Butyl (S)-2-hydroxypropionate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Behavioral Teratology Investigation of 1-Butanol in Rats

Author:

Nelson B.K., Brightwell, W.S., Robertson S.K., Khan A., Krieg Jr. E.F., Massari V.J.

Year:

1989

Bibliographic source:

Neurotoxicology and Teratology 11, 313-315

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test: In a behavioural teratology study, 1-butanol at concentrations of 3000 and 6000 ppm was administered by inhalation to groups of 15 pregnant Sprague-Dawley rats for 7 h/day throughout gestation. Similarly, 18 male rats were exposed with the same concentrations for 7 h/day for 6 weeks and mated to unexposed females.
- Parameters analysed/observed: The offspring of both cohorts were evaluated for signs of developmental neurotoxicity (ascent on a wire mesh screen, rotorod, open field and photoelectrically-monitored activity, running wheel, avoidance conditioning and operant conditioning). Further, brains from 10 offspring were dissected into cerebrum, cerebellum, brainstem, and midbrain on post-natal day 21. Each sample was assayed for protein and the neurotransmitters acetylcholine, dopamine, norepinephrine, serotonin, met-enkephalin, beta-endorphin, and substance P.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

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:

butan-1-ol

Specific details on test material used for the study:

- Name of the test material in the study: 1-butanol
- Purity: ≥ 99 %

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: Males: 429 to 512 g
- Fasting period before study: no data
- Housing: no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

Administration / exposure

Route of administration:

inhalation

Type of inhalation exposure (if applicable):

whole body

Vehicle:

air

Details on exposure:

Exposure was carried out in exposure chambers. No other information on exposure was mentioned in the publication.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

No details on analytical verification of doses were provided. It is stated that concentrations were measured in exposure chambers and charcoal tube samples were collected for periodic confirmatory of concentrations.

Details on mating procedure:

No data

Duration of treatment / exposure:

For the "maternal exposure group" exposure was conducted during days 1-20 of gestation. For the "paternal exposure group" exposure was conducted for 6 weeks.

Frequency of treatment:

7 hours per day

Duration of test:

Offspring were evaluated from days 10-90 post delivery.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 ppm (nominal)

Remarks:

Control

Doses / concentrations 2

Dose / conc.:

3 000 ppm (nominal)

Doses / concentrations 3

Dose / conc.:

6 000 ppm (nominal)

No. of animals per sex per dose:

18 males (paternal exposure group) and 15 females (maternal exposure group).

Control animals:

yes

Details on study design:

- Dose selection rationale: Based upon the results of beforehand conducted teratology study, 6000 ppm was selected as the high concentration (due to slight maternal toxicity) and 3000 ppm was the low concentration evaluated.

Examinations

Maternal examinations:

See box "Any other information on materials and methods incl. tables".

Ovaries and uterine content:

n.a.

Fetal examinations:

See box "Any other information on materials and methods incl. tables".

Statistics:

Data were analysed 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.

Historical control data:

No data provided

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

not specified

Dermal irritation (if dermal study):

not examined

Mortality:

not specified

Body weight and weight changes:

not examined

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Maternal developmental toxicity

Number of abortions:

not examined

Pre- and post-implantation loss:

not examined

Total litter losses by resorption:

not examined

Early or late resorptions:

not examined

Dead fetuses:

not examined

Changes in pregnancy duration:

not examined

Changes in number of pregnant:

not examined

Other effects:

not examined

Details on maternal toxic effects:

Inhalation of 3000 and 6000 ppm had no detectable effect on pregnancy rate after either maternal or paternal exposure.

Effect levels (maternal animals)

Dose descriptor:

NOAEC

Effect level:

6 000 ppm (nominal)

Based on:

test mat.

Basis for effect level:

other: no adverse effects observed

Maternal abnormalities

Abnormalities:

not examined

Results (fetuses)

Fetal body weight changes:

not examined

Reduction in number of live offspring:

not examined

Changes in sex ratio:

not examined

Changes in litter size and weights:

not examined

Changes in postnatal survival:

not examined

External malformations:

not examined

Skeletal malformations:

not examined

Visceral malformations:

not examined

Other effects:

no effects observed

Description (incidence and severity):

Results from behavioural testing of the offspring indicated that there were no significant effects in the ascent test, in the rotorod performance test, on open field performance or operant conditioning. In the photoelectric activity monitor, the counts were significantly lower than controls in the female offspring from paternal animals exposed to 3000 ppm. Analysis of neurotransmitter concentrations in the brains of offspring revealed statistically significant increases in the overall concentration of serotonin (14.48 ± 2.38 vs.7.802 ± 1.48 in controls) and dopamine (0.715 ± 0.127 versus 0.515 ± 0.095 in controls) in offspring of the 6000 ppm group. There were no other statistically significant changes in neurotransmitter concentrations associated with exposure. The data from all tests in this study were within the control data in other research conducted by this laboratory.

Effect levels (fetuses)

Dose descriptor:

NOAEC

Effect level:

6 000 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Any other information on results incl. tables

Analytical results:

Concentrations measured in the exposure chambers approximated the target concentrations of 3000 and 6000 ppm. Mean concentrations were 3010 ± 50 and 6000 ± 80 ppm. Results of periodic confirmatory charcoal tube samples were 3000 ± 90 and 5960 ± 110 ppm.

Applicant's summary and conclusion

Conclusions:

No adverse effects were observed in a behavioural teratology study in rats after exposure to n-butanol. Based on the results, the NOAEL for maternal and paternal animals and their offspring was 6000 ppm.

Executive summary:

In a behavioural teratology study, n-butanol (≥ 99 % purity) was administered to 15 pregnant Sprague-Dawley rats for 7 h/day throughout gestation (GD 1–20) at doses of 0, 3000 and 6000 ppm and were allowed to deliver. In addition, 18 male rats were exposed with the same concentrations for 7 h/day for 6 weeks and were then mated to non-exposed females. The offspring of both cohorts were observed during postnatal days 10–90 for signs of developmental neurotoxic effects by measuring ascent on a wire mesh screen, rotarod and running wheel performance, open-field and photoelectrically-monitored activity, avoidance conditioning and operand conditioning. In addition, the levels of the neurotransmitters acetylcholine, dopamine, norepinephrine, serotonin, met-encephalin, ß.endorphin and substance P were measured in 4 brain regions (cerebrum, cerebellum, brainstem and midbrain) taken from animals on day 21 after birth. No effects on pregnancy rate was found and no general toxicity to maternal and paternal animals was reported. A small number of effects were seen on both the behavioural and neurochemical measures following exposure to 6000 ppm n-butanol, but that no discernable pattern of effects was apparent. Therefore, the NOAEC for maternal, paternal and their offspring was 6000 ppm, which corresponds to 18152 mg/m³.