Bromomethane

Toxicity to reproduction

Administrative data

Endpoint:

two-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1986

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

EU Method B.35 (Two-Generation Reproduction Toxicity Test)

Deviations:

yes

Remarks:

This study differs from the prescribed test method EC 35 in that exposure to the test compound was for 5 as opposed to 7 days per week.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Bromomethane

EC Number:

200-813-2

EC Name:

Bromomethane

Cas Number:

74-83-9

Molecular formula:

CH3Br

IUPAC Name:

bromomethane

Constituent 2

Reference substance name:

Bromomethan

IUPAC Name:

Bromomethan

Details on test material:

Methyl Bromide: Batch no’s: 3/84-707-2, 3/84-702-3 and 3/84-702-4; purity not specified.

Test animals

Species:

rat

Sex:

male/female

Administration / exposure

Duration of treatment / exposure:

For the F0 generation: 4 groups of 25 rats per sex were exposed to the following concentrations of methyl bromide: 0.0, 3.0, 30.0, and 90.2 ppm (equivalent to 0, 3.2, 32 and 96 mg/kg bw) for 6 hours/day, 5 days/week by whole body exposure.
For the F1 generation: 4 groups of 25 rats per sex were exposed to the following concentrations of methyl bromide: 0.0, 3.0, 30.1, and 90.0 ppm (equivalent to 0, 3.2, 32 and 96 mg/kg bw) for 6 hours/day, 5 days/week by whole body exposure.

Details on study design:

Two litters, a and b were produced for each generation.

Examinations

Parental animals: Observations and examinations:

Parental animals were observed at least twice each day for mortality, morbidity, and overt signs of toxicity, and were examined once weekly for the detection of physical changes. Body weights and food consumption were recorded. Mating trials were initiated, and resultant pregnant females were housed individually. They were observed daily during gestation. Females delivered their litters and daily observations of the females and young were conducted throughout lactation. Litters were weaned at 28 days.

Litter observations:

In addition to population counts and body weigh recording, progeny were observed for mortality and behavioral anomalies.
F1a and F2a progeny: any “a” litter progeny displaying aberrant structural development were subjected to necropsy examination.
F1b and F2b progeny: animals from each of treatment groups population were chosen to serve as F1 parental animals.

Postmortem examinations (parental animals):

Surviving F0 and F1 animals were sacrificed after exposure to Methyl Bromide and subjected to gross necropsy.
All parental animals were subjected to gross necropsy examination and microscopic examinations were carried out on reproductive organs and any tissues displaying grossly noted alterations.

Results and discussion

Results: P0 (first parental generation)

Details on results (P0)

Parental animals:
No deaths occurred which were considered the result of Methyl Bromide. All the F0 parental males survived to final sacrifice. Three F0 females died prior to final sacrifice. All F1 parental animals survived to final sacrifice. Pre-mating and final body weight data obtained for F0 parental animals exposed to 3 ppm and 30 ppm Methyl Bromide were comparable to the untreated control animals. Pre-mating and total weight gains calculated for these treated animals were similar to the untreated control animals. Statistically significant reductions were noted for the 90 ppm F0 generation males at 5 of the 10 pre-mating body weight intervals. Pre-mating and total weight gains calculated for the 90 ppm F0 generation males were also reduced when compared to the untreated control males. During the F0 generation, body weight data and pre-mating and total weight gains obtained for the 90 ppm females were similar to the untreated controls. Body weights for the treated parental animals were comparable to the untreated control animals during the F1 generation. During the first generation, body weights for gestating and lactating dams were similar for treated and control groups. A slight body weight depression was noted for the 90 ppm dams during the F2a litter and the 3, 30 and 90 ppm females during the F2b litter were comparable to the untreated control females.

During the first week of the F0 generation, treated females consumed less food than the untreated control females. All other food consumption data for F0 generation treated animals, as well as that obtained for the F1 generation treated animals were comparable to the controls. There was a significant reduction in food intake for the 3, 30, and 90 ppm F0 generation females during the first week. Regarding antemortem observations, no noteworthy observations were seen for parental animals, which were considered the result of exposure to Methyl Bromide. Reproductive performance was not affected by Methyl Bromide exposure.

Pathological Studies:
F0 parental animals: There was a significant decrease in the mean brain weight for the 90 ppm males and females and a significant increase for the 90 ppm female heart to brain weight ratio. A decreased testes (with epididymides) weight to body ratio was seen for the 30 ppm males. The mean testes (with epididymides) weight was comparable to the untreated control males, however, the mean final body weight for the 30 ppm males was somewhat increased, which therefore resulted in the reduced ratio.

Effect levels (P0)

Dose descriptor:

NOEL

Effect level:

30 ppm

Sex:

male/female

Basis for effect level:

other: 30 ppm (equivalent to 32 mg/kg bw)

Remarks on result:

other: Generation not specified (migrated information)

Results: F1 generation

Details on results (F1)

Progeny:
Delivery and population data obtained for the groups of dams exposed to Methyl Bromide were comparable to the untreated control dams during the F0 generation. Progeny survival during the lactation periods was not considered affected by Methyl Bromide exposure. During the F1b litter, slightly fewer 90 ppm progeny survived to lactation days 21 and 28, however this was not statistically significant. Survival indices for the 3 and 30 ppm F1b progeny and all treated groups during the F1a, F2a and F2b litters were comparable to the untreated control progeny.

Progeny body weights:
Body weight data for the 3 ppm progeny were similar to the untreated control progeny during both generations of this study. During the F0 generation, the 30 and 90 ppm progeny body weight data were less than the untreated control during the first (F1a) litter with statistical differences seen using individual body weight data at lactation days 7 (30 ppm) , 14, 21 and 28 and using mean litter weight data at lactation days 21 and 28 (90 ppm males only). Body weights for the F1b progeny revealed sporadic, minimal reductions when compared to the untreated control data with significance noted only for individual data at lactation days 14, 21 and 28 (30 ppm, only); no significant differences was seen for mean litter weight data. During the second generation, body weight data obtained for the 30 and 90 ppm progeny were reduced in comparison to the untreated control progeny. The 30 and 90 ppm individual progeny body weight data revealed significant reductions for the F2a progeny on lactation days 0, 4 and 7 (90 ppm only) and on lactation days 4, 7, 14, 21 and 28 (30 and 90 ppm). Mean litter weight data for the 30 and 90 ppm F2a progeny were statistically reduced on lactation day 14 (90 ppm only), 21 and 28 (males) and F2b progeny on lactation days 14, 21, 28 (30 ppm males, 30 and 90 ppm females).

Progeny development:
Progeny structural development was not altered by Methyl Bromide exposure.

Pathological Studies:
F2b progeny: Final body weight data recorded for the 90 ppm males and the 30 and 90 ppm females were statistically reduced when compared to the untreated control animals. No other significant reductions in final body weights were seen. Statistical analysis of the organ weight data revealed depressions, when compared to the untreated control females, for the 90 ppm female brain, heart, kidneys and liver weights, the 30 ppm female liver weight, and the 30 and 90 ppm female liver to brain weight ratios. The 30 and 90 ppm female brain to body weight ratio was increased when compared to the untreated control females.

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

Gross and microscopic findings:

No gross or microscopic lesions were noted which were attributed to the test article exposure.

Applicant's summary and conclusion

Conclusions:

No deaths, noteworthy antemortem observations or anomalies occurred which were considered the result of Methyl Bromide exposure. Microscopic examination of the reproductive organs and abnormal tissue revealed no treatment related lesions. It can therefore be concluded that the NOEL was 30 ppm (equivalent to 32 mg/kg bw) for male and female rats tested.