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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
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:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Cross-reference
Reason / purpose:
reference to same study
Reference
Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
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:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose:
reference to same study
Principles of method if other than guideline:
Two concentrations of butan-1-ol (3000 and 6000 ppm) were administered by inhalation to separate groups of 15 pregnant Sprague-Dawley rats for 7 hr per day throughout gestation ; 18 male rats were similarly exposed for 7 hr per day for 6 weeks, and mated to unexposed females.
GLP compliance:
no
Justification for study design:
SPECIFICATION OF STUDY DESIGN FOR EXTENDED ONE-GENERATION REPRODUCTION TOXICITY STUDY WITH JUSTIFICATIONS [please address all points below]:

- Premating exposure duration for parental (P0) animals
- Basis for dose level selection
- Inclusion/exclusion of extension of Cohort 1B
- Termination time for F2
- Inclusion/exclusion of developmental neurotoxicity Cohorts 2A and 2B
- Inclusion/exclusion of developmental immunotoxicity Cohort 3
- Route of administration
- Other considerations, e.g. on choice of species, strain, vehicle and number of animals [if applicable]
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: (P) Males: mean: 429-512 g; Females: mean: no data


ENVIRONMENTAL CONDITIONS
no data
Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
not specified
Vehicle:
air
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentrations measured in the exposure chambers approximated the target concentrations of 3000 and 6000 ppm. Mean (±s.d.) 1-butanol concentrations were 3010 (±50) and 6000 (±80) ppm, and results of periodic confirmatory charcoal tube samples were 3000 (± 90) and 5960 (± 110) ppm, respectively .
Duration of treatment / exposure:
females: Exposure period: day 1 - 20 of gestation
males: 6 weeks before mating
Frequency of treatment:
7 h/d
Remarks:
Doses / Concentrations:
0, 3 000, 6 000 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
0, 9 250, 18 500 mg/m3 air
Basis:
nominal conc.
No. of animals per sex per dose:
15 females per dose
18 males per dose
Control animals:
yes
Statistics:
Data were analyzed using multivariate analysis of variance (MANOVA) on tests with multiple dependent measures, followed by analysis of variance (ANOVA) on each dependent variable if a significant MANOVA was observed. If only one dependent variable was obtained, ANOVA was used, followed by the Tukey Range Test to determine which cell means differed from one another.
Dose descriptor:
NOAEC
Effect level:
18 500 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Pregnancy rate
Dose descriptor:
NOAEC
Generation:
F1
Effect level:
18 500 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Developmental neurotoxicity
Reproductive effects observed:
not specified

Read-across justifications and data matrices are presented in IUCLID section 13.

Conclusions:
Female rats exposed to 6 000 ppm (18 500 mg/m3) n-butanol throughout gestation and male rats exposed to 6 000 ppm (18 500 mg/m3) n-butanol for six weeks prior to mating showed no effects on fertility or pregnancy rate.
Executive summary:

In a reliable developmental neurotoxicity study groups of 18 male Sprague-Dawley rats were exposed to concentrations of 0, 3000, or 6 000 ppm n-butanol for 7 hours/day for 6 weeks. These males were then mated to non-exposed female rats of the same strain. In a separate experiment, groups of 15 pregnant female rats were exposed to concentrations of 0, 3 000, or 6 000 ppm for 7 hours/day from gestation Day 1-20. These females were then allowed to deliver. The offspring from these two groups were then observed for signs of developmental neurotoxic effects. Offspring were examined from postnatal days 10-90 for the following measures: ascent on a wire mesh screen, rotorod, open-field and photoelectrically-monitored activity, running wheel, avoidance conditioning, operant conditioning. Acetylcholine, dopamine, norepinephrine, serotonin, met-enkephalin, beta-endorphin and substance P neurotransmitter levels were measured from the cerebrum, cerebellum, brainstem, and midbrain.

No detectable effect on pregnancy rate was found after either maternal or paternal exposure. In the 6 000 ppm (18 500 mg/m3) group, 4 of the 78 (5%) behavioral measures, and 4 of the 64 (6%) neurochemical measures differed from those of controls. However, no dose-response correlation was observed. Thus, the NOAEL for the P and F1 generation is 18 500 mg/m3.

Data source

Reference
Reference Type:
publication
Title:
Behavioral Teratology Investigation of 1-Butanol in Rats
Author:
Nelson BK, Brightwell WS, Robertson SK, Kahn A, Krieg Jr EF, Massari VJ
Year:
1989
Bibliographic source:
Neurotoxicology and Teratology 11: 313-315

Materials and methods

Principles of method if other than guideline:
Two concentrations of butan-1-ol (3000 and 6000 ppm) were administered by inhalation to separate groups of 15 pregnant Sprague-Dawley rats for 7 hr per day throughout gestation ; 18 male rats were similarly exposed for 7 hr per day for 6 weeks, and mated to unexposed females.
GLP compliance:
no
Justification for study design:
SPECIFICATION OF STUDY DESIGN FOR EXTENDED ONE-GENERATION REPRODUCTION TOXICITY STUDY WITH JUSTIFICATIONS [please address all points below]:

- Premating exposure duration for parental (P0) animals
- Basis for dose level selection
- Inclusion/exclusion of extension of Cohort 1B
- Termination time for F2
- Inclusion/exclusion of developmental neurotoxicity Cohorts 2A and 2B
- Inclusion/exclusion of developmental immunotoxicity Cohort 3
- Route of administration
- Other considerations, e.g. on choice of species, strain, vehicle and number of animals [if applicable]

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
Name of test material (as cited in publication): 1-butanol

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: (P) Males: mean: 429-512 g; Females: mean: no data


ENVIRONMENTAL CONDITIONS
no data

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
not specified
Vehicle:
air
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentrations measured in the exposure chambers approximated the target concentrations of 3000 and 6000 ppm. Mean (±s.d.) 1-butanol concentrations were 3010 (±50) and 6000 (±80) ppm, and results of periodic confirmatory charcoal tube samples were 3000 (± 90) and 5960 (± 110) ppm, respectively .
Duration of treatment / exposure:
females: Exposure period: day 1 - 20 of gestation
males: 6 weeks before mating
Frequency of treatment:
7 h/d
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 3 000, 6 000 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
0, 9 250, 18 500 mg/m3 air
Basis:
nominal conc.
No. of animals per sex per dose:
15 females per dose
18 males per dose
Control animals:
yes

Examinations

Statistics:
Data were analyzed using multivariate analysis of variance (MANOVA) on tests with multiple dependent measures, followed by analysis of variance (ANOVA) on each dependent variable if a significant MANOVA was observed. If only one dependent variable was obtained, ANOVA was used, followed by the Tukey Range Test to determine which cell means differed from one another.

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

Dose descriptor:
NOAEC
Effect level:
18 500 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Pregnancy rate

Results: F1 generation

Effect levels (F1)

Dose descriptor:
NOAEC
Generation:
F1
Effect level:
18 500 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Developmental neurotoxicity

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Read-across justifications and data matrices are presented in IUCLID section 13.

Applicant's summary and conclusion

Conclusions:
Female rats exposed to 6 000 ppm (18 500 mg/m3) n-butanol throughout gestation and male rats exposed to 6 000 ppm (18 500 mg/m3) n-butanol for six weeks prior to mating showed no effects on fertility or pregnancy rate.
Executive summary:

In a reliable developmental neurotoxicity study groups of 18 male Sprague-Dawley rats were exposed to concentrations of 0, 3000, or 6 000 ppm n-butanol for 7 hours/day for 6 weeks. These males were then mated to non-exposed female rats of the same strain. In a separate experiment, groups of 15 pregnant female rats were exposed to concentrations of 0, 3 000, or 6 000 ppm for 7 hours/day from gestation Day 1-20. These females were then allowed to deliver. The offspring from these two groups were then observed for signs of developmental neurotoxic effects. Offspring were examined from postnatal days 10-90 for the following measures: ascent on a wire mesh screen, rotorod, open-field and photoelectrically-monitored activity, running wheel, avoidance conditioning, operant conditioning. Acetylcholine, dopamine, norepinephrine, serotonin, met-enkephalin, beta-endorphin and substance P neurotransmitter levels were measured from the cerebrum, cerebellum, brainstem, and midbrain.

No detectable effect on pregnancy rate was found after either maternal or paternal exposure. In the 6 000 ppm (18 500 mg/m3) group, 4 of the 78 (5%) behavioral measures, and 4 of the 64 (6%) neurochemical measures differed from those of controls. However, no dose-response correlation was observed. Thus, the NOAEL for the P and F1 generation is 18 500 mg/m3.