
level of containment may be implemented than has been assumed in the exposure
calculations and the time workers spend working directly with naphthalene may be much
less than has been assumed. Unless more details are provided in registrations about the
way processes are currently operated it will not be possible to refine these worst case
estimates.
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 91 December 2018
The information provided in registrations and from Sucker et al about exposure to
naphthalene during the manufacture of abrasives suggests that additional control
measures should be implemented to further limit the release of naphthalene to air during
activities involving direct handling of naphthalene i.e. weighing, mixing, sieving, pressing
and moulding (see section 7.12.1.1.4 for details).
Very little information is available about the formulation, military use and service life of
naphthalene containing smoke bombs/grenades. This is another sector where naphthalene
exposures may be sufficiently high that workers retain a residual body burden from one
week to the next. Further information should be obtained to clarify working practices in
this sector. Decisions can then be taken about the need (or not) to implement additional
control measures e.g. containment or LEV to limit the release of naphthalene particulate
and vapour to air.
In summary, in addition to the conclusion that the existing EU-wide OEL for naphthalene
should be revised, the following recommendations are made:
To ensure that it is transparent in the exposure scenario how all relevant work
activities are covered, either a specific contributing scenario for routine cleaning
and maintenance activities should be provided or registrants should indicate which
of the already chosen contributing scenarios apply to these activities. Registrants
should update registrations with this information without undue delay.
To allow authorities to better understand the current operating conditions and any
risk management measures that are used, and to put the exposure estimates into
context, all registrants should provide additional descriptions of the the
tasks/activities that are performed and the risk management measures that are
applied for all uses covered in their CSRs. Registrants are recommended to update
registrations with this information without undue delay.
All sectors of industry where there is a potential for exposure to levels of
naphthalene that could approach or exceed 10 mg/m
3
(8-hr TWA) should consider
gathering information on levels in air and corresponding biological levels under
current working conditions. Where there is evidence that body burdens in workers
regularly exceed background levels at the start of the working week, operating
conditions and risk management measures should be re-examined. The Biologischer
Arbeitsstoffreferenzwert (BAR) of 35 µg total urinary 1- and 2-naphthol/L urine
established by the German Research Foundation (Deutsche
Forschungsgemeinschaft, DFG) may be a useful benchmark to use for this
assessment. If it appears necessary to reduce worker exposure, additional controls
should be implemented in accordance with the hierarchy of control described in the
Chemical Agents Directive (98/24/EC). In addition to the sectors covered in this
evaluation, it may also be useful to investigate exposure to naphthalene in other
sectors such as those where UVCB mixtures are used which contain naphthalene as
an impurity and sectors where naphthalene is emitted as a process by-product.
7.14. Additional information
UK CA literature search for human health
To ensure that the dossier included all relevant publications, the eMSCA performed a
literature review on naphthalene (human health effects and human exposure). The
strategy for the review was to search for naphthalene and its synonyms in conjunction with
defined key words that are specific to the areas identified as a concern in the CoRAP. Two
databases were employed which cover many areas of science (Pubmed and Toxnet).
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 92 December 2018
The following search terms were adopted:
naphthalene or albocarbon or dezodorator or “moth flakes” or naphthaline or “tar camphor”
or “white tar” or “NSC 37565” or “202-049-5” or “91-20-3”
in combination with
irritat* or irritant* or sensiti* or hypersensiti* or expose* or exposure* or exposing or
breath* or respir* or inhale* or inhalation or allerg* or toxic* or intoxic* or poison* or
disease* or illness* or morbid* or mortalit* or neurodegen* or neurotoxic* or
neurobehavio* or “nervous system*” or neuropatholog* or brain or derma* or cancer* or
carcinogen* or carcinoma* or reproduct* or reprotox* or fertilit* or mutagen* or mutat*or
genotoxic* or gene or genes or genetic* or immunotoxic* or immune* or immuni*or
hepato* or terato* or cell or cells or cytotox* or metabolis* or “endocrine disrupt*”
or
expose* or exposure* or exposing or work* or consumer* or domestic or monitor* or
surveillance or occupation* or paraoccupation* or [“1-naphthol”]
Substance Evaluation Conclusion document EC No 202-049-5
UK MSCA 93 December 2018
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Bailey et al. (2015) Hypothesis-based weight-of-evidence evaluation and risk assessment
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Bogen (2008) An Adjustment Factor for Mode-of-Action Uncertainty with Dual-Mode
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Bogen et al. (2008) Naphthalene metabolism in relation to target tissue anatomy,
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BUA (1989). Naphthalene. BUA Report 39. GDCh-Advisory Committee on Existing
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Buckpitt et al. (2013) Kinetics of naphthalene metabolism in target and non-target tissues
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Applied Pharmacology 270 (2013) 97-105
Campbell et al. (2014) A hybrid CFD-PBPK model for naphthalene in rat and human with
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1-12
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Dermal exposure to jet fuel JP-8 significantly contributes to the production of urinary
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Chauhan et al. (2014) Naphthalene Poisoning Manifesting as Hemoglobinuria. Toxicology
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Cichocki et al. (2014) Sex Differences in the Acute Nasal Antioxidant/ Antielectrophilic
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Daisy BH, Strobel GA, Castillo U, Ezra D, Sears J, Weaver DK, Runyon JB (2002).
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Danish Ministry of the Environment (November 2014) Survey of naphthalene (Part of the
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7.16. Abbreviations
% Percentage
°C degrees Celsius
ALT Alanine aminotransferase
AST Aspartate aminotransferase
ASTDR Agency for Toxic Substances and Disease Registry
ATH Atypical tubule hyperplasia
ATP Adenosine Triphosphate
bw bodyweight
BAR Biologischer Arbeitsstoffreferenzwert
CC16 Club cell protein 16
CFPD Computational Fluid-Particle Dynamics
CLP Classification, labelling and packaging (of substances and mixtures)
cm Centimetre
CoRAP Community Rolling Action Plan
CPN Chronic progressive nephropathy
CSR Chemical Safety Report
CYP Cytochrome P450
d Day
DD Dihydrodiol dehydrogenase
DF Deposition Fraction
DNA Deoxyribonucleic acid
DMEL Derived Minimal Effect Level
DNEL Derived No Effect Level
DSD Dangerous Substances Directive
EC European Commission
ECETOC TRA European Centre for Ecotoxicology and Toxicology of Chemicals Targeted
Risk Assessment
ECHA European Chemicals Agency
EH Epoxide hydrolase
eMSCA evaluating Member State Competent Authority
EPA Environmental Protection Agency
ES Exposure Scenario
ESR Existing substances regulation
EU European Union
g Gramme
G6PD Glucose-6-phosphate dehydrogenase
GC Gas chromatography
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GC/FID Gas chromatography – Flame Ionisation Detection
GC/MS Gas chromatography – mass spectrometry
GLP Good laboratory practice
GSH Glutathione
HEC Human Equivalent Concentration
hPa Hectopascal
HPV High production volume
IARC International Agency for Research on Cancer
IL-6 Interleukin 6
IL-8 Interleukin 8
ILV Indicative limit value
IOELV Indicative occupational exposure limit
IPA Institut für Prävention und Arbeitsmedizin der Deutschen Gesetzlichen
Unfallversicherung
IPCS International Programme on Chemical Safety
ISO International Organisation for Standardisation
IUCLID International Uniform Chemical Information Database
IUPAC International Union of Pure and Applied Chemistry
kg Kilogram
kJ Kilojoule
km Kilometre
K
ow
Octanol-water partition coefficient
kPa Kilopascal
L Litre
LDH Lactate dehydrogenase
LEV Local Exhaust Ventillation
LOAEC Lowest Observed Adverse Effect Concentration
LOAEL Lowest Observed Adverse Effect Level
LOD Limit of detection
Log Logarithmic value
LOQ Limit of quantitation
m Metre(s)
m
3
cubic metres
M Molar
MS Mass spectrometry
m/z Mass to charge ratio
μg Microgram
µM micromoles
MoA Mode of Action
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UK MSCA 99 December 2018
mg Milligram
min Minute
mL Millilitre
MMP-9 Matrix metalloproteinase-9
mol Mole
MPa Mega pascal
MSCA Member State Competent Authority
MTD Maximum Tolerated Dose
NADPH Nicotinamide adenine dinucleotide phosphate
nm Nanometre
nmol nanomoles
NOAEL No observed adverse effect level
NOEC No-observed effect concentration
NOEL No observed effect level
NTP National Toxicology Program
OC Operational condition
OECD Organisation for Economic Co-operation and Development
OEL Occupational exposure limit
p Statistical probability
Pa Pascal
PBPK Physiologically based pharmacokinetic
PC Product category
pKa Acid dissociation constant
pg Picogramme
PP 5-phenyl-1-pentyne
ppb Parts per billion
PPE Personal Protective Equipment
ppm Parts per million
PROC Process Category
psi Pounds per square inch
QSAR Quantitative structure-activity relationship
r
2
Correlation coefficient
RAR Risk assessment report
RCR Risk characterisation ratio
REACH Registration, Evaluation, Authorisation and Restriction of Chemicals (EU
Regulation No. 1907/2006)
RMM Risk Management Measures
RPE Respiratory protective equipment
RRS Risk reduction strategy
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SCC Strictly controlled conditions
SCOEL Scientific Committee on Occupational Exposure Limits
SD Sprague Dawley
t Tonne
TEDX Endocrine Disruption Exchange
TIMP-1 Tissue inhibitor of metalloproteinase
TG Test Guideline
TWA Time-weighted average
UK United Kingdom
US United States
UV Ultraviolet
UVCB Substances of unknown or variable composition, complex reaction products
and biological materials
V
max
maximum rate of reaction
WHO World Health Organisation
wt. Weight
