Titanium tetrabutanolate

Toxicity to reproduction

Some information in this page has been claimed confidential.

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

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 for cross-reference:

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 or test system 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

Test material information

Constituent 1

Constituent 2

Reference substance name:

Butan-1-ol

EC Number:

200-751-6

EC Name:

Butan-1-ol

Cas Number:

71-36-3

Molecular formula:

C4H10O

IUPAC Name:

1-Butanol

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 or test system 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 / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0, 3 000, 6 000 ppm
Basis:
nominal conc.

Doses / concentrations 2

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.