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Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
published in 1989
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Information provided to support arguments based on read across between similar substances. The study was not conducted according to specific test guidelines but was considered to follow sound scientific principles consistent with achieving the developmental toxicity endpoint

Data source

Reference
Reference Type:
publication
Title:
Evaluation of the Teratogenic Potential of Octyl Acetate in Rats
Author:
Daughtrey WC, Wier PJ, Traul KA, Biles RW & Egan GF
Year:
1989
Bibliographic source:
Fundamental & Applied Toxicology 13, 303-309 (1989)

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:
Standard developmental toxicity study, performed with the read-across substance octyl acetate
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Reference substance name:
Octyl acetate
EC Number:
203-939-6
EC Name:
Octyl acetate
Cas Number:
112-14-1
IUPAC Name:
octyl acetate
Constituent 2
Reference substance name:
108419-32-5
Cas Number:
108419-32-5
IUPAC Name:
108419-32-5
Test material form:
other: liquid
Details on test material:
octyl acetate (CAS RN 108419-32-5) is a liquid isomeric mixture of acetates composed of 12% CHlCOOC7H15 , 76% CHlCOOC.H17, and the balance CHlCOO4HI9.
The vapor pressure is 0.75 mm Hg at 20°C, and the initial boiling point is 186°C.

The purity and stability of the test material were verified by gas chromatography and infrared analysis.
Stability was assessed by repeat analysis of the sample.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
Virgin male and female Sprague-Dawley rats approximately 6 weeks of age were obtained from Charles River Breeding Laboratories and quarantined for a 3-week period.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on exposure:
Octyl acetate (CAS RN 108419-32-5) was administered via oral gavage to pregnant Sprague-Dawley rats on Gestation Days 6 through 15 at dose levels of 0, 0.1, 0.5, and 1.0 g/kg bw
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no details
Details on mating procedure:
Females were confirmed to have mated by observation of a copulatory plug in the vagina or by observation of sperm in a vaginal rinse. This was designated as Gestational Day (GD) O. Females confirmed to have mated were randomly assigned to one of four experimental groups of 22 mated female rats.
Duration of treatment / exposure:
Octyl acetate (CAS RN 108419-32-5) was administered via oral gavage to pregnant Sprague-Dawley rats on Gestation Days 6 through 15 at dose levels of 0, 0.1, 0.5, and 1.0 g/kg bw
Frequency of treatment:
Ten days, daily administration
Duration of test:
Gestation day 6 to 15 for dose administration and dams terminated on gestation day 20
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 0.1, 0.5, and 1.0 g/kg
Basis:
nominal conc.
No. of animals per sex per dose:
22 mated females per group
Control animals:
yes, concurrent vehicle
Details on study design:
The animals were observed daily for clinical signs of toxicity throughout the study. Maternal body weights and food consumption were measured on GDs 0, 3, 6, 9, 12, 16, and 20. All animals were sacrificed and examined by gross necropsy on GD 20. For the first 20 pregnant females of each dose group, the uteri were removed and their contents examined for the number of live and dead foetuses and resorptions. Ovarian corpora lutea were counted. All foetuses were weighed, sexed, examined externally for gross abnormalities, and measured to determine crown-rump distance. One-half of the foetuses from each litter were decapitated, and their heads were fixed in Bouin's solution for subsequent examination by the Wilson (1973) technique. The viscera of these foetuses were examined for abnormalities by the Staples technique, All foetuses were eviscerated and processed for skeletal staining with alizarin red stain. Only those foetuses that had not been decapitated were examined for skeletal malformations

Examinations

Maternal examinations:
The animals were observed daily for clinical signs of toxicity throughout the study. Maternal body weights and food consumption were measured on GDs 0, 3, 6, 9, 12, 16, and 20. All animals were sacrificed and examined by gross necropsy on GD 20.
Ovaries and uterine content:
For the first 20 pregnant females of each dose group, the uteri were removed and their contents examined for the number of live and dead foetuses and resorptions. Ovarian corpora lutea were counted.
Fetal examinations:
For the first 20 pregnant females of each dose group, the uteri were removed and their contents examined for the number of live and dead foetuses and resorptions. Ovarian corpora lutea were counted. All foetuses were weighed, sexed, examined externally for gross abnormalities, and measured to determine crown-rump distance. One-half of the foetuses from each litter were decapitated, and their heads were fixed in Bouin's solution for subsequent examination by the Wilson (1973) technique. The viscera of these foetuses were examined for abnormalities by the Staples (1974) technique, All foetuses were eviscerated and processed for skeletal staining with alizarin red stain. Only those foetuses that had not been decapitated were examined for skeletal malformations.
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 the following methods. 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. Foetal weights and crown-rump lengths were analyzed using individual foetal values by a standard nested analysis of variance, with values nested within dams and dam's nested within groups. If differences in groups were indicated, the least-significant difference 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%le\'el, 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.
Indices:
No data
Historical control data:
no data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Details on maternal toxic effects:
No females died in the control, low-dose, or mid-dose groups. In the high-dose group two animals died, one each on GDs 10 and 12, respectively. Maternal animals in the high dose group exhibited elevated incidences of alopecia, rales, red nasal discharge and anal-genital staining. A statistically significant reduction in mean body weight, compared with control, was observed in the high-dose group (1 g/kg bw). The reduction in body weight was evident when measured on GDs 9, 12, 16, and 20. The effect was most evident during the first several days of dosing, when these animals actually lost weight (GDs 6-9). Statistically significant reductions in mean body weight and body weight changes were also observed in the mid-dose group (0.5 g/kg) at several time points, and these reductions appeared to occur in an ordered response to dose. There were dose-related decreases in food consumption, compared with control, in the high-and mid-dose groups for the Day 6-9, 9-12, and 12-16 intervals; the most marked effect was observed during the Day 6-9 interval

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:

There were no statistically significant differences between control and treated group mean values for the uterine implantation parameters evaluated. Although there was a slight increase in resorptions in the high dose group as compared with controls, the difference was not statistically significant. There were no significant differences or dose-related trends among the groups for foetal body weight and crown-rump distance.
External examinations revealed only two malformations: one in the high-dose group (tail absent) and one in the mid-dose group (micrognathia). Visceral examinations revealed two foetuses in the high-dose group with dilated lateral cerebral ventricles. Groups exhibited comparably low incidences of dilated ureters/distended renal pelvises which are anatomical variations previously observed in historical control foetuses. Foetuses with skeletal malformations were observed in control, low and high dose groups. Malformed (knobby, wavy, or bent) thoracic ribs were seen in one control foetus and one foetus from the low-dose group. Different types of vertebral malformations were observed in four foetuses (four litters) from the high dose group. Various types of skeletal variations generally in the form of incomplete ossification were observed across all groups in approximately equal frequency. The total number of foetuses (litters) with malformations in the control, low-dose, mid-dose, and high-dose groups was 1(1), 1(1), 1(1), and 6(6), respectively. The number of malformed foetuses relative to the total number of live foetuses, the increased incidence at the high dose was not statistically significant. The incidence of litters with at least one malformed foetus (relative to the total number of litters) and the mean percentage of the litter malformed were statistically significant (p <0.05) in the high-dose group.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Maternal toxicity

Group

0 (control)

0.1 g/kg bw

0.5 g/kg bw

1.0 g/kg bw

Mortality (#)

-

-

-

2

Body weight (g)

Day 9

261.0

256.6

27.3

234.7**

Day 16

306.5

300.0

288.0

275.3**

Day 20

368.2

361.3

352.4

338.1*

Weight change (g)

Day 6-9

+12.2

+10.6

+2.4**

-8.1**

Day 0-20

+151.8

+46.55

+138.6

+126.3**

Food consumption (g/rat)

Day 6-9

76.7

72.8

63.7**

49.3**

Day 9-12

803.7

75.5

66.9**

60.5**

Day 12-16

104.3

101.8

92.4*

88.8**

Litter parameters

Group

0 (control)

0.1 g/kg bw

0.5 g/kg bw

1.0 g/kg bw

Corpora lutea (#)

16.0

15.9

16.1

16.5

Implantations (#)

14.7

14.7

14.9

14.8

Resorptions (#)

0.6

0.9

0.6

1.3

Litter size (#)

14.1

13.7

14.2

13.5

Foetal findings

Group

0 (control)

0.1 g/kg bw

0.5 g/kg bw

1.0 g/kg bw

Foetal weight (g) M/F

3.51 / 3.31

3.55 / 3.45

3.62 / 3.45

3.56 / 3.32

External malformations (#)

-

-

1

1

Micrognathia (#)

-

-

1

-

Tail absent (#)

-

-

-

1

Visceral malformations (#)

-

-

-

2

Dilated cerebral ventricles (#)

-

-

-

2

Skeletal malformations (#)

1

1

-

4

Knobbly/wavy/bent ribs (#)

1

1

-

-

Vertebral malformations (#)

-

-

-

4

Litters with malformed foetuses (#)

1

1

1

6*

Proportion malformed foetuses

0.4%

0.4%

0.4%

2.5%

Applicant's summary and conclusion

Conclusions:
The results of this study indicate that octyl acetate administered to rats by oral gavage during the period of organogenesis produced significant maternal toxicity at dose levels of 0.5and 1.0 g/kg bw. Maternal toxicity was evident in the form of body weight loss or reduced body weight gain and depressed food consumption. There were no statistically significant effects on development noted for foetuses of the 0.1 or 0.5 g/kg bw groups. For the 1.0 g/kg bw group, there was a slightly increased incidence of malformations, although the different individual types of malformations observed did not suggest a characteristic pattern. Consideration of the maternal and developmental effects together suggests that maternal body weight loss and decreased food consumption were associated with an increased incidence of total malformations.

A slightly increased incidence of malformations was seen at the highest (and maternally toxic) dose level of 1000 mg/kg bw/d.

The maternal NOAEL was 100 mg/kg bw/day with evidence of maternal toxicity at the highest dose, 1000 mg/kg bw/day.
THe NOAEL for developmental effects, based on skeletal malformations obseved at the high dose, was 500 mg/kg bw/day.
Executive summary:

Octyl acetate was administered via oral gavage to groups of at least 20 pregnant Sprague-Dawley rats on Gestation Days 6 -15 at dose levels of 0, 0.1, 0.5, and 1.0 g/kg bw/d. The dams were weighed and observed for clinical signs of toxicity during pregnancy, and food consumption was measured. On Gestation Day 20 the dams were sacrificed and the foetuses were examined for external, visceral, and skeletal malformations and variations. The mid-and high dose levels resulted in maternal toxicity as evidenced by reductions in body weight gain and food consumption; mortality and signs of clear toxicity were also o. There were no statistically significant effects on embryo-foetal lethality or foetal growth for any treatment group. The number of litters with at least one malformed foetus and the mean percentage of the litter malformed were significantly (p < 0.05) elevated in the high-dose group only. The results of the present study demonstrate that octyl acetate produced some evidence of developmental toxicity at a dose (1.0 g/kg) that was maternally toxic. Developmental toxicity was not observed at the maternally toxic 0.5 g/kg bw/d dose level or the maternally nontoxic dose level (0.1 g/kg bw/d). Therefore, these data indicate that octyl acetate is not a selective developmental toxicant in the rat.