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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2007
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP and appropriate guidelines
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2007
Report date:
2007

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
other: OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Qualifier:
according to guideline
Guideline:
other: EPA Health Effects Test Guidelines: OPPTS 870.3550 Reproduction/ Developmental Toxicity Screening test, July 2000
Qualifier:
according to guideline
Guideline:
other: TSCA test guidleine 40 CFR 799.9355 (comparable to OECD TG No. 421)
GLP compliance:
yes (incl. QA statement)
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Dibromomethane
EC Number:
200-824-2
EC Name:
Dibromomethane
Cas Number:
74-95-3
Molecular formula:
CH2Br2
IUPAC Name:
dibromomethane
Details on test material:
99.4% purity dibromomethane

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
see end point 7.8.1 for details

Administration / exposure

Route of administration:
oral: gavage
Details on exposure:
see end point 7.8.1 for details
Details on study design:
see end point 7.8.1 for details

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Offspring bodyweight, survival, growth and development were unaffected by maternal treatment at dosages of 50, 150 or 500 mg/kg/day. Necropsy findings among offspring did not indicate any effect of maternal treatment at dosages of 50, 150 or 500 mg/kg/day.

Applicant's summary and conclusion

Conclusions:
The reproductive toxicity of dibromomethane was investigated in a reproductive and developmental toxicity screening test in rats (OECD TG No.421) (and OPPTS 8703550).
In this study, dibromomethane was administered via gavage to (10 animals/sex/dose at 0, 50, 150, or 500 mg/kg bw/day for 40 days.
No deaths were observed in either sex. There were no significant treatment-related clinical signs of toxicity.

At 50 or 150 mg/kg bw/day, mating performance, fertility and gestation length were unaffected by treatment. However, treatment at 500 mg/kg bw/day was
associated with an effect on mating performance (increased pre-coital interval) and a reduction in litter size at birth, most probably due to increased in-uteromortality. Treatment at 500 mg/kg/day did not adversely affect fertility, with 8/10 females achieving pregnancy. Necropsy did not indicate any effect of the
test material on adult animals. The NOAEL for reproductive and developmental toxicity was considered to be 150 mg/kg/day.
Executive summary:

Oral (Gavage) Reproduction/Development Toxicity Screening Test in the Rat (Dhinsa and Fulcher 2007) was conducted under GLP standards and in accordance with OECD TG for Testing of Chemicals No.421. (adopted 27 July 1996) and EPA Health Effects Test Guidelines: OPPTS 870.3550 (July 2000). The study was identified as a key study (klimisch rating 1).

The test material (99.4% purity, dibromomethane) was administered by gavage to three groups each of 10 male and 10 female Sprague-Dawley Crl:CD® (SD) IGS BR strain rats, at dose levels of 50, 150 and 500 mg/kg/day, for approximately forty days (two week maturation phase, pairing of maximum 14 days, gestation and early lactation). 

A control group was similarly dosed with vehicle only (Polyethylene Glycol 400).

Clinical signs, bodyweight development, food and water consumption were monitored during the study. Animals were paired one male:one female on day 15 of the study, with females subsequently being allowed to litter and rear their offspring to day 5 of lactation.

During the lactation phase, daily clinical observations were performed on all surviving offspring, together with litter size, offspring weights and assessment of righting reflex.

Surviving males were terminated on Day 43 of the study, with all surviving females and offspring being killed on Day 5post partum. All animals were subjected to a gross necropsy examination and histopathological evaluation of reproductive tissues was performed.

Results: During the lactation phase, daily clinical observations were performed on all surviving offspring, together with litter size, offspring weights and assessment of righting reflex. Offspring were killed on Day 5post partumand were subjected to a gross necropsy examination.

Offspring bodyweight, survival, growth and development were unaffected by maternal treatment at dosages of 50, 150 or 500 mg/kg/day. Necropsy findings among offspring did not indicate any effect of maternal treatment at dosages of 50, 150 or 500 mg/kg/day.

Litter responses:at 500 mg/kg bw/day, litter size was lower than control on Day 1 due to increased post-implantation loss; this loss probably representing death of the offspringin-utero.In addition, one female at this dosage was considered to have lost her litterin-utero. No similar treatment related effects were apparent for animals at 50 or 150 mg/kg bw/day.

At 50 or 150 mg/kg bw/day, offspring bodyweight on day 1 and subsequent survival, growth and development to Day 4 were unaffected by maternal treatment; lower litter weights at 500 mg/kg bw/day reflected the lower litter size. One control female and one female receiving 500 mg/kg bw/day showed total litter loss on Day 1post partum.

No Observed Adverse Effect Level’ (NOAEL) for develeopmental toxicity was not determined in the study. However, can be considered as < 500 mg/kg bw/day.

Conclusion

 

Treatment with dibromomethane at 500 mg/kg bw/day was associated with effect on mating performance and a reduction in litter size at birth, most probably due to increase inin-uteromortality. The ‘No Observed Adverse Effect Level’ (NOAEL) for reproduction observed in this study was considered to be 150 mg/kg/day.