N-butyl 4-oxopentanoate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

supporting study

Study period:

1989

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Justification for type of information:

Justification for Read Across is given in Section 13

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

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Principles of method if other than guideline:

Concentrations of 0, 3000, and 6000 ppm of substance were administered for 7 hr/day on gestation days 1-20 (sperm=0) to groups of 15 pregnant Sprague-Dawley rats (the "maternal" exposure group).
Since exposures could not be conducted simultaneously and there were approximately 5 months between the low and high concentration-exposures, separate control groups were included for each concentration. In addition, groups of 18 male Sprague-Dawley rats (initial mean weights of 429 and 512 g, respectively) were exposed to the same concentrations for 7 hr/day for 6 weeks, and subsequently mated to non-exposed females (the "paternal" exposure group).

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Butyl levulinate_Similar substance 03

IUPAC Name:

Butyl levulinate_Similar substance 03

Test animals

Species:

rat

Strain:

Sprague-Dawley

Administration / exposure

Route of administration:

inhalation: aerosol

Vehicle:

air

Details on exposure:

Concentrations of 0, 3000, and 6000 ppm of test item were administered for 7 hr/day on gestation days 1-20 (sperm=0) to groups of 15 pregnant Sprague-Dawley rats (the "maternal" exposure group).
Since exposures could not be conducted simultaneously and there were approximately 5 months between the low and high concentration-exposures, separate control groups were included for each concentration. In addition, groups of 18 male Sprague-Dawley rats (initial mean weights of 429 and 512 g, respectively) were exposed to the same concentrations of substance for 7 hr/day for 6 weeks, and subsequently mated to nonexposed females (the "paternal" exposure). group).

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.) concentrations were 3010 (±50) and 6000 (±80) ppm, and results of periodic confirmatory charcoal tube samples were 3000 (±90) and 5960 (±110) ppm, respectively.

Details on mating procedure:

No data

Duration of treatment / exposure:

20 days exposure during gestation.

Frequency of treatment:

Daily

Duration of test:

90 days

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

3 000 ppm

Doses / concentrations 2

Dose / conc.:

6 000 ppm

No. of animals per sex per dose:

15 pregnant females per dose

Control animals:

yes, concurrent no treatment

Details on study design:

Dose selection rationale as a follow up of a previous reproductive toxicity study from the same authors.

Examinations

Maternal examinations:

No signs of maternal toxicity.

Ovaries and uterine content:

Not relevant.

Fetal examinations:

Main examinations were focused on neurotoxicity, which is the most affected by alcohols.

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 Turkey Range Test to determine which cell means differed from one another.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects: no effects

Effect levels (maternal animals)

Dose descriptor:

NOAEC

Effect level:

>= 6 000 ppm (nominal)

Based on:

test mat.

Basis for effect level:

other: no adverse toxic effects

Maternal abnormalities

Abnormalities:

no effects observed

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects: no effects

Details on embryotoxic / teratogenic effects:
Results from behavioral testing of the offspring indicated that there were no significant effects on the ascent test, rotorod, 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, F(2,39)=6.01, p=0.01. In avoidance conditioning, there were no effects in the animals tested beginning on day 34; in the animals tested beginning on day 60, both the time receiving shock [the escape period; F(2,43)=39.37, p<0.01] and the total number of times the rats crossed from one side of the cage to the other [escape and avoidance responses plus random side changes during the session; F(2,43)=8.58, p<0.01] were elevated from controls in the offspring whose male parent was exposed to 6000 ppm. At 3000 ppm, the older male offspring from the paternal exposure group required fewer trials to reach criterion in avoidance conditioning, F(2,38) = 6.81, p<0.01, than the other groups.

Effect levels (fetuses)

Dose descriptor:

NOAEC

Effect level:

>= 6 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Only few behavioral or neurochemical alterations detected in the offspring following maternal or paternal exposure to either 3000 or 6000 ppm; no discernable pattern of effects was apparent.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Neurochemical analyses revealed few differences in offspring from exposed and control groups [4 out of 64 (32 measures times the two exposure groups)], and no patterns were discernible.

Applicant's summary and conclusion

Conclusions:

NOAEC (development, rat) >= 6000 ppm (behavioural and neurochemical measures)

Executive summary:

The developmental toxicity of the substance was evaluated in an experimental study whereby the test item was administered by inhalation to groups of 15 pregnant females, plus a group of 18 males which were subsequently mated with a separate group of untreated females, which were exposed to test item concentrations of 3000 and 6000 ppm (plus vehicle control groups) via inhalation for 7 hours a day, 7 days a week, for 20 days during pregnancy. Litters were evaluated until 5 weeks of age for several behaviour parameters and neurotxicology markers.

Few effects were seen on both the behavioral (4/78) and neurochemical (4/68) measures following exposure to 6000 ppm of test item, but no discernable pattern of effects was apparent. Therefore, the NOAEC for development in the rat regarding behavioural and neurochemical measures was set to at least 6000 ppm.