1,2-dichlorobenzene

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Since the already existing two-generation toxicity study exhibits major deficiencies especially in the inhalation part it can not be regarded as reliable for a dossier submission under REACH. The thereby resulting data gap can be either closed by a waiving argument in line with Annex XI or by a testing proposal for a new study. Based on the information gained from repeated dose toxicity studies and considering that a risk assessment is possible even without this endpoint study, together with the fact that one has to balance the data need with animal welfare considerations, conducting of a two-generation reproductive toxicity study is scientifically not of high priority.

Link to relevant study records

Reference

Endpoint:

reproductive toxicity, other

Remarks:

repeated dose toxicity studies

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1985

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Histopathology of reproductive organs in repeated dose toxicity studies

Principles of method if other than guideline:

Several repeated dose toxicity studies were conducted which cover the evaluation of potential toxic effects on the reproductive organs. The National Toxicology Program (1985) administered 1,2-dichlorobenzene by gavage for 13 weeks (0, 30, 60, 125, 250 or 500 mg/kg bw) and two years (0, 60 or 120 mg/kg bw) in male and female rats (F344) and mice (B6C3F1). All studies included the macroscopical and histopathological examination of prostate/testes or ovaries/uterus for all animals or control and high dose group respectively.

Species:

other: rats and mice

Strain:

other: rats (F344) and mice (B6C3F1)

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

corn oil

Duration of treatment / exposure:

13 weeks to 2 years

Frequency of treatment:

daily

Details on study schedule:

Several repeated dose toxicity studies were conducted which cover the evaluation of potential toxic effects on the reproductive organs. The National Toxicology Program (1985) administered 1,2-dichlorobenzene by gavage for 13 weeks (0, 30, 60, 125, 250 or 500 mg/kg bw) and two years (0, 60 or 120 mg/kg bw) in male and female rats (F344) and mice (B6C3F1). All studies included the macroscopical and histopathological examination of prostate/testes or ovaries/uterus for all animals or control and high dose group respectively.

No. of animals per sex per dose:

see chapter repeated dose toxicity

Control animals:

yes

Dose descriptor:

NOAEL

Remarks:

reproductive organs

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: None of the repeated dose toxicity/carcinogenicity studies showed any adverse effect on the reproductive organs.

Reproductive effects observed:

not specified

Several repeated dose toxicity studies were conducted which cover the evaluation of potential toxic effects on the reproductive organs. The National Toxicology Program (1985) administered 1,2-dichlorobenzene by gavage for 13 weeks (0, 30, 60, 125, 250 or 500 mg/kg bw) and two years (0, 60 or 120 mg/kg bw) in male and female rats (F344) and mice (B6C3F1). All studies included the macroscopical and histopathological examination of prostate/testes or ovaries/uterus for all animals or control and high dose group respectively.

None of the studies showed any adverse effect on the reproductive organs. The only effects seen were interstitial-cell tumours of the testis in male rats with a significant positive trend when analyzed by the life-table test, but with a significant negative trend when analyzed by the Cochran-Armitage test. Since this tumour was not considered to be life threatening, the increase detected by the life-table test was discounted.

As confirmed by literature (Mangelsdorf et al. 2003, Ulbrich and Palmer 1995, Janer et al. 2007, Dent 2007, Sanbuissho et al. 2009) histopathological examinations of reproductive tissues in repeated dose toxicity studies on rodents are of high value and high sensitivity for evaluation of reproductive toxicity in males and females.

Executive summary:

Several repeated dose toxicity studies were conducted which cover the evaluation of potential toxic effects on the reproductive organs. The National Toxicology Program (1985) administered 1,2-dichlorobenzene by gavage for 13 weeks (0, 30, 60, 125, 250 or 500 mg/kg bw) and two years (0, 60 or 120 mg/kg bw) in male and female rats (F344) and mice (B6C3F1). All studies included the macroscopical and histopathological examination of prostate/testes or ovaries/uterus for all animals or control and high dose group respectively.

None of the studies showed any adverse effect on the reproductive organs. The only effects seen were interstitial-cell tumours of the testis in male rats with a significant positive trend when analyzed by the life-table test, but with a significant negative trend when analyzed by the Cochran-Armitage test. Since this tumour was not considered to be life threatening, the increase detected by the life-table test was discounted.

As confirmed by literature (Mangelsdorf et al. 2003, Ulbrich and Palmer 1995, Janer et al. 2007, Dent 2007, Sanbuissho et al. 2009) histopathological examinations of reproductive tissues in repeated dose toxicity studies on rodents are of high value and high sensitivity for evaluation of reproductive toxicity in males and females.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

500 mg/kg bw/day

Study duration:

chronic

Species:

other: rats and mice

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Existing data on fertility

A two-generation reproductive toxicity study with 1,2-dichlorobenzene which was administered by inhalation (target exposure of 0, 50, 150 or 400 ppm) to CD rats during F0 and F1 generation including their pups, was performed between 1987 and 1989 by Bio/dynamics INC. As a result of the study the NOAEL and LOAEL for adults were 50 ppm (305 mg/m³) and 150 ppm (915 mg/m³) respectively and for reproductive toxicity and offspring growth and development were 150 ppm (915 mg/m³) and 400 ppm (2440 mg/m³) respectively. Since the study demonstrates major deficiencies especially in the inhalation part, this study is not regarded as reliable for a dossier submission under REACH. For further details and justification of unreliability see study summary and/or repeated dose inhalation toxicity waiving.

Several repeated dose toxicity studies were conducted which gave also evidence on possible toxic effects on the reproductive organs. The National Toxicology Program (1985) administered 1,2-dichlorobenzene by gavage for 13 weeks (0, 30, 60, 125, 250 or 500 mg/kg bw) and two years (0, 60 or 120 mg/kg bw) in male and female rats (F344) and mice (B6C3F1). All studies included the macroscopical and histopathological examination of prostate/testes or ovaries/uterus for all animals or control and high dose group respectively. None of the studies showed any adverse effect on the reproductive organs. The only effects seen were interstitial-cell tumours of the testis in male rats with a significant positive trend when analyzed by the life-table test, but with a significant negative trend when analyzed by the Cochran-Armitage test. Since this tumour was not considered to be life threatening, the increase detected by the life-table test was discounted. Furthermore, Robinson et al. (1991) assessed the oral toxicity of 1,2-dichlorobenzene for male and female rats (Sprague-Dawley) by administering 0, 25, 100 or 400 mg/kg bw for 90 days by gavage. Like in the former studies no adverse effect on the reproductive organs neither on macroscopic investigation, organ weight analysis nor histopathology were noted.

As outlined in the waiving for toxicity to reproduction, histopathological changes on the reproductive organs in repeated dose toxicity studies are indicative of effects on fertility. Since histological examinations of the reproductive organs are covered in the studies described above, these repeated dose toxicity studies should be considered as sensitive and sufficient enough information to evaluate toxicity on fertility.

Conclusion

Since the already existing two-generation toxicity study exhibits major deficiencies especially in the inhalation part it can not be regarded as reliable for a dossier submission under REACH. The thereby resulting data gap can be either closed by a waiving argument in line with Annex XI or by a testing proposal for a new study.

Based on the information gained from repeated dose toxicity studies and considering that a risk assessment is possible even without this endpoint study, together with the fact that one has to balance the data need with animal welfare considerations, conducting of a two-generation reproductive toxicity study is scientifically not of high priority. Fur a comprehensive discussion on fertility see enclosed waiving statement taking into account an ECHA “Substance Evaluation Draft Decision for comments by addressees” received by registrant on April 29. 2014 conducted by the Hungarian National Institute of Chemical Safety.

Short description of key information:
Since the already existing two-generation toxicity study exhibits major deficiencies especially in the inhalation part it can not be regarded as reliable for a dossier submission under REACH. The thereby resulting data gap can be either closed by a waiving argument in line with Annex XI or by a testing proposal for a new study. Based on the information gained from repeated dose toxicity studies and considering that a risk assessment is possible even without this endpoint study, together with the fact that one has to balance the data need with animal welfare considerations, conducting of a two-generation reproductive toxicity study is scientifically not of high priority.

In developmental studies in rats and rabbits, developmental effects were only seen in rats at maternally toxic doses (400 ppm, 2400 mg/m3).

Justification for selection of Effect on fertility via oral route:
As confirmed by literature (Mangelsdorf et al. 2003, Ulbrich and Palmer 1995, Janer et al. 2007, Dent 2007, Sanbuissho et al. 2009) histopathological examinations of reproductive tissues in repeated dose toxicity studies on rodents are of high value and high sensitivity for evaluation of reproductive toxicity in males and females.

Effects on developmental toxicity

Description of key information

1,2-dichlorobenzene was tested for its ability to cause teratogenesis and fetotoxicity in pregnant female New Zealand white rabbits similar to EU guideline B.31. According to the results of the present study the inhalation of 1,2-dichlorobenzene in a dose of up to 2.4 mg/L air for 6 h/d during day 6 to18 of gestation did not cause significant teratogenicity or fetotoxicity in female New Zealand White rabbits. The incidence of malformation was not significantly increased in any of the exposure groups compared to controls.
1,2-dichlorobenzene was tested for its ability to cause teratogenesis and fetotoxicity in pregnant female Fisher 344 rats similar to EU guideline B.31. According to the results of the present study the inhalation of 1,2-dichlorobenzene in a dose of up to 400 ppm for 6 h/d during day 6 to 15 of gestation did not cause significant teratogenicity or fetotoxicity in female Fisher 344 rats. The incidence of malformation was not significantly increased. Thus, under the conditions tested here, the test substance 1,2-dichlorobenzene does not have any significant teratogenic or fetotoxic effect on organogenesis in F344 rats (Hayes WC et al., 1985).

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions (effects on preimplantation and late pregnancy were not examined (exposure on day 0 to 5 and day 19 to 28 of gestation; some maternal and fetal oberservations missing)

GLP compliance:

not specified

Species:

rabbit

Strain:

New Zealand White

Route of administration:

inhalation

Duration of treatment / exposure:

days 6 through 18 of gestation

Frequency of treatment:

6 h/d

Details on study design:

Sex: female
Duration of test: the dams were sacrificed on day 19 of gestation

Abnormalities:

not specified

Developmental effects observed:

not specified

All exposure levels: no significant effects on reproductive parameters.  
3 mg/l: slight maternal toxicity, evidenced by non-significant decreases in maternal body weight gain and liver weights (absolute and relative) and slight hepatic changes at necropsy observable among the pregnant rabbits.

Conclusions:

All exposure levels: no significant effects on reproductive parameters.  

Executive summary:

All exposure levels: no significant effects on reproductive parameters.  

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

400 mg/m³

Species:

rat

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

1,2-dichlorobenzene was tested for its ability to cause teratogenesis and fetotoxicity in pregnant female New Zealand white rabbits similar to EU guideline B.31. According to the results of the present study the inhalation of 1,2-dichlorobenzene in a dose of up to 2.4 mg/L air for 6 h/d during day 6 to18 of gestation did not cause significant teratogenicity or fetotoxicity in female New Zealand White rabbits. The incidence of malformation was not significantly increased in any of the exposure groups compared to controls.

1,2-dichlorobenzene was tested for its ability to cause teratogenesis and fetotoxicity in pregnant female Fisher 344 rats similar to EU guideline B.31. According to the results of the present study the inhalation of 1,2-dichlorobenzene in a dose of up to 400 ppm for 6 h/d during day 6 to 15 of gestation did not cause significant teratogenicity or fetotoxicity in female Fisher 344 rats. The incidence of malformation was not significantly increased. Thus, under the conditions tested here, the test substance 1,2-dichlorobenzene does not have any significant teratogenic or fetotoxic effect on organogenesis in F344 rats (Hayes WC et al., 1985).

Toxicity to reproduction: other studies

Description of key information

No study available.

Justification for classification or non-classification

According to CLP classification criteria (Regulation (EC) No 1272/2008) a classification is not justified.