1-bromobutane

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Read across to 1-bromopropane. Whole-body inhalation exposure of Crl:CD(SD)IGS BR rats and the resulting offspring to vapor concentrations of 1-Bromopropane (100, 250, 500 and 750 ppm [F0 only]) for 6 hours per day, 7 days per week for a minimum of 70 days prior to mating and continuing until euthanasia produced no post-exposure clinical observations different from the control group animals exposed to filtered air. There were no mortalities related to exposure in the F0 generation. One F1 male in the 500 ppm group was euthanised in extremis during the second week of exposure. Body weight data (parental and pup) were reduced in the 500 (F0, F1 and F2) and 750 ppm (F0) groups. No macroscopic or microscopic pathology in brain tissue was observed. Complete lack of offspring was observed at exposures to 750 ppm, and a statistically decreased number of offspring compared to the control group was observed at exposures to 500 ppm (both generations). Non-statistically significant reductions in the number of offspring were observed in 250 ppm group for both generations. Fertility indices were statistically significantly reduced for the F0 500 ppm group. Reductions (not statistically significant) were observed in the 100, 250 and 500 ppm F1 groups. Extended estrous cycle lengths and an increase in the number of animals for which estrous cycle length could not be determined were observed in the 250 (F1), 500 (F0 and F1) and 750 (F0) ppm groups. The number of days between pairing and coitus were increased in the 500 and 750 ppm F0 groups. Reductions in organ weights were observed in the ovaries (500 and 750 ppm group F0 females), epididymides in the 250 (F0), 500 (F0 and F1) and 750 (F0) ppm group males, prostate (250, 500 and 750 ppm group F0 males), seminal vesicles (500 and 750 ppm group F0 males), pituitary in the 500 (F1) and 750 (F0) ppm group males and spleen in the F2 male and female weanlings. Organ weight differences from the control group values were also observed in the thymus (increase), liver (increase) and brain (decrease) in some groups. Generally, absolute values were different in treated animals compared to the control group values, but not when weights were expressed relative to body weights. Absolute brain weights were in the expected range for age, sex and strain, and no clinical or microscopic changes were correlated with the weight differences. No pathology associated with the thymus weight increases, and increased lipid vacuolation and glycogen content of the liver was considered reversible, and not of biological significance. Spermatogenic endpoints were adversely affected in the 500 (F0 and F1) and 750 (F0) ppm group males. Microscopic findings were observed in the ovaries in the 500 (F0 and F1) and 750 (F0) ppm group females.

Link to relevant study records

Reference

Endpoint:

two-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Read across to structural analogue.

Justification for type of information:

Please see attached justification for read across in Section 13.

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.3800 (Reproduction and Fertility Effects)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Remarks:

Doses / Concentrations:
100, 250, 500 and 750 ppm
Basis:
nominal conc.
750 ppm not used for F1 generation.

Remarks:

Doses / Concentrations:
99, 252, 505 and 750 ppm for the F0 generation
Basis:
analytical conc.
mean measured

Remarks:

Doses / Concentrations:
100, 252 and 504 ppm for the F1 generation.
Basis:
analytical conc.
mean measured

Key result

Dose descriptor:

NOAEL

Effect level:

100 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: body weight gain and food consumption/food efficiency

Remarks on result:

other: equates to NOEC value (503 mg/m3) NOEC value of 503 mg/m3)

Key result

Dose descriptor:

NOAEL

Effect level:

100 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Developmental effects

Remarks on result:

other: Generation: F1 and F2 (migrated information)

Remarks:

equates to NOEC value (503 mg/m3) NOEC value of 503 mg/m3

Mortality / viability:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

100 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Reproductive effects

Reproductive effects observed:

not specified

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

503 mg/m³

Study duration:

subchronic

Species:

rat

Additional information

Toxicity to reproduction is assessed via the use of read across to the structural analogue n-propyl bromide (1 -bromopropane).

Only one of the four studies available for this endpoint identified a quantitative NOAEL value which provided clear evidence of impaired fertility as a result of exposure to n-propyl bromide. This was a reliable study conducted to GLP using standard test methods and as such this value has been used as the key value for effects on fertility.

Whole-body inhalation exposure of Crl:CD(SD)IGS BR rats and the resulting offspring to vapor concentrations of 1-Bromopropane (100, 250, 500 and 750 ppm [F0 only]) for 6 hours per day, 7 days per week for a minimum of 70 days prior to mating and continuing until euthanasia produced no post-exposure clinical observations different from the control group animals exposed to filtered air. There were no mortalities related to exposure in the F0 generation. One F1 male in the 500 ppm group was euthanised in extremis during the second week of exposure. Body weight data (parental and pup) were reduced in the 500 (F0, F1 and F2) and 750 ppm (F0) groups. No macroscopic or microscopic pathology in brain tissue was observed. Complete lack of offspring was observed at exposures to 750 ppm, and a statistically decreased number of offspring compared to the control group was observed at exposures to 500 ppm (both generations). Non-statistically significant reductions in the number of offspring were observed in 250 ppm group for both generations. Fertility indices were statistically significantly reduced for the F0 500 ppm group. Reductions (not statistically significant) were observed in the 100, 250 and 500 ppm F1 groups. Extended estrous cycle lengths and an increase in the number of animals for which estrous cycle length could not be determined were observed in the 250 (F1), 500 (F0 and F1) and 750 (F0) ppm groups. The number of days between pairing and coitus were increased in the 500 and 750 ppm F0 groups. Reductions in organ weights were observed in the ovaries (500 and 750 ppm group F0 females), epididymides in the 250 (F0), 500 (F0 and F1) and 750 (F0) ppm group males, prostate (250, 500 and 750 ppm group F0 males), seminal vesicles (500 and 750 ppm group F0 males), pituitary in the 500 (F1) and 750 (F0) ppm group males and spleen in the F2 male and female weanlings. Organ weight differences from the control group values were also observed in the thymus (increase), liver (increase) and brain (decrease) in some groups. Generally, absolute values were different in treated animals compared to the control group values, but not when weights were expressed relative to body weights. Absolute brain weights were in the expected range for age, sex and strain, and no clinical or microscopic changes were correlated with the weight differences. No pathology was associated with the thymus weight increases, and increased lipid vacuolation and glycogen content of the liver was considered reversible, and not of biological significance. Spermatogenic endpoints were adversely affected in the 500 (F0 and F1) and 750 (F0) ppm group males. Microscopic findings were observed in the ovaries in the 500 (F0 and F1) and 750 (F0) ppm group females.

Short description of key information:

All toxicity to reproduction studies performed on n-propyl bromide were conducted using the inhalation route of exposure as due to the physicochemical properties of the substance this is the most likely route of exposure.

Five studies were available for this endpoint:

Toxicity to reproduction.001: NOAEL: 100 ppm (equal to a NOAEC of 503 mg/m3)

Toxicity to reproduction.002: No definitive conclusion possible

Toxicity to reproduction.003: Study terminated early due to insufficient fertility.

Toxicity to reproduction.004: No quantitative value established. Study concluded that the substance is a potential reproductive toxicant to men.

Toxicity to reproduction.005: No quantitative value established. Activation of 1-bromopropane via CYP2E1 may contribute to the male reproductive toxicity.

Effects on developmental toxicity

Description of key information

All toxicity to reproduction studies performed on n-propyl bromide were conducted using the inhalation route of exposure as due to the physicochemical properties of the substance this is the most likely route of exposure.

Two studies were available for this endpoint:

Developmental toxicity / teratogenicity.001 (full study): NOEL: maternal toxicity and fetal toxicity: 100 ppm; teratogenicity: 996 ppm

Developmental toxicity / teratogenicity.002 (range finding study): NOEL: maternal toxicity: 100 ppm

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Additional information

Toxicity to reproduction is assessed via the use of read across to the structural analogue n-propyl bromide (1 -bromopropane).

The studies do provide suspicion of developmental toxicity as a result of exposure to n-propyl bromide. The lowest NOEL value established for the developmental toxicity of n-propyl bromide is 100 ppm (equal to 503 mg/m³).

Justification for classification or non-classification

Toxicity to reproduction is assessed via the use of read across to the structural analogue n-propyl bromide (1 -bromopropane).

Based upon the results of read across to the analogue, the substance does meet the criteria for classification as a substance that should be regarded as if it would impair fertility in humans. In addition, the substance also meets the criteria for classification as a substance that should be regarded as causing concern for humans owing to possible developmental toxic

As such the substance is classified as a Reproductive toxicant Category 1B on Annex VI of the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 by manner of read across.