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Key value for chemical safety assessment

Genetic toxicity in vivo

Description of key information
Not sufficient evidence of the ability of allyl bromide to induce an effect
Link to relevant study records
Reference
Endpoint:
in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
Remarks:
Type of genotoxicity: chromosome aberration
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study conducted in compliance with agreed protocols, with no deviations from standard test guidelines and no methodological deficiences, which do not affect the quality of the relevant results. The study report was conclusive, done to a valid guideline and the study was conducted under GLP conditions.
Qualifier:
equivalent or similar to
Guideline:
EPA OPPTS 870.5395 (In Vivo Mammalian Cytogenetics Tests: Erythrocyte Micronucleus Assay)
GLP compliance:
yes
Type of assay:
micronucleus assay
Species:
mouse
Strain:
other: FVB/N - C57BL/6 - Tg.AC hemizygous- p53 haploinsufficient mice
Sex:
male/female
Details on test animals and environmental conditions:
See paragraphe 7.7
Route of administration:
oral: gavage
Vehicle:
Corn oil
Details on exposure:
At the end of the 40-week studies of paragraphe 7.7, peripheral blood samples were obtained from male and female mice from each strain. Smears were immediately prepared and fixed in absolute methanol. The methanol-fixed slides were stained with acridine orange and coded. Slides were scanned to determine the frequency of micronuclei in 2,000 normochromatic erythrocytes (NCEs) in each of up to 15 mice per group. In addition, the percentage of polychromatic erythrocytes (PCEs) in a population of 1,000 erythrocytes was determined as a measure of bone marrow toxicity.
Duration of treatment / exposure:
40-week study
Frequency of treatment:
Groups of 15 male and 15 female FVB/N and C57BL/6 mice received 0 or 8 mg allyl bromide/kg body weight in corn oil by gavage, in a volume of 10 mL/kg body weight, 5 days per week for 40 weeks. Groups of 15 male and 15 female Tg.AC hemizygous and p53 haploinsufficient mice received 0, 0.5, 1, 2, 4, or 8 mg allyl bromide/kg body weight in 10 mL/kg corn oil by gavage, 5 days per week for 40 weeks. Vehicle control mice received corn oil only.
Post exposure period:
None
No. of animals per sex per dose:
15 males and 15 females per group
Control animals:
yes, concurrent vehicle
Positive control(s):
Positive control groups of 15 male and 15 female Tg.AC hemizygous mice received dermal applications of 1.25 μg TPA in 100 μL acetone (12.5 μg TPA/L solution), three times per week until removal from study. Positive control mice were removed after the appearance of 20 or more skin papillomas and discarded. The TPA solution was applied to the clipped dorsal skin from the mid-back to the interscapular area.
Tissues and cell types examined:
Necropsies and microscopic examinations were performed on all mice except positive controls. The heart, right kidney, liver, lung, right testis, and thymus were weighed. At necropsy, all organs and tissues were examined for grossly visible lesions, and all major tissues were fixed and preserved in 10% neutral buffered formalin, processed and trimmed, embedded in paraffin, sectioned to a thickness of 4 to 6 μm, and stained with hematoxylin and eosin for microscopic examination. For all paired organs (e.g., adrenal gland, kidney, ovary), samples from each organ were examined.
Statistics:
The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958). Animals found dead of other than natural causes or missing were censored from the survival analyses; animals dying from natural causes were not censored. Statistical analyses for possible dose-related effects on survival used Cox’s (1972) method for testing two groups for equality and Tarone’s (1975) life table test to identify dose-related trends. All reported P values for the survival analyses are two sided.
Sex:
male/female
Genotoxicity:
negative
Toxicity:
no effects
Negative controls validity:
valid
Additional information on results:
The frequency of micronucleated erythrocytes was assessed in each of the four mouse strains treated with allyl bromide for 40 weeks. Results in all four strains of mice were concluded to be negative; in addition, no significant, consistent changes in the percentage of polychromatic erythrocytes (reticulocytes) among total erythrocytes were observed in any of the four strains.
Some observations of note in these micronucleus tests include the small increase in micronucleated erythrocytes seen in the single dosed group (8 mg/kg) of female C57BL/6 mice that was evaluated for micronucleus frequency. Although the P value was significant (<0.05), these results were judged to be negative because the small increase represented less than half a micronucleus per 1,000 cells, which is not biologically relevant. In the male p53 haploinsufficient mice, one dosed group (1.0 mg/kg) showed a small but significant increase (P=0.0006) in micronucleated erythrocyte frequency, but none of the three higher doses showed an effect; therefore, this small increase at a single dose concentration in one sex, even though statistically significant (P<0.005), was not considered sufficient evidence of the ability of allyl bromide ti induce effect in this assay.
Conclusions:
Interpretation of results (migrated information): negative
Not sufficient evidence of the ability of allyl bromide to induce an effect in this assay
Executive summary:

The frequency of micronucleated erythrocytes was assessed in male and female mice for each of the four mouse strains administered allyl bromide by corn oil gavage for 40 weeks. Results in all four micronucleus studies with allyl bromide were concluded to be negative; in addition, no significant changes in the percentage of polychromatic erythrocytes (reticulocytes) among total erythrocytes were observed in any of the four strains of mice.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Additional information

Additional information from genetic toxicity in vivo:

The frequency of micronucleated erythrocytes was assessed in male and female mice for each of the four mouse strains administered allyl bromide by corn oil gavage for 40 weeks. Results in all four micronucleus studies with allyl bromide were concluded to be negative; in addition, no significant changes in the percentage of polychromatic erythrocytes (reticulocytes) among total erythrocytes were observed in any of the four strains of mice.


Justification for selection of genetic toxicity endpoint
Study in vivo is retained.

Justification for classification or non-classification

The frequency of micronucleated erythrocytes was assessed in male and female mice for each of the four mouse strains administered allyl bromide by corn oil gavage for 40 weeks. Results in all four micronucleus studies with allyl bromide were concluded to be negative; in addition, no significant changes in the percentage of polychromatic erythrocytes (reticulocytes) among total erythrocytes were observed in any of the four strains of mice.