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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information
 No relevant adverse effects on reproductive tissues/organs were detected at the highest applied dose (588 mg/kg/day)in a 90 day gavage study (McCauley, 1995)
    
    

No relevant adverse effects on reproductive tissues/organs were detected at the highest applied dose (588 mg/kg bw/d).

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
588 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Comparable to guideline study with acceptable restrictions
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No relevant adverse effects on reproductive tissues/organs were detected at the highest applied dose (588 mg/kg bw/d) in a sub-chronic toxicity study.


Short description of key information:
Male and female Sprague-Dawley rats received 1,3-dichlorobenzene daily doses of 0, 9, 37, 147 or 588 mg/kg bw/day by corn oil gavage for 90 consecutive daily. All rats were observed daily for physiological and behavioral responses and for mortality. Body weights and food and water consumeption were recorded weekly throughout the study. Blood samples were collected at necropsy for hematologic and serum chemistriy measurements prior to necropsy. A gross and histopathological examination was performed on all major organs inclusive reproductive organs/tissues (gonads, seminal vesicles, prostate, preputial or clitoral gland).
No relevant adverse effects on reproductive tissues/organs were detected at the highest applied dose (588 mg/kg bw/d) in a sub-chronic toxicity study.

Justification for selection of Effect on fertility via oral route:
A valid subchronic toxicity study with a detailed histopatological investigation of the reproductive organs in rats is available.

Effects on developmental toxicity

Description of key information
A valid developmental study in rats with m-dichlorobenzene is available. Several developmental toxicity studies with o- and p-dichlorobenzene (as structural analogues or surrogates) in rats and rabbits were assessed and reported by the MAK Commission (DFG Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area).
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Scientifically acceptable method; limited documentation; limit dose not reached.
Principles of method if other than guideline:
A teratological evaluation following oral administration of trichloro- and dichlorobenzene isomers to the rat.
GLP compliance:
not specified
Species:
rat
Strain:
Sprague-Dawley
Route of administration:
oral: gavage
Vehicle:
not specified
Details on mating procedure:
no data
Duration of treatment / exposure:
6th - 15th day of gestation
Frequency of treatment:
daily
Duration of test:
15 days
No. of animals per sex per dose:
no data
Control animals:
not specified
Details on study design:
Sex: female
Dose descriptor:
other: maternal toxicity
Effect level:
200 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: Maternal toxicity was not reported at 200 mg/kg bw (highest applied dose)
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified
1,3-dichlorobenzene revealed no teratological effects.
Executive summary:

1,3-dichlorobenzene was administered by gavage to pregnant Sprague-Dawley rats on their 6th - 15th day of gestation. Dosages were 50, 100 or 200 mg/kg bw/day.

Maternal weight gain, changes in microscopic examination and 15 biochemical parameters were used to evaluate maternal toxicity. Fetal changes were measured by litter size, fetal weight, deciduoma, skeleton and visceral examination, residue analysis and microscopy.

1,3-dichlorobenzene revealed no teratological effects.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
200 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
scientifically acceptable and sufficient documented
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

m-dichlorobenzene was administered by gavage to pregnant Sprague-Dawley rats on their 6th - 15th day of gestation. Dosages were 50, 100 or 200 mg/kg bw/day. Maternal weight gain, changes in microscopic examination and 15 biochemical parameters were used to evaluate maternal toxicity. Fetal changes were measured by litter size, fetal weight, deciduoma, skeleton and visceral examination, residue analysis and microscopy. m-dichlorobenzene revealed no teratological effects at the highest applied dose.

Read across with o-dichlorobenzene and p-dichlorobenzene:

The German Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (MAK Commission) evaluated the toxicological data for 1,3-dichlorobenzene and documented the results in the MAK-Collection for Occupational Health and Safety (available online: http://onlinelibrary.wiley.com/book/10.1002/3527600418/topics).

For the assessment of developmental toxicity the results of studies on the developmental toxicity of 1,3-dichlorobenzene and its 1,2-dichlorobenzene and 1,4-dichlorobenzene isomers are summarized and discussed by the MAK Commission. No relevant teratogenic effects were found in all 3 isomers (MAK 2013).

Ortho-dichlorobenzene was investigated in developmental studies in rats and rabbits and p-dichlorobenzene was tested in rabbits. Groups of bred rats and inseminated rabbits were exposed to 0,100,200, or 400 ppm (0.6, 1.2 or 2.4 mg/liter air) of o-dichlorobenzene, groups of inseminated rabbits were exposed to 0, 100, 300, or 800 ppm (0.59, 1.77, and 4.72 mg/liter) of p-dichlorobenzene. Animals were exposed for 6 hr/ day on Days 6 through 15 (rats) or 6 through 18 (rabbits) of gestation.

Inhalation of up to 400 ppm (2.4 mg/l) of o-dichlorobenzene was not teratogenic or fetotoxic in rats, and neither o-dichlorobenzene nor p-dichlorobenzene was teratogenic or fetotoxic in rabbits at exposure levels up to 400 or 800 ppm (2.4 or 4.72 mg/l), respectively.

In an additional study, 5 groups of pregnant CD rats were treated by gavage on days 6 through 15 of gestation with 0, 250, 500, 750 or 1000 mg/kg/day of p-dichlorobenzene.

Signs of embryotoxicity were limited to an increase in skeletal variations (500 mg/kg and higher) and to a reduction in fetal weight at 1000 mg/kg dose level. Since these embryotoxic effects were associated with a reduction in food consumption and weight gain of the exposed dams, they could be a consequence of maternal suffering rather than of a direct effect of the chemical on the embryonic development. The MAK Commission as the authors of the study concluded, that p-dichlorobenzene, by oral exposure, is not teratogenic in the rat.

Justification for read-across with o-dichlorobenzene and p-dichlorobenzene:

Ortho- and para-dichlorbenzene have a close similarity in molecular structure; they differ only in the relative placement of the chloro groups on the benzene ring. The close similarity is demonstrated by the similarity of chemical/physical properties, environmental fate parameters and toxicological endpoints (Synthetic Organic Chemical Manufacturers Association (SOCMA) Chlorobenzene Producers Association (CPA). March 31, 2003. http://www.epa.gov/oppt/chemrtk/pubs/summaries/chlrbnzs/c13650rt.pdf. ).

The Chlorobenzene Producers Association (CPA) under the umbrella of the Synthetic Organic Chemical Manufacturers Association (SOCMA) submitted to EPA (U.S. Environmental Protection Agency) in 2002 a category justification for a chlorobenzenes category. The category consists of four chlorobenzenes - monochlorobenzene (CASRN 108-90-7), 1,2-dichlorobenzene (CASRN 95-50-1), 1,3-dichlorobenzene (CASRN 541-73-1) and 1,2,3-trichlorbenzene(CASRN 87-61-6) and the supporting chemicals 1,4-dichloro-benzene (CASRN 106-46-7) and 1,2,4-trichlorobenzene (CASRN 120-82-1).

The U.S. Environmental Protection Agency concluded in the Risk-Based Prioritization Document from April 2009:

http://www.epa.gov/hpvis/rbp/Category_Chlorobenzenes_Web_April%202009.pdf

“The category consists of mono-, di- and tri-chlorobenzenes. All four category members and the

two supporting chemicals have a benzene ring in which one, two or three hydrogen atoms are

replaced by chlorine atoms. The two category members 1,2- and 1,3-dichlorobenzene and

supporting chemical 1,4-dichlorobenzene, are isomers – the placement of the chlorines on the

benzene ring being in the ortho, meta, and para positions, respectively. Likewise, the supporting

chemical, 1,2,4-trichlorobenzene, is an isomer of the category member, 1,2,3-trichlorobenzene

with the difference being a chlorine in the para position rather than the meta position. Based on

similarities in structure, physical-chemical properties, environmental fate and toxicity, the

chemicals in this category are grouped and evaluated together. Data for the tested category

members are extrapolated to provide estimates of similar properties for the untested members.

1,2-Dichlorobenzene (sponsored chemical), 1,4-dichlorobenzene and 1,2,4-trichlorobenzene

(both supporting chemicals) have been assessed under the OECD High Production Volume

Chemicals Program and the evaluations published by the United Nations Environmental

Program (UNEP).

EPA agrees with the category justification and further accepts this category for prioritization in the ChAMP.”

The use of 1,2-dichlorobenzene and 1,4-dichlorbenzene as supporting substances (structural analog or surrogate) for read-across is justified based on the evaluation by EPA and the MAK Commission.


Justification for selection of Effect on developmental toxicity: via oral route:
key study is used

Toxicity to reproduction: other studies

Additional information

no data

Justification for classification or non-classification

In the repeated dose studies no relevant adverse effects on reproductive tissues/organs were detected at the highest applied doses.

The available developmental study with m-dichlorobenzene revealed no teratological effects. Additional developmental toxicity studies with o- and p-dichlorobenzene (as structural analogues or surrogates) in rats and rabbits were assessed and reported by the MAK Commission (DFG Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area). These studies also give no indication of a teratogenic potential for dichlorobenzenes.

Therefore a classification for toxicity to reproduction is not justified.