Document ID: EPA-HQ-OPP-2007-0937-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-12-12T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF	

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: September 27, 2007

MEMORANDUM

SUBJECT:	para-Dichlorobenzene:  HED Chapter of the Reregistration
Eligibility Decision Document (RED).  PC Code: 061501, Case #: 3058, DP
Barcode: D334021.

		Regulatory Action: Phase 1 Reregistration Action

		Risk Assessment Type: Single Chemical No Aggregate

FROM:	William H. Donovan, Ph.D., Chemist & Risk Assessor

		Seyed Tadayon, Chemist		

Reregistration Branch 3

		Health Effects Division (7509P)

 

			AND

		George Ghali, Ph.D., Toxicologist

		Toxicology Branch

		Health Effects Division (7509P)

 

THROUGH:	Catherine Eiden, Branch Chief 

		Reregistration Branch 3

		Health Effects Division (7509P)

 

			 

TO:		Molly Clayton, Chemical Review Manager

		Reregistration Branch	2

		Special Review & Reregistration Division (7508P) 

Attached is the Health Effect Division’s preliminary risk assessment
for the para-dichlorobenzene RED.  This risk assessment document was
based on information contained in the following memos:

Occupational and Residential Exposure Assessment:  S. Tadayon, D341252,
27-SEP-2007.

Incident Report:  M. Hawkins & H. Allender, D334455, 25-JUN-2007.

CARC Report:  J. Kidwell, TXR No. 0054616, 05-JUN-2007.

Table of Contents

  TOC \o "1-3" \u  1.0	Executive Summary		  PAGEREF _Toc178138556 \h  3 

2.0	Ingredient Profile		  PAGEREF _Toc178138557 \h  7 

3.0	Hazard Characterization/Assessment	  PAGEREF _Toc178138558 \h  9 

3.1	Hazard and Dose-Response Characterization	  PAGEREF _Toc178138559 \h
 9 

3.1.1	Database Summary	  PAGEREF _Toc178138560 \h  9 

3.1.2  Toxicological Effects and Dose Response	  PAGEREF _Toc178138561
\h  10 

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)	  PAGEREF
_Toc178138562 \h  14 

3.3	Hazard Characterization for Women and Children	  PAGEREF
_Toc178138563 \h  14 

3.3.1	Adequacy of the Toxicity Database	  PAGEREF _Toc178138564 \h  15 

3.3.2	Evidence of Neurotoxicity	  PAGEREF _Toc178138565 \h  15 

3.3.3	Developmental Toxicity Studies	  PAGEREF _Toc178138566 \h  15 

3.3.4	Reproductive Toxicity Study	  PAGEREF _Toc178138567 \h  16 

3.3.5	Pre-and/or Postnatal Toxicity	  PAGEREF _Toc178138568 \h  17 

3.3.6	Recommendation for a Developmental Neurotoxicity Study	  PAGEREF
_Toc178138569 \h  18 

3.4	Hazard Identification and Toxicity Endpoint Selection	  PAGEREF
_Toc178138570 \h  18 

3.4.1	Incidental Oral (Short-Term)	  PAGEREF _Toc178138571 \h  18 

3.4.2	Inhalation Exposure (Short-Term)*	  PAGEREF _Toc178138572 \h  19 

3.4.3	Inhalation Exposure (Intermediate-Term)	  PAGEREF _Toc178138573 \h
 20 

3.4.4	Inhalation Chronic Reference Concentration (cRfC)	  PAGEREF
_Toc178138574 \h  21 

3.4.5	Dermal Absorption	  PAGEREF _Toc178138575 \h  22 

3.4.6    Dermal Exposure (Short- and Intermediate-Term)	  PAGEREF
_Toc178138576 \h  22 

3.4.7. 	Level of Concern for Margin of Exposure	  PAGEREF _Toc178138577
\h  23 

3.4.8.   Recommendation for Aggregate Exposure Risk Assessments	 
PAGEREF _Toc178138578 \h  23 

3.4.9	Classification of Carcinogenic Potential	  PAGEREF _Toc178138579
\h  23 

3.6	Endocrine disruption	  PAGEREF _Toc178138580 \h  26 

4.0	Public Health and Pesticide Epidemiology Data	  PAGEREF
_Toc178138581 \h  27 

5.0	Dietary Exposure/Risk Characterization	  PAGEREF _Toc178138582 \h 
28 

6.0	Residential (Non-Occupational) Exposure/Risk Characterization	 
PAGEREF _Toc178138583 \h  28 

7.0	Aggregate and Cumulative Risk Assessments and Risk Characterization	
 PAGEREF _Toc178138584 \h  33 

8.0	Cancer Risk		  PAGEREF _Toc178138585 \h  34 

9.0  	Occupational Exposure/Risk Pathway	  PAGEREF _Toc178138586 \h  36 

10.0	Data Needs and Label Recommendations	  PAGEREF _Toc178138587 \h  36

Appendix A:  Toxicology Assessment		  PAGEREF _Toc178138588 \h  37 

Appendix B:  Methodologies for Inhalation Risk Calculations and Human
Equivalent Concentration Arrays		  PAGEREF _Toc178138589 \h  65 

Appendix C:  Review of Human Research	  PAGEREF _Toc178138590 \h  68 

 1.0	Executive Summary

Background

para-Dichlorobenzene is classified as a fumigant insecticide due to its
relatively high vapor pressure and repellant effect on insects.  The
para-dichlorobenzene found in indoor air originates mainly from moth
repellents used to protect clothing and from deodorants that are used in
the household.  para-Dichlorobenzene is used to control moths, molds,
and mildew, and to deodorize restrooms and waste containers.  At room
temperature, para-dichlorobenzene is a white solid with a strong,
pungent odor.  When exposed to air, it sublimates to produce vapors.  It
is the vapor that acts as a deodorizer or insect killer.  Most people
can smell para-dichlorobenzene in the air at very low levels.  It also
has applications in fumigants, insecticides, lacquers, paints, and seed
disinfection products.  The present assessment primarily considers
indoor uses of para-dichlorobenzene as all outdoor uses have been
voluntarily cancelled except for an empty beehive use. 

Hazard Characterization

The toxicity of para-dichlorobenzene is thought to be due to direct
binding of the epoxide or other oxidative metabolites to cellular
proteins. The metabolism of para-dichlorobenzene is initiated by the
oxidation of the aromatic moiety to an epoxide, a reaction catalyzed by
cytochrome P450 isozymes. The epoxide, an initial metabolite of
para-dichlorobenzene, may then undergo hydrolysis to dichlorophenol,
which is thought to be associated with nephropathy, bind directly to
cellular proteins, or conjugate with glutathione.  para-Dichlorobenzene
is rapidly absorbed following oral or inhalation exposure, accumulates
primarily in the liver and kidney, and is rapidly excreted, mainly via
the urine (the majority excreted in 48 hours).  It is moderately acutely
toxic via the oral and dermal routes of exposure; and of low to medium
toxicity via the inhalation route.  Although it is not a dermal
sensitizer, it is moderately irritating to skin and a strong eye
irritant.  Dermal penetration is considered to be very slow although a
dermal absorption factor was not determined.  Oral studies in rodents
and non-rodent species indicate that the liver and kidney are common and
primary target organs/tissues.  Decreased body weight, reduced organ
weights, and changes in hematological parameters are considered some of
the common effects for this chemical. Risk was assessed using regulatory
endpoints that were based on adverse effects in the most sensitive
species tested for the particular exposure route and duration under
consideration.  

Approaches to evaluate the carcinogenicity risk of para-dichlorobenzene
have evolved as more data have become available.  Based on the existing
database plus recent comprehensive rat and mouse inhalation
carcinogenicity studies in 2005 by Asio et. al., there is evidence that
a non-mutagenic mode of action (MOA) involving mitogenesis (i.e.,
provides a selective growth advantage to spontaneously-initiated
precancerous/cancerous cells) is plausible for para-dichlorobenzene
induced liver tumors in mice.  Generally, when the CARC determines that
there is a plausible MOA for a carcinogen, HED does not conduct a
low-dose linear extrapolation for cancer.  However, the IRIS program is
currently reviewing the mode of action evidence for para-dichlorobenzene
and has not yet made a determination of non-linearity.  Accordingly, for
the purposes of the present assessment, HED is presenting a linear
low-dose extrapolation risk for cancer. 

Exposure Scenarios

Because of the volatile nature of para-dichlorobenzene, inhalation
exposure is the most likely route for human exposure under the current
use profile. Duration of exposure may vary from acute,
short/intermediate to long-term exposure. Oral exposure is unlikely and
may be limited to episodic incidental ingestion by children. Dermal
exposures are expected to be limited, as well.

 TC \l2 "5.2  Dietary Exposure and Risk 

Residential Risk

Residential Handler Exposure:  HED anticipates handler 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 for residential handlers. 
Exposure data does exist for short-term exposure from postapplication
inhalation exposure to areas treated with para-dichlorobenzene, and this
exposure scenario has been assessed.  HED assumes that the short-term
postapplication inhalation assessment is protective for handler
inhalation exposure since measured concentrations of
para-dichlorobenzene would likely be greater due to the time allotted in
the exposure study for the product to accumulate in the enclosed areas
that were treated. 

Handler exposure durations are expected to be short-term (1-30 days). 
Intermediate-term (1- 6 months) or long-term (> 6 months) exposures are
not expected for this particular use.  Naphthalene   SEQ CHAPTER \h \r 1
data (MRID# 437165-01) were used to assess exposures from hand
applications.  A MOE of 100 or more is sufficient to protect adults from
residential handler exposures to para-dichlorobenzene.  Risk estimates
for all applicator scenarios (closets and drawer) are below the level of
concern (MOEs ≥ 100) at the baseline level (i.e., without use of
gloves).

≥ 30).

Residential Episodic Ingestion:  HED does not consider ingestion of
mothballs to be a routine behavior in which ingestion occurs on a
regular basis, but instead considers this an episodic event. 
Accordingly, an assessment of episodic incidental ingestion was
performed.  As the short-term incidental oral NOAEL is 25 mg/kg/day, the
short-term oral MOE for incidental ingestion of one mothball by a
toddler is 0.16 (compared to a target MOE of 100) and is, therefore, of
concern to HED.  HED performed additional calculations to determine the
dose level required to result in a MOE of 100.  Based on these
calculations, oral consumption of anything greater than 0.25 mg/kg/day
para-dichlorobenzene results in a MOE less than 100 and is considered a
risk of concern by HED.  This oral dose of para-dichlorobenzene, 0.25
mg/kg/day, is equivalent to a 15 kg toddler consuming 0.16% of one 2.35
g mothball.  HED believes the risk estimate for mothball ingestion is
conservative as it is based on comparison of an episodic (one-time
event) to a toxic endpoint reflecting repeated short-term exposures.

Aggregate Risk

An aggregate risk assessment was not conducted for para-dichlorobenzene
since there is no food, water, or outdoor exposure to this chemical. 
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. 

Occupational Risk

The only occupational use of para-dichlorobenzene arises from use in
empty beehives.  Exposure from this activity is expected to be no higher
than the handler (dermal) and post application (inhalation) exposures
from the indoor residential use of mothballs which was assessed.  Risk
estimates for residential handler and post application exposures are
protective of this occupational use and below levels of concern. As a
result, HED believes a separate risk assessment for occupational
exposures (handler and post application) is not warranted and was not
conducted for para-dichlorobenzene.

Cancer Risk

Cancer risk estimates resulting from exposures to para-dichlorobenzene
were calculated for homeowners handling mothballs (dermal), and
individuals living in homes treated with mothballs and inhaling mothball
vapors using a linear low dose extrapolation model.  

 

Estimated cancer risks for dermal exposures of adults handling mothballs
during application are below HED’s levels of concern (risks are below
1 x 10-6 using the linear approach).  For individuals living in homes
treated with mothballs and inhaling mothball vapors, the cancer risk
estimates could be as high as 6 x 10-5.  

The linear low dose extrapolation model provides a range of cancer
risks. As with all linear low dose extrapolation models, the range is
bracketed by an upper bound and a lower bound on these risks.  The 6 x
10-5 cancer risk estimate represents an upper bound on cancer risk for
exposures to para-dichlorobenzene but the cancer risk could be as low as
zero.  This is independent of the strengths and weaknesses of the cancer
data.  HED believes that the carcinogenic risks are below the upper
bound and may be closer to zero for para-dichlorobenzene for several
reasons as follows.  Available evidence as described in Section 3.4.9
(Classification of Carcinogenic Potential) of this document, indicates
that the mechanism leading to tumor formation in the livers of mice
after exposure to para-dichlorobenzene is based on sustained mitogenic
stimulation and proliferation of hepatocytes.  This information forms
the basis of a plausible mode of action (MOA) for tumorigenesis in the
mice livers. In addition, the BMCL 10  (the lower limit of the benchmark
concentration central estimate for a 10% response above background. 
Note:  a 10% response is at the limit of sensitivity in most cancer
bioassays) for hepatocellular adenoma or carcinoma formation in female
mice is 22.9 mg/m3.  If the    BMCL 10 is compared to the measured
concentrations of para-dichlorobenzene in people’s homes (0.021 mg/
m3), the   BMCL 10 is 1000 times higher than actual exposures.  That is,
there is a 1000-fold margin of safety between the concentration at which
there is a 10% tumor response in test animals, at the lowest measurable
incidence, and actual measured exposure in people’s homes. 
Consequently, HED believes the carcinogenic risk from this use is not of
concern for the following reasons: 1) there is mechanistic data to
support a lower cancer risk estimate based on a mitogenic mode of
carcinogenic action, 2) conservatisms in the exposure estimates, and 3)
a large margin of safety between estimated human exposure and the point
at which there is a measurable (10%) tumor response. 

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.  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 studies in which adult
human subjects were exposed (either intentionally or unintentionally) to
a pesticide or other chemical.  These studies (Appendix C) have been
determined to require a review of their ethical conduct, and have
received that review.  It was concluded that there are no regulatory
barriers to EPA’s reliance on these studies in its actions under FIFRA
(J.M. Carley, 4/24/2007 & J.M. Carley, 9/27/2007).

Recommendations

The registrant should conduct a confirmatory chamber study to determine
levels of para-dichlorobenzene in the air resulting from use of
mothballs at the maximum label rate.  The short-term post application
inhalation risk levels were estimated using surrogate exposure data from
a naphthalene mothball study.  However, para-dichlorobenzene has a
higher vapor pressure than naphthalene and the concentration of
para-dichlorobenzene in the air from mothball uses may exceed that of
naphthalene.  A targeted exposure study using para-dichlorobenzene
mothballs will ensure that the short-term inhalation exposures and risks
to para-dichlorobenzene as a result of mothball use have not been
underestimated.

All risk scenarios evaluated for para-dichlorobenzene resulted in risk
levels below HED’s level of concern except for episodic incidental
oral ingestion of mothballs by toddlers.  A possible risk mitigation
step to address this scenario might include the use of special packaging
to block children from reaching the active ingredient.

2.0	Ingredient Profile

  TC \l1 "2.0	Ingredient Profile 

para-Dichlorobenzene is a fumigant insecticide and has been widely used
as a moth repellant to protect garments from insect damage.  It is also
used for the control of lice and ticks in and around birdcages, and also
as a bathroom deodorant.  The maximum application rate for mothballs is
1.0 lb ai/50ft3 and mothballs should last for six months.

Table 2.1.  Test Compound Nomenclature

Chemical Structure	

Empirical Formula	C6H4Cl2

Common Name	para-dichlorobenzene or 1,4-dichlorobenzene

IUPAC name	p-dichlorobenzene

CAS Name	1,4-dichlorobenzene

CAS Registry Number	106-46-7

Chemical Class	Fumigant insecticides

  TC \l2 "2.3	Physical and Chemical Properties 

Table 2.2.  Physiochemical Properties

Parameter	Value	Reference

Molecular Weight	147	D304943, S. Mathur, 07-FEB-2005

Melting point	53 C

	Boiling point	174 C

	Density	1.458 @ 25 C

	Water solubility (20°C)	0.007% @ 23 C

	Flammability	66 C

	Vapor pressure (20°C)	0.40 mm Hg; sublimes at ambient temperatures 

	Physical state	Crystalline solid

	Color	White

	



Table 2.3.  Summary of Use Directions for Products Containing
para-dichlorobenzene.

Reg.No	%AI	Product Name	Use/Pest	Equipment	Max App Rate Qty	Max App Rate
Unit/Area

081433-00005	99.6	IMS MOTH CRYSTALS	HUMAN CLOTHING 

 

 

 

 

 

 

 

 

 	Product container

	9.96	lb 1K cu.ft

081433-00004	99.8	IMS MOTH CAKE

	0.0104	lb cu.ft

081433-00003	99.6	IMS MOTH BLOCK

	0.0104	lb cu.ft

081433-00002	99.8	IMS MOTHBALLS

	0.0104	lb cu.ft

070305-00003	100	PARA MOTHBALLS CEDAR SCENTED

	0.02	lb cu.ft

070305-00002	99.9	PARA MOTHBALLS CEDAR SCENTED

	0.02	lb cu.ft

070305-00001	99.5	PARA MOTHBALLS

	0.0199	lb cu.ft

010937-00001	99.9	AUSTIN'S MOTH CONTROL

	0.3122	lb bag

002915-00026	99.7	FULLER BRUSH CO. PERFUMED DEODORANT BLOCK

	0.0249	lb cu.ft

001475-00157	99.9	REEFER-GALLER NO-MOTH CLOSET HANGER

	0.0201	lb cu.ft

001475-00144	99.68	OLD FASHIONED LAVENDER SCENTED MOTH SACHETTES

	0.0208	lb cu.ft

001475-00143	99.68	MOTH-TEK PAPER COVERED MOTH BALL PACKETS

	35	packets 15 cu.ft

001475-00113	99.68	REEFER-GALLER NO-MOTH CLOSET HANGER

	0.0196	lb cu.ft

001475-00040	99.9	ENOZ MOTH CAKE VAPORIZER

	0.02	lb cu.ft

001475-00039	99.9	PARA MOTHBALLS CEDAR SCENTED

	19.98	lb 1K cu.ft

001475-00007	99.9	ENOZ 

ARADICHLOROBENZENE MOTH CAKE

	0.02	lb cu.ft

043576-00002	50	FEATHER GLO BIRD-CAGE-DEFENDER	BIRDS

0.0313	lb cage

002517-00022	50	DOUBLE DUTY BIRD GUARD

	1	container cage (L)

001903-00006	50	8 IN 1 BIRD PROTECTOR

	0.0234	lb cage

061671-00002	100	COLUMBIA PARA-DICHLOROBENZENE	BEEHIVES-EMPTY

0.1875	lb hive

058630-00003	98.6	VARPEL ROPE	INDOOR PREMISES	Rope applicator	9.86	ft 1K
cu.ft



3.0	Hazard Characterization/Assessment  TC \l1 "3.0	Hazard
Characterization/Assessment 

3.1	Hazard and Dose-Response Characterization  TC \l2 "3.1	Hazard and
Dose-Response Characterization 

3.1.1	Database Summary  TC \l3 "3.1.1	Database Summary 

Studies available and considered 

Material available for review consisted of data evaluation records
(DERs) for the following studies:

Acute toxicity- Oral-rat, dermal-rat (dermal rabbit – waived),
inhalation-rat, primary eye irritation-rabbit, primary dermal
irritation-rabbit, dermal sensitization-guinea pig,  inhalation
neurotoxicity- rat

Subchronic toxicity- Oral-dog (28-day), inhalation-dog (28-day),
inhalation- rat (thirteen-week), inhalation-mouse (thirteen-week),
inhalation neurotoxicity – rat, 21-day dermal-rat (substituted the
21-day dermal – rabbit).

Chronic toxicity/Carcinogenicity- Oral-rat (combined chronic toxicity
/carcinogenicity-NTP), oral-mouse (carcinogenicity- NTP), inhalation-rat
(chronic toxicity/carcinogenicity), inhalation mouse (chronic
toxicity/carcinogenicity), oral-dog (one-year). 

Mutagenicity- a battery of mutagenicity and genetic toxicity studies
including: 1) gene mutation (reverse mutation in Salmonella typhimurium
with and without metabolic activation, Chinese Hamster Ovary (CHO)
cell/HGPRT forward mutation, and gene mutation in Drosophila/SLRL); 2)
structural chromosomal aberration (in vivo cytogenetics in rats,
dominant lethal assay in mice, in vivo micronucleus in mice, in vitro
cytogenetics (CHO/SCE), in vitro cytogenetics (CHO/CA), and in vivo
cytogenetics (rat BA/CA); and 3) other genotoxic tests (in vivo / in
vitro unscheduled and scheduled DNA synthesis assay in mouse
hepatocytes, in vivo / in vitro unscheduled and scheduled DNA synthesis
assay in rat kidney cells, and BALB/3T3 cell transformation assay.  

Reproductive/developmental toxicity - Inhalation developmental toxicity
studies in rats and rabbits; inhalation 2-generation reproductive
toxicity in rats.

Other- Metabolism in the rat, and

Mechanistic studies in rodents (open literature).  TC \l4 "3.1.1.1
Studies available and considered (animal, human, general literature) 

Mode of action, metabolism, toxicokinetic data

para-Dichlorobenzene is a white, volatile, colorless crystal.  It is
used in air fresheners, as moth repellent in mothballs and crystals, as
well as for mildew control and other pesticide applications. Other uses
of this chemical include the use as germicide, and as intermediate in
the manufacture of 2,5-dichloroaniline, pharmaceuticals, and
polyphenylene sulfide resins (Lewis, R. J., Sr (Ed). Hawley’s
Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand
Rheinhold Co., 1993, p. 378; IARC 1999; U.S. EPA, 1981).

The toxicity of para-dichlorobenzene is thought to be due to direct
binding of the epoxide or other oxidative metabolites to cellular
proteins. The metabolism of para-dichlorobenzene is initiated by the
oxidation of the aromatic moiety to an epoxide, a reaction catalyzed by
cytochrome P450 isozymes. The epoxide, an initial metabolite of
para-dichlorobenzene, may then undergo hydrolysis to dichlorophenol,
which is thought to be associated with nephropathy, bind directly to
cellular proteins, or conjugate with glutathione. Dichlorophenol may be
oxidized further to dichlorocatechol and dichlorohydroquinone, or
conjugated with glutathione, glucuronic acid, or sulfate.  Quinones and
hydroquinones, other oxidative metabolites of para-dichlorobenzene, are
thought to be associated with hepatotoxicity. Despite their reactivity
with cell macromolecules, metabolites of para-dichlorobenzene generally
exhibit minimal affinity to bind to DNA.

Toxicokinetic data in the rat and mice show that para-dichlorobenzene is
rapidly absorbed after oral administration or inhalation exposure in
rats and mice. Absorption is faster via oral exposure than inhalation,
and faster in mice than rats regardless of the route of administration. 
The principal route of elimination of para-dichlorobenzene is by renal
excretion of the dichlorophenol and its conjugates, with the majority
excreted in the urine in 48 hours.  The amount excreted in feces and the
expired air constitutes 10% of the dose.  The highest tissue
concentration was observed in liver and kidneys.  

Sufficiency of studies/data

Based on the current use profile for para-dichlorobenzene (a non-food
chemical), it is concluded that the available toxicology database is
considered adequate to support the re-registration of this chemical. 

3.1.2  Toxicological Effects and Dose Response

Acute Toxicity

para -Dichlorobenzene is considered moderately toxic on an acute basis
by the oral and dermal routes and is classified as “Category III”. 
It is considered of low to medium toxicity by the inhalation route and
is classified as “Category IV”. It is categorized as “Category
II” and “Category III” for primary eye and dermal irritation,
respectively.  para-Dichlorobenzene did not induce delayed contact
sensitivity “dermal sensitization” when tested in guinea pigs.  

Dermal Toxicity and Absorption

In the 21-day dermal toxicity study, no dermal or systemic toxicity were
observed up to the highest dose level of 300 mg/kg/day.  No study was
available for the calculation of a dermal absorption factor for
para-dichlorobenzene. However, based on the current use profile, dermal
exposure is not a likely route for human exposure.  Dermal penetration
is considered to be very slow based on a dermal LD50 of over 6000 mg/kg
and a NOAEL of >300 in a 21 day dermal toxicity study in the rat.   

Subchronic/Chronic

The toxicity of para-dichlorobenzene has been investigated in several
animal species by the oral and inhalation routes under chronic and
subchronic exposure conditions.  The volatility of this material makes
the inhalation route the most likely route of human exposure under the
current use profile as a moth repellent.  Oral exposure is unlikely
under the current use profile, and may be limited to incidental
ingestion by children.  Inhalation exposure may range in duration from
short- or intermediate- to long-term or chronic exposure.  Oral studies
in rodents and non-rodent species indicate that the liver and kidney are
common and primary target organs/tissues.  Decreased body weight,
reduced organ weights, and changes in hematological parameters are
considered some of the common effects for this chemical. 

Animal and human data available on this chemical suggest that the liver
and the renal system are major target organs for the toxicity of
para-dichlorobenzene.  Hepatic effects have been reported in humans
following several months of exposure to air saturated with mothball
vapors, causing death of victims as a result of acute liver atrophy and
subsequent liver failure.  Liver atrophy and liver cirrhosis were
reported in other human subjects exposed to moth ball vapors (Cotter
1953). Hepatocellular hypertrophy, hepatocellular proliferation,
increased liver weights, induction of microsomal enzymes and renal
effects were also reported in experimental animals exposed orally or by
inhalation to para-dichlorobenzene.  

Hepatic effects such as increased absolute and relative liver weights
and elevated ALT, AST, and GGT and decreased albumin level were observed
in both sexes of dogs after chronic feeding (MRID No. 43988802). These
hepatic changes were accompanied by microscopic alterations including
hepatocellular hypertrophy, hepatocellular pigment deposition, bile
duct/ductile hyperplasia, nodular hyperplasia, bile stasis and hepatic
portal inflammation. The increase in absolute and relative liver weights
and the  treatment-related histopathological changes, were also observed
in a four-week oral and inhalation studies in dogs (MRID No’s.43988801
and 41822801).

Hepatic effects and general body weight and organ weight changes were
also observed in rodent studies under subchronic and chronic oral and
inhalation exposure.  In a subchronic inhalation toxicity study in rats
(S. Aiso et. al., 2005a), exposure to para-dichlorobenzene vapor induced
hepatotoxicity in both sexes and nephropathy and hematological changes
in males. Hepatotoxicity in both sexes was characterized by increased
liver weight, hepatocellular hypertrophy, and increased serum levels of
total cholesterol. Liver necrosis and increased serum levels of AST and
ALT, which indicate hepatocellular death, did not occur in any of the
treated rats.  On the other hand renal lesions occurred only in males
and manifested as hyaline droplets in the proximal tubular epithelial
cells, and were stained positively with anti-2u-globulin, suggesting
excessive accumulation of 2u-globulin in the epithelial cells causing
2u-globulin nephropathy.  Granular casts were formed in the tubular
lumen, resulting from the necrotic desquamation of the renal tubular
epithelium.  Papillary mineralization in the renal pelvis and increased
serum levels of BUN and creatinine were noted.  Decreases in red blood
cell counts, hemoglobin concentration, hematocrit and mean corpuscular
volume and increased spleen weight were observed in the treated males. 
Hepatotoxicity was observed also in a subchronic toxicity study in male
and female mice (S. Aiso et. al., 2005a) following inhalation exposure
to para-dichlorobenzene.  The hepatotoxicity was characterized by
increased liver weight, hepatocellular hypertrophy, and increased serum
levels of total cholesterol. Liver necrosis and increased serum levels
of AST and ALT were observed in the exposed mice. In a chronic
inhalation toxicity study in rats and mice (S. Aiso et. al., 2005b)
reduced body weight gain, increased renal mineralization, and renal
pelvic hyperplasia were observed in rats. Renal nephropathy and hepatic
toxicity were also observed in a chronic toxicity study in mice but with
no reduction in body weight.  Nephropathy was observed to occur in males
at a much higher frequency than females.  Hepatocellular degeneration,
liver focal necrosis, and liver cell size alteration were observed in
both males and females. 

Developmental/Reproductive

para-Dichlorobenzene did not cause frank teratogenic alteration in
either rats or rabbits treated via inhalation.  In a developmental
toxicity study (MRID No. 42619601), rats were treated with
para-dichlorobenzene at the rate of 0, 50, 200, or 600 ppm.  At 50 ppm,
there were no treatment-related effects.  Decreases in maternal body
weight gain and food consumption were observed during dosing in the 200
and 600 ppm groups.  Skeletal variation manifested as delayed cervical
centra ossification at No. 5, 6 and 7 in the 600 ppm group was observed.
 In another developmental toxicity study (MRID No. 40568001), rabbits
were treated with para-dichlorobenzene at the rate of 0, 100, 300, or
800 ppm.  The treatment did not cause frank teratogenic effects up to
the highest dose of 800 ppm, but resulted in decreased maternal body
weight gain and some developmental alterations manifested as effects on
retroesophageal right subclavian artery at this level.  On the other
hand para-dichlorobenzene was associated with some reproductive effects
in rats.  In a two-generation reproductive toxicity study (MRID No.
41108801), male and female rats were exposed to vapors of
para-dichlorobenzene at concentration levels of 0, 50, 150 or 450 ppm. 
The highest dose tested was associated with increased number of litters
with reduced live pups, reduced pup weights, and reduced 4-day survival.
 The lowest dose level of 50 ppm was associated with nephropathy in
males resulting from accumulation of hyaline droplets, an effect that is
considered species and gender specific and unique to male rats.

Neurotoxicity

Acute and subchronic neurotoxicity studies have been performed with
para-dichlorobenzene.  In rats, acute exposure to para-dichlorobenzene
at the rate of 50, 200 or 600 ppm (MRID No. 43350601), caused decreased
forelimb and hindlimb grip strengths and motor activity in males but not
females at the high-dose.  However, these effects were transient and no
treatment-related gross pathological or neuropathological findings were
evident.  Under subchronic exposure conditions to the same
concentrations of para-dichlorobenzene (MRID No. 43350602), the FOB
evaluation indicated significant increase in the number of rearings by
high dose males, but not females.      

Mutagenicity

para-Dichlorobenzene is unlikely to operate via a mutagenic mode of
action.  It was found to be negative in the reverse gene mutation assay
in Salmonella with and without metabolic activation, and forward gene
mutation assay in the Chinese Hamster Ovary (CHO) cells. 
para-Dichlorobenzene was negative in in vitro cytogenetic studies; it
did not induce chromosomal aberrations in rat bone marrow cells, and was
not clastogenic to Chinese Hamster Ovary (CHO) cells in the presence and
absence of metabolic activation.  para-Dichlorobenzene was also negative
in the micronucleus assay in mouse, unscheduled DNA synthesis in male
and female mice, and the mammalian micronucleus assay.  Therefore, the
weight of the evidence from the genotoxicity database supports the
conclusion that there is no mutagenicity concern for
para-dichlorobenzene or its main metabolite (2,5-dichlorophenol).  This
conclusion is consistent with a number of other reviews including the
2004 European Union Risk Assessment Report (European Union Risk
Assessment Report: 1,4-dichlorobenzene, 2004. Volume 48, European
Commission Joint Research Centre, European Chemicals Bureau, 158 pp.).

Carcinogenicity

para-Dichlorobenzene was associated with increased incidences of renal
tumors in male rats when administered orally but not via inhalation
under experimental conditions.  The male rat kidney tumors were judged
to have been produced via the nongenotoxic-cytotoxic alpha-2u-globulin
pathway (CARC, 2007) which is considered to be specific to the male rat
with no counterpart for human beings (CARC, 2007; U.S. U.S. EPA 2006. 
Toxicological Review of Dichlorobenzenes.  In support of summary
information of the Integrated Risk Information System (IRIS), Revised
Final Draft, May 2006. EPA/635/R-03/015).

  

para-Dichlorobenzene was associated with the induction of hepatic tumors
in both sexes of mice when administered orally or by inhalation.  As
discussed in Section 3.4.9, convincing evidence from the open literature
is available to support a mitogenic/promotional mode of action for the
induction of these mice liver tumors (CARC, 2007).

Endpoint Selection

An endpoint was chosen to assess risk from episodic (short-term)
incidental oral exposure.  A NOAEL of 25 mg/kg/day generated in the
28-day feeding study in dogs, based on increased liver weight in males
and females, increased alkaline phosphatase and irritation of the
gastrointestinal tract in females observed at the next higher dose
level, LOAEL, of 75 mg/kg/day was selected.  There was no end-point
identified that could be attributable to an acute exposure to generate
an acute oral RfD for any sub-population.  

An endpoint of 150 ppm was chosen to estimate risks from short-term
(1-30 days) inhalation exposure.  It was generated in a 28-day
inhalation toxicity study in dogs and based on decreased body weight and
food consumption, hematological and clinical chemistry changes,
increased absolute and relative liver weight, liver histopathological
changes, and decreased absolute heart weight and absolute and relative
adrenal weights seen in both sexes at the next higher concentration at a
LOAEL of 500 ppm. 

An endpoint of 55 ppm was chosen to assess risk from intermediate-term
(1-6 months) inhalation exposure.  It was generated in a thirteen month
inhalation toxicity study in mice and based on hematological changes
observed in females at the next higher concentration at a LOAEL of 120
ppm.

An endpoint of 20 ppm was chosen to estimate risk from chronic (over 6
months) inhalation exposure.  It was generated in a two year inhalation
toxicity/carcinogenicity in rats and based on changes in the olfactory
epithelium observed in females at the next higher dose at a LOAEL of 75
ppm. 

A dermal NOAEL of 300 mg/kg may be used as the point-of-departure for
the residential dermal short-term exposure scenario.  In the absence of
a dermal absorption study, 100% absorption is assumed.  

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)

The absorption, distribution, metabolism and excretion (ADME) of
14C-para-dichlorobenzene was investigated in male and female F344 rats
and in female B6C3F1 mice following oral and inhalation exposures (MRID
41697801).  para-Dichlorobenzene was rapidly absorbed after oral and
inhalation exposure.  Absorption after inhalation exposure was poor in
relation to oral exposure.  Mice demonstrated increased absorption vs.
rats after both oral and inhalation exposure.  Significant tissue
distribution was observed in the kidney, liver, fat and residual carcass
of treated rats and mice.  Excretion was relatively rapid at all doses
tested, with a majority of the test material excreted in the urine in 48
hours.  Feces and expired air were also significant routes of
elimination constituting approximately 10% of the administered oral
dose. Urinary metabolites identified were the sulfate and glucuronide
conjugates of the 2,5-dichlorophenol.  Mice demonstrated increased
glucuronidation vs. rats. Induction of glucuronidation appeared to occur
after repeated oral but not inhalation exposure in male rats.  Tissue
clearance half life was also reduced by repeated oral and inhalation
exposure.  Clearance kinetics was largely bi-exponential, with the
exception of male rat kidney, which showed mono-exponential kinetics
after oral exposure.  Binding of radioactivity to -2-globulin was
suggested as an explanation for the increased half-life of elimination
from male rat kidney.

3.3	Hazard Characterization for Women and Children

  TC \l3 "3.1.4	FQPA 

The available database is considered adequate to characterize any
potential for prenatal or postnatal risks for infants and children based
on the current use profile for para-dichlorobenzene.  The data available
on para-dichlorobenzene included two acceptable prenatal inhalation
developmental toxicity studies in rats and rabbits, and a two-generation
inhalation reproduction study in rats.  The data provided no indication
of increased sensitivity of either fetal animals to in utero exposure to
para-dichlorobenzene or offspring exposed post-natally to
para-dichlorobenzene.  On this basis, the population subgroups of
infants and children are sufficiently protected and an additional
uncertainty factor is not warranted for exposure under the current use
profile. 

Furthermore, the NOAEL of 20 ppm generated in the chronic inhalation
toxicity/carcinogenicity study and the NOAEL of 55 ppm generated in the
thirteen week inhalation toxicity study in rats provided the most
sensitive endpoint for all exposure duration scenarios.  The regulatory
endpoints defined above exceed effect levels seen in the developmental
and reproductive toxicity studies in rats and rabbits, and therefore
will be protective of all population subgroups including infants and
children.   

3.3.1	Adequacy of the Toxicity Database

The available database is considered adequate to characterize any
potential for prenatal or postnatal susceptibility for infants and
children based on the current use and exposure profile for
para-dichlorobenzene.  The data included an acceptable two-generation
inhalation reproductive toxicity study in rats (MRID No. 41108801) and
prenatal developmental toxicity studies in rats (MRID No. 42619601) and
rabbits (MRID No. 40568001).  

 

3.3.2	Evidence of Neurotoxicity

Findings from the acute and subchronic neurotoxicity studies (MRID
No’s. 43350601 and 43350602) indicated no major concern for
neurotoxicity or the need for a developmental neurotoxicity study.  In
an acute neurotoxicity screening study (MRID No. 43350601), male and
female Sprague-Dawley rats (10/sex/dose) were exposed for four hours to
para-dichlorobenzene vapors at 0, 50, 200 or 600 ppm (0, 0.3, 1.2, or
3.6 mg/l, respectively).  All animals survived to terminal sacrifice
without the appearance of any adverse clinical signs.  Only transient
decreased forelimb and hindlimb grip strengths and decreased motor
activity in the high-dose males were observed at the peak time in males
of the highest dose group.  No treatment-related gross pathological or
neuropathological findings were evident. 

In a subchronic neurotoxicity study (MRID No. 43350602), male and female
Sprague-Dawley rats (10/sex/dose) were exposed by inhalation to the same
concentrations of para-dichlorobenzene for 6 hr/day, 5 days/week for 14
weeks.  With the exception of one low-dose female, whose death was not
attributed to treatment, all animals survived to terminal sacrifice
without the appearance of any adverse clinical signs except for the
increase in the number of rearings in males of the high-dose group. 

3.3.3	Developmental Toxicity Studies

  TC \l3 "3.3.3	Developmental Toxicity Studies 

para-Dichlorobenzene was not associated with frank teratogenic effects
in rats or rabbits. In a developmental toxicity study in rats (MRID No.
42619601), females were exposed to para-dichlorobenzene by inhalation at
a target concentration of 0, 50, 200, or 600 ppm for 6 hours per day on
gestation days 6 through 15.  There was a statistically significant
decrease in body weight and body weight gain in the mid- and high- dose
groups during gestation, and a statistically significant decrease in
group mean food consumption during dosing.  With the exception of a
possible decrease, of no statistical significance, in group mean litter
size at 200 and 600 ppm, all other reproductive parameters appeared to
be similar for all groups.  Group mean absolute liver and kidney weights
were about the same for all treatment groups, but the relative (as % of
body weight) weights for both of these organs were significantly (p <
0.05) greater at 600 ppm. This is considered to be due to a decreased
group mean terminal body weight at this dose.  No treatment – related
external or visceral variations were detected.  There were some skeletal
variations reported in the 600 ppm fetuses manifested as a statistically
significant (p < 0.01) increase in the number of litters with
unossified cervical centra No. 5, 6, and 7.  The maternal NOAEL/LOAEL
was 50/200 ppm based on decreased body weight and body weight gain and
reduced food consumption.  The developmental NOAEL/LOAEL was 200/600 ppm
based on delayed cervical centra ossification at No. 5, 6, and 7. 
Results of this study did not provide any evidence of increased
susceptibility of the fetus (in utero) in relation to adult animals.  

In a second developmental toxicity study (MRID No. 40568001), New
Zealand rabbits were exposed to vapor of para-dichlorobenzene through
the inhalation route at the target concentrations of 0, 100, 300, or 800
ppm.  There was no treatment-related mortality.  The high dose group had
statistically significant lower body weight gain between day 6 and 18 of
gestation.  The high dose group animals gained significantly lower
weight than the corresponding controls between days 6 and 18 of
gestation.  However, the lack of data on food consumption did not allow
the determination as whether the lower body weight gain was due to the
effect of the chemical on curbing the appetite of animals or due to some
other systemic effects.  No change in the absolute or relative mean
weights of liver or kidneys was observed. No fetal alterations were
observed in treated animals in relation to controls except for two minor
alterations; pale liver, and retroesophageal right subclavian which was
found to be significantly higher in the 300 and 800 ppm group,
respectively.  The chemical is not considered teratogenic. The LOAEL for
maternal toxicity (depression of body weight gain) was 800 ppm (HDT)
while the NOAEL was 300 ppm. The LOAEL for developmental toxicity
(retroesophageal right subclavian artery) was 800 ppm and the NOAEL 300
ppm.  Results of this study did not provide any evidence of increased
susceptibility of the fetus (in utero) in relation to adult animals.  

 

3.3.4	Reproductive Toxicity Study

In a 2-generation reproduction study (MRID 41108801)
para-dichlorobenzene was administered by inhalation to male and female
Sprague Dawley (CD) rats/sex/dose at target test atmosphere
concentrations of 0, 50, 150 and 450 ppm for 10 weeks, and then bred to
produce F1 litters. Randomly selected F1 pups/sex/group were exposed to
the test atmosphere for eleven weeks and then bred to produce F2
litters. Exposure was for six hours per day, seven days per week, for
ten or eleven weeks prior to breeding, for the first 19 days of
gestation and postnatal day 5 until weaning. 

Increase in toxic clinical signs in F0 and F1 male and female parents
were only observed in the high dose group.  High dose F0 males had
reduced body weight throughout the exposure period. High dose F1 female
parents had significantly lower body weight (P < 0.01). Gestational body
weights of high dose F0 females significantly decreased (P < 0.01)
beginning at day 7 throughout gestation accompanied by lower food
consumption which was consistent with the reduction in body weights. 
There was no clear indication of treatment-related effect on
reproductive parameters.  The latent time for mating for both
generations was increased in the 450 ppm group, with the difference
being more pronounced in the F0 parents than in the F1 parents. The
total number of pups born per litter was not affected by treatment in
either F1 or F2 litters; however, live births were reduced in F2 pups (P
< 0.01).  Four day survival was reduced in high dose F1 and F2 pups, but
not affected in low or intermediate dose pups.  No treatment related
effects on survival were reported on pups after day 4. High dose pups
from both generations had significantly reduced body weights at birth (P
< 0.01).  Differences in the body weights of high dose pups persisted
through the 28 day lactation period.  The absolute and relative liver
weights of F0 male rats were significantly increased in mid and high
dose groups. Absolute and relative kidney weights were significantly
increased in a dose related fashion in all treated groups.  Organ weight
effects in F1 males were less pronounced in the F0 males. Absolute liver
weights were increased only in the high dose group, but relative liver
weights were increased in the high and mid-dose groups.  Absolute kidney
weights increased significantly in mid and high dose F1 males.  Relative
kidney weights expressed as percent of body weight and percent of brain
weight increased in a dose related fashion in all treated groups
although the increase as percent of brain weight in the low dose group
was not statistically significant.  Brain and testes weights expressed
as percent of body weight were significantly increased (P < 0.01) in
high dose F1 males only. For F0 female rats, absolute and relative liver
weights were increased in the 150 ppm and 450 ppm treatment groups.
Histopathological effects in adult female rats were limited to
significantly increased hepatocellular hypertrophy in the high dose
group.  The response in F1 females (14/28, P < 0.01) was more pronounced
than in F0 females (7/27, P < 0.05).  Similar liver effects were seen in
high dose, adult males from the F0 and F1 generations.  Hepatocellular
hypertrophy was significantly increased in both groups (P <0.01), and
hepatocellular swelling (F1) and hepatocellular cytoplasmic vacuolation
(F0) were increased although not significantly. The kidneys of adults,
male F0 and F1 rats reflected the most significant adverse response. 
All treated male rats exhibited hyaline droplet nephrosis. Although this
lesion also occurred in 11/27 and 10/28 control rats, the severity and
frequency were increased in the treated animals.  A number of other
kidney lesions were reported in treated males.  These effects were
increased in both generations but appeared to be more pronounced in the
F0 males than in the F1 males.  No treatment related histopathological
effects were reported in F2 weanlings of either sex.  No treatment
related histopathological effects were reported for the reproductive
organs of any group.  The NOAEL/LOAEL for reproductive toxicity was
considered to be 150/450 ppm based on litters with reduced numbers of
live pups and 4-day survival.  The NOAEL/LOAEL for offspring toxicity
was 150/450 ppm based on decreased mean pup body weight and decreased
pup survival. The LOAEL for systemic toxicity was considered to be 50
ppm, the lowest dose tested (for males - based on hyaline droplet
formation and renal nephropathy in males of all treated groups) and the
NOAEL/LOAEL for systemic toxicity in females was 150/450 ppm based on
liver changes.  The male kidney effect is a species specific effect, and
is unique to male rats.  The results of this study did not provide any
evidence of increased susceptibility of the offspring in relation to
adult animals. 

3.3.5	Pre-and/or Postnatal Toxicity

3.3.5.1  Determination of Susceptibility

The  TC \l4 "3.3.6.1	Determination of Susceptibility  available evidence
from the two developmental toxicity studies and the two-generation
reproductive toxicity study, suggests that there is no concern for pre-
and/or post-natal toxicity resulting from exposure to
para-dichlorobenzene.

There was no quantitative or qualitative evidence of increased
susceptibility following in utero exposure of para-dichlorobenzene in
rats or rabbits in the developmental toxicity studies. No frank
developmental toxicity was observed in the rat at the highest dose
tested (600 ppm). Only some skeletal variations manifested as delayed
cervical centra ossification at No. 5, 6, and 7 were observed at this
level.  Maternal toxicity effects observed at 600 ppm (LOAEL) included
decreased body weight and body weight gain and food consumption.  

In the rabbit, there were no developmental effects observed at the
highest dose tested (800 ppm).  At the highest dose level tested
maternal toxicity was manifested as depression of body weight gain.  The
only soft tissue variation observed at this dose level was a
retroesophageal right subclavian artery.

In the two-generation reproductive toxicity study in rats conducted by
inhalation, the NOAEL/LOAEL for reproductive toxicity was considered to
be 150/450 ppm based on litters with reduced numbers of live pups and
4-day survival.  The LOAEL for systemic toxicity was considered to be 50
ppm, the lowest dose tested.  It should be emphasized here that the
systemic NOAEL/LOAEL is based on hyaline droplets accumulation in the
renal system, which is considered species specific, unique to the rat,
and thus irrelevant to risk assessment in man.  

3.3.5.2	Degree of Concern Analysis and Residual Uncertainties  TC \l4
"3.3.6.2	Degree of Concern Analysis and Residual Uncertainties  for Pre-
and/or Postnatal Susceptibility

The available data suggests the lack of qualitative or quantitative
evidence of pup susceptibility following exposure to
para-dichlorobenzene via inhalation in the developmental and
reproductive toxicity studies.  Therefore, there are no residual
uncertainties regarding pre- and post-natal sensitivity.  

3.3.6	Recommendation for a Developmental Neurotoxicity Study

Based on the available toxicity data, there is no evidence to support
the need for a developmental neurotoxicity study.

  TC \l2 "3.4	Safety Factor for Infants and Children 

3.4	Hazard Identification and Toxicity Endpoint Selection  TC \l2 "3.5
Hazard Identification and Toxicity Endpoint Selection 

3.4.1	Incidental Oral (Short-Term)

Study Selected:  4 -Week Feeding - Dog

MRID No.: 43988801 

Executive Summary:  See Appendix A, Guideline § 870.3150 

Dose and Endpoint for Risk Assessment: NOAEL = 25 mg/kg based on
increased liver weight in males and increased alkaline phosphatase and
liver weights and gastrointestinal tract irritation in females seen at
the next higher dose, LOAEL, of 75 mg/kg/day.

Thus, the endpoint for risk assessment is 25/100 = 0.25 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors: An Uncertainty Factor
(UF) of 100 was used to account for both interspecies extrapolation
(10X) and intraspecies variations (10X).  Because available data do not
suggest a susceptibility concern for infants and children, therefore, it
was determined that there is no need for an additional uncertainty
factor. 

3.4.2	Inhalation Exposure (Short-Term)*   

   TC \l3 "3.5.7	Inhalation Exposure (Short-, Intermediate- and
Long-Term) 

Study Selected:  28-Day Inhalation Toxicity - Dog

MRID No.: 41822801

Executive Summary:  See Appendix A, Guideline § 870.3465 

Dose and Endpoint for Risk Assessment: NOAEL = 150 ppm (nominal conc.),
168 ppm (analytical concentration) based on decreased body weight and
food consumption, hematological and clinical chemistry changes, 
increased absolute and relative liver weight, liver histopathological
changes, decreased absolute heart weight and absolute and relative
adrenal weights seen in both sexes at the next higher concentration,
LOAEL, of 500 ppm. 

Duration Adjusted Exposure Concentration (DAEC), or Dosimetrically
Adjusted NOAEL based on the target concentration, NOAELADJ = 150 ppm x
6h / 24 h x 5 days / 7 days = 26.8 ppm 

To convert the exposure level from ppm to mg/m3 the following equation
is used:

Exposure level in ppm x molecular weight / 24.45

    

= 26.8 ppm x 147 / 24.45 = 160.8 mg/m3 

  

Where 147 is the molecular weight for para-dichlorobenzene, and 24.45 is
a constant. 

OR  

Based on the analytical concentration of 168 ppm, the NOAELADJ = 168/150
x 160.8 = 180.0 mg/m3   

Para-Dichlorobenzene in this case behaves as category 3 gas.  To
calculate the human equivalent concentration (HEC) for a category 3 gas
the following equation is applied:

  

 

Where (Hb/g)A / (Hb/g)H is the ratio of the blood:gas (air) partition
coefficient of the chemical for the laboratory animal species to the
human value.  When Hb/g values are unknown (as is the case here), the
default value of (Hb/g)A / (Hb/g)H = 1 is recommended.

Therefore, in this case the NOAELHEC is the NOAEL or the analogous
effect level dosimetrically adjusted to human equivalent concentration
(NOAELADJ) = 180.0 mg/m3).

By applying these values to the following equation, and assuming that
(Hb/g)A/(Hb/g)H =1

 

	NOAEL(HEC)= 180.00 mg/m3 x 1 = 180 mg/m3

RfC = NOAEL(HEC) / UF 

RfC = 180 mg/m3/ 30  = 6 mg/m3    

Comments about Study/Endpoint/Uncertainty Factors:  An Uncertainty
Factor UF) of 30 was used to account for both interspecies extrapolation
(3X), intraspecies variations (10X).  Traditionally, the uncertainty
factor for interspecies extrapolation is 10X.  The 10X is often
considered to be made up of two components, each equal to a half-log
value (3.16 for pharmacokinetics – how a chemical gets to the target
tissue, and 3.16 for pharmacodynamics – how the target tissue responds
to the chemical).  A full interspecies factor of 10X was not used in
this case because the RfC methodology developed by EPA was followed
(EPA, 1994) in which dosimetry adjustments were used to derive a
NOAEL(HEC), , which accounts for the pharmacokinetic component of the
interspecies extrapolation, thus allowing a reduction of the
interspecies factor from 10X to 3X. 

3.4.3	Inhalation Exposure (Intermediate-Term)

   TC \l3 "3.5.7	Inhalation Exposure (Short-, Intermediate- and
Long-Term) 

Study Selected:  13-Week Inhalation Toxicity - Rat

MRID No.: (S. Aiso et. al., 2005a)

Executive Summary:  See Appendix A, Guideline § 870.3465 

Dose and Endpoint for Risk Assessment:  NOAEL = 55 ppm based on
hematological changes seen at the next higher dose, LOAEL, of 120 ppm. 

Duration Adjusted Exposure Concentration (DAEC), or Dosimetrically
Adjusted NOAEL based on the target concentration,  NOAELADJ = 55 ppm x
6h / 24 h x 5 days / 7 days = 9.8 ppm = 59 mg/m3    

Para-dichlorobenzene in this case, again, behaves as category 3 gas.  To
calculate the HEC for a category 3 gas the following equation used
earlier is applied:

 

NOAELHEC = NOAELADJ = 59 mg/m3   

Where the ratio of (Hb/g)A / (Hb/g)H  = 1   

RfC  = 59mg/m3 divided by the uncertainty factor of 30

RfC = 2 mg/ m3    

    

Comments about Study/Endpoint/Uncertainty Factors:  An Uncertainty
Factor UF) of 30 was used to account for both interspecies extrapolation
(3X), intraspecies variations (10X). (See above for an explanation of
the 10X to 3X reduction in the interspecies UF).    

3.4.4	Inhalation Chronic Reference Concentration (cRfC) 

Study Selected:  Combined Chronic Inhalation Toxicity/Oncogenicity - Rat

MRID No.: S. Aiso et. al., 2005b

Executive Summary:  See Appendix A, Guideline § 870.4300 

Dose and Endpoint for Risk Assessment:  NOAEL = 20 ppm based on
increased incidences and severity of nasal lesions, changes to the
olfactory epithelium, seen in females at the next higher dose of, LOAEL,
of 75 ppm.  In this study, rats were exposed to concentrations of 0, 20,
75, or 300 ppm for six hours a day, 5 days per week for 104 weeks.  The
actual analytical concentrations were very much in agreement with the
nominal or target concentrations as follows: 0, 19.8, 74.8 or 298.4 ppm.
The incidence of olfactory epithelial lesions of moderate or greater
severity in female rats was 27/50, 29/50, 39/50, and 47/50 for the 0,
20, 75, and 300 ppm groups, respectively.

Duration Adjusted Exposure Concentration (DAEC), or Dosimetrically
Adjusted NOAEL based on the target concentration,  NOAELADJ = 20 ppm x 6
hours / 24 hours x 5 days / 7 days = 3.57 ppm = 21.47 mg/m3  

For changes to the olfactory epithelium, the HEC was calculated using
the equation for a category 1 gas with effects in the extrathoracic (ET)
region as described by U.S. EPA (1994b) and using reference values
provided in U.S. EPA (1988, 1994b) as follows:

	HEC		= Duration Adjusted Exposure Concentration x RGDRET

	RGDRET	= [(VE/SA(ET)) A/(VE/SA(ET))H]

			= (0.24 m3-day/15 cm2)/(20 m3-day/200 cm2)

			= 0.16

where:

	RGDRET	= regional gas dose ratio (extrathoracic region, ET)

	VE		= minute volume (mL/min=cm3/min),

	SA(ET)		= surface area of the extrathoracic region (cm2), and

	A, H		= subscripts denoting animal (A) and human (H).

The RGDR of 0.16 suggests that, because of the physiological differences
between animals and humans, effects in humans are expected to occur at
an exposure concentration approximately 6-fold lower than in rats. 

The HECs for the chronic rat study are therefore 0, 0.56, 2.1, and 8.5
ppm for exposure concentrations of 0, 20, 75 or 300 ppm, respectively.
To convert ppm into mg/m3, a conversion factor of 6.01 was used (for
1,4-dichlorobenzene 1 ppm equals 6.01 mg/m3 at 25 degrees Celsius and
760 mm Hg). 

The corresponding HECs are 0, 3.4, 12.6 and 51.1 mg/m3 for the 0, 20,
75, and 300 ppm exposure concentrations, respectively.  

The RfC can be calculated by dividing the NOAELHEC by the appropriate
uncertainty factor (UF) as follows: 

RfC = 3.4 / 30 = 0.11 mg/m3        

Comments about Study/Endpoint/Uncertainty Factors:  An Uncertainty
Factor (UF) of 30 was used to account for both interspecies
extrapolation (3X) and intraspecies variations (10X).  (See above for an
explanation of the 10X to 3X reduction in the interspecies UF).       

  TC \l3 "3.5.3	Chronic Reference Dose (cRfD) 

3.4.5	Dermal Absorption

Study Selected:  No dermal absorption study was available. 

MRID No.:  N/A

Executive Summary:  N/A

Dermal Absorption Factor = N/A

3.4.6    Dermal Exposure (Short- and Intermediate-Term) 

  TC \l3 "3.5.6	Dermal Exposure (Short-, Intermediate- and Long-Term) 

Study Selected:  21-day dermal toxicity- rat

MRID No.:  41315001

Executive Summary:  See Appendix A, Guideline § 870.7485 

Dose and Endpoint for Risk Assessment: NOAEL >300 mg/kg; LOAEL >300
mg/kg; no toxicity observed at the highest dose tested.  Although there
is a NOAEL of 300 mg/kg/day from the repeat dose dermal study in the
rat, there is no LOAEL.  However the LD50 from an acute dermal study in
the rat is at least 6000 mg/kg/day.  The combination of LD50 and the
repeat dose dermal study NOAEL provide the basis for a dermal risk
assessment that is likely to be conservative and protective for dermal
exposures. Dermal exposures are not a significant route of exposure.

Comments about Study/Endpoint/Uncertainty Factors:  An Uncertainty
Factor (UF) of 100 was used to account for both interspecies
extrapolation (10X) and intraspecies variations (10X).  

_______________

*The source of the equations used in the calculations of the human
equivalent and RfC is the Methods for Derivation of Inhalation Reference
Concentrations and Application of Inhalation Dosimetry
(EPA/600/8-90/066F; October, 1994).  Also see Appendix B for further
information regarding the methodology used in this analysis.  

3.4.7. 	Level of Concern for Margin of Exposure  TC \l3 "3.5.8	Level of
Concern for Margin of Exposure 

Table 3.5.6   Summary of Levels of Concern for Risk Assessment.

Route	Short-Term

(1 - 30 Days)	Intermediate-Term

(1 - 6 Months)	Long-Term

(> 6 Months)

Residential Exposure

Dermal	100	N/A	N/A

Inhalation	30	30	30

Incidental Oral	100	N/A	N/A

3.4.8.   Recommendation for Aggregate Exposure Risk Assessments

Based on the exposure under the current use profile, an aggregated
exposure risk assessment is not appropriate. 

3.4.9	Classification of Carcinogenic Potential

[See J. Kidwell, TXR. No. 0054616, 05-JUN-2007]

In its meeting of 02/21/2007, the HED/OPP Cancer Assessment Review
Committee (CARC) determined that para-dichlorobenzene has been tested
adequately by the oral and inhalation routes in two acceptable
carcinogenicity studies in rats and mice.  The treatment was associated
with increased liver tumors in both sexes of mice dosed orally or
exposed to para-dichlorobenzene via inhalation, and increased incidences
of renal tumors in male, but not female,  rats when the chemical was
administered orally but not via inhalation.  The male rat kidney tumors
were judged to have been produced via the nongenotoxic-cytotoxic
alpha-2u-globulin pathway which is considered to be specific to the male
rat with no counterpart for human beings, and thus, not relevant for
human cancer risk assessment.  

In accordance with the EPA’s Final Guidelines for Carcinogen Risk
Assessment (March 2007), the CARC classified para-dichlorobenzene as
“Not Likely to be Carcinogenic to Humans” based on evidence that a
non-mutagenic MOA involving mitogenesis was established for
para-dichlorobenzene induced liver tumors in mice and that the
carcinogenic effects are not likely below a defined dose that does not
perturb normal liver homeostasis (e.g., increased liver cell
proliferation).  Mitogenic chemicals act by promoting the clonal
expansion of preneoplastic cells by stimulating cell proliferation.  A
mitogenic chemical stimulates cell proliferation in the target organ
without obvious cytotoxicity or cell death.  Another important feature
of this MOA is that the mitogenic effect is not persistent over time;
instead it is resolved and then is manifested within proliferative foci
which are considered preneoplastic lesions.  Through continuous
exposure, it is these preneoplastic lesions that develop into tumors. 
This liver mode of action is generally associated with an increase in
metabolizing enzymes.  In the case of para-dichlorobenzene, there is a
good dose correlation between liver tumors, hepatic microsomal enzyme
induction and cell proliferation in the absence of overt liver toxicity
consistent with mitogenesis.  Dose concordant morphologic
characteristics, i.e., liver hypertrophy and liver weight increases,
were consistent with this mitogenic mouse liver response.  

3.5.	Summary of Toxicological Doses and Endpoints for
para-Dichlorobenzene for Use in Human Risk Assessments  TC \l3 "3.5.11
Summary of Toxicological Doses and Endpoints for [Chemical] for Use in
Human Risk Assessments 

Table 3.5  Toxicological Doses and Endpoints for para-dichlorobenzene
for Use in Dietary and Non-Occupational Human Health Risk Assessments

Exposure/

Scenario	Point of Departure	Uncertainty/ Safety Factors	RfD, PAD, Level
of Concern for Risk Assessment	Study and Toxicological Effects

Acute Dietary (General Population, including Infants and Children)	

No exposure expected

Acute Dietary

(Females of child-bearing age, 13-49 years of age)

	Chronic dietary  (All Populations)

	Incidental Oral Short-Term (1-30 days)	NOAEL=25 mg/kg/day	UFA=10x

UFH=10x

	Residential LOC = 100	4-Week oral toxicity study-dog (MRID 43988801) 

NOAEL= 25 mg/kg/day

LOAEL=75 mg/kg/day, based on increased liver weight in males and
increased alkaline phosphatase and liver weight, irritation to GI tract
in females.

Incidental Oral Intermediate-Term (1-6 months)	

No exposure expected

Dermal Short-Term (1-30 days)	NOAEL= > 300 mg/kg/day	UFA = 10x

UFH = 10x

	Residential LOC = 100	3-Week dermal-rat

(MRID 41315001)

NOAEL > 300 mg/kg/day (HDT)

LOAEL = > 300 mg/kg/day.

Dermal Intermediate-Term (1-6 months)	

No exposure expected

Inhalation Short- Term (1-30 days)	NOAEL = 150 ppm (nominal conc.), 168
ppm (analytical conc.)

Duration Adjusted Exposure Conc. (DAEC) = 168 ppm x 6h/24h x 5 days / 7
days = 30 ppm 

NOAELADJ= 180.36 mg/m3

NOAELHEC = 180.36 mg/m3	UFA=3x

UFH=10x

	Residential LOC = 30	28-Day inhalation toxicity - dog (MRID 41822801)

Decreased body weight and food consumption, hematological and clinical
chemistry changes,  increased absolute and relative liver weight, liver
histopathological changes, decreased absolute heart weight and absolute
and relative adrenal weights seen in both sexes at the next higher dose,
LOAEL, of 500 ppm. 

Inhalation Intermediate-Term (1-6 months)

	NOAEL = 55 ppm

Duration Adjusted Exposure Conc. (DAEC) = 55 ppm x  6h/24h x 5 days / 7
days = 9.8 ppm

NOAELADJ = 58.92 mg/m3

NOAELHEC = 58.92 mg/m3	UFA = 3x

UFH= 10x

	Residential LOC = 30	13-Week Inhalation toxicity -rats (MRID No. N/A,
open literature publication, S. Aiso et al., 2005a)

Hematological changes seen at the next higher dose, LOAEL, of 120 ppm. 

Inhalation- Chronic exposure (6-12 months)	NOAEL = 20 ppm (nominal
concentration), 19.8 ppm (analytical concentration)

Duration Adjusted Exposure Conc. (DAEC), NOAELADJ = 19.8 ppm x  6h/24h x
5 days / 7 days =  3.54  ppm 

NOAELHEC =  0.56 ppm or 3.4 mg/m3

	UFA = 3x

UFH= 10x

	Residential LOC = 30	Chronic Inhalation  Toxicity/carcinogenicity - rat
(MRID N/A, open literature study, S. Aiso et al., 2005b).

Olfactory epithelium changes observed at the next higher dose, NOAEL, of
75 ppm

Cancer (oral, dermal, inhalation)	Not Likely to be Carcinogenic to
Humans below doses that do not perturb normal liver homeostasis.

  

Based on the IRIS evaluation draft document of May 2006, the slope
factor linear approach was suggested.  “The recommended inhalation
risk unit for para-dichlorobenzene is 4x10-3(mg/m3)-1  , based on
hepatocellular tumors in male and female mice….”   Use of the linear
approach would provide a worst case screening level analysis.

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 (intraspecies).  UFH = potential variation in
sensitivity among members of the human population (interspecies).  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).   PAD = population
adjusted dose (a = acute, c = 

chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level
of concern.  N/A = not applicable. DAEC = Duration 

Adjusted Exposure Conc.

 

3.6	Endocrine disruption  TC \l2 "3.6	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 recommendations of its Endocrine Disruptor and Testing
Advisory Committee (EDSTAC), EPA determined that there was a 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 additional appropriate screening and/or testing protocols being
considered under the Agency’s EDSP have been developed,
para-dichlorobenzene may be subjected to further screening and/or
testing to better characterize effects related to endocrine disruption.

4.0	Public Health and Pesticide Epidemiology Data  TC \l1 "4.0	Public
Health and Pesticide Epidemiology Data 

[See M. Hawkins & H. Allender, D334455, 25-JUN-2007]

Incident report information for para-dichlorobenzene was gleaned from
the following sources:

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

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

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

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

The summary findings for the period 1993 to 2005 for
para-dichlorobenzene, mainly from PCC data are:

The proportion of symptomatic cases among those exposed in all
population groups evaluated (occupation, non-occupational, children)
were not significantly different from the overall, national composite
average.  Specifically, the proportion of symptoms among those followed
and the proportion hospitalizations among those seen at a health care
facility (HCF) is lower than the composite of all chemicals.  

Among children under the age of six, there were 3165 exposure cases to
para-dichlorobenzene while the entire population has 4480; children
represent the largest portion of the total exposed in the population,
70.6%. 

There was an average of about 344 exposures per year, 33 symptomatic
cases per year, and 38 cases per year seen in a heath care facility
across all population groups.

An irregular decreasing annual trend is evident in the 12 year-span of
data collected; the number of total exposed cases was reduced by half in
this period.

Although ratios for para-dichlorobenzene are below the composite
average, the number of exposures to children indicates that
opportunities for prevention exist and in order to prevent exposure,
actions restricting access to the active ingredient should be taken if
possible.  This could include special packaging and other limitations to
prevent children from reaching the active ingredient. 

Recommendations

Although the proportion of exposed children is actually less than the
composite of children exposed to ALL pesticides, given the potential
toxicity of the chemical, unknown long-term effects of exposure, and
ease of exposure to children given the usage profile (use of loose
mothballs in and around the home), additional public health protection
measures may be warranted.  These may include special packaging and
other limitations to block children from reaching the active ingredient
in addition to increased warning label language.

	

5.0	Dietary Exposure/Risk Characterization  TC \l1 "5.0	Dietary
Exposure/Risk Characterization 

As there are no food or water uses for para-dichlorobenzene, no dietary
exposure is expected for this chemical.  

				

6.0	Residential (Non-Occupational) Exposure/Risk Characterization  TC
\l1 "6.0	Residential (Non-Occupational) Exposure/Risk Characterization 

[See S. Tadayon, D341252, 27-SEP-2007].

para-Dichlorobenzene is registered as an insecticide and has been widely
used by the general population as a moth repellant to protect garments
from insect damage. It is also used for the control of lice and ticks in
and around bird cages, and for beetle proofing in dwellings.  Usually,
mothballs are expected to last for weeks or even months during which
para-dichlorobenzene emits slowly as evidenced by the odor in the room
and the house where the mothball is located.  para-Dichlorobenzene is
marketed in a variety of end-use products for homeowner use.  Since
para-dichlorobenzene exposure is significantly higher in mothballs, this
assessment will focus on para-dichlorobenzene exposure from mothballs
only and considered worst case scenario.  The exposure from the rest of
the products containing para-dichlorobenzene is not expected to exceed
that of mothballs.  Table 2.3 summarizes the use directions for products
containing para-dichlorobenzene.

Residential Handler Exposure and Risk

The term “handler” applies to individuals who mix, load, and apply
the pesticide product.  HED anticipates handler 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 for residential handlers.  Exposure data
does exist for short-term exposure from postapplication inhalation
exposure to areas treated with para-dichlorobenzene, and this exposure
scenario has been assessed.  HED assumes that the short-term
postapplication inhalation assessment is protective for handler
inhalation exposure since measured concentrations of
para-dichlorobenzene would likely be greater due to the time allotted in
the exposure study for the product to accumulate in the enclosed areas
that were treated. 

Handler exposures occur during the application of mothballs using hands
as the method of application. Handler exposure durations are expected to
be short-term (1-30 days).  Intermediate-term (1- 6 months) or long-term
(> 6 months) exposures are not expected for this particular use.  

Surrogate data on naphthalene   SEQ CHAPTER \h \r 1 (MRID# 437165-01)
were used to assess dermal exposures from hand applications as no
comparable study for para-dichlorobenzene was available.    

Residential Handler Exposure Assumptions

The following assumptions were used in estimating risks from residential
handler exposure to para-dichlorobenzene:

The body weight of an adult handler is 70 kg;

The percent ai in the products ranges from 99.5 to 99.9 percent by
weight based upon the labels;

The master label rate of 0.02 lb ai/ft3 is applied to an indoor space;

The applicator treats 3 closets 600 ft3 (each closet measures 5 feet
width, 5 feet length and 8 feet height) in a day;

The applicator treats 3 dresser 90 ft3 (5 drawers per dresser and 6 ft3
per drawer).

Unit Exposure Data

MRID # 437165-01- a study titled “Estimation of Homeowner Exposure to
LX1298-01

(Naphthalene) Resulting from Simulated Residential Use as an Insect
Repellent” was submitted

in support of naphthalene re-registration.  This study was used as a
surrogate to estimate handler  

dermal exposure to para-dichlorobenzene.  

Study Summary: The purpose of this study was to estimate the potential
for dermal exposure to the homeowner’s hands during application of
naphthalene. LX1298-01, a mothball formulation, containing 99.5% (0.995
g ai/g product) of the active ingredient (ai) naphthalene, was applied
as an insect repellent by placing mothballs in a closet and a dresser
drawer at the maximum application rate of 1.0 lb ai/50 ft3 in designated
bedrooms at three different locations near Valdosta, Georgia.

For the applicator exposure cotton gloves were used to determine dermal
exposure as the mothballs were placed in the treated zones. Table 6.1
provides a summary of the applicator hand exposure as mg/lb ai.  The
overall average naphthalene hand exposure for three test sites, was
0.053 mg/lb ai handled.  

Table 6.1	Applicator Hand Exposure 

Trial	

Naphthalene Residue - Both Hands (mg/lb ai handled)

92-298-01-21H-02	0.00807

92-298-01-21H-03	0.104

92-298-01-21H-04	0.0465

Mean	0.053

Residential Handler Risk Estimates

The short-term dermal risk estimates (i.e. MOEs) for residential
handlers are presented in Table 6.2 below and all of the MOEs are
greater than 100 and therefore the risks are not of concern.

Table 6.2 – Residential Handler Short-Term Risks for
para-Dichlorobenzene

Use Scenario	Area Treated

Ft3	Application Rate lb ai/Ft3	Dermal

Unit Exposure

mg/lb ai	Dermal Dose mg/kg/day	Dermal MOE*

Handler Exposures from Mothball  Application

Closets

Drawer	600

90	0.02

0.02	0.053

0.053	0.0091

0.00134	33,000

224,000

*All of the MOEs exceed the target MOE of 100 and therefore the risks
are not of concern.

Dermal MOE = Short-term NOAEL (300 mg/kg/day) / dermal daily dose
(mg/kg/day)

Where, dermal dose = daily unit exposure (mg/lb ai)  x application rate
x amount handled per day  / body weight (70 kg adult).

Residential Handler Risk Characterization

There were no chemical specific data addressing the use of a hand for
indoor mothballs applications.  The exposures for the hand application
for residential exposure scenarios were based on surrogate data from a
naphthalene mothball application in a closet and a dresser drawer.  Use
of dermal unit exposure from application to an enclosed area (i.e.,
closet or drawer) for indoor applications is appropriate.  The estimates
for mothball application are based on very limited data from a single
study in which only 3 reliable replicates were available and therefore
exposure estimates are of low confidence.  However, as the calculated
dermal MOEs are so large, low confidence in the dermal exposure data
does not change HED’s conclusion that this exposure route results in
low risk to residential handlers.

Residential Post Application Scenarios

The term “post application” describes individuals who are exposed to
pesticides after entering areas previously treated with pesticides. 
para-Dichlorobenzene post application inhalation exposures may occur
after applications of para-dichlorobenzene are made to residential areas
such as closets and dresser drawers.  Dermal exposures were not assessed
because no dermal contact is expected after a complete sublimation
(dissipation) of para-dichlorobenzene mothballs.  The following post
application scenarios were assessed for individuals in areas treated
with mothballs:

1)	Adult inhalation exposure from mothball application;

2)  Children episodic mothball ingestion.  

Post Application Exposure Data

No chemical specific post application data was submitted in support of
para-dichlorobenzene reregistration.  Thus, to assess
para-dichlorobenzene post application exposure scenarios, HED considered
data from the following sources: 1) MRID # 437165-01: “Estimation of
Homeowner Exposure to LX1298-01 (Naphthalene) Resulting from Simulated
Residential Use as an Insect Repellent”; 2) EPA sponsored studies
entitled “Total Exposure Assessment

Methodology (TEAM)”; and 3) levels of 2,5-dichlorophenol measured in
urine samples from participants in the National Health and Nutrition
Examination Survey (NHANES), 1999-2002, and reported in the Third
National Report on Human Exposure to Environmental Chemicals.    

The naphthalene homeowner exposure study was used a surrogate for
estimating para-dichlorobenzene levels for the short-term inhalation
exposure scenario.  HED determined that this study provided the best
currently available estimate of exposure levels to para-dichlorobenzene
vapors for short-term durations (1-30 days) since it was based on the
maximum label use rate for naphthalene (which matches that of
para-dichlorobenzene) as measured in three houses.  Concentrations were
measured over a three day period near the treatment location (closets
and drawers) and throughout the house.  For the purpose of this
assessment, risk estimates were computed for the averaged naphthalene
concentrations measured near treatment areas and throughout the house. 
Thus, the averaged exposure levels corresponding to these locations were
0.85 and 0.66 µg/m3, respectively.  Due to the similar use rates and
retreatment rates for mothballs containing naphthalene and
para-dichlorobenzene, HED anticipates that the exposure levels of these
chemicals from mothball uses are similar.  However, to verify this
expectation, the registrant should conduct a confirmatory chamber study
to determine levels of para-dichlorobenzene in the air resulting from
use of mothballs at the maximum label rate.        

For the purpose of estimating risks due to intermediate-, long-term and
cancer exposure scenarios, HED made use of data reported from the TEAM
studies.  The TEAM studies were conducted in 1984 and 1987 in and around
Los Angeles and Contra Costa county.  The TEAM studies measured
exposures to 20-25 Volatile Organic Compounds (VOCs) in the air,
drinking water, and exhaled breath of 650 persons in 4 states.  These
studies dealt with VOCs, carbon monoxide, pesticides, and particles,
often comparing indoor and outdoor exposures to these contaminants at
the same geographical location and within the same households.  In the
early studies, exhaled breath and shoulder-mounted monitors were used to
measure personal-air exposures to VOCs in the study subjects.  These
studies revealed the role of various human activities in bringing
individuals into contact with chemicals indoors.  Mean indoor
para-dichlorobenzene concentrations measured in the TEAM studies during
the winter ranged from 20.2 to 36.2 µg/m3.  During the summer,
para-dichlorobenzene concentrations were considerably lower with means
ranging from 4.0 to 13.8 µg/m3.

The most recent reported study was conducted in Woodland, California, in
the spring of 1990. The mean concentration of para-dichlorobenzene in
125 samples was 16 µg/m3, with a range from below the quantifiable
limit of 0.26 µg/m3  to 300 µg/m3.  The mean from this springtime
study lies between the summer and winter means measured in the earlier
TEAM studies

These data indicate a seasonal dependence of the para-dichlorobenzene
levels.  HED used the maximum mean seasonal concentration of 36.2 µg/m3
(winter value) to assess the intermediate-term exposure scenario.  For
long-term and cancer assessments, HED used an average of the seasonal
values (21 µg/m3).

Although the data from the NHANES studies were not directly used in the
present risk assessment, HED compared the levels reported to those
obtained from the TEAM studies. Acknowledging the inherent uncertainties
involved in extrapolating 2,5-dichlorophenol levels in urine (creatinine
corrected) samples to levels of para-dichlorobenzene in the air, it is
noteworthy that the geometric mean value obtained from the 1999-2000
survey years for individuals age 6 and older converts to an air
concentration of 16 µg/m3  para-dichlorobenzene.  This level is quite
similar to the average seasonal value of 21 µg/m3  used for the
long-term inhalation exposure analysis reported in Table 6.3, and
provides additional confidence in the levels used to assess long-term
exposures to para-dichlorobenzene.

  

As no acute endpoint was selected, HED used the short-term incidental
oral endpoint of 25 mg/kg/day to estimate risk from episodic ingestion
of one mothball. 

Residential Post Application Exposure Assumptions

Label recommended application rate of 0.02 lb ai/ft3 ;

One mothball weighs 2.35 grams;

For short-term exposures, mean concentrations of 0.85  and 0.66 mg/m3
were used to estimate exposures near treated areas and in treated homes,
respectively;

For intermediate-term exposures, a maximum mean concentration of 36.2
ug/m3 was used;

For long-term exposures, an average concentration of 21ug/m3 was used. 
This value was calculated by assuming the fall and spring values are the
same (as no fall value was reported).  Therefore, the average long-term
concentration is computed as [(winter 36 ug/m3) + (summer 14 ug/m3) +
(spring 16 ug/m3) + (fall 16 ug/m3)] /4. 

Inhalation assessment was only conducted for adults, as these risk
values are protective for children.  Adult and toddler inhalation
exposure estimates are the same because endpoints derived from the
inhalation toxicity studies (all durations) were adjusted for
pharmacokinetic (PK) differences when NOAEL Human Equivalent
Concentrations (HECs) were calculated.  

Residential Post Application Exposure and Risk Estimates

The exposure and risk estimates for the residential post application
scenarios are presented in Table 6.3.  All of the MOEs for
post-application inhalation exposures, regardless of duration, exceed
the target MOE of 30, and are not of concern.  The risk estimate for
episodic ingestion of mothballs results in a MOE < 100 and therefore is
of concern.

Table 6.3 – Para-dichlorobenzene Residential Post Application Risk 

Source of  exposure	Exposed Population	MOE*

Inhalation Short –Term 

Mothballs	Adult (Accessing Treated Areas)	212

	Adult (Inhabiting Treated Home)	273

Inhalation Intermediate –Term 

Mothballs	Adult	1650

Inhalation Long –Term 

Mothballs	Adult	160

	Episodic mothball Ingestion 

	Mothballs	Toddler	<1

*  Except for the episodic mothball ingestion scenario, all of the MOEs
are greater than the target MOE of 30 and therefore the risks are not of
concern.

Short-term inhalation risk = NOAEL of 180.4 mg/m3/mean air concentration
(from Naphthalene study MRID #437165-01) 0.85 mg/m3 for accessing
treated areas or 0.66 mg/m3 for inhabiting treated homes;

Intermediate-term inhalation risk = NOAEL of 58.9 mg/m3/ mean air
concentration from TEAM study 36 ug/m3;

Long-term inhalation risk =NOAEL of 3.4 mg/m3/ mean air concentration
from TEAM study 21 ug/m3;

Episodic mothball ingestion oral dose to toddler = [Mothballs ingestion
rate (2.35 g/day) x Fraction of ai of mothball formulations (99.5%) x
1,000 mg/g] / bw (15 kg);

Episodic mothball ingestion risk = NOAEL (25 mg/kg/day) for short-term
assessments)/155.8 (mg/kg/day) oral dose.

HED does not consider ingestion of mothballs to be a routine behavior in
which ingestion occurs on a regular basis, but instead considers this an
episodic event.  As the short-term incidental oral NOAEL is 25
mg/kg/day, the short-term oral MOE for incidental ingestion of one
mothball by a toddler is 0.16 (compared to a target MOE of 100) and is,
therefore, of concern to HED.  HED performed additional calculations to
determine the dose level required to result in a MOE of 100.  Based on
these calculations, oral consumption of anything greater than 0.25
mg/kg/day para-dichlorobenzene results in a MOE less than 100 and is
considered a risk of concern by HED.  This oral dose of
para-dichlorobenzene, 0.25 mg/kg/day, is equivalent to a 15 kg toddler
consuming 0.16% of one 2.35 g mothball. HED believes the risk estimate
for mothball ingestion is conservative as it is based on comparison of
an episodic (one-time event) to a toxic endpoint reflecting repeated
short-term exposures.

7.0	Aggregate and Cumulative Risk Assessments and Risk Characterization

Since para-dichlorobenzene does not have any food or water uses, an
aggregate risk assessment is not appropriate.  HED did not aggregate
adult dermal exposures while handling naphthalene products with
inhalation post-application exposures because there were no dermal
effects noted at the highest dose tested (HDT).  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. 

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mode of toxicity, EPA has not made a common
mode of toxicity finding as to para-dichlorobenzene and any other
substances, and para-dichlorobenzene does not appear to produce a toxic
metabolite produced by other substances.  For the purposes of this risk
assessment, EPA has not assumed that para-dichlorobenzene shares a
common mode of toxicity with other substances.  Therefore, a cumulative
risk assessment is not appropriate at this time.

8.0	Cancer Risk TC \l2 "7.5	Cancer Risk 

Generally, when the CARC determines that there is a plausible MOA for a
carcinogen, HED does not conduct a low dose linear extrapolation for
cancer. However, the IRIS program is currently reviewing the mode of
action evidence for para-dichlorobenzene and has not yet made a
determination of non-linearity.  Accordingly, for the purposes of the
present assessment, HED is presenting a linear low-dose extrapolation
risk for cancer. 

It should be noted that a draft IRIS document on para-dichlorobenzene
was recently circulated for external peer review (Revised Final Draft,
May 2006. EPA/635/R-03/015).  The IRIS program concluded that a cancer
risk assessment should be based on a low-dose linear extrapolation model
and its final draft of May 2006 provided two slope factors for hepatic
tumors in male and female mice. The first was based on oral exposure
(table 5-5, page 136), 1.7x10-2 (mg/kg/day)-1 and 4.0x10-3 (mg/kg/day)-1
for males and females, respectively.  The second was based on inhalation
exposure (pages 141 and 142), 4.5x10-3 (mg/m3)-1 and 4.3x10-3 (mg/m3)-1,
for males and females, respectively.  They recommended an overall unit
risk for both males and females of 4x10-3(mg/m3)-1 based on inhalation
exposure. This unit risk should not be used with exposures exceeding the
point of departure (23mg/m3), because above this level the fitted
dose-response model better characterizes what is known about
para-dichlorobenzene inhalation carcinogenicity. In addition to the
slope factors, the draft IRIS document provided Bench Mark Concentration
Doses at which a 10% response for liver tumors was seen in the mice (BMC
10) and its 95% lower bound (BMCL 10) based on inhalation exposures. The
(BMC 10) and (BMCL 10) for hepatocellular adenoma or carcinoma in female
mice were 41.3 mg/m3 and 22.9 mg/m3, respectively.

Cancer risk estimates resulting from exposures to para-dichlorobenzene
were calculated for homeowners handling mothballs and individuals living
in homes treated with mothballs and inhaling mothball vapors. A Lifetime
Average Daily Dose (LADD) is calculated and then multiplied by a slope
factor of 4x10-3(mg/m3)-1, which was calculated by IRIS, based on dose
response data for hepatic tumors in male and female mice exposed to
para-dichlorobenzene via inhalation. The estimates of cancer risk are
based on the assumption of low dose linearity (presented in Tables 8.1
and 8.2) and range from 7.1 x 10-9 for dermal exposure during the
application of mothballs to 6.0 x 10-5 for post-application inhalation
exposure to mothballs.

HED notes that in estimating the cancer risk for dermal exposures of
homeowners handling mothballs, we are comparing dermal exposures to
inhalation endpoints. The team decided to assess cancer risks for dermal
exposures using an inhalation endpoint since systemic effects (liver
tumors) were noted in the inhalation studies for para-dichlorobenzene.
The slope factor is based on these systemic effects. If the toxic
effects after inhalation exposures were localized (nose only) and not
systemic, it would not be appropriate to include a cancer risk for
dermal exposures that relied upon a toxic endpoint for localized effects
resulting from inhalation exposures.  

Handler Cancer Risk Calculation 

For the residential handler cancer risk estimate, a highly conservative
assumption that adult individuals are exposed annually for 50 years out
of a 70 year lifetime was used. In addition, the cancer risk estimates
are conservative because the LADD calculated for dermal exposures do not
include a dermal absorption factor, that is, 100% dermal absorption has
been assumed. 

Estimated para-dichlorobenzene cancer risks for dermal exposures of
handlers are presented below in Table 8.1. Cancer risk estimates are
below 1 x 10-6 using the slope factor approach.  

Table 8.1.  Estimated para-Dichlorobenzene Cancer Risks for Adults
During Mothball Application (Dermal Exposures)

Application Method	

Exposed Individual	

Location	Dermal Average Daily Dose (mg/kg/day)	

LADD (mg/kg/day)	

Upper Bound on Cancer Risk Estimate 

Hand	Adult	Closet	0.0091	3.55e-5	4.9e-8

Drawer	0.00134	5.20e-6	7.1e-9

Average daily Dermal dose = daily unit exposure (mg/lb ai) x application
rate x amount handled per day / body weight (70 kg adult (mg/day) LADD =
  Daily Dose (Dermal Dose) (mg/kg/day) * 2 days/365 * 50/70 (50 years
handler exposure; 70 years lifetime assumption)

Cancer Risk = LADD * slope factor (1.4e-3 mg/kg/day)

The  slope factor  4x10-3(mg/m3)-1) was converted to 1.4 e-3 mg/kg/day. 
It was assumed that the breathing rate for an adult is 1 m3/h (24 hrs a
day) and the body weight is 70 kg. 

Post application Cancer Risk Calculation 

Estimated para-dichlorobenzene cancer risks for post application
inhalation exposures are presented below in Table 8.2.

Table 8.2.  para-Dichlorobenzene Post Application Cancer Risk Assessment
for Inhalation Exposures

Exposed Individual	Inhalation Average Daily Dose (ug/m3)	

LADD (ug/m3)	

Upper Bound on Cancer Risk Estimate

Adult	21	15	6.0e-5

LADD = Daily Dose (Inhalation Dose) (ug/m3) * 50/70 (50 years homeowner
exposure; 70 years lifetime assumption)

Cancer Risk = LADD * slope factor (4x10--3(mg/m3)-1)

Using linear low dose extrapolation and a slope factor of 4.0x10-3
(mg/m3)-1 the cancer risk estimates could be as high as 6 x 10-5.  For
the residential post application cancer risk estimate, a highly
conservative assumption that homeowners are exposed annually for 50
years out of a 70 year lifetime was used.

The linear low dose extrapolation model provides a range of cancer
risks.  As with all linear low dose extrapolation models, the range is
bracketed by an upper bound and a lower bound on these risks.  The 6 x
10-5 cancer risk estimate represents an upper bound on cancer risk for
exposures to para-dichlorobenzene but the cancer risk could be as low as
zero.  This is independent of the strengths and weaknesses of the cancer
data. HED believes that the carcinogenic risks are below the upper bound
and may be closer to zero for para-dichlorobenzene for several reasons
as follows.  Available evidence as described  above in Section 3.4.9
(Classification of Carcinogenic Potential) of this document, indicates
that the mechanism leading to tumor formation in the livers of mice
after exposure to para-dichlorobenzene is based on sustained mitogenic
stimulation and proliferation of hepatocytes.  This information forms
the basis of a plausible mode of action for tumorigenesis in the mice
livers.  In addition, the BMCL 10 for hepatocellular adenoma or
carcinoma formation in female mice is 22.9 mg/m3 (IRIS Program, 2006). 
If the BMCL 10 is compared to the measured concentrations of
para-dichlorobenzene in people’s homes (0.021 mg/ m3), the BMCL 10 is
1000 times higher than actual exposures. That is, there is a 1000-fold
margin of safety between the dose at which there is a 10% tumor response
in test animals, at the lowest measurable incidence, and actual measured
exposure in people’s homes.  Consequently, HED believes the
carcinogenic risk from this use is not of concern for the following
reasons: 1) there is mechanistic data to support a lower cancer risk
estimate based on a mitogenic mode of carcinogenic action, 2)
conservatisms in the exposure estimates, and 3) a large margin of safety
between estimated human exposure and the point at which there is a
measurable (10%) tumor response.

9.0  	Occupational Exposure/Risk Pathway

The only occupational use of para-dichlorobenzene arises from use in
empty beehives.  Exposure from this activity is expected to be no higher
than the handler (dermal) and post application (inhalation) exposures
from the indoor residential use of mothballs which was assessed.  Risk
estimates for residential handler and post application exposures are
protective of this occupational use and below levels of concern.  As a
result, HED believes a separate risk assessment for occupational
exposures (handler and post application) is not warranted and was not
conducted for para-dichlorobenzene.

10.0	Data Needs and Label Recommendations  TC \l1 "10.0	Data Needs and
Label Recommendations 

The registrant should conduct a confirmatory chamber study to determine
levels of para-dichlorobenzene in the air resulting from use of
mothballs at the maximum label rate.  The short-term post application
inhalation risk levels were estimated using surrogate exposure data from
a naphthalene mothball study.  However, para-dichlorobenzene has a
higher vapor pressure than naphthalene and the concentration of
para-dichlorobenzene in the air from mothball uses may exceed that of
naphthalene.  A targeted exposure study using para-dichlorobenzene
mothballs will ensure that the short-term inhalation exposures and risks
to para-dichlorobenzene as a result of mothball use have not been
underestimated.

All risk scenarios evaluated for para-dichlorobenzene resulted in risk
levels below HED’s level of concern except for episodic incidental
oral ingestion of mothballs by toddlers.  A possible risk mitigation
step to address this scenario might include the use of special packaging
to block children from reaching the active.  

Appendix A:  Toxicology Assessment  TC \l1 "Appendix A:  Toxicology
Assessment 

A.1	Toxicology Data Requirements TC \l2 "A.1  Toxicology Data
Requirements  

The toxicology data requirements (40 CFR 158.340) for non food use for
para-dichlorobenzene are listed in the table below. Use of the new OPPTS
guideline numbers does not imply that the new (1998) guideline protocols
were used in conducting these studies.

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 (non-rodent)	

870.3200    21-Day Dermal	

870.3250    90-Day Dermal	

870.3465    90-Day Inhalation		no

no

cr

no

cr	-

-

yes

-

yes

870.3700a  Developmental Toxicity (rodent)	

870.3700b  Developmental Toxicity (non-rodent)	

870.3800    Reproduction		yes

yes

cr	yes

yes

yes

870.4100b  Chronic Toxicity (non-rodent)	

870.4200b  Carcinogenicity (mouse)	

870.4300    Chronic Toxicity /Carcinogenicity (rat)		cr

cr

cr	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 Neurotoxicity. (hen)	

870.6100b  90-Day Delayed Neurotoxicity (hen)	

870.6200a  Acute Neurotoxicity Screening Battery (rat)	

870.6200b  90-Day Neurotoxicity Screening Battery (rat)	

870.6300    Developmental. Neurotoxicity		no

no

cr

cr

no	-

-

yes

yes

-

870.7485    General Metabolism	

870.7600    Dermal Penetration		yes

no	yes

no

Special Studies for Ocular Effects

Acute Oral (rat)	

Subchronic Oral (rat)	

Six-month Oral (dog)		

no

no

               no	

-

-

-

A.2  Toxicity Profiles 

 TC \l2 "A.2  Toxicity Profiles 

Table A.2.1	Acute Toxicity Profile – para-Dichlorobenzene 

Guideline No.	Study Type	MRID No.	Results	Toxicity Category

870.1100

81-1	Acute oral – rat	40521001	LD50 = 3863 mg/kg (males)

LD50 = 3790 mg/kg (females), Core-minimum	III

870.1200

81-2	Acute dermal - rat	40521001	LD50 >6000 mg/kg, Core - minimum	III

870.1300

81-3	Acute inhalation – rat	41410901	LC50 = > 6.00 mg/L, highest
attainable concentration, Core-guideline	IV

870.2400

81-4	Primary eye irritation – rabbit	42205301	Conjunctivitis and
corneal opacity cleared in 10 days, iritis cleared in 72 hours,
vascularization of the cornea cleared in 10 or 13 days. The maximum
total irritation scores ranged from 20 to 47 indicating a mild irritant,
Core-guideline.	II

870.2500

81-5	Primary dermal irritation – rabbit	42205302	Moderate to severe
erythema, persisted for 48-72 hours in most animals. Primary irritation
index (PII) = 2.9	III

870.2600

81-6

	Skin sensitization – guinea pig	42205303	Negative under the condition
of the test. Core-guideline. 	-

Table A.2.2	Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 	Study Type	MRID No. (year)/ Classification /Doses	Results

870.3100

870.3150

870.3150

	90-Day oral toxicity (rat)

             &

90-Day oral toxicity (dog)

28-day feeding  (dog)

	Requirements waived for both rodents and non-rodents (HED Doc. No.
007023). 

However, an open literature article (S. Aiso et al., 2005a) addressed
the requirements in rodents in both rats and mice as described below. 

43988801 (1995)

M/F: 25, 75, 150 or 300 mg/kg/day.

Core-Supplementary

	                                       -

NOAEL M/F: 25 mg/kg/day

LOAEL M/F: 75 mg/kg/day, based on effects on liver weight in males of
the 75 mg/kg/day, increased alkaline phosphatase and liver weights, and
irritation to the gastrointestinal tract in females of the 75 mg/kg/day.

870.3465

	90-Day inhalation toxicity (rat)	S. Aiso (2005b)

M/F: 25, 55, 120, 270, or 600 ppm. 

MRID number: N/A Published study, Core-classification: N/A.	NOAEL (M/F)
= 120 ppm 

LOAEL (M/F) = 270 ppm

Based on renal toxicity in males, body weight and organ weights changes
in males and females. 

870.3465

870.3465	90-Day inhalation toxicity (rat)

28-Day inhalation (dog).	S. Aiso (2005b)

M/F: 0, 25, 55, 120, 270, or 600 ppm 

MRID No. N/A

Published study, Core Classification: N/A

41822801 (1991)

M/F: 0, 50, 150 or 500 ppm. 

Core-Supplementary	

NOAEL (M/F) = 55 ppm 

LOAEL (M/F) = 120 ppm 

Based on hematological changes in males observed at 120 ppm.

NOAEL = 150 ppm

LOAEL = 500 ppm based on decreased mean body weight and food consumption
in both males and females, changes in hematological (elevated levels of
hemoglobin, hematocrit, mean corpuscular volume, and erythrocytes) and
clinical chemistry parameters (increased SGOT, SGPT, alkaline
phosphatase, triglycerides), increased absolute and relative liver
weights in both sexes      of the 500 group (and males of the 150 ppm
group) accompanied by treatment-related histopathological
changes-lipidosis, increased  adrenal absolute and relative weights  in
both sexes of the 500 ppm.  Decreased organ weights including heart
weight in both sexes of the 500 ppm group, and kidneys of the males of
the 50 and 150 ppm groups. 

870.3200

	21- Day dermal toxicity  (rat- substituted for  rabbit, HED Doc. No.
007023)	41315001 (1989)

M/F: 0, 75, 150 or 300 mg/kg

Acceptable/minimum	NOAEL> 300 mg/kg (HDT)

LOAEL > 300 mg/kg

870.3700a

	Prenatal inhalation developmental toxicity (rat)	42619601 (1992)

0, 50, 200 and 600 ppm    for GD 6-15.

Acceptable/minimum	Maternal NOAEL = 50 ppm 

Maternal LOAEL = 200 ppm, based on decreased maternal mean body weight,
body weight gains and food consumption during dosing.

Developmental NOAEL = 200 ppm  

Developmental LOAEL = 600 ppm, based on delayed cervical centra
ossification at No. 5, 6 and 7.

870.3700b

	Prenatal inhalation developmental toxicity  (rabbit)	

40568001 (1982)

0, 100, 300 and 800 ppm  

for GD 6-15.

Acceptable/minimum	

Maternal NOAEL = 300 ppm  

Maternal LOAEL = 800 ppm, based on depression of body weight gain.

Developmental NOAEL = 300 ppm 

Developmental LOAEL = 800 ppm, based on retroesophageal right
subclavian.  

870.3800

	Two- generation inhalation reproduction and fertility effects  (rat)
41108801 (1989)

0, 50, 150 and 450 ppm 

Acceptable/minimum	Parental Systemic NOAEL (M) = not established, (F) =
150 ppm.

Parental Systemic LOAEL (M) = 50 ppm based on accumulation of hyaline
droplets and nephropathy observed in males of all dose groups, (F) = 450
ppm based on liver changes.

Offspring NOAEL=150 ppm  

Offspring LOAEL= 450 ppm, based on decreased mean pup weight, and
decreased pup survival.

Reproductive NOAEL (M/F) = 150 ppm 

Reproductive LOAEL (M/F) = 450 ppm based on reduced number of live pups
and 4-day survival. 

870.4100b

	Chronic oral toxicity – capsule  (dog)	43988802 (1996)

M/F: 0, 10, 50 and 150 mg/kg/day

Acceptable, no Core grade was assigned.	NOAEL (M/F): 10 mg/kg/day 

LOAEL (M/F): 50 mg/kg/day based on increased liver weight, clinical
chemistry findings, and histopathological changes in the liver.  

870.4300a

870.4300a

870.4300a

	Chronic oral toxicity/ Carcinogenicity

(rat)

Chronic inhalation  toxicity/ Carcinogenicity- inhalation -(rat)

Chronic toxicity/ Carcinogenicity- inhalation -(mouse)

	40521005 (1987)

M: 0, 150, and 300 mg/kg/day

F: 0, 300, and 600 mg/kg/day

No Core grade was assigned

S. Aiso et. al. (2005b).

M/F: 0, 20, 75 or 300 ppm.

Core Classification: N/A, no Core grade was assigned

S. Aiso et. al. (2005b).

M/F: 0, 20, 75 or 300 ppm.

Core Classification: N/A, no Core grade was assigned

	NOAEL (M/F): 150 mg/kg/day in males and 300 mg/kg/day in females. 

LOAEL (M/F):  300 mg/kg/day for males and 600 mg/kg/day in females,
based upon depression of body weight

Evidence of carcinogenicity in males.

NOAEL = 20 ppm

LOAEL=75 ppm, based on increased incidences and severity of eosinophilic
globules of the olfactory epithelium having marked grade of severity in
females.

No evidence of carcinogenicity in either males or females.

NOAEL( M/F)=75 ppm

LOAEL= (M/F)=300 ppm, based on reduced body weight in males, increased
incidences of nasal lesions in females, and increased liver and kidney
weights in males and females.

Evidence of carcinogenicity in males and females. 

870.4300

	Carcinogenicity – oral (mouse)	40521005 (1987)

M/F: 0, 300, 600 mg/kg/day.

No Core grade was assigned	NOAEL ( M/F): not established

LOAEL (M/F):<300 mg/kg/day based on nephropathy, and liver
histopathological changes, cytomegaly, karyomegaly.

Evidence of carcinogenicity in males and females.

870.5100	Gene Mutation -

Salmonella typhimurium Reverse Mutation Assay	40568002 (1983), dose
levels: 1, 3.3, 10, 33, and 100. µg/plate. 

S. typhimurium strains: TA98, TA100, TA1535, TA1537.

Acceptable	Negative

870.5100 

	Gene Mutation -

Salmonella typhimurium Reverse Mutation Assay	40568003 (1983), dose
levels: 51.2, 102.4, 204.8, 409.2, 1638.4, 3276.8, 6552.6 and 13105.2
µg/plate, +/- S9.

S. typhimurium strains: TA98, TA100, TA1535, TA1537 and TA1538.

Acceptable/guideline	Negative

870.5100 

	Gene Mutation - Salmonella typhimurium Reverse Mutation Assay	40521004
(1978),

dose levels: 0.6, 2.4, 12, 60, 180, and 600 µg/plate +/- S9.

S. typhimurium  strains: TA98, TA100, TA1535 and TA1537;  

Unacceptable	Inconclusive

Positive control was cytotoxic but did not induce mutagenic response. 

870.5275	Sex-linked recessive lethal test in Drosophila melanogaster
40521007 (1984), dose levels: 6000, 13200, 13300 ppm/hour via inhalation
route.

Acceptable 	Negative for induction of sex-linked recessive lethal. 

870.5100	In vitro forward mutation in Chinese hamster ovary cells
40521007 (1984), dose levels ranging from 25 to 250 µg/ml

Acceptable	Negative for HGPRT mutants  with or without metabolic
activation at dose levels ranging from 25 to 250 µg/ml

Acceptable

870.5300	In vitro forward mutation in Chinese hamster ovary cells
40521014 (1986), dose levels ranging from 50 to 400 µg/ml

Acceptable	Negative for forward gene mutation with and without metabolic
activation at dose levels of 50 to 400 g/ml..

870.5300 

	In vitro mammalian cell gene mutation test in Chinese hamster ovary
cells (CHO/HGPRT)	40521007 (1984), dose levels: 20, 60, 80, and 100
µg/ml without metabolic activation, and 40, 80, 120 µg/ml with
metabolic activation.  Acceptable	Negative for induction of SCE with and
without metabolic activation

870.5375 

	Chromosomal Aberration in vitro in the rat bone marrow cells	40521007
(1984), dose levels: 200, 400, 800 mg/kg by ip injection.

Acceptable	 Negative for induction of chromosomal aberration in rat bone
marrow cells.

870.5450 

	Dominant lethal test in mice	40521011 (1995), dose levels: 75, 225, and
450 ppm via inhalation route (5 days, 6 hours/day)

Unacceptable, no cytotoxicity was seen

	Negative for dominant lethal

870.5395 

	In vivo Mammalian Micronucleus Test in mice	40521012 (1986), dose
level: 2000 mg/kg 

Acceptable	Negative in males and females

870.5550 

	In Vivo/In Vitro unscheduled DNA synthesis in mice	40521008 (1987),
dose levels: 300, 600, and 1000

mg/kg.  

Acceptable	Negative in males and females

870.6200a

	Acute inhalation neurotoxicity screening battery	43350601 (1994), dose
levels: M/F: 0, 50, 200 or 600 ppm (0, 0.3, 1.2 or 3.6 mg/l)

Acceptable/guideline	NOAEL:  200 ppm in males, and 600 ppm (HDT) in
females  

LOAEL: 600 ppm in males based on decreased forelimb and hindlimb grip
and motor activity. No systemic effects were observed

870.6200b

	Subchronic inhalation neurotoxicity screening battery	43350602 (1994),
dose levels: M/: F 0, 50, 200 or 600 ppm (0, 0.3, 1.2, or 3.6 mg/l).

Acceptable/guideline	NOAEL: 200 ppm in males and 600 ppm (HDT) in
females. 

LOAEL: 600 ppm in males based on a statistically significant increased
number of rearings in males. 

870.7485

	Metabolism and pharmacokinetics in male and female F344 rats, and male
B6C3F1 mice by oral and inhalation routes.	41697801 (1990), 

Acceptable/Core minimum	para-Dichlorobenzene was rapidly absorbed after
oral and inhalation exposure. Absorption after inhalation exposure was
poor in relation to oral exposure. Mice demonstrated increased
absorption vs rats after oral and inhalation exposure. Significant
tissue distribution was observed in kidney, liver, fats and residual
carcass.  Excretion was relatively fast at all doses tested, with the
majority excreted in the urine and feces by 48 hours.  Feces and expired
air were also significant routes of elimination (approximately 10% of
the administered oral dose). Urine metabolites identified were the
sulfate and glucuronide 0f 2,5-dichlorophenol. Mice demonstrated
increased glucurinidation vs rats. Glucurinidation appeared to occur
after repeated oral dosing but not inhalation exposure in male rats.
Tissue clearance half life was also reduced by repeated oral and
inhalation exposure. Clearance kinetics was largely bi-exponential, with
the exception of male rat kidney, which showed mono exponential kinetics
after oral exposure.  Binding of radioactivity to -2  globulin was
suggested as an explanation for the increased half-life of elimination
from male rat kidney.

870.7600	Dermal penetration

	N/A	A dermal absorption study is not available and is not required. 
The volatile nature of p-dichlorobenzene and the use profile indicate
that the inhalation route is the major route of human exposure. Dermal
penetration exposure is not a likely route of exposure and thus a dermal
absorption factor is not required for risk assessment in this case. 

A.3  Executive Summaries TC \l2 "A.3  Executive Summaries 

A.3.1	Subchronic Toxicity

870.3465  90-Day inhalation Toxicity – Rat 

In a subchronic inhalation study (S. Aiso et al. Japan Bioassay Research
Center, Japan Industrial Safety and Health Association, J Occup Health
2005; 47:249-260), groups of 10 male and 10 female Fisher 344 rats were
exposed to para-dichlorobenzene by inhalation for 6 hours per day, 5
days per week for 13 weeks at concentration levels of 0, 25, 55, 120,
270, or 600 ppm. The animals were observed daily for clinical signs and
mortality. Body weight and food consumption were measured once a week.
Blood samples were taken for hematology and biochemistry. All animals
underwent necropsy. Tissues were taken for histopathology and
microscopic examination. Kidney tissues were tested
immunohistochemically for binding of anti-2-globulin.

2u-globulin, suggesting excessive accumulation of 2u-globulin in
the epithelial cells. Granular casts were formed in the tubular lumen,
resulting from the necrotic desquamation of the renal tubular
epithelium. Papillary mineralization in the renal pelvis and increased
serum levels of BUN and creatinine were noted. These renal changes
indicated 2u-globulin nephropathy. Decreases in red blood cell
counts, hemoglobin concentration, hematocrit and mean corpuscular volume
and increased spleen weight occurred in the treated males. The NOAEL is
set by the authors at 120 ppm, and the LOAEL is set at 270 ppm, based on
the renal toxicity in males.  However, the NOAEL/LOAEL was established
by the scientific reviewer of this study at 55/120 ppm based on
hematological changes in males. On the basis of the findings of this
study, the maximum tolerated dose for a 2-yr bioassay inhalation study
of the rat carcinogenicity study was estimated to be 300 ppm. This study
is not classified.

	 	90-Day Inhalation Toxicity – Mouse

In a subchronic inhalation study (S. Aiso, et al. Japan Bioassay
Research Center, Japan Industrial Safety and Health Association, J Occup
Health 2005; 47:249-260), groups of 10 male and 10 female BDF1 mice were
exposed to para-dichlorobenzene by inhalation for 6 hours per day, 5
days per week for 13 weeks at concentration levels of 0, 25, 55, 120,
270, or 600 ppm. The animals were observed daily for clinical signs and
mortality. Body weight and food consumption were measured once a week.
Blood samples were taken for hematology and biochemistry. All animals
underwent necropsy. Tissues were taken for histopathology and
microscopic examination. Kidney tissues were tested
immunohistochemically for binding of anti-2-globulin.

The exposure to para-dichlorobenzene vapor induced hepatotoxicity in the
mice of both sexes. Hepatotoxicity was characterized by increased liver
weight, hepatocellular hypertrophy, and increased serum levels of total
cholesterol. Liver necrosis and increased serum levels of AST and ALT
were observed in the exposed mice. The NOAEL is 120 ppm, and the LOAEL
is 270 ppm, based on the hepatic changes in mice. On the basis of the
findings of this study, the maximum tolerated dose for a 2-yr bioassay
inhalation study of the mouse carcinogenicity study was estimated to be
300 ppm.  This study is not classified.

  28-Day Inhalation Toxicity – Dog

In a range finding study (MRID No. 41822801), eight month old Beagle
dogs weighing 9.2 – 11.5 kg (males) and 7.4 – 9.4 kg (females) were
acclimated to laboratory conditions for 9 weeks and then treated in
groups of 2 per sex per dose group with p-dichlorobenzene via inhalation
at concentrations of 0, 50, 150 or 500 ppm (particle size ranged from
4.1 to 6.2 microns, geometric standard deviation 3.2 to 4.4), 6 hours a
day, 5 days per week for 28 days. It should be noted that the target 500
ppm concentration was not achieved and the mean nominal inhalation
chamber concentration was determined to be 329 + 96 ppm. 

One male of the 500 ppm group died on test day 26 and one female in the
same group appeared to be emaciated and dehydrated during the last week
of treatment. However, there was no indication whether these were
treatment-related effects. Other treatment related effects in the high
dose group included decreased mean body weights (17 % in males and 22 %
in females) in four weeks, decreased food consumption in both sexes,
changes in hematological parameters (increased hemoglobin, 19% in males
and 14% in females; increased hematocrit, 30% in males and 18% in
females; and erythrocytes, 15% in males and 16% in females). 
Significant changes in the clinical chemistry parameters were observed
in both males and females of the 500 ppm group.  Relative and absolute
organ weight changes were also observed in males and females of the 500
ppm group at termination.  These changes included increased absolute and
relative liver weights in males, increased absolute and relative adrenal
weights, and decreased relative and absolute spleen weights, and
decreased heart weight in both males and females. 

In the 150 ppm group, the treatment resulted in some organ weight
changes including increased absolute and relative liver weights in males
and decreased absolute and relative spleen weights in both males and
females and decreased heart weights in both males and females. Decreased
spleen weight was also observed in both males and females in the 50 ppm
group.  No histopathological changes in these organs were reported.  It
should be noted that the reliability of such findings is limited because
of the extremely limited number of animals used in such a study which
precludes statistical analysis. 

The NOAEL/LOAEL in this study can be set at 150/500 ppm based on
decreased mean body weight and food consumption in both males and
females, changes in hematological and clinical chemistry parameters and
changes in absolute and relative organ weights in both males and
females. 

            

    28-Day Feeding – Dog

In a four-week range finding study (MRID No. 43988801), groups of 5-6
months old Beagle dogs, 2/sex/dose, weighing 5.1-10.4 kg (males) and 5.2
to 8.5 Kg (females)  were administered para-dichlorobenzene orally in
gelatin capsules, 5 days a week at doses level of 25, 75, 150 or 300
mg/kg/day for four weeks.  Both males from the 300 mg/kg/day group died
during the study.  One of them was thought to be a result of dosing
administration. Decreased body weight gains were observed in the 150 and
300 mg/kg/day groups. Elevated clinical chemistry parameters were
observed in the 150 mg/kg/day males and in the 75, 150, and 300
mg/kg/day females.  At necropsy, absolute and relative liver weights
were increased in the 75 and 150 mg/kg/day males and 75, 150, and 300
mg/kg/day females. However, food consumption appeared to be normal. 
There were no adverse effects on hematology or urine analysis.  In
addition, irritation of the gastrointestinal tract was noted in both
males and females.  In both the 300 mg/kg/day males, the entire mucosal
surface of the intestinal tract had red/purple/black discoloration which
thought to be due to severe irritation by the test material.  Females
also exhibited irritation of the gastrointestinal tract. One female from
each of the 75, 150 and 300 mg/kg/day groups had a red/purple/black
mucosal surface of the duodenum and/or the jejunum. 

In the 150 mg/kg/day males, alkaline phosphatase, ALT, AST, direct
bilirubin and total bilirubin were all substantially increased and total
protein and albumin were decreased.  Females in the 75, 150 and 300
mg/kg/day groups appeared to have an increase in alkaline phosphatase.
The 300 mg/kg/day females also appeared to have a slight increase in
GGT. Total protein and albumin were significantly decreased in the 300
mg/kg/day females. 

The NOAEL/LOAEL was considered to be 25/75 mg/kg/day based on effects on
liver weight in males of the 75 mg/kg/day, increased alkaline
phosphatase and liver weights, and irritation to the gastrointestinal
tract in females of the 75 mg/kg/day.

21/28-Day Dermal Toxicity – Rat

In a repeated dose dermal toxicity study (MRID 41315001),
para-dichlorobenzene, (100% ai) was dissolved in light mineral oil
vehicle and applied to the shaved skin of five adult Sprague-Dawley
rats/sex/dose at dose levels of 0, 75, 150, or 300 mg/kg daily for six
hours per day, five days a week for three weeks. The test material was
prepared so that 2ml/kg/dose to be applied at each treatment. The test
area was covered with a polyethylene patch. After six hours, the patch
was removed and residual test material wiped away. Animals were observed
twice daily for signs of toxicity and mortality. Body weight was checked
twice before the initiation of the treatment and weekly thereafter. Food
consumption was checked daily.  Blood was collected before treatment and
at termination for hematological and clinical analysis. Ophthalmological
examination was not performed in this study. No treatment related
effects were reported. The NOAEL is considered to be 300 mg/kg/day, the
highest dose tested. This study is acceptable, classified as Core –
minimum and thus satisfies the guideline requirement 82-2 for a repeated
dose dermal toxicity study.  

A.3.2	Prenatal Developmental Toxicity

	870.3700a Prenatal Developmental Toxicity Study – Rat

In a developmental toxicity study in rats (MRID No. 42619601), four
groups of 25 CD rats (63 days old males weighing 271-305 grams, and 56
days old females weighing 175-208 grams) were used. Mating was carried
out so that one male was mated to one female. Females with vaginal plugs
were taken and individually housed. Females were exposed to
para-dichlorobenzene vapor at a target concentration of 0, 50, 200, or
600 ppm for 6 hours per day on gestation days 6 through 15. Control
animals were exposed to filtered air. Morbidity and mortality checks
were made twice daily and the rats were observed for clinical signs
before, during, and after exposure. Food consumption was recorded at
three days intervals. Body weights were recorded on days 0, 6, 9, 12,
15, 18, and 21 of gestation. Females were sacrificed by carbon dioxide
and necropsied on gestation day 21. The following were examined grossly:
uterus, ovaries (including corpora lutea), cervix, vagina, peritoneal
cavity and thoracic cavity. Liver and kidneys were weighed. Livers,
kidneys and upper as well as lower respiratory tracts including nasal
turbinates were reserved. Live and dead fetuses plus resorption sites
were noted and recorded. Uteri which appeared to be non-gravid were
examined for early resorptions. Live fetuses were weighed and given
external examinations. About 50% of the fetuses in each litter were
examined for visceral abnormalities by modification of a method
described by Staples. These fetuses were decapitated and the heads fixed
in Bouin’s solution for craniofacial examination (modification of
Wilson). All live fetuses (intact and decapitated) were eviscerated and
processed with Alizarin Red S for skeletal examinations. Only intact
(not decapitated) were examined for skeletal changes.

 0.01) increase in the number of litters with unossified cervical
centra No. 5, 6, and 7 were reported in the 600 ppm group. There were
non-significant increases in the number of fetuses with unossified
centra No. 5 and 6 at all 3 doses. The increased incidences of
individual skeletal variations indicated a consistent profile of
slightly delayed development/ossification in the cervical region of
fetuses from the 600 ppm group.  

The maternal NOAEL/LOAEL was 50/200 mg/kg/day based on decreased mean
body weight, body weight gain and reduced food consumption.  The
developmental NOAEL/LOAEL was 200/600 mg/kg/day based on delayed
cervical centra ossification at No. 5, 6, and 7.  There were no
treatment-related teratogenic effects. The study is classified as
Core-minimum data and considered acceptable under guideline 83-3 for a
developmental toxicity in rats.

	870.3700b Prenatal Developmental Toxicity Study - Rabbit

In a developmental toxicity study in rabbits (MRID No. 40568001), four
groups of 29 to 30 New Zealand rabbits weighing between 3.5 and 4.5 kg
were artificially inseminated and subsequently the pregnant rabbits were
exposed to vapor of para-dichlorobenzene with purity of 99.9% through
the inhalation route at the target concentration level of 0, 100, 300,
or 800 ppm.   Pregnant rabbits were exposed to the test material from
day 6 through 18 of gestation. Control animals were exposed to filtered
air in identical chambers. Body weights for all animals were checked on
days 6, 9, 12, 15, 19, and 29 of gestation.  All animals were sacrificed
by carbon dioxide asphyxiation and the maternal livers and kidneys were
removed, weighed, and preserved for histopathological examination. 

At sacrifice, the uterine horns were extracted and the following data
recorded: 1) number and position of fetus in utero, 2) number of live
and dead fetuses, 3) number and position of resorption sites, 4) number
of corpora lutea, 5) sex, body weight, and crown – rump length of each
fetus, and 6) any gross external alterations. One - half of the fetuses
of each litter was dissected immediately and examined for soft tissue
alterations. All fetuses were preserved in alcohol, eviscerated, cleared
and stained with alizarin red-S and examined for skeletal alterations. 

There was no treatment-related mortality.  The high dose group had
statistically significant lower body weight gain between days 6 and 18
of gestation. The high dose group animals gained significantly lower
weight than the corresponding controls (28 vs 185 g for the high dose vs
the controls) between days 6 and 18 of gestation. However, the lack of
data on food consumption did not allow the determination as to whether
the lower body weight gain was due to the effect of the chemical on
curbing the appetite of animals or due to some other systemic effects.
No change in the absolute or relative mean weights of liver or kidneys
was observed No fetal alterations were observed in treated animals in
relation to controls except for two minor alterations; pale liver, and
retroesophageal right subclavian which were found to be significantly
higher in the 300 and 800 ppm group, respectively. The chemical is not
considered teratogenic. The LOAEL for maternal toxicity (depression of
body weight gain) was 800 ppm (HDT) while the NOEL was 300 ppm. The
LOAEL for developmental toxicity (retroesophageal right subclavian
artery) was 800 ppm and the NOEL 300 ppm. This study is core minimum and
satisfies the guideline requirement for a developmental study in
rabbits.

A.3.3	Reproductive Toxicity

	870.3800 Reproduction and Fertility Effects – Rat

In a 2-generation reproduction study (MRID 41108801),
para-dichlorobenzene (100% a.i.) was administered by inhalation to
twenty eight  (6 week old) male and female Sprague Dawley (CD)
rats/sex/dose at target test atmosphere concentrations of 0, 50, 150 and
450 ppm for 10 weeks, and then bred to produce F1 litters. Twenty-eight
randomly selected F1 pups/sex/group were exposed to the test atmosphere
for eleven weeks and then bred to produce F2 litters. Exposure was for
six hours per day, seven days per week, for ten or eleven weeks prior to
breeding, for the first 19 days of gestation and postnatal day 5 until
weaning. 

Increase in toxic clinical signs in F0 and F1 male and female parents
were only observed in the high dose group. High dose F0 males had
reduced body weight throughout the exposure period. High dose F1 female
parents had significantly lower body weight (P < 0.01). Gestational body
weights of high dose F0 females significantly decreased (P < 0.01)
beginning at day 7 throughout gestation accompanied by lower food
consumption which was consistent with the reduction in body weights. 

There was no clear indication of treatment-related effect on
reproductive parameters. The latent time for mating for both generations
was increased in the 450 ppm group, with the difference being more
pronounced in the F0 parents than in the F1 parents. The total number of
pups born per litter was not affected by treatment in either F1 or F2
litters; however, live births were reduced in F2 pups (P < 0.01). Four
day survival was reduced in high dose F1 and F2 pups, but not affected
in low or intermediate dose pups. No treatment related effects on
survival were reported on pups after day 4. High dose pups from both
generations had significantly reduced body weights at birth (P < 0.01).
Differences in the body weights of high dose pups persisted through the
28 day lactation period.

The absolute and relative liver weights of F0 male rats were
significantly increased in mid and high dose groups. Absolute and
relative kidney weights were significantly increased in a dose related
fashion in all treated groups. Organ weight effects in F1 males were
less pronounced in the F0 males. Absolute liver weights were increased
only in the high dose group, but relative liver weights were increased
in the high and mid-dose groups. Absolute kidney weights increased
significantly in mid and high dose F1 males. Relative kidney weights
expressed as percent of body weight and percent of brain weight
increased in a dose related fashion in all treated groups although the
increase as percent of brain weight in the low dose group was not
statistically significant. Brain and testes weights expressed as percent
of body weight were significantly increased (P0.01) in high dose F1
males only. For F0 female rats, absolute and relative liver weights were
increased in the 150 ppm and 450 ppm treatment groups. 

Histopathological effects in adult female rats were limited to
significantly increased hepatocellular hypertrophy in the high dose
group. The response in F1 females (14/28, P < 0.01) was more pronounced
than in F0 females (7/27, P <0.05). Similar liver effects were seen in
high dose, adult males from the F0 and F1 generations. Hepatocellular
hypertrophy was significantly increased in both groups (P < 0.01), and
hepatocellular swelling (F1) and hepatocellular cytoplasmic vacuolation
(F0) were increased although not significantly. The kidneys of adults,
male F0 and F1 rats reflected the most significant adverse response. All
treated male rats exhibited hyaline droplet nephrosis. Although this
lesion also occurred in 11/27 and 10/28 control rats, the severity and
frequency were increased in the treated animals. A number of other
kidney lesions were reported in treated males. These effects were
increased in both generations but appeared to be more pronounced in the
F0 males than in the F1 males. No treatment related histopathological
effects were reported in F2 weanlings of either sex. No treatment
related histopathological effects were reported for the reproductive
organs of any group.  The NOAEL/LOAEL for reproductive toxicity was
considered to be 150/450 ppm based on litters with reduced numbers of
live pups and 4-day survival. The NOAEL/LOAEL for offspring toxicity was
150/450 ppm based on decreased mean pup body weight and decreased pup
survival. The LOAEL for systemic toxicity was considered to be 50 ppm,
the lowest dose tested (for males) and the NOAEL/LOAEL for systemic
toxicity in females was 150/450 ppm based on liver changes. This study
is acceptable (minimum) and satisfies the guideline requirement for a
2-generation reproductive study.

A.3.4	Chronic Toxicity

	870.4100 Chronic Oral Toxicity – Dog

In a one-year oral toxicity study (MRID 43988802), para-dichlorobenzene
(99.9% a.i.) was administered to beagle dogs (5/sex/dose) by capsule at
dose levels of 0, 10, 50, or 150 mg/kg/day. Three animals (2 males and 1
female) in the highest dose and one male control animal died during the
study. Due to unexpected severe toxicity at the highest dose, the
initial dose of 150 mg/kg/day was adjusted to 100 mg/kg/day for males
during the 3rd week, and a further decrease to 75 mg/kg/day was made for
both sexes at the beginning of the 6th week of the study. Both males and
females at the highest dose level were untreated during the fourth and
fifth weeks to allow recovery. Lower dose level animals were
administered the test material continuously at the original dose levels.
All treatment-related clinical signs were primarily limited to severely
affected animals at the highest dose level. These clinical signs
included hypoactivity, dehydration, decreased defecation, blood-like
fecal color, emesis, emaciation, and/or pale (oral) mucosa.

Group mean body weight did not show a significant difference from the
control in either sex. However, cumulative body weight gain at the
highest dose showed a significant deficit during the first month of the
study. Following reduction of the dose and adjustment of food
availability, surviving dogs in this high dose group resumed a more
comparable weight gain pattern for the remained period of the study. A
mild anemia (decreased RBC counts and HCT levels) in both sexes at the
early stage (month 6) was observed in the high dose animals. At the end
of the study, the mild anemia was resolved which correlated with
microscopic findings of rib and sternal marrow erythroid hyperplasia in
females and splenic excessive hematopoiesis and megakaryocyte
proliferation in both sexes indicating a compensatory response to the
earlier anemia.

Elevated alkaline phosphatase, ALT, AST, and GGT levels and a decreased
albumin level observed in both sexes at the mid- and high-dose levels,
indicated hepatic effects of the test material. These findings were
supported by increases in absolute and relative liver weights (both
sexes) and microscopic findings in the liver including hepatocellular
hypertrophy, hepatocellular pigment deposition, bile duct/ductile
hyperplasia, nodular hyperplasia, bile stasis and hepatic portal
inflammation. Kidney collecting duct epithelial vacuolation was present
in a high-dose male and at all dose levels in females. This lesion was
considered a possible effect of the test material at the mid and high
doses in females where it was accompanied by increased kidney weights
and grossly observed renal discoloration. In this study, the NOAEL/LOAEL
is 10/50 mg/kg/day, based on increased liver weight, histological
findings in the liver, and clinical chemistry data. This study is
acceptable and satisfies the 83-1 guideline requirement for a chronic
feeding study in dogs.

A.3.5	Carcinogenicity

	870.4300  Combined Chronic Oral Toxicity/Carcinogenicity – Rat 

The combined chronic toxicity/carcinogenicity of para-dichlorobenzene
was investigated by the National Toxicology Program (NTP) in F344/N
rats. In this study (MRID 40521005), p-dichlorobenzene was administered
by gavage in corn oil to groups of 50 male and 50 female rats, at dosage
levels of 0, 150, or 300 mg/kg/day in males and 0, 300, or 600 mg/kg/day
in females, 5 days/week for 104 weeks. 

The following signs of generalized toxicity and non-neoplastic pathology
changes occurred in the males: (a) decreased survival at the high dose
level (26/50 or 52% died by termination of the study vs. 11/50 or 22% in
controls); (b) reduced body weight gain at the high dose level (5-8%);
(c) renal mineralization at both dose levels tested (4/50 or 8% minimal
severity, controls; 46/50 or 92% mild to moderate severity, low dose,
47/50 or 94% moderate to high severity high dose): and (4) renal pelvic
hyperplasic at both dose levels tested (1/50 or 2% controls 30/50 or 60%
low dose 31/50 or 62% high dose). The decreased survival rate in high
dose males did not become significantly different from control animals
until week 97, a time when tumors had already appeared in most treated
animals. In addition many of the high dose males that died had leukemia
thereby raising the question of whether this lesion was the cause of
death.

 

The treatment did not cause any significant increases in tumors in
treated females, while it produced a dose-related increase in the
incidence of tubular cell adenocarcinomas of the kidney in males (1/50;
3/50; 7/50 in the control, low dose and high dose, respectively). One
tubular cell adenoma was observed in a high dose male rat. The increased
tumorigenic responses seen at the highest dose level also exceeded the
average historical control incidences for similar tumors obtained both
in studies at the test laboratory and in all NTP studies overall.  These
malignant tumors are uncommon in male F344/N rats. They have been
observed in only 4/1098 (0.4%) corn oil gavage controls in previous NTP
studies. The elevation in tumor incidences was characterized by reduced
latency. Evidence to support a reduced latency period for
adenocarcinomas development in the high dose animals was also present
(i.e. the first adenocarcinomas in the high dose group occurred at
treatment week 45, and the second and third occurred at treatment weeks
90 and 98, respectively, whereas these tumors were first observed at 104
weeks and 101 weeks in the control and low dose groups, respectively).
There was a marginal increase in the incidence of mononuclear cell
leukemia in dosed male rats compared with that in vehicle controls
(5/50; 7/50; 11/50 in the control, low dose and high dose,
respectively).

Administration of para-dichlorobenzene to male rats increased the
average severity of nephropathy and caused epithelial hyperplasia of the
renal pelvis (1/50; 30/50; 31/50 in the control, low dose and high dose
respectively), mineralization of the collecting tubules in the renal
medulla (4/50; 46/50; 47/50 in the control, low dose and high dose,
respectively), and focal hyperplasia of the renal tubular epithelium
(0/50; 1/50; 9/50 in the control, low dose and high dose, respectively).
There were increased incidences of nephropathy in both low and high dose
female compared with vehicle controls (21/50; 32/50; 41/50 in the
control, low dose and high dose, respectively). 

The LOAEL for systemic toxicity (depression of body weight) was 300
mg/kg/day in male rats and 600 mg/kg/day in female rats. The NOAEL was
150 mg/kg/day in males and 300 mg/kg/day in females. 

	870.4300   Combined Chronic inhalation Toxicity/Carcinogenicity - Rat		

In another carcinogenicity study (S. Aiso et al. 2005),
para-dichlorobenzene (purity greater than 99.9%) was administered by
inhalation to groups of 50 F344 rats of both sexes at a target
concentration of 20, 75, or 300 ppm for 6 hours/day, 5 days/week for two
years. A group of 50 rats of either sex, serving as control, was handled
in the same manner but was exposed to clean air only.  Air
concentrations of para-dichlorobenzene vapor in the exposure chambers
were monitored at an interval of 15 minutes by gas chromatography and
were maintained approximately constant.  

The highest dose level tested was selected on the basis of a thirteen
week inhalation study in rats (S. Aiso et al. J. Occup Health 2005; 47:
249-260).  In this thirteen week study, the animals were exposed by
inhalation to concentration of para-dichlorobenzene ranging from 25 ppm
to 600 ppm for 6 hours/day, 5 days per week for 13 weeks.  Control
groups were also included and exposed to clean air under the same
conditions. The treatment induced hepatotoxicity in rats of both sexes. 
It should be noted that similar hepatotoxicity occurred also in another
thirteen week study in mice conducted by the same workers. But there
were characteristic differences in the induced hepatotoxicity in mice
and rats:

“First, the mouse liver was more responsive to para-dichlorobenzene
than the rat liver as shown by the hepatocellular hypertrophy, the
increased  relative liver weight, and the retarded growth rate in mice
at lower exposure concentrations than the rats.  Secondly, the affected
hepatocytes of the para-dichlorobenzene exposed mice were characterized
by centrilobular hypertrophy with varying nuclear size and shape, and
coarse chromatin and inclusion bodies in the nucleus, whereas such
nuclear changes were not observed in the hypertrophic hepatocytes of the
para-dichlorobenzene exposed rats. Thirdly, both liver necrosis and
increased serum levels of AST and ALT, indicative of hepatocellular
death, were  observed in male mice of the 600 ppm, whereas neither liver
necrosis nor increased serum levels of the transaminases occurred in any
of the para-dichlorobenzene rats of either sex.”  	

The treatment did not alter the spontaneous tumor profile in either male
or female rats by this route although oral administration in a previous
oral study conducted by NTP (MRID No. 40521005)) was associated with
increased incidences of renal tumors in males. 

 

In this study, significant increases in absolute and relative organ
weights were observed in the liver of males and females and in the
kidney of males of the high dose group. No macroscopic lesions were
observed in the organs of any of the treated groups.  Incidence of
centrilobular hypertrophy of hepatocytes was increased in males of the
high dose group.  Increased incidences of papillary mineralization and
hyperplasia of the pelvic urothelium in the kidney were observed in
males of the high group. No histopathological changes indicative of
2 globulin in the epithelial cells of renal proximal tubules
were observed in the inhalation carcinogenicity study, although both the
hyaline droplets and the granular casts in the proximal tubules of male
rats were noted earlier in the thirteen week inhalation study. 

2 globulin, observed in the proximal tubular epithelial
cells. Granular casts were observed in the tubular lumen, resulting from
the necrotic desquamation of the renal tubular epithelium. Papillary
mineralization in the renal pelvis and increased serum levels of BUN and
creatinin were observed.  These renal changes are indicative of
2 globulin nephropathy.  Hematological toxicity in male rats
was manifested as decreases in red blood cell counts, hemoglobin
concentration, hematocrit and mean corpuscular volume and increased
spleen weight.

Incidences of the eosinophilic globules in the nasal cavity were
increased in the olfactory epithelium with marked grade of severity in
the females of the middle (75 ppm) and high (300 ppm) dose groups
(severity scores of  either 2+ or 3+ [scale of 1-3; 3 being most severe]
– 27/49, 29/46, 39/46, and 47/50 in control, low, mid, and high dose
females) and in the respiratory epithelium having slight grade of
severity in the high dose females. The increased incidences of the
eosinophilic globules were closely associated with a marked decrease in
the number of olfactory cells in the olfactory epithelium of the 75 and
300 ppm-exposed females. Incidence of the respiratory metaplasia of the
nasal gland epithelium was increased in the females exposed to 300 ppm.
The eosinophilic globules were abundantly present in both the supporting
cells of the olfactory epithelium and the ciliated and non-ciliated
cells of the respiratory epithelium.  The NOAEL for the nasal lesions in
rats was considered to be 20 ppm.

870.4200  Carcinogenicity – Mouse

The carcinogenicity of para-dichlorobenzene was investigated by the
National Toxicology Program (NTP) in B6C3F1 mice (MRID 40521005).  
para-Dichlorobenzene was administered by gavage in corn oil to groups of
50 male and 50 female mice, at dosage levels of 0, 300, or 600
mg/kg/day, 5 days/week for 104 weeks. The selection of the dose levels
tested in this study was based on a 90-day study which established that
dose levels of 675 mg/kg/day or higher resulted in systemic toxicity
while the low dose of 375 mg/kg/day was a NOAEL.

Hepatocellular adenomas, carcinomas, and adenomas plus carcinomas
combined were significantly elevated in both males and females of the
high dose group. In addition there were positive trends for all three
categories of tumors in both sexes. Among the hepatocellular carcinomas
seen in the high dose males were four hepatoblastomas, a more uncommon
and malignant type of liver tumor than hepatocellular carcinomas.
Neither liver hyperplasia nor a reduction in the latency period to tumor
development occurred in males or females. The tumor incidences
associated with para-dichlorobenzene treatment were as follows: 
hepatocellular carcinomas in high dose males (14/50; 11/49; 32/50 for
the control, low- and high-dose, respectively) and females (5/50; 5/48;
19/50 for the control, low- and high-dose, respectively) and
hepatocellular adenomas in dosed males (5/50; 13/49; 16/50 for the
control, low- and high-dose, respectively) and high dose females (10/50;
6/48; 21/50 for the control, low- and high-dose, respectively).
Hepatoblastomas were observed in four high dose males, but not in the
control group. This rare tumor has not occurred in 1091 male vehicle
control mice in NTP studies. An increase in thyroid gland follicular
cell hyperplasia was observed in dosed males (1/47; 4/48; 10/47 for the
control, low- and high-dose, respectively), and there was a marginal
positive trend in the incidence of follicular cell adenomas of the
thyroid gland in females (0/48; 0/45; 3/46 for the control, low- and
high-dose, respectively). Pheochromocytomas (benign or malignant,
combined) of the adrenal gland occurred with a positive trend in dosed
male mice, and the incidence in the high dose group was significantly
greater than in the vehicle controls (0/47; 2/48; 4/49 for the control,
low- and high-dose, respectively). The incidence of adrenal gland
medullary hyperplasia in males was 2/47, 4/48, and 4/49. Focal
hyperplasia of the adrenal gland capsule was also observed in dosed male
mice (11/47; 21/48; 28/49 for the control, low- and high-dose,
respectively).

Historical control data have been provided for liver tumors in B6C3F1
mice by the NTP (Toxicologic Pathol. 12:126-135, 1984; Handbook of
Carcinogen Testing, Noyes Pubs., N.J. p. 291, 1984). In male mice,
historical control rates were as follows: adenoma (10.3%; range 0-24%);
carcinoma (21.3%; range 8-36%); combined (31.1%, range 16-58). In female
mice, historical control rates were as follows: adenoma (4.0%; range
0-18%); carcinoma (4.1%; range 0-15%); combined (7.9%, range 0-20%).
Comparison of these data with the tumor incidences in the actual study
indicates that the following liver tumors were outside of the historical
control ranges: (1) adenomas, carcinomas, and adenomas/carcinomas
combined in high dose males and high dose females; and (2) concurrent
control incidences of adenomas, and adenomas/carcinomas combined, in
female mice. In addition, the incidence of hepatoblastomas in high dose
male mice exceeded the NTP historical control incidence (0/3500 or 0%).

           

In terms of general toxic effects, para-dichlorobenzene-treated mice
exhibited no increase in mortality and no reduction in body weight gain
compared to control animals. The following non-neoplastic pathology
changes occurred at the mid- and high-dose levels in both males and
females: (a) nephropathy (males, 12% control, 24% low dose, 32% high
dose; Females, 0% control, 6% low dose, 7% high dose); (b)
hepatocellular degeneration (males, 0% controls, 73% low dose , 78% high
dose; females, 0% control, 17% low dose, 72% high dose); (c) liver focal
necrosis ( male,2% control, 8% low dose, 60% high dose); and (d) liver
cell size alteration (males, 0% control, 78% low dose, 80% high dose;
females 0% control, 8% low dose, 54% high dose). Survival of male and
female mice and mean body weights were comparable between the
para-dichlorobenzene-treated and the control animals throughout the
study.

The LOAEL for systemic toxicity in male and female mice was not
established in this study. Systemic toxicity was observed in both sexes
receiving either the low or the high dose and consisted of nephropathy,
hepatocellular degeneration with cell necrosis and liver cell size
alteration (cytomegaly and karyomegaly). 

	

	870.4200   Inhalation Carcinogenicity  – Mouse

In another carcinogenicity study (S. Aiso et al. 2005b),
para-Dichlorobenzene (purity greater than 99.9%) was administered by
inhalation to groups of 50 BDF1 mice of both sexes at a target
concentration of 20, 75, or 300 ppm for 6 hours/day, 5 days/week for two
years. A group of 50 rats of either sex, serving as control was handled
in the same manner, but was exposed to clean air only.  Air
concentrations of para-dichlorobenzene vapor in the exposure chambers
were monitored at an interval of 15 minutes by gas chromatography and
were maintained approximately constant.  

The selection of the dose levels used in this study was based on the
results of a thirteen-week inhalation toxicity study of
para-dichlorobenzene in mice (S. Aiso et al. J. Occup Health 2005; 47:
249-260).  In this study the animals were exposed by inhalation to
concentration of para-dichlorobenzene ranging from 25 ppm to 600 ppm for
6 hours/day, 5 days per week for 13 weeks.  Control groups were also
included and exposed to clean air under the same conditions. The
treatment caused retardation in the growth rate of male mice, and
induced hepatotoxicity in mice of both sexes.  

	

In this carcinogenicity study, the treatment was associated with a
statistically significant increase in the incidences of hepatocellular
carcinomas, hepatoblastomas and hepatic histiocytic sarcomas in males of
the high dose group, and increased incidences of hepatocellular adenomas
and carcinomas and hepatoblastomas in females of the high dose group. 
Incidences of histiosystic sarcoma in different tissues of male and
female mice were also increased. There was no difference in the growth
rate between the treated and non-treated mice of either sex except for
the 300 ppm male group, highest dose tested, which exhibited
significantly decreased body weight gain of 12%, at the end of the two
years. No difference in food consumption was observed between the
treated and the control groups. Absolute and relative liver weights were
significantly increased in males and females of the high dose group. 
Absolute and relative kidney weights in females and relative kidney
weights in males were significantly increased in the high dose group.

An increase in the number of males and females bearing liver nodules was
observed in both sexes of the high dose group.   No significant increase
in the incidence of altered cell foci in the liver was observed in
either males or females. Increased incidence of centrilobular
hypertrophy of hepatocytes was observed in males of the high dose group.
There was no histopathological change indicating hepatocellular injury
in both sexes of any of the treated groups. 

Incidence of the respiratory metaplasia of the nasal gland epithelium
increased in females of the high dose (300 ppm), and was significantly
increased in the 75 ppm male group.  Increased incidence of the
respiratory metaplasia of the olfactory epithelium with slight severity
was noted in males of the 75 ppm group.  The respiratory metaplasia was
manifested as replacement of the olfactory epithelium with the
respiratory-like mucosal epithelium in which those epithelial cells were
similar to the ciliated cells of normal respiratory epithelium.  

Survival rates decreased in all treated male groups (39/49, 31/49,
32/50, and 30/49 in the control, 20 ppm, 75 ppm, and 300 ppm,
respectively).  The decrease in survival rate did not appear to be
dose-dependent.  However, according to the author, only the decrease in
the survival rate of the 300 ppm male group was significant in the
Kaplan-Meier survival analysis.  A total of 19 deaths consisting of 12
liver tumors deaths, 3 other tumor deaths and 4 non-neoplastic deaths
occurred in the 300 ppm group while 3 liver tumor deaths, 3 other tumor
deaths and 4 non-neoplastic deaths were observed in the control group. 
There was no difference in survival rate between the treated female
groups and the control group (28/50, 25/50, 23/49, 26/50 for the
control, 20, 75, and 300 ppm respectively).”  The NOAEL/LOAEL was
considered to be 75/300 ppm, based on reduced body weight in males,
increased incidences of nasal lesions in females, and increased liver
and kidney weights in males and females.

	   

A.3.6	Mutagenicity

870.5100, Bacterial reverse mutation test

MRID 40521004

Unacceptable 	Salmonella typhimurium.  Para-dichlorobenzene with 99.5%
a.i. was negative in all strains tested including TA98, TA100, and
TA1537 within the concentration range of 0.6 to 600 (g/plate with and
without activation and up to cytotoxic concentration (600 (g/plate). The
study is deficient but other published control studies indicated that
para-dichlorobenzene was negative in the Salmonella reverse mutation
test with and without metabolic activation.  

870.5100, Salmonella / mammalian microsomal reverse mutation assay.

MRID 40568002

Adequate 	Salmonella typhimurium.  Para-dichlorobenzene was negative in
all strains tested within the concentration range of 1 to 100 (g/plate
with and without activation.. The study was published in
“Environmental Mutagenesis Supplement 1, 1983” by Haworth et al and
entitled : “Salmonella Mutagenicity Test Results for 250 Chemicals”
and appears to be adequate and can be used as supportive data in
determining para-dichlorobenzene mutagenicity.  

870.5100, Salmonella / mammalian microsomal reverse mutation assay.

MRID 40568003

Acceptable 	Salmonella typhimurium.  Para-dichlorobenzene was negative
in all strains tested including within the concentration range of 51.2
to 13105.2 (g/plate with and without metabolic activation. The study was
published in “Mutation Research, 116 (1983)” by Shimiza et al. and
entitled “Structural Specificity of Aromatic Compounds with Special
Reference to Mutagenic Activity in Salmonella typhimurium – a Series
of Chloro- Flouro-Nitrobenzene Derivatives” . The study appears to be
adequate and can be used as supportive data in determining
para-dichlorobenzene mutagenicity  

870.5300, In vitro mammalian cell forward gene mutation test

MRID 40521007

Acceptable	Negative for inducing forward mutations at the
hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus in Chinese
hamster ovary (CHO) cells exposed to test article ranging from 25 to 250
(g/ml with and without metabolic activation.

870.5300, In vitro mammalian cell forward gene mutation test

MRID 40521013

Acceptable	Forward gene mutation in mammalian cells in vitro (CHO/HGPRT)
was negative for inducing forward mutations in hypoxanthine-guanine
phosphoribosyl transferase (HGPRT) locus in Chinese hamster ovary (CHO)
cells exposed to test article up to cytotoxic level and including
concentrations range of 50 to 400 (g/ml, with or without metabolic
activation.

870.000, In vivo gene mutation in insects (Drosophila/SLRL).  

MRID 40521007

Acceptable	Negative for the induction of sex-linked recessive lethal in
Drosophila melanogaster adult males at concentrations ranging from 6,000
to 13,000 ppm/hour (inhalation route). 

870.5395, In vivo mammalian erythrocyte micronucleus test: mouse

MRID 43368447

Acceptable/Guideline	Negative for inducing micronuclei in polychromatic
erythrocytes of mice treated orally with a single dose of test article
up to 225 mg/kg, which caused ataxia and death.

870.5395, In vivo mammalian  micronucleus test: mouse

MRID 40521012

Acceptable	Para-dichlorobenzene was not genotoxic in male and female
mice at dose level of 2500 mg/kg. 

870.5375, Chromosomal aberration in vitro test (CHO cells) 

MRID 43368448

Acceptable/Guideline	Chromosomal damage in CHO cells was positive for
inducing structural chromosomal aberrations in Chinese hamster ovary
(CHO) cell cultures, with/without metabolic activation, to test article,
but only at cytotoxic concentrations, 200 (g/ml –S9, and 1000-1250
(g/ml +S9.

870.5375, Chromosomal aberration in vitro test (CHO cells) 

MRID 43868210

Acceptable/Guideline	 Negative for chromosomal damage in CHO cells
without metabolic activation at levels up to the cytotoxic doses ((204
μg/ml; 18- or 42-hour cell treatments).  Positive for chromosomal
damage in metabolically activated (+S9) over a narrow dose range
(987-1270 μg/ml) that included severely cytotoxic doses ((1270 μg/ml-
18-hour recovery).  Structural aberrations and polyploidy cells were
also significantly increased at 1020 and 1270 μg/ml after 41-hour
recovery time

870.5550 In vivo / in vitro unscheduled and scheduled DNA synthesis in
mouse hepatocytes. 

MRID 40521008

Acceptable 	Para-dichlorobenzene was not genotoxic in male or female
mice at dose levels between 300 and 1000 mg/kg/day. 

A.3.7	Neurotoxicity

	870.6200 Acute Neurotoxicity Screening Battery

In an acute neurotoxicity study (MRID No. 43350601), male and female
Sprague-Dawley rats (10/sex/dose) were exposed for four hours to
para-dichlorobenzene vapors at 0 (air only), 50, 200 or 600 ppm (0, 0.3,
1.2, or 3.6 mg/l, respectively). Neurobehavioral screening, consisting
of Functional Observational Battery (FOB) and motor activity, was
performed before treatment and as soon as possible after exposure (time
of peak effect), and at days 7 and 14. At 14 days, 5 animals / sex of
the control and 600 ppm dose groups were sacrificed and perfusion fixed
for neuropathological evaluation; the remaining animals were examined
grossly.

All animals survived to terminal sacrifice without the appearance of any
adverse clinical signs. Significant FOB findings were decreased forelimb
and hindlimb grip strengths and decreased motor activity in the
high-dose males when measured at the peak time of effect. The
neurobehavioral effects were transient and not observed at the Day 7 and
14 observations. No treatment-related gross pathological or
neuropathological findings were evident.

Based on the results of this study, the LOEL was 600 ppm in males
(decreased forelimb and hindlimb grip strength and decreased motor
activity) and not achieved in females; the NOEL was 200 ppm in males and
600 ppm in females.

This study is classified as Core - Guideline and satisfies guideline
requirements for an acute neurotoxicity screening battery (§81-8) in
the rat.

 	870.6200 Subchronic Neurotoxicity Screening Battery

In a subchronic neurotoxicity study (MRID No. 43350602), male and female
Sprague-Dawley rats (10/sex/dose) were exposed to para-dichlorobenzene
vapors at 0 (air only), 50, 200 or 600 ppm (0, 0.3, 1.2 or 3.6 mg/l,
respectively) for 6 hr/day, 5 days/week (excluding holidays) for 14
weeks. Neurobehavioral screening, consisting of FOB and motor activity,
was performed before treatment and during Weeks 4, 8, and 13. At study
termination, 5 animals / sex / dose were sacrificed and perfusion fixed
in situ for neuropathological evaluation; the remaining animals were
examined grossly.

With the exception of one low-dose female, whose death was not
attributed to treatment, all animals survived to terminal sacrifice
without the appearance of any adverse clinical signs. FOB evaluations at
Weeks 4, 8, and 13 revealed statistically significant increases in the
number of rearings by high-dose males. No other treatment-related FOB
findings or changes in motor activity were observed. No
treatment-related gross pathological or neuropathological findings were
observed.

Based on the results of this study (increased number of rearings), the
LOAEL was 600 ppm in males and not achieved in females; the NOEL was 200
ppm in males and 600 ppm in females. This study is classified as Core -
Guideline and satisfies guideline requirements for a subchronic
neurotoxicity screening battery (§82-7) in the rat.

A.3.8	Metabolism

	870.7485	Metabolism – Rat

In a metabolism study (MRID No. 41697801), the disposition and kinetics
of 14C-para-dichlorobenzene was investigated in male and female Fischer
344 rats and B6C3F1 mice following both oral and inhalation exposures.
In rats, oral exposure was conducted at single doses of 149 and 305
mg/kg, and repeated oral exposure at 309 mg/kg. Inhalation exposures
were conducted in male rats at 160 and 502 ppm (455 and 645 mg/kg), and
in female rats at 161 and 496 ppm (308 and 678 mg/kg). In mice, single
oral exposures of 310 and 638 mg/kg were conducted, as were inhalation
exposures at 158 and 501 ppm (631 and 1240 mg/kg). Intravenous dosing
was performed in male rats at doses of 216 and 217 mg/kg.

Para-dichlorobenzene was rapidly but incompletely absorbed after oral
and inhalation administration. Absorption after inhalation exposure was
poor in comparison to oral exposure, but mice demonstrated increased
absorption relative to rats after both oral and inhalation exposure.
Significant tissue distribution was observed in the kidney, liver, fat,
and residual carcass of dosed rats and mice. Excretion was relatively
rapid at all doses tested, with a majority of radioactivity eliminated
in the urine and feces by 48 hours. No biologically significant
sex-related differences in excretion were noted. Repeated oral dosing
did not significantly alter the disposition of para-dichlorobenzene in
male rats. Potential accumulation of para-dichlorobenzene in tissues is
suggested from reported beta elimination half lives.

Fecal elimination of 14C-para-dichlorobenzene derived radioactivity was
apparently the result of unabsorbed test chemical, although definitive
proof was not provided. Enterohepatic recirculation of
para-dichlorobenzene has been previously demonstrated.

Urinary metabolites of 14C-para-dichlorobenzee were isolated and
tentatively identified by reversed phase HPLC with radiochemical
detection. Major metabolites reported were the sulfate and glucuronide
conjugates of the oxidative product 2,5-dichlorophenol. In rats, the
sulfate conjugate of 2,5-dichlorophenol was the major metabolite
identified from rats exposed orally or by inhalation. Induction of
glucuronidation appeared to occur after repeated oral but not inhalation
exposure in male rats. Tissue clearance half life was also reduced by
repeated oral and inhalation exposure in male rats, as well as in female
rats exposed at the high inhalation concentration of
para-dichlorobenzene. Clearance kinetics were largely bi-exponential
after oral exposure but not inhalation exposure. Differences in
disposition and biotransformation of para-dichlorobenzene from oral or
inhalation exposure, with the exception of percent absorption, were
minor and were not considered biologically significant.

This metabolism study in the rat is classified as acceptable and
satisfies the guideline requirement for a metabolism study (85-1) in the
rat.

	870.7600	Dermal Absorption – Rat

Because of the volatile nature of this material and the use profile, the
inhalation route is considered the major route of human exposure and the
dermal exposure is miniscule. Therefore, dermal absorption appears to be
irrelevant in this case.   

A.3.9	Special/Other Studies 

Mechanistic studies in rats and mice are summarized in the Health
Effects Division- Cancer Assessment Review Committee (CARC) report of
2007.

A.4	References ( in MRID order)

MRID Number				Citation Reference	

40521001	Gains, T., and Linder, R. (1986). Acute toxicity of pesticides
in adult and weanling rats. Fundamental and Applied Toxicology.
&:299-308

40521005	National Toxicology Program (1987). Toxicology and
carcinogenesis studies of 1,4-dichlorobenzene in F344/N rats and B6C3F1
mice. NTP TR 319. US Dept. of Health and Human Services: US Government
Printing Office. 198 p.

40568001	Hayes, W.: Gushow, T.; John, J. (1982). para-Dichlorobenzene:
Inhalation teratology study in rabbits: File No. K-1323-(12).
Unpublished study prepared by Dow Chemical U.S.A. 350 p.

40568005	Dill, G.; Peters, A. (1979). para-Dichlorobenzene: Subchronic
toxicity study mice: Subcontract No. 76-34-106002. Unpublished study
prepared by Batelle’s Columbus Laboratories. 27 p.

40568008	Riley, R.; Chart, I.; Doss, A.; et al. (1980). 
para-Dichlorobenzene:  Long term inhalation study in the rat: CTL Report
No. CTL/P/447. Unpublished study prepared by Imperial Chemical
Industries Ltd. 169 p.

40568012	Tyl, R. (1988).  para-Dichlorobenzene: Two generation
reproduction study of inhaled para-dichlorobenzene in Sprague-Dawley
(CD) rats: Laboratory Project ID: 86-81-90605. Unpublished compilation
prepared by Bushy Run Research Center. 49 p.

41108801	Tyl, R.; Neeper-Bradley, T. (1989). para-Dichlorobenzene: Two
generation reproduction study of inhaled Para dichlorobenzene in
Sprague-Dawley (CD) rats: Laboratory Project ID 86-81-90606. Unpublished
study prepared by Union Carbide Bushy Run Research Center. 757 p.

41315001	Auletta, C. (1989). A 21-day dermal toxicity study in rats with
para-dichlorobenzene: Final Report: Lab Project No. 88-3384; 89953;
Method No. BD-004-89. Unpublished study prepared by Bio/dynamics, Inc.
250 p.

41410901	Newton, P. (1990). An acute inhalation toxicity study of
para-dichlorobenzene in the rat. Lab project number 89-8230. Unpublished
study prepared by Biodynamics, Inc. 67 p.

41697801	Wilson, A.; Hall, L.; Dudek, B. et al. (1990). Pharmacokinetics
study of 1,4-dichlorobenzene (p-DCB) in the F344 rat and B6C3F1 mouse
following inhalation and oral administration: Lab Project Number: EHL
88083. Unpublished study prepared by Monsanto Co. 325 p.

41822801	Newton, P. (1991). Four week inhalation toxicity study of
para-dichlorobenzene in the dog: Final Report: Lab Project Number:
88-8148: CB-18.0-DOG/INH-BIO/D. Unpublished study prepared by
Bio/dynamics, Inc. 202 p.

42205301	Morris, T. (1992). Primary eye irritation study in rabbits:
Para-Dichlorobenzene: Lab Project Number: 91-8305-21 (B). Unpublished
study prepared by Hill Top Biolabs, Inc. 16 p.

42205302	Morris, T. (1992). Primary skin irritation study in rabbits:
Para-Dichlorobenzene: Lab Project Number: 91-8305-21 (A). Unpublished
study prepared by Hill Top Biolabs, Inc. 15 p.

42205303	Morris, T. (1992). Delayed contact hypersensitivity in guinea
pigs (Buehler Technique): Para-Dichlorobenzene: Lab Project Number:
91-8305-21 (C). Unpublished study prepared by Hill Top Biolabs, Inc. 24
p.

42619601	Neeper-Bradley, T.; Kubena, F. (1992). Developmental toxicity
study of maternally inhaled paradichlorobenzene vapor in CD rats: Lab
Project Number: 91N0110. Unpublished study prepared by Union Carbide
Chemicals and Plastics Co., Inc. 381 p.

43350601	Li, A.; Thake, D.; Kaempfe, T. (1994). Acute neurotoxicity
study of para-dichlorobenzene in Sprague-Dawley rats: Lab Project
Number: 93097: EHL/93097: MSL/13617. Unpublished study prepared by
Monsanto Environmental Health Lab. 303 p.

43350602	Branch, D.; Li, A.; Thake, D.; et al. (1994). Subchronic
neurotoxicity study of para-dichlorobenzene in Sprague-Dawley rats: Lab
Project Number: 93098: EHL/93098: MSL/13604. Unpublished study prepared
by Monsanto Environmental Health Lab. 360 p.

43988801	Harrington, R.; Thake, D. (1995). Four week range-finding study
of para-dichlorobenzene administered by capsule to Beagle dogs: Lab
Project Number: ML-94-090: EHL/94058: 13915. Unpublished study prepared
by Monsanto Co. 173 p.

43988802	Naylor, M.; Stout, L. (1996). One year study of
p-dichlorobenzene administered orally via capsule to beagle dogs: Lab
Project Number: ML-94-210: EHL 94093: 148-062. Unpublished study
prepared by Ceregen, A Unit of Monsanto Co. and Experimental Pathology
Labs, Inc. 471 p.

Open Literature References:

Aiso, Shigetoshi;  H. Arito, H. Nishizawa , Kasuke Nagano, Seigo
Yamamoto, Taijiro 

Matsushima. (2005a). Thirteen week inhalation toxicity of
para-dichlorobenzene in mice 

and rats. J. Occup Health (2005), 47:249-260.   

Aiso, Shigetoshi; Tetsuya Takeuchi, Heihachiro Arito, Kasuke Nagano,
Seigo

Yamamoto, and Taijiro Matsushima. (2005b). Carcinogenicity and chronic
toxicity in

mice and rats exposed to para-dichlorobenzene for two years. J. Vet.
Med. Sci., (2005).

(67)10:1019-1029. 

Appendix B:  Methodologies for Inhalation Risk Calculations and Human
Equivalent Concentration Arrays   TC \l1 "Appendix A:  Toxicology
Assessment 

METHODOLOGIES FOR INHALATION RISK CALCULATIONS

The RfC methodology applies a dosimetric adjustment that takes into
consideration not only the differences in ventilation rate (MV) but also
the physicochemical properties of the inhaled compound, the type of
toxicity observed (e.g. systemic vs. port of entry) and the 
pharmacokinetic (PK) but not pharmacodynamic (PD) differences between
animals and humans.  Based on the RfC guidance (1994), the methodology
for RfCs derivation is an estimate of the quantitative dose-response
assessment of chronic non-cancer toxicity for individual inhaled
chemicals and includes dosimetric adjustment to account for the
species-specific relationships of exposure concentration to
deposited/delivered dose. This adjustment is influenced by the
physicochemical properties of the inhaled compound as well as the type
of toxicity observed (e.g. systemic vs. port of entry), and takes into
consideration the PK differences between animals and humans.  Though the
RfC methodology was developed to estimate toxicity of inhaled chemicals
over a lifetime, it can be used for other inhalation exposures (e.g.
acute and short-term exposures) since the dosimetric adjustment
incorporates mechanistic determinants of disposition that can be applied
to shorter duration of exposures provided the assumptions underlying the
methodology are still valid.  These assumptions, in turn, vary depending
on the type of toxicity observed and will be discussed later on in this
document.  Thus the derivation of a HEC for inhaled gases is described
by the following equation:

Where:

PODstudy: Point of departure identified in the critical toxicology study

Danimal exposure: Duration of animal exposure (hrs/day; days/wk)

Danticipated exposure: Anticipated human duration of exposure (hrs/day;
days/wk)

RGDR: Regional Gas Dose Ratio

	



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1) all the concentrations of inhaled gas within the animal’s body are
periodic with respect to time (i.e. periodic steady state - the
concentration vs time profile is the same for every week).  Periodicity
must be attained for at least 90% of the exposure.

2) in the respiratory tract, the air, tissue, capillary blood
concentration are in equilibrium with respect to each other.

3) systemically, the blood and tissue concentrations are in equilibrium
with respect to each other.

In the case of chloropicrin, the physicochemical properties and
metabolism data for the compound indicate that these conditions (i.e.
periodicity and equilibrium between different compartments) will be
achieved in a very short period of time.  Under these conditions,
therefore, the use of the RfC methodology to estimate acute inhalation
risk is appropriate.    

When the critical toxic effect in a study occurs in the respiratory
tract (i.e port of entry effects), the RGDR is not related to the
blood:gas partition coefficient of the compound but rather the ratio of
the minute volume (MV) to the surface area (SA) of the affected region. 
In these instances, attaining periodicity or equilibrium between the
compartments is not critical (since the effect is a function of the
direct interaction between the inhaled compound and the affected region
in the respiratory tract) and the RGDR may be calculated using the
following equation:

Where:

	MV animal: Minute volume for the test species (varies depending on body
weight)

SA animal: Surface area of the affected region in animals

MV human: Minute volume for humans (default value is 13.8 l/min)

SA human: Surface area of the affected region in humans

The MV animal is calculated using the allometric scaling provided in
USEPA (1988a).  The equation for calculation of the MV animal is:

lnMV animal = b0 + b1ln(BW)

Where:

ln MV animal : natural logarithm of the minute volume

b0 : species specific intercept used in the algorithm to calculate
minute volumes based on body weight

b1: species specific coefficient used in the algorithm to calculate
minute volumes based on body weight

ln BW: natural logarithm of the body weight (expressed in kg)

The values for the species-specific parameters used to calculate the MV
animal based on body weight and the values for the surface areas of
various regions of the respiratory tract (extrathoracic, thoracic, and
pulmonary) are provided in the EPA document “Methods for Derivation of
Inhalation Reference Concentrations and Application of Inhalation
Dosimetry” (1994).

 [MMAD]) and the geometric standard deviation (g), which is then used
to determine the RDDR.  The RDDR is a multiplicative factor used to
adjust an observed inhalation particulate exposure concentration of an
animal (A) to the predicted inhalation particulate exposure
concentration for a human (H) that would be associated with the same
dose delivered to the rth region or target tissue.

	RDDRr = (RDDr/Normalizing Factor)A

		     (RDDr/Normalizing Factor)H  

MMAD and g defined from an aerosol inhalation study.  The values for
the species-specific parameters used to calculate the RDDR are provided
in the EPA document “Methods for Derivation of Inhalation Reference
Concentrations and Application of Inhalation Dosimetry.” 

The magnitude of the UFs applied is dependent on the methodology used to
calculate risk.  The RfC methodology takes into consideration the PK
differences but not the PD differences.  Consequently, the UF for
interspecies extrapolation may be reduced to 3X (to account for the PD
differences) while the UF for intraspecies variation is retained at 10X.
 Thus, the UF when using the RfC methodology is customarily 30X.

The different toxicities of para-dichlorobenzene via the inhalation
route of exposure appear to be both dose- and time-dependent.  At the
shortest exposure period (28-day inhalation toxicity study in dogs),
general toxicity (such as the reduction in body weight and food
consumption, hematological and clinical chemistry changes) and target
organ effects (such as liver, heart, and adrenal weight changes) were
observed at the highest concentration of 500 ppm with a NOAEL of 150
ppm. Similar general toxicity such as hematological changes, were
observed in the 90-day inhalation toxicity study in rats at 120 ppm with
a NOAEL of 55 ppm. Finally, following chronic inhalation exposure,
treated animals showed nasal effects, but no systemic toxicity, at the
lowest dose tested of 20 ppm.  The nasal lesion (ET) is therefore
considered the most protective point of departure (PoD) or the lowest
human equivalent concentration (HEC) for the chronic exposure RfC. It
should be noted that, the shorter duration studies show different
effects at higher concentrations and there were no ET effects observed. 
Therefore there is no need to develop an array table as recommended
during the para-dichlorobenzene RARC meeting of 6/7/2007.

Appendix C:	Review of Human Research

Studies reviewed for ethical conduct:

1)  No MRID - PHED Surrogate Exposure Guide

2)  Naphthalene homeowner study:

MRID 43716501

㄀$摧৮þЀ摧৮þကntial Use as an Insect Repellent.  Unpublished
study prepared by Landis International, Inc. and Pharmaco LSR Inc. under
Project No. 93-9083.  100 p.  

3)  Total Exposure Assessment Methodology (TEAM) Study:

MRID 47173701

Pellizzari, E., et al., (1989) Development and Implementation of
Exposure Assessment Procedures for Toxic Air Pollutants in Several Los
Angeles County, CA, Communities. Unpublished report prepared by Research
Triangle Institute under Contract No. A5-174-33 and RTI Project No.
3686/00-01F.  Unpaginated.  

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