Dibromomethane

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

publication

Title:

DATA ADEQUACY ASSESSMENT Dibromomethane, CAS No. 74-95-3

Author:

Environmental Science Center SRC, Inc.

Year:

2010

Bibliographic source:

U.S. Environmental Protection Agency

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

not specified

Test material

Test material information

1

Reference substance name:

Dibromomethane

EC Number:

200-824-2

EC Name:

Dibromomethane

Cas Number:

74-95-3

Molecular formula:

CH2Br2

IUPAC Name:

dibromomethane

Test animals

Species:

rat

Strain:

other: Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Sprague-Dawley Crl:CD (SD) IGS BR rats obtained from Charles River (UK) Limited, Margate, Kent; 268 – 336g (males); 176 – 226g (females) and approximately 8 weeks old at the start of treatment

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: PEG 400

Details on exposure:

Animals were exposed during a two-week maturation phase, pairing, gestation, and early lactation.

Details on mating procedure:

Pairing of animals within each dose group was undertaken on a one male: one female basis on Day 15 of the study, with females subsequently being allowed to litter and rear their offspring to Day 5 of lactation.

Duration of treatment / exposure:

40 days

Doses / concentrations

Remarks:

0(control.),50,150,500 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

10/sex(group

Control animals:

yes

Details on study design:

The test material was administered by gavage to three groups each of ten male and ten female Sprague-Dawley Crl:CD® (SD) IGS BR strain rats, for approximately forty days (to include a two week maturation phase, pairing, gestation and early lactation) at dose levels of500, 150 and 50 mg/kg/day . A control group of ten males and ten females was similarly dosed with vehicle alone (Polyethylene glycol 400).
Clinical signs, bodyweight development, food and water consumption were monitored during the study.
Pairing of animals within each dose group was undertaken on a one male: one female basis 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 the surviving females and offspring being killed on Day 5 post partum .
All animals were subjected to a gross necropsy examination and histopathological evaluation of reproductive tissues was performed.

.

Results and discussion

Results: P0 (first parental generation)

Details on results (P0)

Treatment-related effects were observed at 500 mg/kg-bw/day and included: decreased body weight gain and lower food conversion efficiency in females during gestation, reduced food intake in females during gestation, increased pre-coital interval, increased gestation length, decreased litter size and increased post-implantation loss. Decreased absolute and body weight-relative epididymal and testes weights were observed at 150 and 500 mg/kg-bw/day in the parental males in the absence of histopathological effects.

Effect levels (P0)

1

Dose descriptor:

NOAEL

Remarks:

systemic toxicity

Effect level:

ca. 150 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other:

Remarks on result:

other: highest dose tested

2

Dose descriptor:

LOAEL

Remarks:

systemic toxicity

Effect level:

ca. 150 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

other: (based on reduced body weight gain and food conversion efficiency in dams during gestation and lower food intake in dams during lactation

Remarks on result:

other: highest dose tested

3

Dose descriptor:

NOAEL

Effect level:

ca. 150 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: systemic toxicity

Remarks on result:

other:

4

Dose descriptor:

LOAEL

Remarks:

reproductive/developmental toxicity

Effect level:

ca. 500 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: increased pre-coital interval, reduced litter size, and increased post-implantation loss

5

Dose descriptor:

NOAEL

Remarks:

reproductive/developmental toxicity

Effect level:

ca. 150 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: on increased pre-coital interval, reduced litter size, and increased post-implantation loss)

Results: F1 generation

Effect levels (F1)

Dose descriptor:

NOEL

Generation:

F1

Effect level:

>= 150 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

other: post implantation loss

Any other information on results incl. tables

One male, receiving 500 mg/kg/day, was killed in extremis on Day 2 of the study and one control female was found dead on Day 41 of the study; neither of these death were considered to be a consequence of treatment.

There were no significant treatment-related clinical signs of toxicity observed at 50, 150 or 500

mg/kg/day. At 500 mg/kg/day, lower bodyweight gain was apparent for females during gestation, compared to control, but this was consider

ed to be a consequence of the lower litter size at this dosage. At 500 mg/kg/day, lower food conve

rsion efficiency was apparen for females during gestation compared to control, reflecting the lower weight gain observed during this phase of the study. Food intake was lower during lactation and was attributed to the lower physiological demand on parent females due to the smaller litter size.

At 500 mg/kg/day, there was a clear increase in pre-coital interval, compared with control, with only four females mating during the first four

days of pairing. Copulation plug count was generally lower than control, but fertility was not adversely affected with eight females achieving

pregnancy. Gestation length of these females tended to be longer than control, possibly influenced by lower litter size.

At 500 mg/kg/day, litter size was lower than control on Day 1 due to increased post-implantation

loss; this loss probably representing death of the offspring in utero. In addition, one female at this dosage was considered to have lost her litter in-utero. At 50, 150 or 500 mg/kg/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/day reflected the lower litter size. One control female and one female receiving 500 mg/kg/day showed total litter loss on Day 1 postpartum.

Necropsy findings among adult animals and their offspring did not indicate any effect on maternal treatment at dosages of 50, 150 or 500 mg/kg/day.

At 500 mg/kg/day, males showed lower absolute and bodyweight-relative epididymal and testes weights compared to control. At 150 mg/kg/day, absolute and bodyweight relativ testes weights were also lower than control. In the absences of any treatment-relate histopathological effects at 500 mg/kg/day, these differences in male reproductive organ weights were considered to be of equivocal toxicological significance. Microscopic examination of adult reproductive tissues did not reveal any treatment-related effects at dosages of 50, 150 or 500 mg/kg/day.

Applicant's summary and conclusion

Conclusions:

Treatment with Dibromomethane at 500 mg/kg/day was associated with a clear effect on mating performance and a reduction in litter size at birth, most probably due to increased in-utero mortality. The `No Observed Adverse Effect Level' (NOAEL) for reproduction observed in this study was considered to be 150 mg/kg/day.