Document ID: EPA-HQ-OPP-2008-0343-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-05-14T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

April 18, 2008

MEMORANDUM

SUBJECT:	Naphthalene:  Phase 2 Amendment:  Response to Registrant
Submitted Error Only Comments In Reference to “Naphthalene: HED
Chapter for the Reregistration Eligibility Decision Document (RED)”

PC Code:  055801	DP Barcode:   335941

Decision No.: 374031	Registration No.:  N/A

Petition No.: N/A	Regulatory Action:  Phase 2 (Error Correction)

Risk Assessment Type: Single Chemical/No Aggregate	Case No.:  0022

TXR No.:  N/A	CAS No.:  91-20-03

MRID No.:  N/A	40 CFR: N/A (Non-Food/Non-Feed)

FROM:	Danette Drew, Senior Scientist

		Wade Britton, MPH, Industrial Hygienist

                         John Liccione, Toxicologist

 Peter Savoia, Chemist

 Reregistration Branch 3

		 Health Effects Division (7509P)

AND:		Vicki Dellarco, Senior Science Advisor

		Health Effects Division (7509P)

 			

THROUGH:	Catherine Eiden, Branch Chief 

		Reregistration Branch 3

		Health Effects Division (7509P)

	

TO:		Molly Clayton

		Reregistration Branch 2

		Special Review and Reregistration Division (SRRD) (7508P)

Attached is the Health Effect Division’s (HED) Phase 2 amended risk
assessment for the naphthalene RED.  Error correction comments were
submitted by Landis International on April 1, 2008 (“Registrant 30-day
Response to Agency-Error corrections Preliminary Risk Assessment for the
Reregistration Eligibility Decision for Naphthalene received March 3,
2008) and are incorporated in the attached amendment. This document
supersedes the document “Naphthalene:  HED Chapter of the
Reregistration Eligibility Decision Document (RED).  PC Code: 055801,
DP#335946” dated February 28, 2008.

		

1.0 Executive Summary

Use Profile

Naphthalene is used as a moth repellant for the protection of wool
clothing and as an animal repellant against nuisance vertebrate pests.
Naphthalene is registered for uses in and around the home. In the home,
it can be used to repel moths from clothing stored in enclosed areas or
closed containers and as an indoor (attic) animal repellant. Outdoors,
naphthalene may be used as an animal repellant and is applied as a
narrow band around target areas to be protected (houses, wood piles,
trash cans, flower beds, etc).  Naphthalene is a non-food/non-feed
pesticide.

Naphthalene is a white, crystalline solid which volatilizes to create a
characteristic odor.  In a sealed container, naphthalene vapors build up
to levels toxic to both the adult and larval forms of many moths
destructive to wool clothing.  In addition, naphthalene’s odor can be
used to repel vertebrate animals.

Naphthalene products are formulated as mothballs, flakes, dusts, and
granules and are labeled for application by hand. Re-treatments are
recommended when product and odor dissipate. Even though this pesticide
may be applied by hand, which could result in some dermal exposure,
inhalation is the main route of exposure expected based on
naphthalene’s chemical nature and use pattern. Inhalation exposures
may result from homeowners applying the pesticide, or to residents who
inhabit homes that have been treated. Additionally, inhalation exposures
can occur when an enclosed treated area, where the compound has been
allowed to concentrate in the air, is temporarily accessed or opened.
Oral exposures, on the other hand, are not as likely to occur. Since
naphthalene is a non-food use pesticide, there are no dietary exposures
expected from food. Dietary exposures via drinking water may be possible
assuming the product is indeed entering drinking water sources as a
result of outdoor home uses.  There is also a possibility that a child
may try to eat the applied product as it is encountered indoors or out.
This scenario, however, can be considered episodic (a one time only
incidental ingestion).

Hazard Characterization

Based on the use pattern, the standard toxicology database for
naphthalene is complete for assessing dermal and oral exposure risks to
humans. Although standard inhalation rodent toxicity studies are
available, some mechanism studies have raised the issue of notable
species differences (in regard to respiratory toxicity and metabolism)
and the applicability of the rodent model as a default approach to
estimate human risk following inhalation exposures.  There is support
from published studies and ongoing research on naphthalene that indicate
that risk estimates, would be considerably less than those using default
procedures when known species differences between rodents and humans
(including humans) in metabolism and respiratory toxicity are factored
into the estimates.  The mechanism data are not yet complete and ongoing
research, when completed, is expected to significantly refine the
potential toxicity hazard associated with human exposure to naphthalene
via inhalation. No new standard toxicology data are being required at
this time.

Standared test guideline studies indicate that naphthalene is acutely
toxic in the rat via the oral and inhalation routes of exposure.  In the
rabbit, it is a moderate acute dermal toxicant.  It is a moderate skin
and eye irritant in the rabbit.  Naphthalene is not a dermal sensitizer
in guinea pigs. In rats, critical effects of acute toxicity were hunched
posture, shaking and reduced motor activities.  

Cataracts have been observed in rabbits, rats and mice, but only at high
dose levels (greater than or equal to 500 mg/kg/day).  Cataracts have
been noted in human case reports but exposure information is lacking and
there are no well conducted  epidemiology studies that have verified
this effect.  

Hemolytic anemia has also been reported in humans (acute oral or
inhalation exposure) but information on exposure levels were lacking. 
Hemolytic anemia has not been observed in the laboratory animal studies.

Subchronic toxicity of naphthalene is manifested by body weight changes,
organ weight changes and /or clinical signs of toxicity following gavage
treatment to rats.

Naphthalene inhalation studies include nose-only, i.e., compound
introduced directly to the nose (4-week, 13-week, and subchronic 90-day
neurotoxicity) and chamber studies (2 year) in rodents, which involves
whole body exposures.  These studies indicate that naphthalene is a
nasal toxicant in rodents at low experimental concentrations.

In a 90-day dermal toxicity study in the rat, effects were noted only at
the high dose of 1000 mg/kg/day. Because effects were seen only at the
limit dose, dermal toxicity is not likely a concern.

Based on an overall review of the database there was evidence of
neurotoxicity at the port of entry (e.g., loss of olfactory neurons
following inhalation exposure).  Hunched posture and decreased motor
activity following oral treatment were also reported, however, these
effects were secondary  to a high dose bolus gavage administration in
the oral toxicity studies.  Although decreased brain weights in female
mice were reported in a published study (Shopp et al. 1984, this effect
was not observed in male mice or rats of any sex, not supported by the
NTP mouse oral study.  No behavioral or neurohistopathological effects
were noted in any available study that included these measurements.

 There was no evidence of developmental toxicity in the rat or rabbit.  

The toxicological (test guideline) database for naphthalene, a non-food
use pesticide, is considered complete.  Although there is no
reproductive study on naphthalene, it is not required for this nonfood
use pesticide.  In the case of the risk assessment following oral
exposure, an extra uncertainty factor of 10 has been applied to the
chronic RfD to account for extrapolation from subchronic to chronic oral
exposure, in addition to the 100-fold uncertainty factor applied to
account for inter and intraspecies differences.  The composite
uncertainty factor of 1000-fold would address the lack of reproductive
toxicity data. 

The results of mutagenicity studies indicate that naphthalene was
negative for gene mutations in bacteria, micronuclei induction in mice,
DNA damage in primary rat hepatocytes, and mutation at the HGPRT or TK
loci in human lymphoblastoid cells.  The few positive results were
limited to effects on sister chromatid induction and chromosomal
aberrations in vitro in Chinese hamster ovary.  Naphthalene undergoes
extensive oxidative metabolism to form naphthoquinones, which are
thought to generate reactive oxygen species.  It is possible that the
reactive oxygen species may result in DNA damage.

In chronic inhalation studies, carcinogenic effects have been observed
in both rats and mice following inhalation exposure. In the rat study,
nasal tumors included neuroblastomas of the olfactory epithelium and
adenomas of the respiratory epithelium.  Female mice exhibited increased
incidences of alveolar/bronchiolar adenomas, and adenomas and carcinomas
combined. The carcinogenic and noncarcinogenic potential of naphthalene
is currently undergoing review by EPA Integrated Risk Information System
(IRIS).  Naphthalene has not been subjected to a full EPA/International
Programme of Chemical Safety (IPCS) framework for the analysis of a
cancer mode of action (MOA) and relevancy of animal MOA to human
carcinogenicity. 

A quantitative human health risk assessment has been performed for oral
and dermal exposure routes.  An inhalation quantitative cancer risk
assessment or derivation of an inhalation reference concentration (RfC)
for the nonfood pesticidal uses of naphthalene was not performed in this
assessment.  This is because HED has determined that it would not be
accurate at this time to quantify human health risk estimates for
non-cancer and cancer inhalation exposures to naphthalene using standard
default procedures because of the notable differences in respiratory
toxicity and metabolism between rodents and primates. As mentioned
above, there is support from published studies and ongoing research on
naphthalene that indicate that risk estimates, factoring in known
species differences between rodents and humans (including humans) in
metabolism and respiratory toxicity, would be considerably less than
those using default procedures.  

The primary adverse outcome reported in the available studies using
rodents (rats and mice) exposed to naphthalene by the inhalation route
is respiratory tract (nose and lung) tumors.  Naphthalene clearly
induced nasal tumors (adenomas and neuroblastomas) in rats. In mice,
there was also some evidence of lung tumors in female mice, but this was
less convincing than the tumor response in rats. The nasal tumors in
rats was associated with cytotoxicity.  Inflammation, degeneration,
metaplasia, hyperplasia occur before nasal tumors.  Cytotoxicity and
regenerative proliferation is a plausible mode of action for
naphthalene-induced respiratory effects.  Studies are ongoing to further
investigate this mode as well as the involvement of different CYP
isoforms, different naphthalene metabolites, genotoxicity and reactive
oxygen species.

 

There is available research indicating that metabolic activation by
Cytochrome P-450 (CYP) to naphthalene-1,2-oxide is a required step for
naphthalene’s respiratory toxicity (unmetabolized naphthalene is not
the cause of the cytotoxicity or tumors) and that there are notable
species differences in respiratory effects and in the metabolism (i.e.,
stereoselectivity of metabolite formation, CYP expression) of
naphthalene between rodents and primates. Details on the metabolism of
naphthalene are presented in Section 3.0.  Mice are more sensitive to
pulmonary toxicity from naphthalene, whereas the rat is more sensitive
to nasal toxicity associated with naphthalene exposure.  This apparent
species difference to naphthalene toxicity may be related to species
difference in metabolism, deposition and the anatomy of  respiratory
system.  Available research to date indicates that the metabolism
pathway in rodents is more active than in primates including humans
(i.e., primates have a slower rate of formation of the active
metabolite). Levels of CYP-associated metabolism of naphthalene in
rodents are about 10-100X greater than measured in the lungs of 
nonhuman primate and humans (Buckpitt 2005).  The low rates of
naphthalene metabolism observed in human and monkey lung suggest that
rodents do not accurately predict human pulmonary response to
naphthalene (Baldwin 2004).  Nasal CYP expression in monkeys is
significantly lower than the rat (Baldwin 2004), and there is ongoing
research to further examine aspects of nasal metabolism of naphthalene
in rodents and primates.

Although rodents are most likely to be more susceptible to
naphthalene’s respiratory effects (cytotoxicity and tumors) than
humans, the human relevance of the rodent respiratory tract tumors is
not clear at this time.  The issue of whether naphthalene poses a human
health concern at ambient exposures will be informed to large degree by
an explanation of the process by which naphthalene is absorbed,
distributed, metabolized, and eliminated by the body (pharmacokinetics).
The pharmacokinetic (PK) model that will quantify the species difference
is not available now, but is forthcoming in approximately 2-3 years.

 

 Because rodents are likely more susceptible to naphthalene’s
potential respiratory effects than humans, it would be inaccurate to
quantify non-cancer and cancer inhalation risks in humans based on
default methods which do not incorporate the critical metabolic and
dosimetric differences between primates and rodents; to do so would
likely result in inaccurate  estimates of  human risk.  Studies have
demonstrated that models that incorporate species differences in gas
dosimetry (anatomical, physiological,  biochemical and biophysical
aspects) reveal that human nasal tissue dosimetry is significantly less
susceptible to gas exposures than comparable rodent tissue (Andersen et
al. 2000; Frederick et al. 1998; 2002).  Thus, no quantification of
either non-cancer or cancer inhalation risks to humans is provided in
this assessment.

OPP  considered a hierarchy of available information on naphthalene
(metabolism, toxicity) and approaches (e.g., default RfC  and cancer
methodology, PBPK models) and considers the most scientifically reliable
approach to be one that is more integrative of all the available
information relating to dosimetry, species metabolic differences,
pharmacokinetic and pharmacodynamic uncertainties, and one that
incorporated critical research currently in progress on naphthalene. 
This integrative approach would provide a more accurate approach to
characterize inhalation risk to naphthalene.   OPP has characterized the
inhalation toxicity hazards and then directly compared anticipated human
exposure to naphthalene with 1) the doses found to result in no adverse
effects in rodents (NOAELs) and 2) the doses found to result in toxic
outcomes in rodents (LOAELs). That is, the levels (mg/m3) of naphthalene
measured in a study simulating naphthalene-based mothball use inside a
home (and ambient levels of naphthalene in homes where naphthalene-based
mothballs may or may not have been used) were compared directly to the
NOAELs and LOAELs identified in the rodent inhalation studies. This
comparison is informational and provides a sense of the difference
between expected ambient levels of naphthalene that humans may be
exposed to and the levels that cause no effect, as well as a toxic
effect, in rodents.

The detailed characterization of the uncertainties associated with using
rodent studies to estimate inhalation risk to humans is found in Section
3.5 of this document. The comparison of ambient naphthalene levels to
NOAELs and LOAELs can be found in Section 5.4.1 and are also presented
below in this Executive Summary [Residential Postapplication
(Inhalation)].

Dietary Exposure

There are no agricultural or any food related pesticide uses of
naphthalene.   Therefore, no dietary exposure from food is expected. 
However, there is potential for drinking water exposure due to the
outdoor uses of naphthalene. Using a screening modeling tool (FIRST),
EFED calculated peak and annual average surface water Estimated
Environmental Concentrations (EEC). These values represented the
high-end use rate of naphthalene on ornamentals and were used to conduct
unrefined acute and chronic dietary (water only) risk assessments using
DEEM-FCID™. 

 The acute and chronic risk estimates were found to be well below the
100% Reference Dose (RfD) level of concern. Overall dietary exposure to
naphthalene (pesticidal uses) via drinking water is expected to be
insignificant.

Residential Exposure/Risk

	Residential Handlers (Dermal)

HED has determined that there is potential for short-term exposure in
residential settings during the application process for homeowners who
purchase and use naphthalene-containing products.  Applications of
naphthalene can be made indoors and outdoors and are expected to be
short-term in duration due to the intermittent nature of use associated
with these products. HED anticipates both handler dermal and inhalation
exposure during the application process; however, appropriate inhalation
handler exposure data are not available to assess this scenario,
therefore, only dermal exposure was assessed.

Margins of Exposure (MOEs) for residential handlers were calculated
using standard assumptions and the results of an exposure study,
“Estimation of Homeowner Exposure to LX1298-01 (Naphthalene) Resulting
from Simulated Residential Use as an Insect Repellent,” (MRID
43716501), in which dermal handler exposure data were derived from the
monitoring of a person weighing out and placing mothballs in a closet
and dresser at three different locations. 

Residential handler MOEs (indoor and outdoor) were much greater than 100
and, therefore, not of concern to HED. Overall dermal exposure to
handling naphthalene products, indoors and outdoors, is expected to be
insignificant.

          Residential Postapplication (Inhalation)

HED has determined that there is potential for adult and toddler
inhalation exposure from naphthalene applications made indoors for moth
treatments and animal repellency, and to a lesser extent, outdoors for
animal repellency.  While labels specify that treated indoor areas
should be airtight to be effective, HED anticipates that naphthalene
will volatilize and be inhaled by adults accessing treated areas (i.e.,
containers, dresser drawers, closets, etc.) and by adults and toddlers
that inhabit treated areas exposed to ambient concentrations of
naphthalene. Exposures from accessing treated areas are expected to be
acute (approximately 15 minutes) in duration and exposures from
inhabiting treated areas are short-(<1 month), intermediate- (1-6
months), and long-term (>6 months) in duration.  

Since the data available to date indicate that rodents are more likely
to be susceptible to the respiratory effects of naphthalene than humans,
the use of rodents as a model without application of species scaling
accounting for species differences in dosimetry and metabolism would
likely  result in inaccurate estimates of human risk. Therefore, rather
than quantifying inhalation risks to humans, the levels of ambient
naphthalene measured in the  human exposure study  were compared
directly to the  levels resulting in a 1) no adverse effects in the
rodent studies (NOAELs) and 2) a toxic effect in rodents (LOAELs). This
comparison provides a sense of the difference between actual naphthalene
concentrations that a human may encounter and the doses which elicit
either no adverse response or a toxic response in rodents. 

Anticipated acute and short-term exposures were calculated using
standard assumptions and the results of the aforementioned exposure
study (MRID 43716501).  Inhalation exposure data from the study apply to
exposure durations ranging from 15 minutes (person accessing treated
closets and dresser drawers) to 24 hours (average air concentration
surrounding treated closets, dresser drawers, and beds). Anticipated
acute and short-term exposures to naphthalene in residences are 20X and
30X below the rodent dose (NOAEL) resulting in no adverse effects,
respectively. Anticipated acute and short-term exposures to naphthalene
in residences are 60X and 80X below the rodent dose (LOAEL) resulting in
respiratory toxicity (olfactory epithelium lesions), respectively.

Anticipated intermediate- and long-term exposures were also calculated
using standard assumptions; however, because of the lack of a
naphthalene-specific study of an appropriate duration, a different
exposure study was used to assess these durations of exposure
(Polycyclic Aromatic Hydrocarbon Exposure of Children in Low-Income
Families, Chuang et al., 1999).  This study was conducted to observe
exposures to polycyclic aromatic hydrocarbons (PAHs), including
naphthalene, inside of 24 homes from air, dust, soil, and food. This
study is not specific to intermediate- or long-term exposure durations,
nor does naphthalene necessarily originate from a mothball source;
however, it has been identified as the best data source to account for
naphthalene volatilization and dissipation over time. Due to the
uncertainty associated with the use of an exposure study which is not
specific to the duration assessed, HED selected the most conservative
exposure value (i.e., maximum concentration observed) to represent
intermediate- and long- term exposure levels. Based on the highest
measured naphthalene levels from this study, intermediate-term exposures
to naphthalene in residences are 540X below the rodent dose (NOAEL)
resulting in no adverse health effects. [Note: a NOAEL was not
identified in the chronic inhalation studies (rodents) for long-term
exposure so that comparison has not been done]. Intermediate- and
long-term exposures to naphthalene in residences are 1000X and 5400X
below the rodent dose (LOAEL) resulting in respiratory toxicity
(olfactory epithelium lesions), respectively.

Generally, in the absence of information on kinetics/dynamics, it is
assumed that humans may be 10 times more sensitive than animals (10X
interspecies factor). The current research indicates that humans are
less sensitive than rodents because of differences in rate of
bioactivation of naphthalene as well as anatomical and physiological
differences in the nose and respiratory tract. These critical
differences between primates and rodents have not been accounted for in
this assessment. Thus, with consideration of differences in dosimetry
and species metabolism of naphthalene, the margins of exposure for human
inhalation risk assessment are likely larger than the differences
calculated here between the rodent NOAELs and LOAELs and the ambient
naphthalene levels. 

Studies determining the differences in nasal metabolism of naphthalene
between rodents and primates are part of ongoing research.  There are no
data to indicate that humans have a slower rate of clearance, but if
they did, then there would be a longer time for humans to produce the
active metabolite.  These issues are being addressed in current
pharmacokinetic model research. 

Residential Postapplication (Episodic Ingestion)

	

HED has determined there is potential that a toddler may ingest
formulations used for indoor or outdoor treatments of naphthalene.  In
order to assess this exposure route, HED estimated the risk of a toddler
ingesting a single mothball.   In addition, HED estimated the amount of
a single mothball that a toddler could ingest to result in a MOE = 100.
While labels specify that indoor moth treatments be made in airtight
containers, it is assumed that a toddler could potentially access these
areas and ingest naphthalene products. Incident data indicate that
ingestion of naphthalene by children primarily occurs by accessing
products labeled for indoor use.

Toddler episodic ingestion of one naphthalene mothball results in a MOE
< 100 (MOE=0.32) and, therefore, is of concern to HED.  An oral dose of
0.5 mg/kg/day would be required to result in a MOE = 100.  This dose is
equivalent to toddler episodic (incidental) ingestion of 0.32% of one
mothball (7.5 of 2350 total mg). While it is not expected that a toddler
would intentionally ingest an entire mothball, that scenario cannot be
completely discounted.

Aggregate Risk

An aggregate risk assessment for all expected routes of exposure was not
performed as there is no common toxicity among all the routes of
exposure. A short-term aggregate risk assessment could be performed by
combining short-term incidental oral exposure and average/background
dietary (in this case drinking water) exposures. However, a short-term
aggregate risk assessment was not performed for naphthalene since the
short-term incidental oral exposure risk estimate alone exceeds the
level of concern and combining with other routes of exposure would only
further exceed the level of concern.

Occupational Exposure/Risk

Naphthalene moth repellant products are not registered for occupational
use and, therefore, occupational exposure and risk is not anticipated
and has not been assessed.

Epidemiology Studies 

Three studies were submitted and reviewed by HED which explored the
possible association between exposure to components of jet fuel,
including naphthalene, and incident cancer among both private and
military aerospace personnel. An additional recently published
epidemiology study concerning the association between non-occupational
exposure to naphthalene as a component of mothballs and non-Hodgkin’s
lymphoma (NHL) is also included in this review.  

Three of the four studies utilized an ecologic exposure assessment
method (indirect exposure method) and evaluated exposure to jet fuel in
association with cancer.  The question HED is addressing concerns
exposure to naphthalene and adverse health outcomes.  Given the
non-specific exposure measure (jet fuel) and the potentially significant
exposure misclassification reflected in these three studies, inference
concerning the association between naphthalene exposure and incident
cancer is severely limited based upon these studies alone. These studies
are considered non-informative to the current naphthalene risk
assessment and characterization.

The finding of a 2-fold increased risk of non-Hodgkins lymphoma among
women in upstate New York in a study of non-occupational exposure to
mothballs is suggestive of a possible association. However, as it is not
known if the mothballs in this study were those containing naphthalene.
This study does not contribute to the current naphthalene risk
assessment and characterization.

Incident Reports

In order to complete the incident report for naphthalene (M. Hawkins and
H. Allender, D336085), four databases were consulted for poisoning
incident data.  These include: OPP Incident Data System (IDS), Poison
Control Centers (PCC), California Department of Pesticide Regulation,
and National Institute of Occupational Safety and Health’s Sentinel
Event Notification System for Occupational Risks (NIOSH SENSOR).  The
summary findings from the incident report for the period 1993 to 2005
for naphthalene are:

Naphthalene produces a higher proportion of acutely toxic incidents
requiring medical attention when compared to the composite average of
all other pesticides. There is a pattern of statistically significant
results in cases seen in a health care facility.  This pattern observed
in the combined population (occupational, non-occupational, children) is
largely due to the frequency and severity of pesticide poisoning among
children less than 6 years;

Exposure to children is much higher than a typical pesticide;

Naphthalene PCC data show average results of about 11,647
exposures/year, 133 symptomatic cases/year, and 310 cases/year seen in a
heath care facility; 

No apparent annual trend is evident in the 13 year-span of data
collected; and

NIOSH/SENSOR data indicate that indoor uses of naphthalene are
responsible for a large number of cases. 

The large majority of incidents for children under 6 years of age were
from ingestion of mothball products for indoor use.

Recommendations from the incident report for residential naphthalene use
are as follows:

In order to prevent exposures (oral) to children, actions restricting
the access to the active ingredient should be taken. This could include
packaging changes and other limitations to block children from coming
into contact with the active ingredient.

The reported symptoms to naphthalene exposure include: neurological
(headache, dizziness, and drowsiness/lethargy), gastrointestinal (nausea
and vomiting), ocular (eye pain, irritation, and inflammation, and
lacrimation), respiratory (upper respiratory pain, shortness of breath,
coughing and choking).

Environmental Justice Considerations

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human health risk assessment, in
accordance with U.S. Executive Order 12898, "Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations,"   HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf" 
http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures. 
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by the USDA under the Continuing
Survey of Food Intake by Individuals (CSFII) and are used in pesticide
risk assessments for all registered food uses of a pesticide.  These
data are analyzed and categorized by subgroups based on age, season of
the year, ethnic group, and region of the country.  Additionally, OPP is
able to assess dietary exposure to smaller, specialized subgroups and
exposure assessments are performed when conditions or circumstances
warrant.  Whenever appropriate, non-dietary exposures based on home use
of pesticide products and associated risks for adult applicators and for
toddlers, youths, and adults entering or playing on treated areas
postapplication are evaluated.  Further considerations are currently in
development as OPP has committed resources and expertise to the
development of specialized software and models that consider exposure to
bystanders and farm workers as well as lifestyle and traditional dietary
patterns among specific subgroups.

Review of Human Research

This risk assessment relies in part on data from a study in which adult
human subjects were intentionally exposed to a pesticide or other
chemical.  This study (Appendix B) has been determined to require a
review of its ethical conduct, and has received that review. It was
concluded that there are no regulatory barriers to EPA’s reliance on
this study in its actions under FIFRA (J. Carley, 4/24/07). Another
study involving human subjects (Chuang et al., 1999) used in part in
this assessment, does not meet the regulatory definition of research
involving intentional human exposure and is therefore not required to
undergo ethical review. It was determined that “there are no
regulatory, ethical, or policy barriers” to using this study in the
naphthalene assessment (electronic communication, J. Carley to C. Eiden,
2/20/08).

Ingredient Profile

Naphthalene is used as a moth treatment for the protection of woolen
clothing and as an animal repellant against nuisance vertebrate pests. 
All registered products of naphthalene are intended for residential uses
only.  The moth treatment use is registered for indoor only and is
labeled for treatment of indoor storage areas (containers, drawers, and
storage closets). The animal repellant use is labeled for indoor (attics
and wall voids) and outdoor (around the perimeter of domestic dwellings,
ornamental gardens, flower beds, lawns, or any area to be protected such
as wood piles, utility houses, barns, and trash cans) use.  

Naphthalene is a white, crystalline solid which volatilizes to create a
characteristic odor.  In a sealed container, naphthalene vapors build up
to levels toxic to both the adult and larval forms of many moths
destructive to wool clothing.  In addition, naphthalene’s odor can be
used to repel vertebrate animals.

Naphthalene products for use within the home are formulated as mothballs
or flakes, while outdoor products are formulated as dusts, flakes, and
granules.  Percent active ingredient of indoor-use products range from
99.7-100%, and from 7-99.9% for outdoor-use products.  

Registered labels for indoor, moth treatment use recommend keeping the
product in an airtight space for a minimum of seven days.  Re-treatment
is recommended when the mothballs have dissipated.  Since moths are
active all year, there is the potential for continual treatment indoors.
 One moth control label recommends re-treatment twice per year. 
Re-treatment for indoor/outdoor repellant uses are recommended as needed
to maintain odor intensity.  Hot weather, wind, and rain may diminish
the effectiveness of the product and necessitate re-treatment.   

Naphthalene treatments for indoor moth treatment use and indoor/outdoor
repellant use are labeled for application by hand. 

Summary of Registered Uses

Table 2.1 .  Summary of Registered Naphthalene Uses

Indoor Use

Product	Use Site	Formulation	% Active Ingredient	App. Rate for the Area
to be Treated

ENOZ® Old Fashioned Moth Balls 

(1475-74)	Indoor storage areas (containers and storage closets)	Moth
Ball	99.95	1 ounce per 3 ft3 - 

0.25 lb ai  /  Average Garment Bag (12 ft3)

0.33 lb ai  /  Large Trunk (15 ft3)

1 lb ai       /  Small Closet (50 ft3)

ENOZ® Old Fashioned Moth Flakes 

(1475-75)	Indoor storage areas (containers and storage closets)	Flake
99.95	1 ounce per 3 ft3 - 

0.25 lb ai  /  Average Garment Bag (12 ft3)

0.33 lb ai  /  Large Trunk (15 ft3)

1 lb ai       /  Small Closet (50 ft3)

ENOZ® Cedar Pine Moth Balls

(1475-120)	Indoor storage areas (containers and storage closets)	Moth
Ball	99.85	1 ounce per 3 ft3 -

0.25 lb ai  /  Average Garment Bag (12 ft3)

0.33 lb ai  /  Large Trunk (15 ft3)

1 lb ai       /  Small Closet (50 ft3)

Chaperone Squirrel and Bat Repellant 

(2724-685)	Attics and wall voids

and

Indoor storage areas (containers and storage closets)	Flake	100	1 pound
per 400 ft3 

1 ounce per 3 ft3 - 

0.25 lb ai  /  Average Garment Bag (12 ft3)

0.33 lb ai  /  Large Trunk (15 ft3)

1 lb ai       /  Small Closet (50 ft3)

Dr. T’s Rabbit, Squirrel, Bat & Bird Repellant

(58630-2)	Attics and wall voids	Flake	99.95	1 pound per 400 ft3

I-Ching Naphthalene Moth Balls 

(80305-1)	Indoor storage areas (containers and storage closets)	Moth
Ball	99.9	1 ounce per 3 ft3 - 

0.25 lb ai  /  Average Garment Bag (12 ft3)

0.33 lb ai  /  Large Trunk (15 ft3)

1 lb ai       /  Small Closet (50 ft3)

IMS Old Fashioned Moth Balls 

(81433-6)	Indoor storage areas (containers and storage closets)	Moth
Ball	99.95	1.5 ounces per 3 ft3 -

0.37 lb ai / Average Garment Bag (12 ft3)

0.36 lb ai / Large Trunk (15 ft3)

1.1 lb ai / Small Closet (50 ft3)

Moth Avoid Brand Traditional Moth Balls

(83424-2)	Indoor storage areas (containers and storage closets)	Moth
Ball	99.7	1 ounce per 3 ft3 - 

0.25 lb ai  /  Average Garment Bag (12 ft3)

0.33 lb ai  /  Large Trunk (15 ft3)

1 lb ai       /  Small Closet (50 ft3)

Outdoor Use

F&B Rabbit and Dog Chaser

(4-465)	Soil treatment on ornamental plants, paved areas	Dust	 15	0.45
lb ai/ treated area (3 lb container)

(assuming entire contents used to treat area)

ENOZ® Skat!

(1475-146)	Around the perimeter of ornamental plants	Flake	99.45	2.5 lb
ai/ treated area (2.5 lb container)

(assuming entire contents used to treat area)

Dr. T’s Snake-A-Way Snake Repellant

(58630-1)	Around the perimeter of domestic dwellings (outdoors), wood
piles, utility houses, barns, trash cans, flower beds, and gardens
Granule	7	0.28 lb ai/treated area (4 lb container) 

2 lb ai/ treated area  (28 lb container)

(assuming entire contents used to treat area)

Dr. T’s Rabbit, Squirrel, Bat & Bird Repellant

(58630-2)	Around the perimeter of ornamental plants	Flake	99.95	4 lb ai/
treated area (4 lb container)

24 lb ai/ treated area (24 lb container)

(assuming entire contents used to treat area)

2.2	Structure and Nomenclature

 

Empirical Formula	C10H8

Common Name	Naphthalene

IUPAC name	Naphthalene

CAS Name	Naphthalene

CAS Registry Number	91-20-3

Chemical Class	Fumigant insecticides

2.3	Physical and Chemical Properties

Table 2.3.  Physiochemical Properties

Parameter	Value	Reference

Molecular Weight	128.17	D322965, D. Rate, 12/20/05

Melting point/range	80.2°C

	pH	NA

	Density	1.162

	Water solubility 	Water: 31 mg / L @25°C (insoluble)

Є221 = 133000

Є286 = 9300

Є312 = 289

	

Hazard Characterization/Assessment

 3.1  Hazard and Dose-Response Characterization

Database Summary

Based on the use pattern, the standard toxicology database for
naphthalene is complete for assessing dermal and oral exposure risks to
humans. Although standard inhalation rodent toxicity studies are
available, some mechanism studies have raised the issue of notable
species differences (in regard to respiratory toxicity and metabolism)
and the applicability of the rodent model without appropriate
dosimentric adjustments and scaling as a approach to estimate human
risk.  The mechanism data are not complete and ongoing research, when
completed, is expected to refine the potential toxicity hazard
associated with human exposure to naphthalene via inhalation. No
additional test guideline data are being required at this time.

Sufficiency of studies/data

Based on the use pattern, the toxicology database for naphthalene is
complete and adequate for dermal and oral risk assessment.  Studies
include the following:

Acute Neurotoxicity:  acute oral neurotoxicity study in the rat

Subchronic Neurotoxicity:  subchronic inhalation neurotoxicity study in
the rat

Developmental:  National Toxicology Program (NTP) rabbit and rat
developmental studies

Subchronic oral:   90-day rat and mouse studies;  published mouse study

Subchronic inhalation:  13 week rat study; 90-day neurotoxicity in the
rat study

Chronic inhalation:  NTP rat and mouse studies

Mutagenicity: battery of mutagenicity assays

Metabolism:  several published studies

Dermal Toxicity – 90-day dermal toxicity in the rat

Mode of action, metabolism, toxicokinetic data

The Registrant did not provide mode of action data. However, several
published literature studies have addressed the role of
cytochrome-P450-associated metabolic intermediates as the potential
underlying mode of action of naphthalene-induced respiratory tract
neoplastic and nonneoplastic lesions.  Buckpitt et al. (2002) identified
various metabolic intermediates of naphthalene, in particular,
1,2-naphthalene oxide, 1,2-naphthoquinone, and 1,4-naphthoquinone, that
are involved in the formation of respiratory tract lesions in rodents. 
These metabolites are considered reactive and can covalently bind to
various cellular proteins resulting in cellular damage.

A further mechanism for 1,2-naphthoquinone has also been suggested
(Bolton et al. 2000).  This mechanism involves the enzymatic and
nonenzymatic redox cycling of the quinone with subsequent generation of
reactive oxygen species (ROS) and lipid peroxidation, resulting in
cellular damage.  

Species susceptibility to naphthalene-mediated respiratory tract
toxicity has been recognized (Buckpitt et al. 1992; 1995).  With regard
to lung toxicity, the mouse is considered more susceptible than the rat.
 This difference has been correlated to the higher rates of formation of
the epoxide 1R,2S-naphthalne oxide in lung microsomes and isolated
airways of mice compared to rats (Buckpitt et al. 1992; 1995).  With
regard to acute nasal injury to naphthalene, the rat is considered to be
the most sensitive (Plopper et al. 1992).  These data suggest
differences in  metabolism and toxicity and species susceptibility to
naphthalene.   

Toxicological Effects

Acute toxicity

Naphthalene is acutely toxic in the rat via the oral (Category III) and
inhalation (Category II) routes of exposure.  In the rabbit, it is a
moderate acute dermal toxicant   (Category  III).   It is a moderate
(Category III) skin and eye irritant in the rabbit.  Naphthalene is not
a dermal sensitizer in guinea pigs. 

Cataracts  

Cataracts have been reported in several published studies (ATSDR 2005)
on rabbits, rats and mice; however, these effects were noted  at high
oral doses (greater than or equal to 500 mg/kg/day).  Cataracts have not
been observed at lower oral doses in the NTP rat and mouse studies or in
the published mouse study (Shopp et al 1984). Although there have been
reports of humans exhibiting cataracts following oral, dermal or
inhalation exposure, exposure levels were not identified and there are
no well conducted epidemiology studies verifying these reports (ATSDR
2005).

Hemolytic Anemia 

A number of  reports have documented hemolytic anemia in humans
following acute oral or inhalation exposure to naphthalene, however,
information on dose levels were not available (ATSDR 2005).  There was
no evidence of hemolytic anemia in rats or mice (ATSDR 2005). 

Subchronic oral 

ment at doses ≥ 200 mg/kg/day.  These studies are discussed below.

The most sensitive effect noted in a subchronic (13-week) rat study (NTP
1980a) was decreased body weight gain.  Body weight gain decrements
exceeding 10% were observed in both males and females administered 200
or 400 mg/kg/day.  At the highest dose level, clinical signs included
lethargy, hunched posture, and roughened hair coats.  High-dose rats
also exhibited marginal decreases in hemoglobin and hematocrit levels. 
Males in this group also displayed a moderate increase in neutrophils
and decrease in lymphocytes.  Minimal to moderate renal histological
lesions (renal cortical focal lymphocytic infiltrate and focal tubular
or cortical diffuse regeneration) were noted in male rats treated with
200 mg/kg/day and 400 mg/kg/day.  There were no renal lesions in treated
females, however, several females treated with 400 mg/kg displayed
moderate lymphoid depletion of the thymus.  No effects were observed at
100 mg/kg/day (NOAEL).

Clinical signs of toxicity, including rough hair coats and lethargy,
were observed in male and female B6C3F1 mice exposed to 200 mg/kg/day
(high dose) for 13 weeks (NTP 1980b).  The signs were transient and
noted only during weeks 3 and 4.  No effects were observed at 100
mg/kg/day (NOAEL).  

No clinical signs of toxicity were noted in a published 90-day study in
CD-1 mice administered naphthalene at dose levels of naphthalene up to
133 mg/kg/day (Shopp et al. 1984). No immunological effects were
detected following application of an immunotoxicity test battery.  There
were no biologically significant effects on mortality or body weights. 
Absolute weights of the brain, liver and spleen were statistically
significantly decreased (>10%) in the high-dose females (133 mg/kg, the
LOAEL).  Relative spleen weights were significantly decreased by 24% in
these females.  However, no histological examinations were performed on
organs to assess significance of organ weight changes.  No effects were
noted at 53 mg/kg/day (NOAEL).

Shopp et al. also presented results of a 14-day study on naphthalene in
the same strain of mouse.  Mortality was noted in the high-dose (267
mg/kg/day) males and females.  Mean body weight in the high-dose males
was significantly decreased by 13% (data were insufficient to calculate
overall bodyweight gain decrement).  Organ weight changes at the high
dose included decreased absolute thymus weights (males), decreased
absolute and relative spleen weights (females), and increased absolute
and relative lung weights (females).  However, histological examination
of these organs was not performed to assess significance of organ weight
alterations.  No effects were seen at 53 mg/kg/day (NOAEL).  

Nasal lesions (inhalation)

Naphthalene has been well-studied by the inhalation route of exposure,
including nose-only (4-week, 13-week, and subchronic 90-day
neurotoxicity) and chamber studies (2 year) in rodents.  These studies
indicate that naphthalene is a nasal toxicant at low concentrations, and
that nasal lesions are the most sensitive endpoint via this route of
exposure.  Similar nasal lesions were noted in these studies.

Nasal nonneoplastic lesions noted in the 4-week (nose-only) inhalation
study (MRID 42934901) in the rat included slight disorganization,
rosette formation, basal cell hyperplasia, erosion, atrophy, and
degenerate cells in the olfactory epithelium, loss of Bowman’s glands,
hypertrophy of respiratory epithelium, rosette formation in the septal
organ of Masera and fusion of turbinates.  Based on increased incidence
and severity the LOAEL is 10 ppm and the  NOAEL is 3 ppm. 

Moderate degenerative changes in the olfactory epithelium, moderate to
marked atrophy of olfactory epithelium, minimal to moderate erosion of
olfactory epithelium, moderate hyperplasia of basal cells in olfactory
epithelium, moderate rosette formation in olfactory epithelium, loss of
Bowman’s glands, hypertrophy of respiratory epithelium were noted in a
13-week (nose-only) inhalation study (MRID 42835901) in the rat
following exposure to 10 or 60 ppm naphthalene.  Similar findings were
noted in rats at the low dose (2 ppm), but these changes were minimal. 
However, several of the low-dose rats exhibited some loss of Bowman’s
glands.   The LOAEL is 2 ppm based on minimal nasal lesions and some
loss of Bowman’s gland.  A NOAEL was not identified; however, a NOAEL
of 1 ppm was identified in a similar inhalation study (MRID 44856401)
conducted in the same laboratory (study discussed below).  This similar
study is a co-critical study and used to derive a NOAEL for nasal
lesions following nose-only exposures.

The results of the 13-week study (MRID 42835901) were supported by a
similarly conducted subchronic 90-day inhalation rat neurotoxicity study
(MRID 44856401) in the same laboratory.    Findings included slight
hyperplasia of the respiratory/transitional epithelium in the rostral
region, slight to moderate atrophy/disorganization of the olfactory
epithelium, slight to moderate hyperplasia of the olfactory epithelium,
slight rosettes of the olfactory epithelium, slight inflammatory exudate
in the airway, moderate erosion/necrosis of the olfactory epithelium,
and loss of Bowman’s glands and olfactory nerve fibers in rats exposed
to 10 or 60 ppm naphthalene.  There were no apparent lesions of
toxicological significance in rats treated with 1 ppm naphthalene (LOAEL
= 10 ppm; the NOAEL = 1 ppm). There were no treatment-related effects on
brain weight or neuropathology or clear evidence of direct behavior
effects.   

In a NTP chronic inhalation (chamber) study in the rat (NTP 2000) nasal
lesions were observed at all concentration levels (10, 30, or 60 ppm)
and included atypical (basal cell) hyperplasia, atrophy, chronic
inflammation, and hyaline degeneration of the olfactory epithelium;
hyperplasia, squamous metaplasia, hyaline degeneration, and goblet cell
hyperplasia of the respiratory epithelium; and glandular hyperplasia and
squamous metaplasia. The severities of olfactory epithelial and
glandular lesions increased with increasing exposure concentration. 
Survival in the exposed groups was similar to chamber controls.  Mean
body weight gains in the high-dose (60 ppm) males were significantly
decreased throughout the study.  The LOAEL is 10 ppm based on nasal
lesions, and a NOAEL was not identified.

Nasal lesions were also observed in a NTP chronic inhalation chamber
study (NTP 1992) in the mouse at all concentration levels (10 and 30
ppm) and consisted of increased incidence and severity of chronic
inflammation, metaplasia of the olfactory epithelium, and hyperplasia of
respiratory epithelium.  There was also increased incidence and severity
of chronic inflammation in the lung.  The LOAEL is 10 ppm, and a NOAEL
was not identified.

Dermal

In a 90-day dermal toxicity study in the rat (MRID 40021801), effects
were noted only at the high dose of 1000 mg/kg/day. These effects
included excoriated skin and papules in both sexes; atrophy of
seminiferous tubules in the males; and nonneoplastic lesions in the
cervical lymph node (hyperplasia), liver (hemosiderosis), thyroid
(thyroglossal duct cysts), kidneys (pyelonephritis), urinary bladder
(hyperplasia) and skin (acanthosis, hyperkeratosis) in females.  The
NOAEL was 300 mg/kg/day.  These results indicate that dermal toxicity is
of low concern.

Neurotoxicity

Based on an overall review of the database (including acute oral
neurotoxicity study and a subchronic inhalation neurotoxicity study; 
Section 3.3), there was evidence of  neurotoxicity  at the port of entry
(i.e., loss of olfactory neurons following inhalation exposure). 
Although hunched posture and decreased motor activity following oral
treatment were reported, these effects were secondarily to a high dose
bolus gavage administration in the oral toxicity studies. There were no
effects on brain weights or brain neurohistopathology in any of the NTP
studies with naphthalene.  Decreased brain weights in female mice were
reported in a published study (Shopp et al. 1984), however, this effect
was not observed in rats (either sex) or in male mice, and not supported
by the NTP mouse oral study.   No behavioral or neurohistopathological
effects were noted in any study.   

Mutagenicity

Three genetic toxicology studies, in accordance with pre-1991 FIFRA
requirements, were submitted.  Results show that naphthalene was
negative for gene mutations in bacteria (Salmonella typhimurium),
micronuclei induction in mice and DNA damage in primary rat hepatocytes.
 Accordingly, these studies satisfy the pre-1991 FIFRA requirements. 
Since that time, naphthalene was tested as part of the National
Toxicology Program (NTP, 1992) for gene mutations in S. typhimurium, and
was negative.  NTP also found that naphthalene was positive for sister
chromatid (SCE) induction and chromosomal aberrations in vitro in
Chinese hamster ovary (CHO).  Published literature showed that
naphthalene was not mutagenic in bacteria (either Salmonella or
Escherichia coli) or mammalian cells (human lymphoblastoid cells at the
HGPRT or TK loci).  With the exception of the positive in vitro
chromosome aberration and SCE induction studies of NTP, naphthalene was
not active at either endpoint in human lymphocytes.    

Several studies in the open literature show that naphthalene undergoes
extensive oxidative metabolism to form naphthoquinones, which are
thought to generate ROS (superoxide anion radical, hydrogen peroxide,
hydroxyl radical and o-semiquinone anion radicals) via redox cycling
(Bolton, 2000).  A number of investigators have reported evidence of
naphthalene-induced oxidative damage by ROS (reviewed in Stohs, et al.,
2002).   See Section A.3.6.  It is possible that the reactive oxygen
species may result in DNA damage.

Developmental

No evidence of developmental toxicity was evident in the NTP
developmental studies in the rat and rabbit.  In the rat developmental
study, the developmental NOAEL was 450 mg/kg/day (highest dose tested). 
In the NTP main developmental rabbit study, the maternal and
developmental NOAELs were both 120 mg/kg/day (highest dose tested).  In
the NTP range-finding developmental rabbit study, the developmental
NOAEL was 500 mg/kg/day.

Maternal toxicity (persistent clinical signs of lethargy, slow
breathing, rooting behavior, and significant decreases in body
weights/body weight gains and food and water consumption) was apparent
in the developmental rat study (maternal LOAEL = 150 mg/kgday; maternal
NOAEL  = 50 mg/kg/day).  

In the range-finding rabbit developmental study, mortality, decreased
body weights and clinical signs (diarrhea, lethargy) were observed in
maternal rabbits treated with doses ranging from 150 to 500 mg/kg/day.  

Based on available data (rat developmental study, rabbit developmental
study including a range-finder), there is no evidence of developmental
toxicity.  There are no residual uncertainties with regard to in utero
toxicity; and the toxicological database for naphthalene is
substantially complete for a non-food use pesticide.  Although there are
no reproductive toxicity studies, an extra uncertainty factor of 10 has
been applied to exposure scenarios that are based on lifetime exposures
to account for lack of reproductive toxicity and chronic toxicity
studies.

Dose-response

Inhalation (nose-only) toxicity studies on naphthalene have demonstrated
increases in the incidence and severity of nasal lesions with dose, and
time-to-effect dependence, that is, longer-term exposures result in
effects at lower doses than short-term exposures. In the long-term
exposure chamber studies, the LOAELs were 10 ppm; NOAELs were not
identified.  The subchronic inhalation neurotoxicity (nose-only) study
established a NOAEL of 1 ppm.   Dose-related body weight decrement was
noted in the NTP subchronic oral rat study (NOAEL = 100 mg/kg/day).  In
the NTP subchronic mouse study, clinical signs were observed at the
highest dose tested (LOAEL = 200 mg/kg/day; NOAEL = 100 mg/kg/day).  
Dose-related body weight decreases and clinical signs of toxicity were
noted in the NTP developmental rat study (maternal NOAEL = 50
mg/kg/day).  In the 90-day dermal toxicity study in the rat, effects
(atrophy of seminferous tubules in males; various nonneoplastic lesions
in females) were seen only at the limit dose of 1000 mg/kg/day.  The
NOAEL was 300 mg/kg/day.  Therefore, dermal toxicity is of low concern. 
  

3.2    Absorption, Distribution, Metabolism, Excretion (ADME)

Naphthalene undergoes oxidative metabolism by cytochrome P-450
oxygenases resulting in the epoxide 1,2-napthalene oxide (Buckpitt
2002).  The epoxide can spontaneously hydrolyze to naphthols and then
form glucuronic acid or sulfate conjugates.  Alternatively, the epoxide
can be conjugated with glutathione, as mediated by
glutathione-S-transferase.  Through several steps, the glutathionyl
conjugates are converted to mercapturic acids.  The epoxide can also be
enzymatically hydrated by epoxide hydrolase to form
1,2-dihydorxy-1,2-dihydronaphthalene.  The latter compound can then
undergo further reactions (catechol reduction followed by oxidation) to
form 1,2-naphthoquinone.  Figure 1 below depicts the metabolism of
naphthalene and its potential role in the toxicity of naphthalene as
suggested by Buckpitt.  Figure 1 is not meant to be a depiction of the
mode of action of naphthalene. 

FIGURE 1.   Naphthalene Metabolism and Formation of Reactive Metabolites
(Source:  Buckpitt  2002) 

3.3.  Evidence of Neurotoxicity

In inhalation studies, there was evidence of  neurotoxicity  at the port
of entry (i.e., loss of olfactory neurons).  Although hunched posture
and decreased motor activity following oral treatment were reported,
these effects secondary to a high dose bolus gavage administration in
the oral toxicity studies. There were no effects on brain weights or
brain neurohistopathology in any of the NTP studies with naphthalene. 
Decreased brain weights in female mice were reported in a published
study (Shopp et al. 1984), however, this effect was not observed in rats
(either sex) or in male mice, and not supported by the NTP mouse oral
study.   No behavioral or neurohistopathological effects were noted in
any study.

  

The potential neurotoxicity of naphthalene has also been examined in an
acute oral neurotoxicity study in the rat and a subchronic inhalation
neurotoxicity study in the rat.  Neurotoxicity was noted in an acute
oral neurotoxicity study in the rat.  Effects observed on Day 1 in rats
treated with ≥ 400 mg/kg included hunched posture (females), head
shaking behavior (males and females), and decreased motor activity
(males and females).  High-dose (1200 mg/kg) females exhibited elevated
hind quarters and gait abnormalities.  These effects were also noted at
day 7.  All treated males and females displayed increased urination and
defecation on Days 7 and 14.  No treatment-related effects were seen in
landing footsplay or fore- and hind-limb grip strengths on any testing
day.  There was no difference in weight of the brain and pituitary
between the control and treated groups.  Gross and microscopic
examinations of central and peripheral nervous tissue did not reveal any
treatment-related effects. The LOAEL for neurotoxicity of naphthalene in
rats was 400 mg/kg bw based on clinical signs. The NOAEL was not
established.   As mentioned above, these neurotoxic effects most likely
occur secondarily to a high dose bolus gavage administration.  

Lethargy and hunched posture were apparent in F344 rats administered 400
mg/kg/day naphthalene by gavage for 90 days (NTP 1980a).   These
neurotoxic effects most likely occur secondarily to a high dose bolus
gavage administration.   Lethargy and rough hair coat were observed in
B6C3F1 mice given a gavage dose of 200 mg/kg/day naphthalene for 90 days
(NTP 1980b); however, these signs were transient and occurred during
week 3 and 4 of the study.  No clinical signs were reported in a
published 90-day CD-1 mouse study (Shopp et al. 1984).  

Apparent loss of olfactory nerve fibers were noted in the (nose-only)
neurotoxicity study in male and female rats exposed to 10 and 60 ppm
naphthalene.  As mentioned above,  the nerve fiber loss most likely is
related to the localized, irritative portal-of-entry effects of
naphthalene.  The continuous nose-only exposure is not a likely exposure
scenario given the use pattern of naphthalene.   In the NTP chronic
(exposure chamber) inhalation study in the rat, neuroblastomas occurred
in female rats exposed to 10, 30 or 60 ppm naphthalene, while in males
these occurred at 30 or 60 ppm naphthalene.

                      3.3.1 Developmental Toxicity Studies

Well-conducted developmental oral toxicity studies in the rat (NTP 1991)
and the rabbit (1992) were available.  The data provided no indication
of developmental toxicity  in the rat or rabbit.  or increased
quantitative or qualitative susceptibility of rat or rabbit fetuses to
in utero exposure to naphthalene.  Developmental NOAELs are higher than
maternal NOAELs.  

In the rat developmental study, the maternal LOAEL was 150 mg/kgday
based on persistent clinical signs of lethargy, slow breathing, rooting
behavior, and significant decreases in body weights/body weight gains
and food and water consumption.  The maternal NOAEL was 50 mg/kg/day. 
The developmental NOAEL is 450 mg/kg/day (highest dose tested).

In the NTP developmental rabbit study, the maternal and developmental
NOAELs were 120 mg/kg/day (highest dose tested).

                 	 3.3.2  Reproductive Toxicity Study

There are no reproductive toxicity studies on naphthalene, a non-food
use pesticide.  

    	 3.3.3  Additional information from Literature Sources

Published literature on the metabolism and mechanism of action of
naphthalene have been discussed in respective sections of this risk
assessment.  

                         3.3.4  Recommendation for a Developmental
Neurotoxicity Study

As discussed in Section 3.3, neurotoxicity observed in several studies
was related either to localized irritation on the nasal olfactory
epithelium (portal of entry in the inhalation studies), or secondary to
high dose bolus gavage administration in the oral toxicity studies.
There were no effects on brain weights or brain neurohistopathology in
any of the NTP studies with naphthalene.  Decreased brain weights in
female mice were reported in a published study (Shopp et al. 1984),
however, this effect was not observed in male mice or in rats of either
sex, and  not supported by the NTP mouse oral study. No behavioral or
neurohistopathological effects were noted in any study.  Based on the
rat developmental study, and the rabbit developmental (main and
range-finding studies), there was no evidence of developmental toxicity
in the rat or rabbit.    A developmental neurotoxicity study is not
required for naphthalene.  

 3.4 Hazard Identification and Toxicity Endpoint selection

 Acute Reference Dose (aRfD) – Females age 13-49

No appropriate endpoint identified for this population.

Acute Reference Dose (aRfD) – General Population

Study Selected:   Acute Oral Neurotoxicity Study - rat (OPPTS 870.6200a)

MRID No.:  44282801

Dose and Endpoint for Establishing aRfD:  LOAEL = 400 mg/kg based on
hunched posture in females, head shaking in males and females, and
reduced motor activity in males and females.  These clinical signs are
considered to be secondary to bolus administration of a high dose of
naphthalene.  A NOAEL was not identified.

Comments on Study/Endpoint/Uncertainty Factors:  The endpoint selected
occurred following  a single exposure and is relevant for all
populations, including infants and children.  The extrapolated NOAEL (40
mg/kg/day) is comparable to the NOAEL of 50 mg/kg/day identified in
pregnant female rats (NTP developmental rat study).   The data (Day 1)
were not suitable for benchmark dose (BMD) analyses because of the lack
of smooth dose response (i.e., either flat or near maximal response). 
An UF of 1000 was applied to account for a lack of a NOAEL (10x),
inter-species extrapolation (10x) and intra-species variations (10x).   

	Acute RfD =    400 mg/kg/day (LOAEL)   = 0.40 mg/kg/day

			              1000(UF)

Chronic Reference Dose 

Study Selected:     NTP  90-Day Study in the Rat  (1980)

[Subchronic Toxicity Study:  Naphthalene (C52904), Fischer 344 rats. 
Battelle's Columbus Laboratories, Columbus, OH.  Report to the U.S.
Department of Heath and Human Services, National Toxicology Program.]

MRID No.:   n/a 

Dose and Endpoint for Establishing the RfD:  NOAEL = 100 mg/kg/day. 
LOAEL = 200 mg/kgday, based on decreased body weights/body weight gains.
   

Comments on Study/Endpoint/Uncertainty Factors:  The endpoint is based
on the most sensitive effect noted in the subchronic oral rat study. 
The study is supported by the NTP subchronic oral mouse study that
indicated a clear NOAEL of 100 mg/kg/day.  An UF of 1000 was applied to
account for extrapolation from subchronic to chronic exposure and
chronic toxicity studies (10x), inter-species extrapolation (10x) and
intra-species variations (10x).   This composite factor of 1000 was also
address the lack of a reproductive toxicity study for this nonfood use
pesticide.

	Chronic RfD =    100 mg/kg/day (NOAEL)   =0.10 mg/kg/day

			              1000(UF)

Incidental Oral Exposure (Short-Term) 

Study Selected:    NTP Developmental Study in the Rat (NTP  1991):

[Final Report on the Developmental Toxicity of Naphthalene in
Sprague-Dawley (CD) rats.  U.S. Department of Heath and Human Services,
National Toxicology Program.]

MRID No.:   n/a

Dose and Endpoint for Risk Assessment:  The incidental oral endpoint is
based on maternal effects observed in a developmental rat study, and is
the appropriate duration for short-term exposure scenarios.  Maternal
toxicity included persistent clinical signs of lethargy, slow breathing,
rooting behavior, and significant decreases in body weights/body weight
gains and decreased food and water consumption.  The LOAEL is 150
mg/kg/day and the NOAEL is 50 mg/kg/day.  

UF =100x (10x interspecies extrapolation, 10x intraspecies variability)

Comments on Study/Endpoint/Uncertainty Factors:  The  endpoints are
considered relevant to children.  The NOAEL of 50 mg/kg/day is also
considered protective since it is based on the pregnant female rat
(treatment was from GD 6-15) which may be more sensitive than
nonpregnant female rats and male rats after 90-day treatment.  In this
regard, a NOAEL of 100 was identified in both the  NTP 13-week B6C3F1
mouse study and the NTP rat study. The results of a  14- and 90-day
published study on CD-1 mice (Shopp et al. 1984) established a  NOAEL of
53 mg/kg/day.  

Dermal Absorption

There are no in vivo dermal absorption studies.  However, a dermal
absorption factor is not needed since there is an acceptable 90-day
dermal toxicity study in the rat.

Dermal Exposure (Short-Term) 

Study Selected:  90-Day Dermal Toxicity Study in the Rat 

MRID No.:  40021801

Dose and Endpoint for Risk Assessment:  The NOAEL of 300 mg/kg/day from
a 90-day dermal toxicity study in the rat is selected for dermal risk
assessment.  The LOAEL of 1000 mg/kg/day is based on atrophy of
seminiferous tubules in males, and nonneoplastic lesions in the cervical
lymph node (hyperplasia), liver (hemosiderosis), thyroid (thyroglossal
duct cysts), kidneys (pyelonephritis), urinary bladder (hyperplasia) and
skin (acanthosis, hyperkeratosis) in females.  

UF =100x (10x interspecies extrapolation, 10x intraspecies variability)

Comments on Study/Endpoint:  Intermediate- and long-term dermal
exposures are not anticipated.  The dermal risk assessment for
short-term exposure scenarios is conservative since it is based on a
90-day study. 

Inhalation Exposure (All durations)

At this time, dose and endpoints have not been selected for the purposes
of estimating human inhalation risk. See Section 3.5 below.

Recommendation for Aggregate Exposure Risk Assessments

ose only rat study;  13 week nose-only rat study;  subchronic
neurotoxicity rat study;  and chronic exposure chamber rat NTP study) at
≥ 10 ppm naphthalene.  Body weight data in the NTP mouse study was
presented only graphically.    The 90-day dermal toxicity study in the
rat revealed toxicity only at very high dose level (1000 mg/kg/day) that
included atrophy of seminiferous tubules in males, and various
nonneoplastic lesions in females (skin, lymph nodes, liver, thyroid,
kidneys, urinary bladder and skin).  There were no effects on body
weights in the dermal study.    Based on the available data, an
aggregate exposure risk assessment is not supported as there is no
common toxicity among all routes of exposure.  

Classification of Carcinogenic Potential

In the NTP chronic studies, carcinogenic effects have been observed in
both rats and mice following inhalation exposure. 

In the rat, nasal tumors included neuroblastomas of the olfactory
epithelium and adenomas of the respiratory epithelium.  There was also
an increase in the incidences of adenoma of the respiratory epithelium. 
The NTP concluded that “under the conditions of this 2-year inhalation
study, there was clear evidence of carcinogenic activity of naphthalene
in male and female F344/N rats based on increased incidences of
respiratory epithelial adenoma and olfactory epithelial neuroblastoma of
the nose.”  

In the mouse study, male mice had statistically significant increased
incidences of liver adenomas, and adenomas and carcinomas combined. 
Female mice exhibited increased incidences of alveolar/bronchiolar
adenomas, and adenomas and carcinomas combined. 

The NTP concluded that “under the conditions of this 2-year inhalation
study, there was no evidence of carcinogenic activity’ of naphthalene
in male B6C3F1 mice exposed to 10 or 30 ppm.  There was “some evidence
of carcinogenic activity” of naphthalene in female B6C3F1 mice, based
on increased incidences of pulmonary alveolar/bronchiolar adenomas.  

The carcinogenic and noncarcinogenic potential of naphthalene is
currently undergoing review by EPA Integrated Risk Information System
(IRIS). Naphthalene has not been subjected to a full EPA/International
Programme of Chemical Safety (IPCS) framework for the analysis of a
cancer mode of action (MOA) and relevancy of animal MOA to human
carcinogenicity. 

Characterization of Inhalation Hazard

The primary adverse outcome reported in available studies (NTP cancer
bioassay studies) using rodents (rats and mice) exposed to naphthalene
throughout their lives by the inhalation route is respiratory tract
(nose and lung) tumors.  Naphthalene clearly induced nasal tumors in
rats (both male and female).  Specifically, adenomas of the nasal
epithelium and olfactory epithelial neuroblastomas were observed.  In
mice, there was also some evidence of lung tumors in female mice only
(all but one of the neoplasms observed in the female mice were benign),
but this was less convincing than the tumor response in rats. The nasal
tumors in rats appear to be secondary to cytotoxicity because
cytotoxicity is found to occur first and morphologically may represent a
precursor to the nasal tumors. Signs of cytotoxicity include:
inflammation, degeneration, metaplasia, and hyperplasia.  No
significant systemic toxicities (effects distal to the site of exposure,
the nose) or tumors were observed following inhalation exposure in rats
and mice.  

Cytotoxicity and regenerative proliferation is a plausible mode of
action for naphthalene-induced respiratory effects.  Studies are ongoing
to further investigate this mode as well as the involvement  of
different CYP isoforms, different naphthalene metabolites, genotoxicity
and reactive oxygen species.

Information on naphthalene and human cancer is extremely limited.
 Although reports are found in the literature, no conclusions can be
drawn regarding the role, if any, of naphthalene in the induction of
human cancer.  For example, all the cases of laryngeal cancer occurring
in workers involved in the purification of naphthalene involved smokers
who were also exposed to other substances, including coal tar volatiles
(ATSDR 2005; IARC 2002).   However, evidence does indicate that cancers
of the nasal passages are relatively rare in humans, with estimations of
< 1 case/100,000 (Calderon-Garciduefias et al. 1999).

 

A large number of genotoxicity studies are available on naphthalene
(reviewed by ASTDR, 2005, EC-JRC, 2003; IARC, 2002; IPCS, 1998). There
is little evidence that naphthalene induces gene mutations. Some
positive results are reported that suggest naphthalene is clastogenic
(chromosome breaking) in vitro.  In vivo chromosome assays were
negative.  The available data from short-term screening does not
provide a compelling and convincing case that naphthalene is an in
vivo genotoxin. There is some limited evidence suggesting that
naphthalene generates reactive oxygen species, which may possibly lead
to oxidation of DNA and DNA damage. Most of the experimental evidence
suggests that the rodent tumor responses are driven by the metabolism of
naphthalene to cytotoxic metabolites inducing cell injury and subsequent
cell regeneration.  As discussed below, the uncertainty of whether
naphthalene poses a human cancer concern at ambient or environmental
levels of exposure arises because of the potential species differences
in rates of metabolism leading to its toxicity. 

 

Critical research has been published indicating that metabolic
activation is a required step for naphthalene’s respiratory toxicity
(unmetabolized naphthalene is not the cause of the cytotoxicity or
tumors) and that there are notable species differences in the metabolism
of naphthalene between rodents and primates (Buckpitt et al. 1992, 1995,
2002; Bogen et al. 2008).  Available research to date indicates that
the metabolism pathway in rodents is more active than in humans (i.e.,
humans have a slower rate of formation of the active metabolite)
(Buckpitt et al. 1992, 1995, 2002; Bogen et al. 2008). 

Although rodents are likely to be more susceptible to naphthalene’s
respiratory effects (cytotoxicity and tumors) than humans, the human
relevance of the rodent respiratory tract tumors is not clear at this
time.  The issue of whether naphthalene poses a human health concern at
ambient exposures will be informed to large degree by an explanation of
the process by which naphthalene is absorbed, distributed, metabolized,
and eliminated by the body (pharmacokinetics). The pharmacokinetic (PK)
model that will quantify the species difference is not available now but
is forthcoming in approximately 2-3 years. 

 

Because rodents are likely to be more susceptible to naphthalene’s
potential respiratory effects than humans, there may not be a
significant concern for respiratory toxicity in humans exposed at
ambient levels.  It would be inaccurate to quantify non-cancer and
cancer risks in humans based on default methods which do not incorporate
the critical dosimetry and metabolic differences between primates and
rodents.  Thus, no quantification of either non-cancer or cancer
inhalation risks will be provided in this assessment.  Instead of
dose-response modeling, this assessment 1) characterizes the
uncertainties associated with species differences, and 2) estimates the
typical human exposures to ambient naphthalene and directly compares
these to the NOAELs and LOAELs identified in the rodent studies.  This
comparison is informational only and provides a sense of the difference
between expected ambient levels of naphthalene that humans may be
exposed to and the levels that cause no effect, as well as a toxic
effect, in rodents.

The available data indicate that the production of tissue reactive
metabolites, e.g., 1,2-naphthalene oxide, 1,2-naphthoquinone,
1,4-naphthoquinone, may be formed at a slower rate in the human than in
the rat at the same parent compound concentration (Buckpitt et al. 1992,
1995, 2002; Bogen et al. 2008). These reactive metabolites are
critically involved in the respiratory cytotoxicity and tumorigenic
effects of naphthalene (Buckpitt et al. 1992, 1995, 2002; Bogen et al.
2008; Shultz et al. 2001).   Target specificity of response (i.e.,
nasal tissue in rats; lungs in mice), is a reflection of the species
differences in the metabolism of naphthalene and respiratory anatomy and
airflow pattern (Lee et al. 2005; Buckpitt et al. 2002; Bogen et al.
2008).  Species variation in metabolism can be explained by critical
differences in the rate of formation of specific stereoisomeric
metabolites, the levels of cytochrome P450 (specifically CYP2F has been
studied), and catalytic activity of CYP2F.  In regard to
stereoselective pulmonary metabolism of naphthalene, higher rates of the
specific enantiomeric epoxide (1R,2S-naphthalene oxide)  were noted in
mouse lung compared with rats (ATSDR 2005).  Rat, hamster and monkey
lungs preferentially formed the specific enantiomer 1S,2R-naphthalene
oxide with lower rates of formation (ATSER 2005).  The susceptibility of
mouse lung to naphthalene is considered to be related to the higher
rates of formation of 1R,2S-naphthalene oxide (ATSDR 2005).  The
preferential formation of 1S,2R-naphthalene oxide from microsomes
prepared from human lymphoblastoid cells expressing recombinant human
CYP2F1 suggests that humans may be less vulnerable than the mouse to
pulmonary effects of naphthalene (ATSDR 2005).  

In contrast to rodents, primates do not contain significant levels of
CYP2F in the lung, and CYP2F levels in the nose are considerably lower
(Baldwin et al. 2004).   Primates exhibit a slower rate of pulmonary
metabolism of naphthalene, about 100-fold lower than the mouse which has
the highest activity (Buckpitt et al. 1992; Baldwin et al. 2004; Bogen
et al. 2004).  The differences in the rate of metabolism of naphthalene
in nasal tissue may be related to differences in anatomy of nasal
passages, CYP2F expression, and stereochemistry of naphthalene
epoxidation between primates and rodents (Buckpitt et al. 1992). 

 

Since the data available to date indicate that rodents are more
susceptible to the respiratory toxicity of naphthalene, the use of
rodents as a model without application of  appropriate species scaling
accounting for species differences in dosimetry and metabolism would
most likely result in inaccurate estimates of  human risk. Therefore,
the current assessment provides, for informational purpose, a comparison
of points of departure (LOAELs) from animal studies resulting in toxic
outcomes in the rodents and typical ambient levels of naphthalene found
in monitoring studies. A comparison was also made between the animal
study dose in which no adverse effects were found (NOAELs) and ambient
naphthalene levels.

Generally, in the absence of information on kinetics/dynamics, it is
assumed that humans may be 10 times more sensitive than animals (10X
interspecies factor). The current research indicates that humans may
actually be less sensitive than rodents because of differences in rate
of bioactivation of naphthalene as well as anatomical and physiological
differences in the nose and respiratory tract. These critical
differences between primates and rodents have not been accounted for in
this assessment. Thus, with consideration of more appropriate species
scaling and dosimetry, the margins of exposure for human inhalation risk
assessments are likely to be larger than the differences calculated
between the rodent NOAELs and LOAELs and the ambient naphthalene levels.

 

Although the margins of exposure are anticipated to be greater than the
comparison exercise in this assessment, there are uncertainties in the
database. For instance, CYP isoforms other than CYP2F (e.g., CYP2A,
CYP2A13, CYP2J2 which have been detected in olfactory mucosa) and
the potential role of these other CYP isoforms in naphthalene
metabolism have not been studied (Ding and Kaminsky 2003).  While CYP
content in the nasal mucosa is high in many mammalian species, this
apparently is not the case for humans (Ding and Kaminsky 2003).   In
addition, data on the kinetics of naphthalene metabolism in liver
microsomes of humans reveal lower Vmax (maximum rate of bioactivation)
rates and lower affinity of naphthalene for various CYP forms (including
some of those detected in olfactory mucosa and other areas of the
respiratory tract) compared to rodents, suggesting that rodents have a
greater catalytic efficiency of naphthalene metabolism (Cho, Rose and
Hodgson, 2006; Bogen et al. 2008). However, studies confirming that
rodents have a greater catalytic efficiency of naphthalene bioactivation
in nasal tissues compared to primates are still part of ongoing
research.  There are no data to indicate that humans have a slower rate
of clearance, but if they did, then there would be a longer time for
humans to produce the active metabolite.  The metabolic rates of other
CYPs and clearance is being addressed in the current PK model research,
scheduled to be completed in 2-3 years. 

 

3.6    Summary of Toxicological Doses and Endpoints for Naphthalene for
Use in Human Risk Assessments

Table 3.6  Toxicological Doses and Endpoints for Naphthalene for Use in
Human Health Risk Assessments

Exposure/

Scenario	Point of Departure	Uncertainty Factors	Level of Concern for
Risk Assessment	Study and Toxicological Effects

Acute Dietary

All populations including infants and children 	LOAEL =  400 mg/kg/day

	UFA= 10x

UFH = 10x

UFL= 10x

	aRfD=0.4 mg/kg/day

	Acute Oral Neurotoxicity Study - Rat 

NOAEL = not identified.

LOAEL = 400 mg/kg/day based on hunched posture in females, head shaking
in males and females, and reduced motor activity in males and females.  

Chronic Dietary

All populations including infants and children	NOAEL= 100 mg/kg/day 

	UFA= 10x

UFH = 10x

UFS = 10x

	cRfD = 0.1 mg/kg/day

	NTP Subchronic Rat Study

NOAEL = 100 mg/kg/day

LOAEL = 200 mg/kg/day based on significant decreases in body
weights/body weight gains.

Incidental Oral (Short-term; 1-30 days)	NOAEL= 50

mg/kg/day	UFA= 10x

UFH= 10x

	MOE= 100

(residential)	NTP Developmental Rat Study 

NOAEL = 50 mg/kg/day

LOAEL= 150  mg/kg/day based on maternal effects – persistent clinical
signs of lethargy, slow breathing, rooting behavior, and significant
decreases in body weights/body weight gains and decreased food and water
consumption.

Dermal (Short-Term; 1-30 days)

	Dermal NOAEL= 300 mg/kg/day

	UFA= 10x

UFH= 10x

	MOE=  100

(residential)	90-Day Dermal Toxicity Study –Rat 

NOAEL = 300 mg/kg/day

LOAEL = 1000 mg/kg/day based on atrophy of seminiferous tubules in
males, and nonneoplastic lesions in the cervical lymph node
(hyperplasia), liver (hemosiderosis), thyroid thyroglossal duct cysts),
kidneys (pyelonephritis), urinary bladder (hyperplasia) and skin
(acanthosis, hyperkeratosis) in females.  

Inhalation (Short-term; 1-30 days)

	Inhalation 

LOAEL

= 10 ppm or 

52 mg/m3

NOAEL 

= 3 ppm or

16 mg/m3

	N/A

	N/A	4-Week (Nose-Only) Inhalation – Rat

NOAEL = 3 ppm

LOAEL = 10 ppm based increased incidence and severity of nasal lesions
(slight disorganization, rosette formation, basal cell hyperplasia,
erosion, atrophy, and degenerate cells in the olfactory epithelium; loss
of bowman’s glands; respiratory epithelium hypertrophy; rosette
formation in the septal organ of Masera and fusion of the turbinates).  

Inhalation (Intermediate-term; 1-6 months)

	Inhalation

LOAEL

= 2 ppm or

 10 mg/m3

NOAEL

= 1 ppm or

5.2 mg/m3	N/A	N/A	13-Week (nose-only) Inhalation Rat Study;   Subchronic
(nose-only) Neurotoxicity Rat Study 

NOAEL = 1 ppm (Subchronic neurotoxicity study)

NOAEL (13 week inhalation study) – not identified.

LOAEL = 2 ppm  (13 week inhalation study) based on increased incidence
and severity of nasal lesions (degeneration, atrophy and hyperplasia of
basal cells of the olfactory epithelium; rosette formation of olfactory
epithelium; loss of Bowman’s glands; hypertrophy of respiratory
epithelium).  

LOAEL = 10 ppm (subchronic neurotoxicity study) based on
atrophy/disorganization of the olfactory epithelium and hyperplasia of
the respiratory and transitional epithelium.  

Inhalation (Long-term; > 6 months)

	Inhalation LOAEL

= 10 ppm or 

52 mg/m3

	N/A	N/A	NTP ChronicToxicity and Carcinogenicity Studies in the Rat and
Mouse

NOAEL = not identified

LOAEL (rat study) = 10 ppm based on  increased incidence and severity of
atypical (basal cell) hyperplasia, atrophy, chronic inflammation, and
hyaline degeneration of the olfactory epithelium; hyperplasia, squamous
metaplasia, hyaline degeneration, and goblet cell hyperplasia of the
respiratory epithelium; and glandular hyperplasia and squamous
metaplasia.

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key date (i.e., lack of a critical study).  RfD =
reference dose.  MOE = margin of exposure.  LOC = level of concern.  N/A
= not applicable.  

3.7    Endocrine disruption

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other such endocrine effects as the Administrator may designate. 
Following the recommendations of its Endocrine Disruptor Screening and
Testing Advisory Committee (EDSTAC), EPA determined that there was
scientific basis for including, as part of the program, the androgen and
thyroid hormone systems, in addition to the estrogen hormone system. 
EPA also adopted EDSTAC’s recommendation that the Program include
evaluations of potential effects in wildlife.  For pesticide chemicals,
EPA will use FIFRA and, to the extent that effects in wildlife may help
determine whether a substance may have an effect in humans, FFDCA
authority to require the wildlife evaluations.  As the science develops
and resources allow, screening of additional hormone systems may be
added to the Endocrine Disruptor Screening Program (EDSP).

When the appropriate screening and/or testing protocols being considered
under the Agency’s EDSP have been developed, naphthalene may be
subjected to additional screening and/or testing to better characterize
effects related to possible endocrine disruption.

Public Health and Pesticide Epidemiology Data

4.1    Epidemiology Studies

Three studies were submitted which explored the possible association
between exposure to components of jet fuel, including naphthalene, and
incident cancer among both private and military aerospace personnel.
These three studies were reviewed by HED (C. Christensen, DP#339853,
5/31/07). An additional recently published epidemiology study concerning
the association between non-occupational exposure to naphthalene as a
component of mothballs and non-Hodgkin’s lymphoma (NHL) is also
included in this review.  

HED Conclusions:

Three of the four studies presented here utilized an ecologic exposure
assessment method (indirect exposure method) and evaluated exposure to
jet fuel in association with cancer.  The question HED is addressing
concerns exposure to naphthalene and adverse health outcomes.  Given the
non-specific exposure measure (jet fuel) and the potentially significant
exposure misclassification reflected in these three studies, inference
concerning the association between naphthalene exposure and incident
cancer is severely limited based upon these studies alone. These studies
are considered non-informative to the current naphthalene risk
assessment.

The finding of a 2-fold increased risk of NHL among women in upstate New
York in a study of non-occupational exposure to mothballs, of which
naphthalene is often a component, is suggestive of a possible
association. However, as it is not known if the mothballs in this study
were those containing naphthalene. This study does not contribute to the
assessment and characterization of  risks to naphthalene exposure.

4.2  Incident Data

Naphthalene poisoning incident data were reviewed from the following
databases to identify potential patterns of the extent and severity of
the health effects attributed to naphthalene exposure (M.Hawkins and H.
Allender, DP#336085, 6/25/07): 

1 - Cases reported in the Poison Control Center (PCC) Database from 1993
to 2005.

2 - Cases reported in the Incident Data System (Attachment 1) from 1999
to the present.

3 - Cases reported in the California Department of Pesticide Regulation
from 1999 to 2004. 

4 - Cases reported in the NIOSH system from 1998 to 2003.

1.	  SEQ CHAPTER \h \r 1 Poison Control Center Data – 1993-2005

This section discusses results from the Poison Control Center’s Toxic
Exposure Surveillance System (TESS) from the years 1993 through 2005 and
reflects data stratified by population: occupational, non-occupational,
and children. The children class is five years of age or less; this
definition includes children about to become six years old, or up to 72
months old. Cases involving exposures to multiple products and cases
with unrelated medical outcome are excluded.  Also excluded are
intentional exposures, i.e., suicide attempts. There are no apparent
distinctions made for route of exposure (oral, dermal, inhalation).

The PCC data are summarized in such a way that the frequency of
poisoning incidents for naphthalene are compared to the composite of all
pesticides for which the PCC received a non-excluded incident report.
The frequency of events are categorized by health severity category
(i.e., all symptoms, moderate, and major) and by level of health care
received.  A comparative ratio provides a simple measure of the relative
frequency of reported health effects by severity category.  Knowledge of
the ratios of symptoms for a single chemical (or a group of chemicals)
provides a relative measure of the public health impact of the acute
pesticide events. [See memo DP#336085, M.Hawkins and H. Allender,
6/25/07, for tables of comparison. Results are summarized below.]

Summary of PCC results

For the occupational class, the proportion who report symptoms among
those who are followed and the proportion who are seen at a Health Care
Facility (HCF) among those who are exposed are lower than the composite
average.  However, the occurrence of major symptoms and hospitalization
in an ICU are greater than the composite average for those workers who
are naphthalene exposed. [Note: occupational exposures for these data
include pesticide poisoning events that take place at a workplace.  An
occupationally exposed individual in this dataset could be the
applicator or a bystander; no distinction is made in the dataset.]  

While the number of non-occupational naphthalene-exposed adults is
10-fold greater than the number exposed in the occupational environment,
the frequency and severity of symptoms and/or health effects is lower
than the all pesticide exposed composite average for this group.  

The total number of children exposed to naphthalene reported to the PCC
is 10-fold greater than among non-occupationally exposed adults. 
Clearly, exposure opportunities exist for non-occupational exposure to
children.  Among those who are exposed, nearly 1.5x the number of
children are seen at a HCF as compared to the composite average. 
However, many fewer children who are exposed and followed by PCC staff
reported symptoms as compared to the composite average.  The magnitude
of children exposed to naphthalene (15,572) suggests that children
easily reach this chemical. 

Naphthalene produces an average annual exposure for children of 1197
cases. The annual average exposure for a typical pesticide, affecting
children, is 103 cases per year per pesticide. Comparing naphthalene
with a typical pesticide, naphthalene produces about 11.6 times more
exposures than a regular pesticide every year. In order to prevent
exposure, measures restricting the access to the active ingredient
should be taken. This could include special packaging and other
limitations to block children from reaching the active ingredient.

Ratios for the entire population present lower percentages than the
composite with the only exception of cases seen in a health care
facility.  With 21,417 exposures reported in 13 years, or annual average
of 1647 cases per year, naphthalene produces a large number of cases
compared to the average of 183 cases per year produced by a standard
pesticide; this is about than 9 times the average of exposures produced
by a typical pesticide. A reduction of exposure attributed to
naphthalene, especially in children, may represent a significant
prevention opportunity to reduce further human incidents.

 

In total exposure, symptomatic cases, and cases treated in a HCF,
naphthalene shows no trend by year in the 13 year-span of data
collected. Calculations show an average of about 1647 exposures per
year, 133 symptomatic cases per year, and 310 cases per year seen in a
heath care facility. 

Resulting from exposure to naphthalene, the health symptoms observed in
the PCC database were concentrated in six areas, and within each area,
the symptoms were:

Gastrointestinal: nausea, vomiting, and throat irritation

Neurological: headache, dizziness/vertigo, and drowsiness/lethargy

Respiratory: dyspnea, and cough/choke

Ocular: eye irritation/pain, and lacrimation

Dermal: edema, erythema/flushed, and irritation/pain

Miscellaneous: Other symptoms

2. Cases reported in the Incident Data System from 1999 to the present

IDS reported three cases:

Incident#1359-1: A pesticide incident occurred in 1994, when a neighbor,
who lived below a woman’s condominium, applied the product on the
patio for moth control and not to repel cats which is a misuse of the
product.  Three individuals reported coughing and numbness in outer
extremities that got progressively worse over the next several weeks. 
No further information on the disposition of the case was reported.

Incident#2368-1: A pesticide incident occurred in 1994, when a
family’s neighbor, which lived below, applied three boxes of the
product as an animal repellent to her landscape.  A woman, her husband,
and her eleven year old son reported coughing and a headache.  About ten
days later, the woman reported numbness, tingling, and weakness in her
extremities and face.  The woman was treated by four neurologists and
was diagnosed with peripheral neuropathy.  No further information on the
disposition of the case was reported.

Incident#7954-1: A pesticide incident occurred in 1998, when a woman’s
neighbors placed the product in the grassy around their common courtyard
and grounds that are shared by the residents.  The woman, who had a
pre-existing respiratory condition, reported difficulty breathing
whenever she opened her apartment door or windows or whenever she walked
to her parking lot.  No further information on the disposition of the
case was reported.

3. California Pesticide Illness Surveillance Program Data 2000-2004

Detailed descriptions of four cases submitted to the California
Pesticide Illness Surveillance Program (1999-2004) were reviewed.  In
two of these cases, naphthalene was used alone or was judged to be
responsible for the health effects.  In the first case, flakes that were
on top of a container flew into a cashier’s eyes and face when she
picked up a broken package while she checked out an individual in her
line.  The cashier reported eye irritation.  In the second case, a
social worker visited their client’s apartment and noticed a mothball
odor.  The client had placed the mothballs in his apartment to eliminate
cockroaches.  The social worker reported coughing, watery eyes, throat
irritation, and chest congestion. 

4. NIOSH SENSOR

Out of 5,899 reported cases from 1998 to 2003, there are 15 cases
reported in the SENSOR database involving naphthalene. Seven cases were
reported in Texas, four in Washington State, three in Florida, and one
in California; seven cases were males and seven were females with
onecase of unknown gender. The average age of the cases was 46.2 years
old with the youngest case being 22 years old and the oldest case being
76 years old. Two cases in Texas relate to an apartment complex that
applied snake repellant granules to attics. Other two cases in Texas
also relate to another apartment complex that spread mothballs in attics
to repel pigeons, odor was overwhelming and people fell sick. In
addition, in Texas a chemistry teacher was conducting and experiment
with mothballs in a test tube; student dropped test tube in sink and the
teacher reported herself to HCF; no medical treatment was provided. Two
cases in Florida suspect that naphthalene in mothballs used at their
home was causing ill symptoms.  The most common symptoms were classified
in the following five areas:

Nervous/Sensory symptoms: Headache and dizziness

Gastrointestinal: Nausea and vomiting

Ocular symptoms: Eye pain/irritation/inflammation, lacrimation, and
conjunctivitis

Respiratory symptoms: Upper respiratory pain/irritation and
dyspnea/shortness of breath

Miscellaneous symptoms: Acidosis, Alkalosis, and anion gap increase

Study Summary

The summary findings for the period 1993 to 2005 for naphthalene, mainly
for PCC data are:

Naphthalene produces a higher proportion of acutely toxic incidents
requiring medical attention when compared to the composite average of
all other pesticides. There is a pattern of statistically significant
results in cases seen in a health care facility.  This pattern observed
in the combined population (occupational, non-occupational, children) is
largely due to the frequency and severity of pesticide poisoning among
children less than six years old.

Exposure to children is much higher than a typical pesticide.

Naphthalene PCC data show average results of about 11647 exposures/year,
133 symptomatic cases/year, and 310 cases/year seen in a heath care
facility. 

No apparent annual trend is evident in the 13 year-span of data
collected.

For children under six years old, the large majority of exposures were
from ingestion of mothball products marketed for use in the home.

5.0  	Exposure Characterization/Assessment

	

5.1	Dietary Exposure/Risk Pathway

	

	5.1.1 	Food Exposure/Risk Pathway

	

None, since there are no food uses.

	5.1.2   Water Exposure/Risk Pathway	

Environmental Fate and Effects Division’s (EFED) has performed a
drinking water exposure assessment for naphthalene (M. Corbin,
DP#339118, 4/25/07; amended under DP#351119).  No acceptable
environmental fate data have been submitted to support the registration
of naphthalene.  Several environmental fate studies (aerobic soil and
aqueous photolysis) were submitted but deemed to be unacceptable for
risk assessment purposes due to poor material balances, inadequate
sample intervals, and issues with volatile trapping and therefore have
not been used in this assessment.  A single overview of open literature
data (MRID 45346801) provided supplemental data on the
adsorption/desorption and aerobic soil metabolism properties of
naphthalene.

For sorption a total of 13 open literature studies were submitted and
summarized and indicated that the solubility of naphthalene ranged from
30 to 31.7 mg/L and that the Koc ranged from 200 to 1470 for a variety
of soils from North America, Europe and China. The study author
concluded from this review that naphthalene was bound relatively rapidly
to soils with a sustained desorption over days to weeks.  For
biodegradation a total of 15 open literature studies were submitted and
reviewed and found that naphthalene degraded with aerobic soil
metabolism half lives between 3.5 and 40 days with no appreciable
degradation under anaerobic conditions.  Possible degradation processes
affecting naphthalene (and PAH’s in general) include volatilization,
photo-oxidation, bioaccumulation, adsorption, leaching, and microbial
degradation.  

A number of degradates were identified in the various open literature
studies.  The study author proposed a degradation pathway for
naphthalene which ultimately resulted in catechol.  Transitional
degradates included cis-1,2-dihydroxy-1,2-dihydronaphthalene,
1,2-dihydroxy-naphthalene, 2-hydroxchromene-2-carboxylate (HCCA),
trans-o-hydroxy-benzylidenpyruvate (tHBPA), salicyladehyde, and
salicylate.  However, there is no environmental fate data for these
degradates and therefore, exposure estimates are for parent only.  

Aquatic Exposure Modeling

Typically, EFED relies on an integrated approach for conducting exposure
assessments that relies on an analysis of both monitoring data and
modeling.  In the case of naphthalene, no monitoring data that
specifically targets this use pattern are available. Therefore, this
assessment relies solely on modeling.     

EFED has conducted a Tier I aquatic exposure assessment relying on
FIRST.  FIRST (FQPA Index Reservoir Screening Tool, version 1) is a
program to calculate acute as well as longer-term estimated
environmental concentration (EEC) values. It considers reduction in
dissolved pesticide concentration due to adsorption of pesticide to soil
or sediment, incorporation, degradation in soil before washoff to a
water body, direct deposition of spray drift into the water body, and
degradation of the pesticide within the water body.

Given the limited use of this compound and the fact that it is applied
to in a band around ornamentals, planting beds and gardens as a
repellent, an adjustment to the modeled EEC was made assuming 4.1% of a
typical residential lot would be treated (see DP#339118 for
calculations).  The resultant FIRST EEC has been adjusted by this
factor.  Input parameters and for the FIRST modeling are presented in
the table below.

  

Table 5.1.2.1  Summary of FIRST environmental fate data used for aquatic
exposure inputs for naphthalene

Fate Property	Value	MRID (or source)

Solubility in Water	31 mg/L	Product Chemistry

Photolysis in Water	stable	Assumed

Aerobic Soil Metabolism Half-lives	32.6 days (90th % of 9 values)	MRID
45346801

Hydrolysis	stable	Assumed

Aerobic Aquatic Metabolism (water column)	65.2 days 	Twice the aerobic
soil metabolism rate constant

Koc	131	MRID 45346801

Application Efficiency	100 % for granular1	default value

Spray Drift Fraction	0 % for granular	default value

Two scenarios were modeled to represent a high naphthalene use scenario
and at low use scenarios.  The high use scenario was modeled at 10.8
lbs/acre with six applications per year, while the low use scenario was
modeled at 0.56 lbs/acre with six applications per year.  The
application method was modeled as ground application with a granular
formulation.

Table 5.1.2.2  Results of FIRST Modeling for Naphthalene Use on
Ornamentals*

Use Site	Application Rate (lbs/acre)	Number of Applications

(interval)	Peak EEC (ppb)	Annual Average EEC (ppb)

Ornamentals for rabbit & dog repellent	10.8

	6

(2 months)	43.4	6.5

Ornamentals for snake repellent	0.56	6

(2 months)	2.2	0.3

Unaccounted for in this exposure assessment is the fact that naphthalene
is volatile.  No product chemistry data were available but an estimate
of the vapor pressure was made using EpiSuite.  EpiSuite reported an
experimentally derived value for vapor pressure of 8.5 x10-2 mm Hg
(which is consistent with the registrant reported value of 10.5 Pa, or
7.8 x 10-2 mm Hg) and a Henry’s Law Constant of 0.00044 atm-m3/mol
suggesting that naphthalene is volatile.  Given the potential volatility
of this compound and the fact that the Tier I model used to estimate
exposure does not account for volatility as a route of dissipation it is
likely that the exposure estimates derived above are over-predictions of
potential exposure.  It is unclear from the open literature data whether
degradation in the studies reported accounted for the fraction lost due
to volatility or not.  

Finally, Sci-Grow modeling was conducted for both use scenarios to
provide an estimate of the potential loading of naphthalene to
groundwater.  Sci-Grow modeling relied on similar model inputs with the
exception of aerobic soil metabolism which uses the average half life of
14 days.  The results are summarized in Table II.3.  

Table 5.1.2.3  Results of Sci-Grow modeling for naphthalene used on
ornamentals at the high and low application rates

Use Site	Application Rate (lbs/acre)	Number of Applications

(interval)	Annual Average EEC (ppb)

Ornamentals for rabbit & dog repellent	10.8	6

(2 months)	4.5

Ornamentals for snake repellent	0.56	6

(2 months)	0.2

5.2     Dietary Exposure Estimates

There are no agricultural or any food related pesticide uses of
naphthalene, therefore, no dietary exposure from food is expected. 
However, there is a potential for drinking water exposure due to the
outdoor uses of naphthalene. 

Acute and Chronic Dietary Assessments

 

posure Evaluation Model (DEEM-FCID™) which uses food consumption data
from the U.S. Department of Agriculture’s Continuing Surveys of Food
Intakes by Individuals (CSFII) from 1994-1996 and 1998. 

The acute and chronic screening-level drinking water assessments are
conservative evaluations of dietary exposure to naphthalene.  They are
made using the Environmental Fate and Effects Division (EFED)
determination of Estimated Environmental Concentrations (EECs) in water
(M. Corbin, DP#339118, 4/25/07; amended under DP#351119). Using a
screening modeling tool (FIRST), EFED calculated peak and annual average
surface water Estimated Environmental Concentrations (EEC) of 43.4 ppb
and 6.5 ppb, respectively. These values represented the high-end use
rate of naphthalene on ornamentals.

The acute screening-level drinking water assessments using the
DEEM-FCID™ Model were reported at the 95th percentile of exposure for
the general U.S. population and all of its subgroups.  It is based
exclusively on the peak EEC of 43.4 ppb for all direct and indirect
water sources.  Risk estimates were all found to be well below the 100%
acute Reference Dose (aRfD) threshold level of concern.  The acute
exposure for naphthalene was estimated to be 0.0023 mg/kg/day at 0.6% of
the aRfD for the general U.S. population.  In comparison, acute exposure
for the most highly exposed population subgroup, all infants, was
estimated to be 0.0080 mg/kg/day at 2.1% of the aRfD.   

In conjunction, the chronic screening-level drinking water assessment is
another conservative evaluation based exclusively on the annual average
EEC of 6.5 ppb for all direct and indirect water sources.  Risk
estimates were all found to be well below the 100% chronic Reference
Dose (cRfD) threshold level of concern.  The chronic exposure for
naphthalene was estimated to be 0.0001 mg/kg/day at 0.1% of the cRfD for
the general U.S. population.  In comparison, chronic exposure for the
most highly exposed population subgroup, all infants, was estimated to
be 0.0004 mg/kg/day at 0.4% of the cRFD. 

Additional Drinking Water Characterization

As previously noted, a drinking water assessment for naphthalene was
carried out by EFED for its use as a pest repellant outdoors around the
home. This screening level assessment relied on modeling analyses to
calculate EECs for drinking water. Given the potential volatility of
this compound and the fact that the Tier I model used to estimate
exposure does not account for volatility as a route of dissipation it is
likely that the EECs are overestimated. Additionally, the dietary (water
only) assessment used only the high end EECs from a maximum use rate and
the resulting risk estimates, while not of concern, can be considered
upper bound.  Although a number of potential water degradates have been
identified, the drinking water assessment is only for the parent
compound naphthalene. There were no data on the environmental fate of
the degradates, or on the toxicity of the degradates in relation to the
parent. However, given the overall conservative nature of the water
assessment it is unlikely that risks from exposure to naphthalene in
drinking water were underestimated. 

Available water monitoring data, while non-targeted, indicate that
naphthalene was infrequently detected in water supplies, and those
detects were usually well below the Health Reference Level (HRL) of 140
ppb. EPA’s Office of Water has concluded that the regulation of
naphthalene in drinking water is unlikely to represent a meaningful
opportunity for health risk reduction (USEPA, Office of Water Reprt: EPA
815-R-03-014, July 2003). While it is not known if detects in ambient
water are from pesticide or industrial uses, it should be noted that
about 190,000 lbs of naphthalene a year is used for outdoor pest control
compared to more than 1.8 billion lbs naphthalene used for the US jet
fuel market (3/28/07 Naphthalene SMART meeting).

Table 5.2.1  Summary of Screening –Level Drinking Water Exposure and
Risk for Naphthalene

Population Subgroup	Acute Dietary1

(95th Percentile)	Chronic Dietary2

	Dietary Exposure (mg/kg/day)	% aRfD	Dietary Exposure

(mg/kg/day)	% cRfD

General U.S. Population	0.002267	0.6	0.000137	0.1

All Infants 	0.008548	2.1	0.000449	0.4

Children 1-2 years old	0.003557	0.9	0.000203	0.2

Children 3-5 years old	0.003250	0.8	0.000190	0.2

Children 6-12 years old	0.002262	0.6	0.000131	0.1

Youth 13-19 years old	0.001839	0.5	0.000099	0.1

Adults 20-49 years old	0.002101	0.5	0.000128	0.1

Adults 50+ years old	0.001897	0.5	0.000135	0.1

Females 13-49 years old	0.002112	0.5	0.000127	0.1

1 Acute dietary analysis derived from a 0.40 mg/kg/day aRfD.

2 Chronic dietary analysis derived from a 0.10 mg/kg/day cRfD.

5.3    Residential (Non-Occupational) Exposure/Risk Characterization

HED has determined that there is a potential for exposure in residential
settings during the application process for homeowners who purchase and
use pesticide products containing naphthalene.  There is also a
potential for postapplication exposure from inhabiting indoor areas
previously treated with naphthalene (inhalation), as well as, incidental
toddler ingestion of formulations used for indoor/outdoor treatments.

A quantitative exposure assessment was performed for homeowners applying
naphthalene in the residential environment and for toddler incidental
ingestion of naphthalene used for indoor/outdoor treatments. Human
health risk estimates were not calculated for postapplication inhalation
scenarios because of the uncertainties associated with extrapolating
animal (rodent) data to humans as discussed previously in this document.
Rather than quantifying inhalation risks to humans, the levels of
ambient naphthalene measured in the human exposure study were compared
directly to the levels resulting in a 1) no adverse effects in the
rodent studies (NOAELs) and 2) a toxic effect in rodents (LOAELs). This
comparison provides a sense of the difference between actual naphthalene
concentrations that a human may encounter and the doses which elicit
either no adverse response or a toxic response in rodents.

5.3.1     Residential Handler Exposure and Risks

The Agency uses the term “handlers” to describe those individuals
who are involved in the pesticide application process.  The Agency
believes that there are distinct tasks related to applications and that
exposures can vary depending on the specifics of each task.    SEQ
CHAPTER \h \r 1 Job requirements (e.g., the amount of chemical to be
used in an application), the method of application, and the target being
treated can cause exposure levels to differ in a manner specific to each
application event.	

HED has determined that there is potential for exposure in residential
settings during the application process for homeowners who purchase and
use naphthalene-containing products.  According to label instructions,
homeowners must physically place naphthalene formulations into indoor
storage areas and around the perimeter of outdoor areas to be protected.
 HED anticipates handler dermal and inhalation exposure during the
application process. However, appropriate inhalation exposure data are
not available to assess this handler scenario, therefore, only dermal
exposure was assessed. 

Applications of naphthalene are expected to be short-term in nature
because the products are typically applied only intermittently and
usually on a seasonal basis, i.e. when storing winter clothes or when
outdoor pests are active. As a result, no intermediate-term or long-term
assessments were assessed for handlers.  

Residential Handler Scenarios, Data Sources and Assumptions

Scenarios

Hand application of naphthalene formulations for indoor moth treatments

Hand application of naphthalene formulations for indoor/outdoor animal
repellent treatments

Data Sources

Exposure data for residential handler and residential postapplication
were taken from the exposure study, “Estimation of Homeowner Exposure
to LX1298-01 (Naphthalene) Resulting from Simulated Residential Use as
an Insect Repellent (MRID 43716501).” Dermal handler exposure data was
derived from the result of monitoring a person weighing out and placing
mothballs in a closet and dresser at three different locations. 

Assumptions Regarding Residential Applicators

Homeowner handlers are expected to complete all tasks associated with
the use of a pesticide product (e.g., application);

The maximum application rate of 14.4 lb ai/ treated area was used for
indoor moth treatment risk calculations, assuming that 3 closets (600
ft3) and 3 dresser drawers (90 ft3) are treated at 0.0625 lb ai/ 3 ft3;

The maximum application rate of 24 lb ai/ treated area was used for
outdoor repellant treatment risk calculation, assuming the entire
contents of a 24 lb container is used for treatment at 99.95% ai; 

A body weight of 70kg was assumed because the endpoint is not gender
specific; 

Dermal absorption is assumed to be 100%, which is representative of a
conservative assumption of risk; and

Areas for chemical used in the risk assessment are based on Agency
guidance specific to residential use patterns.

Residential Handler Exposure and Risk Estimates

The Margin of Exposures (MOEs) are > 100 and the risks are below EPA’s
level of concern for both dermal exposure scenarios for homeowner
handlers.

Table 5.3.1  Naphthalene Noncancer Risks Attributable to Homeowner
Handler Exposures

Exposure Scenario	Total Applied

(lb ai)	Daily Exposure (mg/ lb ai)	MOE

(LOC = 100)

1 - Apply Moth Treatment by Hand	14.4	0.053	28000

2 – Apply Animal Repellant Treatment by Hand	24  	0.053	17000

5.4    Residential Postapplication Exposure and Risks

The Agency uses the term “postapplication” to describe exposures to
individuals that occur as a result of working in an environment that has
been previously treated with a pesticide (also referred to as re-entry
exposure).  HED has determined that there is potential for adult
inhalation exposure from accessing treated areas (such as containers and
closets) and adult and toddler inhalation exposure from inhabiting homes
previously treated with naphthalene. Additionally, there is a potential
for oral exposures to toddlers from the episodic (incidental) ingestion
of formulations used for indoor/outdoor animal repellency.  

5.4.1     Residential Postapplication Inhalation Exposure and Risk

As previously described, naphthalene applications may be made indoors. 
While labels specify that treated indoor areas (i.e., containers,
dresser drawers, and storage closets) should be airtight to be
effective, HED anticipates that naphthalene will volatilize and be
inhaled by adults accessing treated areas (acute exposure).
Additionally, adults and toddlers that inhabit treated areas may be
exposed to ambient concentrations of naphthalene (short-, intermediate-,
and long-term exposures). 

short-term (≥1 day) inhalation endpoint.  The pairing of an acute
inhalation exposure with a short-term toxicity endpoint can be
considered conservative.  HED used endpoints from short-, intermediate-,
and long-term rodent inhalation toxicity studies for comparison to
ambient naphthalene levels expected from those exposure durations.  

Residential Postapplication Inhalation Exposure and Risk Estimates

Scenarios

Adult:

Acute inhalation from accessing treated areas 

Adult/Toddler:

Short-/intermediate-/long-term inhalation from inhabiting treated area 

Data Sources

Exposure data for residential postapplication inhalation was taken from
the exposure study, “Estimation of Homeowner Exposure to LX1298-01
(Naphthalene) Resulting from Simulated Residential Use as an Insect
Repellent (MRID 43716501).”  Inhalation exposure data was derived for
accessing treated areas (15-minute duration) from the results of air
sampling of an individual accessing a treated drawer and closet, and
performing household tasks (i.e., dusting, sitting in a chair, etc) in a
treated room.  Inhalation exposure data was also derived for inhabiting
a treated area from the results of indoor air sampling in enclosed rooms
in 3 different locations. Air samples were collected continuously (in
8-hour intervals) for 3 consecutive days from devices surrounding
treated closets, dresser drawers, and beds. [A summary of the exposure
study data is provided in DP#335944, W. Britton (note: see amended
version DP#351120 dated 4/10/08).]

HED determined that the exposure data used to assess acute and
short-term exposure to indoor postapplication inhalation exposure to
naphthalene from mothball sources was not appropriate to assess
intermediate- and long-term exposure durations.  As described
previously, naphthalene volatilizes into the treated area and it is
assumed that adults and toddlers who inhabit these areas are potentially
exposed.  Based upon label application timing recommendations for moth
control, it is likely that re-treatment could occur, at a minimum, once
every 1-6 months.  The continued volatilization and dissipation of
naphthalene over time results in a reduced concentration of the chemical
and, likewise, reduced potential for inhalation exposure.  Therefore,
the exposure data used for the acute and short-term duration
overestimates the concentration of naphthalene available for inhalation
over longer term durations.  HED was unable to locate any exposure data
sources which assessed intermediate- and long-term exposure levels to
naphthalene from ‘mothball’ sources.  Exposure data was located,
however, from a study which observed indoor ambient concentrations of
naphthalene in 24 homes (J. Chuang et al.  Polycyclic Aromatic
Hydrocarbon Exposure of Children in Low-Income Families.  Journal of
Exposure Analysis and Environmental Epidemiology.  (1999) 2, pp. 85-98).
  This study is not specific to intermediate- or long-term exposure
durations, nor does naphthalene necessarily originate from a mothball
source; however, it has been identified as the best data source to
account for naphthalene volatilization and dissipation over time. Due to
the uncertainty associated with the use of an exposure study which is
not specific to the duration assessed, HED selected the most
conservative exposure value (i.e., maximum concentration observed) to
represent intermediate- and long- term exposure levels. [A summary of
the exposure study data is provided in DP#335944, W. Britton (note: see
amended version DP#351120 dated 4/10/08).]

Assumptions Regarding Postapplication Inhalation

HED assumes that an individual could access treated areas (i.e.,
containers, dresser drawers, and storage closets) for an exposure
duration of 15 minutes; and

HED assumes that an individual could be exposed continually within their
home (i.e., 24 hours per day) for short-/intermediate-/long-term
duration.

Residential Postapplication Inhalation Exposure and Risk Estimates

A comparison was performed between both the NOAELs and LOAELs from
rodents studies and human exposure studies.  For acute- and short-term
exposure scenarios, the results of an exposure study, “Estimation of
Homeowner Exposure to LX1298-01 (Naphthalene) Resulting from Simulated
Residential Use as an Insect Repellent (MRID 43716501)” were used.
 The 15 minute (acute) and 24 hour (short-term) samples resulted in
average concentrations of 0.85 and 0.66 mg/m3 of naphthalene,
respectively. These values were compared directly to the rodent NOAEL
(16 mg/m3) and LOAEL (52 mg/m3) selected for acute and short-term
exposure durations.

 Anticipated acute and short-term exposures to naphthalene in
residences are 20X and 30X below the rodent dose (NOAEL) resulting in no
adverse effects, respectively. Anticipated acute and short-term
exposures to naphthalene in residences are 60X and 80X below the rodent
dose (LOAEL) resulting in respiratory toxicity (olfactory epithelium
lesions), respectively.

For intermediate- and long-term durations, the results of an exposure
study, “Polycyclic Aromatic Hydrocarbon Exposure of Children in
Low-Income Families (Chuang et al., 1999) were utilized.”  The indoor
ambient samples which pertain to the air concentrations of naphthalene
resulted in a maximum level of 0.0097 mg/m3. This exposure value was
directly compared to the rodent NOAEL (5.2 mg/m3) and LOAEL (10 mg/m3 )
selected for intermediate- term durations and to the LOAEL (52 mg/m3 )
selected for long-term exposure. A long-term NOAEL was not identified in
the rodent chronic inhalation study.

Anticipated intermediate-term exposures to naphthalene in residences are
540X below the rodent dose (NOAEL) resulting in no adverse health
effects. Intermediate- and long-term exposures to naphthalene in
residences are 1000X and 5400X below the rodent dose (LOAEL) resulting
in respiratory toxicity (olfactory epithelium lesions), respectively.

5.4.2    Residential Postapplication Episodic Ingestion Exposure and
Risk 

As previously described, naphthalene applications are made indoors for
moth treatments and indoors/outdoors for animal repellency.  HED
anticipates that toddlers could come in contact with naphthalene
formulations inside a treated home or in treated outdoor areas.  While
labels specify that indoor moth treatments be made in airtight
containers, it is assumed that a toddler could potentially access these
areas and ingest naphthalene products.  Outdoor applications of
naphthalene are labeled for use around the perimeter of areas to be
protected.  While a toddler could potentially access outdoor treated
areas, naphthalene incident reports indicate that a large majority of
incidents for children under six years old are from ingestion of indoor
products.  In order to assess postapplication episodic (incidental)
ingestion of naphthalene, a potential dose was derived from the
assumption of a toddler ingesting one mothball.  HED also estimated the
amount of the mothball that could be ingested by a toddler to result in
a MOE = 100. 

Inhalation and episodic (incidental) ingestion routes of exposure were
not combined for toddlers in order to differentiate the occurrence of a
discrete accidental event (assessed to give a worst-case estimate of
risk) from the expected daily exposure via the inhalation route.  It
would not be appropriate to combine episodic exposure for comparison to
a short-(or longer) term endpoint. 

Scenarios

Toddler

Episodic (incidental) ingestion of naphthalene formulation from
indoor/outdoor exposure

Data Sources

The residential indoor/outdoor postapplication episodic (incidental)
ingestion exposure risk calculations are presented in this section.
Noncancer risks were calculated using the approach described in the
Standard Operating Procedures (SOPs) for Residential Exposure
Assessments, Section: 2.3.1, Postapplication – Incidental Nondietary
Ingestion.  SOPs were used to derive the potential dose rate of a
toddler ingesting one mothball, which was then compared to the
incidental oral endpoint to calculate an MOE.  In addition, HED
estimated the amount of a single mothball that a toddler could ingest to
result in an MOE = 100.  (See DP#335944, Appendix A for algorithms.)

Assumptions Regarding Toddler Episodic Ingestion

One mothball weighs 2.35 grams (or 2350 mg) and the maximum labeled
percent active ingredient is 99.95%;

For the purposes of this risk assessment, HED is assuming that a child
is only ingesting one mothball; and 

3 year old toddlers are expected to weigh 15 kg.

Episodic Ingestion Risk Estimate

Toddler episodic (incidental) ingestion of one naphthalene mothball
results in an MOE < 100 and, therefore, is of concern to HED.  An oral
dose of 0.5 mg/kg/day would be required to result in an MOE = 100.  This
dose is equivalent to toddler incidental ingestion of 0.32% of one
mothball (7.5 of 2350 mg).

6.0 	Aggregate Risk Assessments and Risk Characterization

An aggregate risk assessment for all expected routes of exposure was not
performed as there is no common sensitive endpoint among all routes of
exposure. Generally, a short-term aggregate risk assessment may be
performed by combining short-term incidental oral exposure and
average/background dietary (in this case drinking water) exposures. A
short-term aggregate risk assessment was not performed for naphthalene
since the short-term incidental oral exposure risk estimate alone
exceeds the level of concern and combining with other routes of exposure
would further exceed the level of concern.

7.0	Cumulative Risk Characterization/Assessment

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to naphthalene and any other
substances and naphthalene does not appear to produce a toxic metabolite
produced by other substances. For the purposes of this action,
therefore, EPA has not assumed that naphthalene has a common mechanism
of toxicity with other substances.  For information regarding EPA’s
efforts to determine which chemicals have a common mechanism of toxicity
and to evaluate the cumulative effects of such chemicals, see the policy
statements released by EPA’s Office of Pesticide Programs concerning
common mechanism determinations and procedures for cumulating effects
from substances found to have a common mechanism on EPA’s website at  
HYPERLINK http://www.epa.gov/pesticides/cumulative/.
http://www.epa.gov/pesticides/cumulative/. 

8.0	Occupational Exposure/Risk Pathway

Naphthalene products are not registered for occupational use and,
therefore, occupational exposure and risk is not anticipated and has not
been assessed.

9.0        Data Needs

  

Residential

HED recommends that the registrant conduct an exposure study to
determine levels of naphthalene in indoor air resulting from simulated
residential mothball use over intermediate- and long-term durations. 
Intermediate- and long-term residential indoor postapplication exposure
and risk was estimated using surrogate data from an exposure study which
was conducted to determine indoor ambient levels of naphthalene.  Since
the surrogate exposure study was not duration- or use-specific, it may
potentially underestimate naphthalene exposure and risk.  An appropriate
study is required to confirm that the estimation of residential
postapplication inhalation exposure is protective of human health.  

Toxicology

No new data are currently being required. There is ongoing naphthalene
research to address toxicology issues including:

More accurate assessment of species differences in metabolism and
clearance of naphthalene.

Cell proliferation data to provide linkage to cytotoxicity.

DNA adduct and mutagenicity studies in relevant target tissues in vivo
to confirm lack of direct DNA mutagenicity.

PbPK model under development (2-3 years rough estimate) to better
support the mode of action, and to characterize species differences in
metabolism, and address involvement of multiples enzymes and clearance
in humans versus rodents.  The PBPK model will also provide a more
accurate determination of a human equivalent dose to be used in
inhalation risk assessment.

Appendix A: Toxicology

A.1	Toxicology Data Requirements 

The requirements (40 CFR 158.340) for a food use for naphthalene are in
Table A.1. Use of the new guideline numbers does not imply that the new
(1998) guideline protocols were used.

TABLE A.1 Test 

	

Technical

	

Required	

Satisfied

870.1100	Acute Oral Toxicity	

870.1200	Acute Dermal Toxicity	

870.1300	Acute Inhalation Toxicity	

870.2400	Primary Eye Irritation	

870.2500	Primary Dermal Irritation	

870.2600	Dermal Sensitization		

yes

yes

yes

yes

yes

yes	

yes

yes

yes

yes

yes

yes

870.3100	Oral Subchronic (rodent)	

870.3150	Oral Subchronic (nonrodent)	

870.3200	21/28-Day Dermal	

870.3250	90-Day Dermal	

870.3465	90-Day Inhalation		

yes

yes

yes

no

no	

yes

yes

yes

---

---

870.3700a	Developmental Toxicity (rodent)	

870.3700b	Developmental Toxicity (nonrodent)	

870.3800	Reproduction		

yes

yes

no	

yes

yes

---

870.4100a	Chronic Toxicity (rodent)	

870.4100b	Chronic Toxicity (nonrodent)	

870.4200a	Oncogenicity (rat)	

870.4200b	Oncogenicity (mouse)	

870.4300	Chronic/Oncogenicity		

yes

yes

yes

yes

yes	

yes

yes

yes

yes

yes

870.5100	Mutagenicity—Gene Mutation - bacterial	

870.5300	Mutagenicity—Gene Mutation - mammalian	

870.5375	Mutagenicity—Structural Chromosomal Aberrations	

870.5395	Mutagenicity—Other Genotoxic Effects		

yes

yes

yes

yes	

yes

yes

yes

yes

870.6100a	Acute Delayed Neurotox. (hen)	

870.6100b	90-Day Neurotoxicity (hen)	

870.6200a	Acute Neurotox. Screening Battery (rat)	

870.6200b	Chronic Neurotox. Screening Battery (rat)	

870.6300	Develop. Neuro		

no

no

no

no

no	

---

---

yes

yes 

---

870.7485	General Metabolism	

870.7600	Dermal Penetration		

yes

no	

yes

yes

A.2  Toxicity Profiles

Table A.2.a  Acute Toxicity of Naphthalene.

GDLN

	

Study Type	

MRID	

Results	Tox

 mg/kg (♂+♀)	III

870.1200	Acute Dermal	257229	LD50 >2000  mg/kg (♂+♀)	III

870.1300	Acute Inhalation	257902	LC50 > 0.4 mg/L (77.7 ppm) (♂+♀)	II

870.2400	Primary Eye Irritation	257228	Slight-moderate irritation	III

870.2500	Primary Skin Irritation	257227	Moderate irritation	III

870.2600	Dermal Sensitization	00148173	Nonsensitizer – guinea pig	N/A

Table A.2.b  Subchronic, Chronic and Other Toxicity.

Guideline No./Study Type	Doses tested and Results

Nonguideline

90-Day oral toxicity – rat

NTP 1980a	Doses:  0, 25, 50, 100, 200, or 400 mg/kg/day

NOAEL =  100  mg/kg/day (males/females)

LOAEL =  200 mg/kg/day (males/females) based on decreased body weight
gain.  Renal lesions in males at 200 mg/kg (minimal cortical focal
lymphocytic infiltrate; focal tubular regeneration) and 400 mg/kg
(cortical diffuse tubular degeneration).  At 400 mg/kg/day, clinical
signs (lethargy, hunched posture) and roughened hair coat in both sexes.
 2/10 females at 400 mg/kg displayed moderate lymphoid depletion of
thymus.  

Nonguideline

90-Day oral toxicity – B6C3F1

Mouse

NTP 1980b	Doses:  0, 12.5, 25, 50, 100 or 200 mg/kg/day

NOAEL =  100 mg/kg/day (males/females)

LOAEL =  200 mg/kg/day based on transient clinical signs (rough hair and
lethargy) at weeks 3 and 4.   

Nonguideline

90-Day oral toxicity – CD1

Mouse

Shopp et al. 1984	Doses:  5.3, 53 or 133 mg/kg/day

NOAEL = 53 mg/kg/day  mg/kg/day

Possible LOAEL =  133 mg/kg/day based on  >10% decreases in absolute
weights of the brain, liver and spleen in females and decreased relative
spleen weights in females.  However, no histopathological examinations
were performed.  Decreassed absolute and relative spleen weights also
noted in females after 14 day treatment with 267 mg/kg naphthalene, but
no histological examinations were performed. Mortality observed at 267
mg/kg/day.  Immunotoxicity assays were negative.

870.3250

90-Day dermal toxicity – rat

MRID 40021801

Acceptable guideline	Doses:  0, 100, 300, or 1000 mg/kg/day

NOAEL =  300 mg/kg/day (males/females) 

LOAEL =  1000 mg/kg/day based on atrophy of seminiferous tubules in
males; non-neoplastic lesions in cervical lymph node, liver, thyroid,
kidneys, urinary bladder and skin in females.  Both sexes also displayed
excoriated skin and papules.

870.3700a

Prenatal developmental – rat

NTP 1991	Doses:  0, 50, 150 or 450 mg/kg/day

Maternal NOAEL =  50 mg/kg/day

LOAEL = 150  mg/kg/day based on persistent clinical signs of lethargy,
slow breathing, rooting behavior, and significant decreases in body
weights/body weight gains and food and water consumption.

Developmental NOAEL = 450 mg/kg/day

LOAEL =   not identified

870.3700b

Prenatal developmental – rabbit

NTP 1992	Doses:  0, 20, 80, or 120 mg/kg/day

Maternal NOAEL = 120  mg/kg/day

LOAEL =   not identified

Developmental NOAEL = 120  mg/kg/day

LOAEL =   not identified

870.6200a

Acute Neurotoxicity  (Oral) Study – rat

MRID 44282801

Acceptable Guideline	Doses:  0, 400, 800, or 1200 mg/kg/day

NOAEL =   not identified

LOAEL =  400 mg/kg based on clinical signs (piloerecton, fast
respiration, hunch posture), reduced motor activity, lower body
temperature, and head shaking and increased urination and defecation in
the open field.  

 

870.6200a

Subchronic Neurotoxicity  (inhalation) Study – rat

MRID 44856401

Acceptable Guideline	Concentrations:  0, 1, 10, or 60 ppm

NOAEL =     1ppm

LOAEL =  10  ppm (males/females) based on nasal lesions (loss of
olfactory nerve fibers, loss of bowman’s glands, olfactory epithelium
atrophy/disorganization, olfactory epithelium erosion/necrosis,
olfactory epithelium hyperplasia,  olfactory epithelium inflammatory
exudate in airway, olfactory epithelium rosettes, respiratory epithelium
hyperplasia.

Nonguideline

4-Week Inhalation  – rat

MRID 42934901

Acceptable nonguideline	Concentrations:  0, 1, 3, 10,  30 or 77 ppm. 
6hrs/day; 5 d/wk.

NOAEL =    3 ppm

LOAEL =  10 ppm (males/females) based on increased incidence and
severity of nasal lesions (slight disorganization, rosette formation,
basal cell hyperplasia, erosion, atrophy, and degenerate cells in the
olfactory epithelium; loss of bowman’s glands; respiratory epithelium
hypertrophy; rosette formation in the septal organ of Masera and fusion
of the turbinates).  

870.3465

90-day inhalation – rat

MRID 42835901

Acceptable guideline	0, 2, 10 or 60 ppm .  6hrs/day; 5 d/wk.

NOAEL = not identified

LOAEL = 2  ppm based on increased incidence and severity of nasal
lesions (degeneration, atrophy and hyperplasia of basal cells of the
olfactory epithelium; rosette formation of olfactory epithelium; loss of
Bowman’s glands; hypertrophy of respiratory epithelium).  

Nonguideline

Chronic toxicity/carcinogenicity (chamber) Inhalation – rat

NTP 2000

Acceptable nonguideline	Concentrations:  0, 10, 30, or 60 ppm.   
6hrs/day; 5 d/wk.

NOAEL = not identified.

LOAEL = 10 ppm, based on increased incidence and severity of atypical
(basal cell) hyperplasia, atrophy, chronic inflammation, and hyaline
degeneration of the olfactory epithelium; hyperplasia, squamous
metaplasia, hyaline degeneration, and goblet cell hyperplasia of the
respiratory epithelium; and glandular hyperplasia and squamous
metaplasia.

Nonguideline

Chronic toxicity/carcinogenicity (chamber) Inhalation – mouse

NTP 1992

Acceptable nonguideline	Concentrations:  0, 10,  or 30 ppm.   6hrs/day;
5 d/wk.

NOAEL = not identified.

LOAEL =  10 ppm increased incidence and severity of chronic
inflammation, metaplasia of the olfactory epithelium, and hyperplasia of
respiratory epithelium. There was also increased incidence and severity
of chronic inflammation in the lung.  

870.5265

Gene mutation in S. typhimurium

MRID 42071602

0, TA1535, TA1537 or TA1538 up to cytotoxic concentrations (300
μg/plate ± S9)

870.5265

Gene mutation in S. typhimurium

NTP 2000	Naphthalene was negative in S. typhimurium strains TA98, TA100,
TA1535, TA1537 or TA1538 up to cytotoxic concentrations (100 μg/plate
± S9) in two separate trials using the pre-incubation modification to
the standard assay and S9 derived from hamster and Aroclor 1254-induced
rat livers.

870.5375

CHO  chromosome aberration

NTP 2000	Structural aberrations (types not reported) were observed only
in the presence of S9 activation, over a concentration range of 30 to
67.5 μg/mL.  Based on cell cycle data from the SCE assay, the harvest
time was extended to 20.5 hours to allow accumulation of a sufficient
number of metaphases to score and to demonstrate a clastogenic effect in
the CHO chromosome aberration assay.  

870.5375

CHO   Sister Chromatid Exchange

of 27 to 90 μg/mL ± S9).

870.5395

In vivo mouse bone marrow micronucleus

MRID 42071603

Acceptable	Naphthalene was negative for micronuclei induction in the
bone marrow of CD-1 male and female mice up to the maximum tolerated
dose (250 mg/kg) administered by intraperitoneal injection.  

870. 5550

UDS assay

MRID 42071604

Acceptable	Naphthalene did not induce UDS in primary rat hepatocytes up
to insoluble (≥ 166 μg/mL) and cytotoxic (≥ 50 μg/mL)
concentrations.

Nonguideline

In Vitro Dermal penetration – rat

Acceptable nonguideline	Based on an exposure time of 10 minutes, the
short-term in vitro penetration rate was calculated to be 142.6 μg
equiv/cm2/h.  Based on an exposure time of  60 minutes, the short-term
penetration rate was calculated to be 25.0 μg equiv/cm2/h.  

A.3  	Executive Summaries

A.3.1	Subchronic Toxicity

90-Day Oral Toxicity – Rat

EXECUTIVE SUMMARY:  Rats were administered by gavage to groups of 10
male and 10 female Fischer 344 rats at dose levels of 0, 25, 50, 100,
200, or 400 mg/kg/day, for 5 days/week for 13 weeks (NTP 1980a).  Body
weight gains decrements exceeding 10% was observed in both males and
females administered 200 or 400 mg/kg/day.  At the highest dose level,
clinical signs included lethargy, hunched posture, and roughened hair
coats.  High-dose males and females also exhibited marginal decreases in
hemoglobin and hematocrit levels.  Males in this group also displayed a
moderate increase in neutrophils and decrease in lymphocytes.  Minimal
renal cortical focal lymphocytic infiltrate (1 of 10 males) and minimal
renal focal tubular regeneration (1 of 10 males) were noted in male rats
treated with 200 mg/kg.  One male rat treated with 400 mg/kg naphthalene
exhibited moderate renal cortical diffuse tubular degeneration.  There
were no renal lesions in treated females, however, 2 of 10 females
treated with 400 mg/kg displayed moderate lymphoid depletion of the
thymus.  

The LOAEL = 200 mg/kg/day based on significant body weight decrement. 
The NOAEL = 100 mg/kg/day.

90-Day Oral Toxicity – Mouse

EXECUTIVE SUMMARY:  In this study, groups of 10 male and 10 female
B6C3F1 were administered 0, 12.5, 25, 50, 100 or 200 mg/kg naphthalene
by gavage 5 days/week for 13 weeks (NTP 1980b). Vehicle controls
received corn oil. Animals were observed for clinical signs of toxicity.
 Body weight and food consumption were frequently monitored. 
Hematology, clinical chemistry, and complete necropsy and histology were
performed.  In the high-dose males and females, rough hair coats and
lethargy were noted at weeks 3 or 4.  There were no other effects of
biological significance.

The LOAEL is 200 mg/kg/day based on transient clinical signs of toxicity
(rough hair coat and lethary).  The NOAEL is 100 mg/kg/day.  

90-Day Inhalation – Rat

EXECUTIVE SUMMARY:    In this study, Sprague-Dawley rats, 10/sex/group,
were exposed to naphthalene vapor (purity:  99.9%) for 13 consecutive
weeks( MRID 42835901).  Concentrations were 0, 2, 10 or 60 ppm.   The
parameters monitored included:  clinical observations, body weights,
food consumption, hematology, clinical chemistry, ophthalmoscopy,
necropsy, organ weights, and histology.  

Moderate degenerative changes in the olfactory epithelium, moderate to
marked atrophy of olfactory epithelium, minimal to moderate erosion of
olfactory epithelium, moderate hyperplasia of basal cells in olfactory
epithelium, moderate rosette formation in olfactory epithelium, loss of
Bowman’s glands, hypertrophy of respiratory epithelium were noted in
rats following exposure to 10 or 60 ppm naphthalene.  Similar findings
were noted in rats at the low dose (2 ppm), but these changes were
minimal.  However, several of the low-dose rats exhibited  some loss of
Bowman’s glands.  Significant body weight decrements (≥ 10%) were
observed throughout the study in males and females exposed to 10 or 60
ppm.  

The LOAEL is 2 ppm based on nasal lesions and a NOAEL was not
identified.

90-Day Dermal Toxicity – Rat

EXECUTIVE SUMMARY:  Groups of 10 – 20 male and female Sprague-Dawley
rats were exposed to naphthalene via the dermal route at 0, 100, 300,
and 1000 mg/kg/day.   The test material was applied as a neat solid
under occlusion for 6 hours/day, 5 days/week for 13 weeks.  Rats
(10/group) were sacrificed after 13 weeks of treatment, except for
additional animals (10/group) from each of the control and high-dose
groups that were observed for 4 weeks during a recovery phase. 
Following each exposure, the treatment area was wiped clean, and the
wrap and the test material discarded.  Animals were inspected for
clinical signs, mortality, changes in body weights, food consumption,
ophthalmology, hematology and clinical chemistry, organ weights,
urinalysis, gross necropsy and histopathology.  

There were no effects on mortality, food consumption, body weights,
hematology, clinical chemistry, urinalysis, and organ weights.  At 1000
mg/kg/day, there was excoriated skin and papules in both sexes; atrophy
of seminiferous tubules in the males; and nonneoplastic lesions in the
cervical lymph node (hyperplasia), liver (hemosiderosis), thyroid
(thyroglossal duct cysts), kidneys (pyelonephritis), urinary bladder
(hyperplasia) and skin (acanthosis, hyperkeratosis) in females. 

The LOAEL is 1000 mg/kg/day based on atrophy of seminiferous tubules in
males and various nonneoplastic lesions in females.   The NOAEL was 300
mg/kg/day.  

A.3.2	Prenatal Developmental Toxicity

Prenatal Developmental Toxicity Study – Rat

EXECUTIVE SUMMARY:  In the developmental toxicity study in
Sprague-Dawley CD rats, naphthalene was administered in corn oil by
gavage to 25-26 pregnant rats/dose group during gestation days 6 – 15.
 Dose levels were 0, 50, 150 or 450 mg/kg/day.  Dams and fetuses were
examined for signs of toxicity and teratogenicity.  

Clear evidence of maternal toxicity was noted in the mid- and high-dose
groups.  Maternal toxicity consisted of persistent clinical signs of
lethargy, slow breathing, rooting behavior, and significant decreases in
body weights/body weight gains and food and water consumption.  In
regard to body weight decrement, the mid-dose group exhibited a 31%
reduction in weight gain compared to controls, while the high-dose group
displayed a 53% reduction.  Post-treatment weight gain remained below
control values.  There were no treatment-related mortalities.  

There were no biologically significant effects of naphthalene on number
of corpora lutea per dam, % resorptions or fetal deaths/litter, %
litters with resorptions or deaths, number of live fetuses/litter,
average fetus body weight/litter, % malformed fetuses/litter, % litters
with malformations (external, visceral, skeletal) and % fetuses with
variations/litter.  

The maternal LOAEL is 150 mg/kgday based on persistent clinical signs of
lethargy, slow breathing, rooting behavior, and significant decreases in
body weights/body weight gains and food and water consumption. The
maternal NOAEL is 50 mg/kg/day. 

The developmental NOAEL is 450 mg/kg/day (highest dose tested).

Prenatal Developmental Toxicity Study – Rabbit

EXECUTIVE SUMMARY:  In the NTP developmental rabbit study, naphthalene
was administered in corn oil by gavage at dose levels of 0, 20, 80, or
120 mg/kg/day to pregnant rabbits during gestation days 6 – 19. 
Maternal clinical signs, body weights, and food consumption were
monitored on gestation days 0 – 30.  Fetuses were removed from dams on
gestation day 30, and then subjected to examination for any
treatment-related alterations on growth, viability, and morphological
development.  

There were no effects of naphthalene treatment on survival, maternal
body weights (including corrected gestational weight gain), and food
consumption.

Naphthalene was not fetotoxic.  Average live litter size and average
fetal body were similar between control and treated groups.  There was
no effect of treatment on the incidence of external, visceral, or
skeletal malformations.  Similarly, the incidence of variations or
defects on a fetal or litter basis was unaffected by treatment.  

The maternal and developmental NOAELs are 120 mg/kg/day (highest dose
tested).

A.3.3	Reproductive Toxicity

No reproductive toxicity studies are available.

A.3.4	Chronic Toxicity -  See A.3.5 for Combined Chronic/Carcinogenicity
NTP Inhalation Studies in the Rat and Mouse.  

A.3.5	Carcinogenicity

Combined Chronic/Carcinogenicity Study – Rat

EXECUTIVE SUMMARY:  In this study,  groups of 49 male and 49 female
F344/N rats were exposed to naphthalene by inhalation at concentrations
of 0, 10, 30, or 60 ppm for 6 hours plus T90 (12 minutes) per day, 5
days per week for 105 weeks (NTP 2000).  Additional groups of nine male
and nine female rats were exposed to 10, 30, or 60 ppm for up to 18
months for evaluation of toxicokinetic parameters.  

Survival in the exposed groups was similar to chamber controls. 
Decreased mean body weight was observed at the highest dose level in
males throughout the study (89-91% of control).  Mean body weight gains
in the high-dose group males were decreased by 10.5% (weeks 1-13), 10.9%
(weeks 14-52) and 8.6% (weeks 53-104).  

Nasal lesions were observed at all concentrations levels and included
atypical (basal cell) hyperplasia, atrophy, chronic inflammation, and
hyaline degeneration of the olfactory epithelium; hyperplasia, squamous
metaplasia, hyaline degeneration, and goblet cell hyperplasia of the
respiratory epithelium; and glandular hyperplasia and squamous
metaplasia. The severities of olfactory epithelial and glandular lesions
increased with increasing exposure concentration.  

Nasal tumors included neuroblastomas of the olfactory epithelium and
adenomas of the respiratory epithelium.  Neuroblastomas of the olfactory
epithelium occurred in males exposed to 30 or 60 ppm and in all exposed
groups of females.  The incidences of neuroblastoma occurred with
positive trends in males (p<0.05) and females (p<0.01), and the
incidence in females exposed to 60 ppm was significantly greater
(p<0.01) than that in the chamber controls.  Neuroblastomas have not
been observed in male or female chamber control rats in the NTP database
for animals fed NIH-07 feed in 2-year inhalation studies or in the more
recent, smaller database for control rats fed NTP-2000 feed.  

The incidences of adenoma of the respiratory epithelium occurred with a
positive trend in male rats and were significantly increased in all
exposed groups; the incidences in female rats exposed to 30 or 60 ppm
were also increased, but not significantly.  Nasal adenomas have not
been observed in male or female chamber control rats in the NTP database
for animals fed NIH-07 feed in 2-year inhalation studies or in the more
recent, smaller database for control rats fed NTP-2000 feed.

The NTP concluded that “under the conditions of this 2-year inhalation
study, there was clear evidence of carcinogenic activity of naphthalene
in male and female F344/N rats based on increased incidences of
respiratory epithelial adenoma and olfactory epithelial neuroblastoma of
the nose.  In male and female rats, exposure to naphthalene caused
significant increases in the incidences of non-neoplastic lesions of the
nose.”  

The LOAEL is 10 ppm based on nasal lesions, and a NOAEL was not
identified.

Combined Chronic/Carcinogenicity Study – Mouse

EXECUTIVE SUMMARY:  In this inhalation chamber study, groups of 75 mice
per sex were allocated to dose levels of 0 and 10 ppm, and 150 mice per
sex to the 30 ppm group (NTP 1992). Nasal lesions were observed in all
concentration levels and consisted of increased incidence and severity
of chronic inflammation, metaplasia of the olfactory epithelium, and
hyperplasia of respiratory epithelium. There was also increased
incidence and severity of chronic inflammation in the lung.  

Male mice had statistically significant pair-wise comparisons of the 10
ppm dose group with the controls for liver adenomas, and adenomas and
carcinomas combined, both at p < 0.01.  Only those animals with gross
lesions were examined microscopically for the liver in the 10 ppm dose
group, therefore, the statistical significance of the liver at this dose
group is skewed.  There were no statistically significant trends for
liver or lung tumors in the males and no pair-wise statistical
significance in the lung.  The statistical analyses of the tumors in
male mice were based upon Peto’s Prevalence Test since there were
statistically significant survival disparities among the dose groups.

Female mice had statistically significant trends, and statistically
significant pair-wise comparisons of the 30 ppm dose group with the
controls, for alveolar/bronchiolar adenomas, and adenomas and carcinomas
combined, all at p < 0.01.  The statistical analyses of the tumors in
female mice were based upon Peto’s Prevalence Test since there were
statistically significant survival disparities among the dose groups.

The NTP concluded that “under the conditions of this 2-year inhalation
study, there was “no evidence of carcinogenic activity” of
naphthalene in male B6C3F1 mice exposed to 10 or 30 ppm.  There was
“some evidence of carcinogenic activity” of naphthalene in female
B6C3F1 mice, based on increased incidences of pulmonary
alveolar/bronchiolar adenomas.  

The LOAEL is 10 ppm, and a NOAEL was not identified.

A.3.6	Mutagenicity

Gene Mutations

Naphthalene (99.9%) was not mutagenic in S. typhimurium strains TA98,
TA100, TA1535, TA1537 or TA1538 up to cytotoxic concentrations (300
μg/plate +/-S9) (MRID 42071602).

In the NTP microbial gene mutation assay, naphthalene was negative in S.
typhimurium strains TA98, TA100, TA1535 and TA1537 up to a cytotoxic
concentration (100 μg/plate +/-S9) in two separate trials using the
pre-incubation modification to the standard assay and S9 derived from
hamster and Aroclor 1254-induced rat livers. 

Chromosome Aberrations 

Based on the cell cycle data from the SCE assay (see below) showing cell
cycle delay (indicative of cytotoxicity), an extended harvest time of
20.5 hours was used in the NTP study to allow accumulation of a
sufficient number of metaphases to score and to demonstrate a
clastogenic effect in the CHO chromosome aberration assay.  The positive
response was observed only in the presence of S9 activation, over a
concentration range of 30 to 67.5 µg/mL.  The types of structural
aberrations were not reported. 

In a mouse micronucleus assay (MRID 42071603), naphthalene (99.9%) was
negative for micronuclei induction in the bone marrow of CD-1 male and
female mice up to the maximum tolerated dose (250 mg/kg) administered by
intraperitoneal injection.  At this dose, reduced body tone, abnormal
gait and lacrimation were seen in conjunction with cytotoxic effects on
the target organ (i.e., reduced polychromatic to normochromatic
erythrocytes at all sacrifice times). 

Other Genotoxic Tests 

ble (≥ 166 µg/mL) and cytotoxic (≥ 50 µg/mL) concentrations.

In the NTP SCE assay, naphthalene induced significant and
concentration-related increases in SCEs in CHO cells within a
concentration range of 27 to 90 µg/mL +/-S9.  

Evidence of Oxidative Stress  

Several studies in the open literature show that naphthalene undergoes
extensive oxidative metabolism to form naphthoquinones, which are
thought to generate ROS (superoxide anion radical, hydrogen peroxide,
hydroxyl radical and o-semiquinone anion radicals) via redox cycling
(Bolton, 2000).  A number of investigators have reported evidence of
naphthalene-induced oxidative damage by ROS (reviewed in Stohs, et al.,
2002). 

О2.-) and hydroxyl radical (OH) production.  

In vivo evidence of increased superoxide anion production was also
observed in hepatic and brain tissues in mice (C57BL/6NTac) treated with
naphthalene (Bagchi et al., 2000). As previously mentioned, the
naphthalene metabolite 1,2-naphthoquinone was positive for mutation in 
S. typhimurium TA104, a tester strain sensitive to oxidative damage
(Flowers-Geary, et al., 1996).  Overall, the evidence suggests that the
oxidative metabolism of naphthalene leads to the production of ROS which
may result in oxidative-stress induced cytotoxicity.

Other Published Literature

Using a modified CREST in vitro micronucleus assay, Saskai et al. (1997)
reported that naphthalene (30 µg/ml) induced chromosome breakage-type
micronuclei and naphthalene metabolite 1,4-naphthoquinone (0.10 µg/ml)
induced chromosome loss-type micronuclei in metabolically competent
human lymphoblastoid cells (MCL-5).  However, in vivo studies showed no
induction of micronuclei using either the oral or intraperitoneal (ip)
route in mouse bone marrow cells.  Similarly, naphthalene was negative
for in vivo UDS in rat hepatocytes and failed to induce morphologic cell
transformation in five different cell lines including Fischer rat
embryo, Syrian baby hamster, BALB/c, BALB/c 3T3 or human diploid WI-38
cells.  

In another study, naphthalene did not induce neoplastic transformation
in partially hepectomized F344 rats receiving single oral gavage
administrations of 100 mg/kg.  However, Bagchi et al. (1998, 2000 and
2002), reported that naphthalene caused DNA fragmentation in brain and
liver tissue of C57BL/6NTac dosed once with 158 mg/kg (0.5x LD50), in
Sprague-Dawley rats administered an oral dose of 110 mg/kg/day for 120
days and in p53-deficient mice (C57BL6/6TSG-p53) after single oral doses
of 0.01x, 0.10x or 0.5x LD50.  In these assays, DNA fragmentation was
accompanied by increased lipid peroxidation in the harvested tissues. 
It was, therefore, speculated that, the results were unclear as to
whether the DNA damage was “due to direct effects of naphthalene
metabolites or reactive oxygen species (ROS) or was secondary to cell
death induced at an extranuclear site.” No genetic toxicology studies
were found for sensitive target organs (lung or nasal epithelial
tissues).  

A.3.7	Neurotoxicity

870.6200a   Acute Neurotoxicity Screening Battery – Oral route

EXECUTIVE SUMMARY -  In an acute neurotoxicity study (MRID 44282801),
groups of fasted, 5-7 week-old CD rats (10/sex/dose) were given a single
oral dose of naphthalene (99.9% a.i., batch/lot # 235/50320) in corn oil
at doses of 0, 400, 800, or 1200 mg/kg bw and observed for 14 days. 
Neurobehavioral assessment (functional observational battery and motor
activity testing was performed on all animals pre-treatment, on Day 1 at
estimated time of peak effect (i.e. 2 hours after dosing) and Days 7 and
14 of the observation period.  Cholinesterase activity was not
determined.  Motor activity of all animals was measured for one hour, at
6-minute intervals, immediately after the completion of the Functional
Observation Battery (FOB).  At study termination, 5 animals/sex/group
were euthanized and perfused in situ for neuropathological examination. 
Of the perfused animals, 5/animals/sex from the control and high dose
groups were subjected to histopathological evaluation of brain and
spinal cord.  In addition, peripheral nervous system tissues from all
animals sacrificed were examined. All animals survived to study
termination.   SEQ CHAPTER \h \r 1  Clinical signs from daily cage-side
observation were similar to findings in the FOB (see below).

Absolute body weight was slightly decreased in high dose males on Day 7
and 14 (12% and 9%, respectively) compared to controls.  A dose-related
decrease in body weight gain was noted in all treated animals compared
to controls.  The most pronounced effect on weight gain was during the
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23%, 40%, and 57%, respectively, less in females.  Recovery was
subsequently seen in all treated groups.  Food consumption in females
was unaffected by treatment.  Food consumption among treated males was
reduced on the day of administration (37%, 52% and 67% in low-, mid- and
high-dose groups, respectively).

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ated effects seen in the open field were gait abnormalities in high-dose
females (9/10), and head shaking behavior in males and females from
low-, mid- and high-dose groups (2/10, 4/10 and 6/10 in males and 5/10,
6/10 and 7/10 in females, respectively).  On Day 7, hunched posture
(1/10, 3/10, 5/10 and 6/10) was seen in females at all dose levels with
decreased reactivity during removal from cage in both sexes (6/10, 9/10,
9/10 and 10/10 in males; 4/10, 8/10, 9/10 and 10/10 in females at
control, low-, mid- and high-dose groups, respectively) and an increased
incidence of piloerection in high-dose males (8/10) and all treated
females (5/10, 3/10 and 5/10 at low-, mid- and high-dose, respectively).
 Urination and defecation frequencies were higher in all treated groups
of males and females compared to those of controls.  By Day 14 in both
males and females there was increased urination in all dose groups and
defecation in mid- and high-dose groups.  Body temperature of the
treated female groups was 35.2-36.8°C compared with 38.4°C for the
controls on Day 1, 38.1-38.2°C compared with 38.6°C for controls on
Day 7 and 38.0-38.2°C compared with 38.5°C for controls on Day 14.

No treatment-related effects were seen in landing footsplay or fore- and
hind-limb grip strengths on any testing day.

On Day 1, a marked decrease in motor activity was noted in both sexes in
all treatment groups.  Low and high beam counts for the treated groups
were 63-75% and 78-88%, respectively, less than controls for males and
74-78% and 90-94%, respectively, less than controls for females.  On Day
7, motor activity was significantly reduced compared to controls in all
treatment groups with low and high beam breaks 38-62% and 49-61%,
respectively, less than controls for males and 54-60% and 58-67%,
respectively, less than control levels for females.  Motor activity on
Day 14 was lower compared to that of the controls although to a lesser
extent than on day 7 with low and high beam breaks 27-43% and 36-50%,
respectively, less than control levels for males and 23-40% and 41-42%,
respectively, less for females.

There was no difference in weight of the brain and pituitary between the
control and treated groups.  Gross and microscopic examinations of
central and peripheral nervous tissue did not reveal any
treatment-related effects.

The LOAEL for neurotoxicity of  naphthalene in rats was 400 mg/kg bw
based on clinical signs (piloerection, fast respiration, hunch posture),
reduced motor activity, lower body temperature, and head shaking and
increased urination and defecation in the open field.  The NOAEL was not
established. 

870.6200b   Subchronic Neurotoxicity Screening Battery – Inhalation
route

EXECUTIVE SUMMARY -  In this subchronic inhalation neurotoxicity study
(MRID 44856401) naphthalene  was administered to 10 CD rats/sex/group as
a vapor by dynamic nose-only exposure at target concentrations of 0, 1,
10, or 60 ppm for 6 hours per day, 5 days/week for a total of 13 weeks. 
Overall mean analytical concentrations were 0, 0.99, 10.0, and 62.8 ppm.
 Neurobehavioral assessment (functional observational battery and motor
activity testing) was performed on all animals pre-test and at the end
of Weeks 4, 8, and 13.  At study termination, the animals were
euthanized and perfused in situ.  The first 5 males and 5 females per
group were used for neuropathological examination (control and
high-concentration, only) and microscopic evaluation of the nasal
passages (all treatment groups).  

There were no deaths during the study.  One female from each of the mid-
and high-concentration groups appeared slightly emaciated during Week
12.  Five/10 and 6/10 mid- and high-concentration females and 1/10
mid-concentration males had brown staining of the ventral surface during
Weeks 10-14 with two females from each group also showing brown staining
of the dorsal surface.  At 10 and 60 ppm, mean cumulative body weight
gain was significantly decreased in both sexes compared to controls
(males: -22% and -34%, respectively; females: -26% and -34%; p<0.01).  
Absolute body weight was also decreased in these same groups compared to
their respective controls, with high-concentration males weighing 12-18%
less during Weeks 4-13, mid-concentration males weighing 9-11% less
during Weeks 8-13, high-concentration females weighing 10-14% less
during Weeks 4-13, and mid-concentration females weighing 9-12% less
during Weeks 3-13.  Mean weekly food consumption was decreased in
high-concentration males during Weeks 3-13 (12-16% less than that of
controls) and in mid- and high-concentration females during Weeks 2-13
(10-15% and 10-19% less than controls, respectively). 
High-concentration females spent significantly less total time in
locomotor activity at Week 13 (-38%; p<0.01).  

A number of treatment-related microscopic lesions of the nasal passages
were seen.   Minimal or slight hyperplasia of the
respiratory/transitional epithelium in the rostral region was noted in
all treated animals (vs. no controls), and atrophy/disorganization of
the olfactory epithelium was seen at all exposure levels in both sexes
(in ascending dose order, males: 0/5,1/5, 3/5, 5/5 and females 0/5, 2/5,
5/5, 5/5).  Apparent loss of Bowman’s glands and olfactory nerve
fibers was noted in all animals of both sexes at 10 and 60 ppm.  Other
lesions included erosion/necrosis of the olfactory epithelium (males:
0/5, 0/5, 0/5, 2/5; females: 0/5, 1/5, 5/5, 4/5), hyperplasia of the
olfactory epithelium (males: 0/5, 0/5, 0/5, 5/5; females; 0/5, 0/5, 5/5,
4/5), inflammatory exudate in the airway (males: 0/5, 0/5, 2/5, 3/5;
females: 0/5, 0/5, 5/5, 5/5), and rosettes of the olfactory epithelium
(males: 0/5, 0/5, 1/5, 5/5; females: 0/5, 0/5, 2/5, 3/5).  There were no
treatment related effects on brain weight or neuropathology.  

The LOAEL was 10 ppm based on atrophy/disorganization of the olfactory
epithelium and hyperplasia of the respiratory and transitional
epithelium.  The  NOAEL is 1 ppm.   

Appendix B:	Review of Human Research

Studies reviewed for ethical conduct:

No MRID - PHED Surrogate Exposure Guide

MRID 43716501

Waggoner, T. (1994) Estimation of Homeowner Exposure to LX1298-01
(Naphthalene) Resulting from Simulated Residential Use as an Insect
Repellent.  Unpublished study prepared by Landis International, Inc. and
Pharmaco LSR Inc. under Project No. 93-9083.  100 p.  

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