Octyl acetate

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data is from peer-reviewed journal

Data source

Reference

Reference Type:

publication

Title:

Evaluation of the Teratogenic Potential of Octyl Acetate in Rats

Author:

W. C. DAUGHTREY, P. J. WIER,1 K. A. TRAUL,2 R. W. BILES, AND G. F. EGAN

Year:

1989

Bibliographic source:

Fundamental and Applied Toxicology, 13, 303-309 (1989)

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Principles of method if other than guideline:

Teratogenic Potential toxicity study of Octyl Acetate in Rats

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Octyl acetate

EC Number:

203-939-6

EC Name:

Octyl acetate

Cas Number:

112-14-1

Molecular formula:

C10H20O2

IUPAC Name:

octyl acetate

Constituent 2

Reference substance name:

Acetate C-8

IUPAC Name:

Acetate C-8

Details on test material:

- Name of test material (as cited in study report): Acetate C-8
- Molecular formula (if other than submission substance): C10H20O2
- Molecular weight (if other than submission substance): 172.266 g/mole
- Substance type: Organic
- Physical state: Liquid
- Impurities (identity and concentrations): No data available

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: (P) x wks; 9 weeks old
- Weight at study initiation: 212 - 216 g female
- Fasting period before study: No data available
- Housing: Animals were housed individually (except during the first week of quarantine and during mating) in suspended stainless-steel cages and All animals were identified by uniquely numbered ear tags during the course of the study.
- Diet (e.g. ad libitum): Food (certified Rodent Chow, Ralston Punna Co.)
- Water (e.g. ad libitum): water, ad libitum
- Acclimation period: 3-week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19- 24 °C (monitored daily)
- Humidity (%): 40-70% (monitored daily)
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): 12-hr photoperiod

IN-LIFE DATES: From: To: No data available

Administration / exposure

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Vehicle:

water

Remarks:

Distilled

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Octyl acetate was dissolved in distilled water to give as dose of 0, 100, 500 or 1000 mg/Kg

DIET PREPARATION
- Rate of preparation of diet (frequency): No data
- Mixing appropriate amounts with (Type of food): No data
- Storage temperature of food: No data

VEHICLE
- Justification for use and choice of vehicle (if other than water): Distilled water
- Concentration in vehicle: 0, 100, 500 or 1000 mg/Kg
- Amount of vehicle (if gavage): Dose volumes were based on GD 6 body weights throughout the dosing period
- Lot/batch no. (if required): No data
- Purity: No data

Details on mating procedure:

- M/F ratio per cage: No data avaialble
- Length of cohabitation: No data avaialble
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy Copulatory plug in the vagina
or by observation of sperm in a vaginal rinse were referred to as day 0 of pregnancy
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility. No data avaialble
- Further matings after two unsuccessful attempts: [no / yes (explain)] No data avaialble
- After successful mating each pregnant female was caged (how): Individually
- Any other deviations from standard protocol: No data avaialble

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

10 days

Frequency of treatment:

Daily

Details on study schedule:

- Rationale for animal assignment (if not random): Females confirmed to have mated were randomly assigned to one of four experimental groups of 22 mated female rats.

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 100, 500 and 1000 mg/Kg
Basis:

No. of animals per sex per dose:

Total: 85
0 mg/kg bw : 22 female
100 mg/kg bw :20 female
500 mg/kg bw :22 female
1000 mg/kg bw :21 female

Control animals:

yes, concurrent vehicle

Details on study design:

No data avaialble

Positive control:

No data avaialble

Examinations

Parental animals: Observations and examinations:

Survival, clinical sign, body weight and body weight change and food consumption were observed.

Oestrous cyclicity (parental animals):

Corpora lutea and Resorptions were examined.

Sperm parameters (parental animals):

No data available

Litter observations:

Fetuses weighe and sexed were examined.

Postmortem examinations (parental animals):

Organ weight and gross pathology were examined.

Postmortem examinations (offspring):

Examined externally for gross abnormalities, visceral, and skeletal malformations and variations, and crown-rump distance were measured.

Statistics:

Maternal body weight and body weight change, food consumption, uterine data (i.e., corpora lutea, implants, resorptions), and malformation data were analyzed statistically using
Bartlett's test of homogeneity of variance (Snedecor and Cochran, 1967) was used to determine if the groups had equivalent variances at the 1 % level of significance. If the variances were not significantly different, the groups were compared using a standard one-way analysis of variance (ANOVA). If significant differences among the means were indicated, Duncan's test (Dunnett, 1964) was performed to determine which treated groups differed from control. Fetal weights and crown-rump lengths were analyzed using individual fetal values by a standard nested analysis of variance, with values nested within dams and dams nested within groups. If differences in groups were indicated, the least-significantdifference technique (Snedecor and Cochran, 1967) was used to determine which treated groups differed from control.
If the groups did not have equivalent variances at the 1 % level, then a Kruskal-Wallis test (nonparametric) was used to assess differences in group means (Hollander and Wolf, 1973). If the means were different, a rank sum comparison was used to determine which treatment groups differed from control.

Reproductive indices:

No data avaialble

Offspring viability indices:

No data avaialble

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

not specified

Other effects:

not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Details on results (P0)

Moraltity:
When treated with 1000 mg/kg bw, 2 female rats were died one each on GDs 10 and
12, respectively.
No effect on mortality of 100 and 500 mg/kg bw treated female rats were observed as compared to control.

Clinical signs:
When treated with 1000 mg/kg bw, elevated incidences of alopecia, rales, red nasal discharge, and anal-genital staining were observed in treated female rats ascompared to control.

Body weight:
When treated with 1000 mg/kg bw, A statistically significant decreased in mean body weight on on GDs 9, 12, 16, and 20 were observed as compared with control. The effect was most evident during the first several days of dosing, when these animals actually lost weight (GDs 6-9).

When treated with 500 mg/kg bw, Statistically significant decrase in mean body weight and body weight changes were observed at several time points as compared with control. These decrase in body weight appeared to occur in an ordered response to dose.

Food consumption:
When treated with 500 and 1000 mg/kg bw, dose-related decreases in food consumption for the Day 6-9, 9-12, and 12- 16 intervals were observed as
compared with control.

Reproductive function: estrous cycle
When treated with 1000 mg/kg bw, slight increase in resorptions were observed as compared to control. But, the difference was not statistically significant.

Reproductive performance: No statistically significant effect were observed on Corpora lutea/dam, Implants/litter, Resorptions/litter and Live fetuses/litter as compared to control.

Organ weights: No statistically significant effect were observed Uterine weight of treated female rats as compared to control.

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No effect on survival, clinical sign, body weight, food consumption, reproductive performance and organ weight

Results: F1 generation

General toxicity (F1)

Clinical signs:

not specified

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

Details on results (F1)

Moraltity:
No significant effect was observed on Live fetuses/litter s compared to control.

Body weight:
No significant effect was observed on fetal body weight as compared to control.

Gross pathology:
Tail absent were observed in 1000 mg/kg bw and micrognathia in 500 mg/kg bw as compared to control.

No significant differences or dose-related change were observed on crown rump distance of fetuses were observed as compared to control.

Histopathology:
Visceral examinations:
When treated wtih 1000 mg/kg bw, dilated lateral cerebral ventricles in two fetuses were observed which are anatomical variations previously observed in historical control fetuses.

Skeletal malformations:
When treated wtih 1000 mg/kg bw, Different types of vertebral malformations were observed in four fetuses (four litters) in the form of incomplete ossification but, was not statistically significant as compated to control.

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effect on body weight, gross pathology and histopathology

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

Maternal Body Weight And Body Weight Changes^a

	Dose group
Gestational day	0 g/kg (N=20)	0.1 g/kg (N=20)	0.5 g/kg (N=20)	1. 0 g/kg (N=20)
	Body weight (g)
0	216.7 ±22.5	214.8 ± 16.0	213.7 ± 18.3	212.0± 18.5
3	233.3 ±22.4	232.0 ±17.2	230.1 ± 17.8	227.9 ±19.2
6	248.8 ± 23.0	246.1 ±17.8	244.6 ± 20.0	242.9 ± 20.2
9	261.0 ±24.9	256.6 ±18.4	247.3 ±21.2	234.7 ±24.5**
12	279.9 ± 24.3	273.7 ±19.9	261.1 ±23.4*	247.0 ±25.4"
16	306.5 ± 26.0	300.0 ±23.5	288.0 ±27.1	275.3 ± 24.7**
20	368.5 ±28.0	361.3 ±27.7	352.4 ±34.9	338.1 ±26.7*
20^c	295.3 ±23.0	285.6 ±21.1	272.1 ±26.0*	265.1 ±24.3**
	Body weight change (g)
0-6	32.0 ± 3.8	31.3 ± 4.8	30.9 ± 6.8	30.9 ± 6.0
6-9	12.2 ± 4.1	10.6 ± 5.1	2.7 ± 11.3**	-8.1 ± 12.1**
9-12	18.9 ± 4.2	17.1 ± 4.1	13.8 ± 9.4*	13.5 ± 7.9*
12-16	26.6 ± 6.9	26.3 ± 5.6	26.9 ± 8.6	27.3 ± 8.5
16-20	62.0 ± 6.6	61.3 ± 9.0	64.4 ± 10.8	62.8 ± 5.5
0-20	151.8 ± 13.9	146.5 ± 16.4	138.6 ±25.9	126.3 ± 15.5**
6-20^c	46.6 ± 8.5	39.6 ± 9.6	28.8 ±15.0**	22.2 ± 13.3**

^aValues are means ± SD. N = number of dams.

^b From Day 12, W =20; from Day 16, N= 19.

c Body weight corrected for gravid uterine weight.

* Significantly different from control, p≤0.05.

** Significantly different from control, p≤0.01.

Mean food consumption of pregnant rats^a

	Dose group
Gestational day	0 g/kg	0.1 g/kg	0.5 g/kg	1.0 g/kg
0-3	69.2+ 5.9	69.8 ± 5.6	69.2+ 5.7	67.6 ± 5.7
	(21)*	(19)	(22)	(21)
3-6	76.4+ 6.8	72.3 ± 7.8	73.3 ± 6.2	72.5 ± 5.7
	(20)	(18)	(22)	(21)
6-9	76.7 ± 8.1	72.8 ± 7.2	63.7 ± 11.1"	49.3 ±12.3**
	(22)	(19)	(22)	(21)
9-12	80.7 ± 7.5	75.5 ± 8.5	66.9 ± 9.4"	60.5 ± 19.2"
	(21)	(H)	(21)	(18)
12-16	104.3 ± 10.5	101.8 ± 11.9	92.4+ 13.2*	88.8 ± 9.4"
	(22)	(19)	(19)	(19)
16-20	112.7 db 8.5	111.9± 11.6	109.8 ± 14.0	110.0 ± 10.9
	(22)	(20)	(22)	(19)

^aValues are the means ± SD of the amount of diet consumed expressed in grams per rat.

* N is given in parentheses.

* Significantly different from control, p≤ 0.05.

** Significantly different from control, p≤0.01.

Uterine Implantation Data^a

	Dose group
	0 g/kg (N=20)	0.1 g/Kg (N = 20)	0.5 g/kg (N=20)	1.0 g/kg (N =20)
Corpora lutea/dam	16.0 ± 1.6	15.9 ± 2.2	16.1 ± 2.5	16.5 ±2.6
Implants/litter	14.7 ± 1.5	14.7 ± 2.0	14.9 ± 2.1	14.8 ± 1.9
Resorptions/litter	0.6 ±0.7	0.9 ± 1.2	0.6 ± 0.8	1.3± 1.4
Uterine weight (g)	74.9 ± 9.0	75.6 ±12.1	77.8± 13.1	73.0 ±8.8
Live fetuses/litter	7.9 ± 1.9	7.4 ± 1.8	7.0 ± 1.8	6.7 ±2.2
Male	6.2 ±1.6	6.3 ± 1.8	7.2 ± 1.6	6.8 ± 1.9
Female	14.1 ± 1.6	13.7 ± 2.2	14.2 ± 2.0	13.5 ± 1.7
Total	16.0 ± 1.6	15.9 ± 2.2	16.1 ± 2.5	16.5 ±2.6

^aValues are means ± SD. N = number of litters.

Applicant's summary and conclusion

Conclusions:

NOAEL was considered to be 500 mg/kg bw for P generation and 1000 mg/kg bw for F1 generation when Sprague-Dawley female rats were treated with Octyl Acetate orally by gavage for 10 days of gestation.

Executive summary:

In a Teratogenicity study, Sprague-Dawley female rats were treated withOctyl Acetate in the concentration of 0,100, 500 and 1000 mg/kg bw orally by gavage.2 female rats were died at 1000 mg/kg bw one each on GDs 10 and 12, respectively and elevated incidences of alopecia, rales, red nasal discharge, and anal-genital staining were observed in treated female rats as compared to control. A statistically significant decreased in mean body weight on on GDs 9, 12, 16, and 20 were observed at 1000 mg/kg bw.The effect was most evident during the first several days of dosing, when these animals actually lost weight (GDs 6-9).Statistically significant decrase in mean body weight and body weight changes were observed at several time points at 500 mg/kg bw as compared with control. These decrease in body weight appeared to occur in an ordered response to dose. Similarly, Dose-related decreases in food consumption for the Day 6-9, 9-12, and 12- 16 intervals were observed at 500 and 1000 mg/kg bw as compared with control. Slight increase in resorptions was observed as compared to control. But, the difference was not statistically significant. In addition, No statistically significant effect were observed on Corpora lutea/dam, Implants/litter, Resorptions/litter and Live fetuses/litter and Uterine weight of treated female rats as compared to control in P generation. In F1 generation,No significant effect was observed on fetal body weight as compared to control.Tail absent were observed in 1000 mg/kg bw and micrognathia in 500 mg/kg bwas compared to control. No significant differences or dose-related change were observed on crown rump distance of fetuses were observed as compared to control.Dilated lateral cerebral ventricles in two fetuses were observed at 1000 mg/kg bw which are anatomical variations previously observed in historical control fetuses. Different types of vertebral malformations were observed in four fetuses (four litters) in the form of incomplete ossification at 1000 mg/kg bw. But, were not statistically significant as compared to control. Therefore,NOAEL was considered to be 500 mg/kg bw for P generation and 1000 mg/kg bw for F1 generation whenSprague-Dawley female rats were treated withOctyl Acetate orally by gavage for 10 days of gestation.