Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
11 December 1984 - 14 June 1985
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1985
Report date:
1985

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
The test material was stored outside for 1 month (i.e. not temperature controlled or monitored). The analytical data indicate that the test material was not adversely affected. Other statistics were performed on litters with at least one malformed pup.
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Isooctyl acetate
EC Number:
250-701-2
EC Name:
Isooctyl acetate
Cas Number:
31565-19-2
Molecular formula:
C10H20O2
IUPAC Name:
Acetic acid, isooctyl ester
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Exxon; #2
- Expiration date of the lot/batch: 1 August 1989
- Purity test date: 100% for the purpose of the study

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature



Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: Approximately 9 weeks
- Weight at study initiation: 158-223 g
- Housing: Individual except during the first week of quarantine and during mating. Suspended stainless steel; 10x7x7 inches; no bedding
- Diet (e.g. ad libitum): Certified Rodent Chow (Mash) - ad libitum
- Water (e.g. ad libitum):Automatic watering system - ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-22 °C
- Humidity (%): 40-70 %
- Photoperiod (hrs dark / hrs light): 12 hr light/dark

IN-LIFE DATES: From: 11 December 1984 To: 14 June 1985

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
9 days: GD 6-15
Frequency of treatment:
Daily
Duration of test:
20 days
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
500 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
22
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Gestation day 0, 5, 6, 9, 12, 16 and 20

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: Day 0, 5, 6, 9, 12, 16 and 20

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: Uteri and ovaries

OTHER:
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other:
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: No
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
Statistics:
Body weight, body weight change, food consumption, number of implantation sites, ratio of live fetuses to implantation sites, and ratios of resorptions to
implant sites, total fetuses, resorptions, implants, corpora lutea, total number of dead fetuses, ratio of malformed fetuses per litter, and the ratio of fetuses malformed/total fetuses in litter were analyzed as follows:

A. Bartlett's test of homogeneity of variance was used to determine if the groups have equivalent variances at the ^% level of significance.
1. If the variances were equivalent, the hypothesis that there is no difference in response between the groups was tested using a standard one way analysis of variance. The level of significance for each test is reported. In addition to ANOVA, a linear regression was performed.
To test for a dose response, Duncan's test was performed to determine which treated groups differ from control.

2. If the variances were not equivalent, then a Kruskal-Wallis (non-parametric) test was performed to determine if the treatment effects are equivalent. If there was a difference, a rank sum comparison was used to determine which treatment groups differ from control.

II. Fetal- weights were analyzed, using individual pup weight, by a standard nested analysis of variance with weights nested within dams, and dams nested within groups. If differences in groups- were indicated, the LSD technique was used to determine which treated groups differed from control. Pup sexes were tested separately. All tests were conducted at the 3% level and significance levels reported.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
There were increases in observations of alopecia and anogenital staining in treated animals. There were several animals (5) with red nasal discharge in the 1000 mg/kg group (table 3).
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Ther'e were two unscheduled deaths in the 1000 mg/kg group, animals 410406 and 410410. Both died immediately following dosing on gestation day 12 and 10, respectively. The cause of death could not be determined with certainty.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
There were significant dose related decreases in the body weight on gestation day 12 and 20 (corrected for uterine weight) and for intervals gestation day 6-9, 9-12 and 6-20 at 500 mg/kg and for gestation day 9, 12, 16, 20 and 20 ((C = G weight corrected for weight of the gravid uterus) and for intervals gestation day 6-9, 9-12, 0-20 and 6-20 (C = G weight corrected for weight of the gravid uterus) at 1000 mg/kg (table 1).
Food efficiency:
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
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
The necropsy observations of the mated females were generally unremarkable except for tan to dark red mottling of the lungs, at the following incidences, 4/22, 4/22, 6/22, 8/22 respectively, for the 0.0, 100, 500 and 1000 mg/kg groups. This effect is commonly observed, in this laboratory, in animals euthanized with carbon dioxide.
Neuropathological findings:
not examined

Maternal developmental toxicity

Number of abortions:
not specified
Pre- and post-implantation loss:
not specified
Total litter losses by resorption:
no effects observed
Early or late resorptions:
effects observed, treatment-related
Description (incidence and severity):
Slight increase in resorptions in the high dose group (table 4).
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
effects observed, non-treatment-related
Description (incidence and severity):
Of the 22 animals mated per group, there were 2 not pregnant and one not pregnant in the 100 and 1000 mg/kg groups, respectively.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Basis for effect level:
body weight and weight gain
clinical biochemistry
clinical signs
food consumption and compound intake
mortality

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
There were no significant differences or dose related trends observed.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified
Reduction in number of live offspring:
not specified
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
effects observed, treatment-related
Description (incidence and severity):
Two external malformations were noted - fetus 15 of litter 410509 (500 mg/kg) exhibited apparent micrognathia and fetus 7 of litter 410422 (1000 mg/kg) had no apparent tail.
Description (incidence and severity):
Skeletal evaluations revealed that almost all fetuses exhibited some degree of skeletal variation, generally in the form of some degree of incomplete ossification. All groups exhibited one notable skeletal anomaly, a lack of evidence of one or more vascular foramen of cervical vertebrae #4-#6 (see Table 6). This was not dose related and appeared to be distributed across all test group (table 6).

A total of eight different types of skeletal malformations were observed in this study. Five different types of skeletal malformations were each observed separately, and each was seen in one fetus. These five types were: pterygoid/basisphenoid malformed, sacral vertebral transverse processes malformed, additional area of ossification lateral to transverse process of thoracic ribs, misaligned thoracic centrum, additional thoracic vertebra present.

The other three types of skeletal malformations were seen in more than one fetus. Malformed thoracic ribs (wavy, knobby, bent) were seen in one fetus from Group I and one fetus from Group II. Cervical ribs were seen in one fetus from Group I and four fetuses (single litter) from Group IV. Pubis bones were unossified in one fetus from Group III and three fetuses from Group IV (Table 7).
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Visceral examination revealed no frank malformations. All groups exhibited varying degrees of apparent delayed development of the kidney. This was manifested as dilated renal pelvises or dilated or distended ureter(s); there was apparent hydronephrosis in all groups. These observations did not appear to be related to dose and were distributed among all groups.
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Two 1000 mg/kg group fetuses, from different litters, were found to have dilated lateral cerebral ventricles during the head examinations.

Overall, malformations (external, visceral, head, skeletal) were noted in all groups, 2 fetuses in the 0.0 mg/kg group, 1 fetus in the 100 mg/kg group, 2 fetuses in the 500 mg/kg group and 15 fetuses in the 1000 mg/kg group. there were statistical differences bewteen group I and group IV.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
external malformations
skeletal malformations
visceral malformations
Remarks on result:
not determinable due to adverse toxic effects at highest dose / concentration tested

Fetal abnormalities

Key result
Abnormalities:
effects observed, treatment-related
Localisation:
external: face
external: tail
visceral/soft tissue: central nervous system
Description (incidence and severity):
Two external malformations were noted - fetus 15 of litter 410509 (500 mg/kg) exhibited apparent micrognathia and fetus 7 of litter 410422 (1000 mg/kg) had no apparent tail.
Two 1000 mg/kg group fetuses, from different litters, were found to have dilated lateral cerebral ventricles.

Overall developmental toxicity

Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
1 000 mg/kg bw/day (nominal)
Treatment related:
yes
Relation to maternal toxicity:
developmental effects as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
not specified
Relevant for humans:
not specified

Any other information on results incl. tables

There was no statistically significant effect on the mean number of malformed fetuses per litter. The mean fraction of fetuses with malformations and the incidence of litters with at least one malformed fetus were statistically different among the dose groups.

Applicant's summary and conclusion

Conclusions:
Oxo-octyl acetate was evaluated for its fetotoxic and teratogenic potential when administered orally to Sprague Dawley rats from day 6-15G. There was a slight increase in resorptions and malformations in
the 1000 mg/kg group. These effects were coincident with severe toxicity in the dams, as evidenced by the significant weight loss, depressed food consumption and maternal deaths in this group.

Under the conditions of the experimental methods, Oxo-octyl acetate was maternally toxic and appeared to increase the incidences of resorptions and malformations in Sprague Dawley rats, but only at a dose of 1000 mg/kg that was maternally toxic.
Executive summary:

The test material, Oxo-octyl acetate (MRD-85-505), was administered by oral gavage to mated female Sprague Dawley rats from day 6 to day 15 of gestation (G) to assess its teratogenic potential. Groups of 22 animals were dosed at 0, 100, 500, and 1000 mg/kg. The test animals were weighed and examined externally during the course of the study and food consumption was measured.

 

All mated females were sacrificed on day 20G and examined by gross necropsy. For the first 20 pregnant animals of each dose group (19 for the 1000 mg/kg group), the intact uteri were weighed, with ovaries attached; the uterine contents were then evaluated for live and dead fetuses and early and late resorptions. Corpora lutea were also counted.

 

All live and dead fetuses were weighed, examined externally for gross abnormalities and were measured to determine crown-rump distance. Fetuses were euthanized by CO2 inhalation. Approximately one half of the fetuses from each litter were decapitated; the heads were preserved in Bouin's fixative and subsequently sectioned and examined by the Wilson technique. The viscera of these fetuses were examined by the Staples technique. All fetuses were eviscerated and processed for skeletal staining with Alizarin Red stain. Only those fetuses which had not been decapitated were examined for skeletal malformations and ossification variations.

 

There was a dose related decrease in body weight gain in the day 6-9G interval and for the 9-12G interval. This was reflected in the overall measurements for 0-20G and 6-20C. (C = G weight corrected for weight of the gravid uterus.) There was a dose related decrease in food consumption for the day 6-9G and 9-12G intervals and, to a lesser extent, for the 12-16G intervals.

 

Notable physical observations of the mated females included dose related increased observations of alopecia, rales, red nasal discharge and anogenital staining. Two of the 1000 mg/kg group animals died during gestation (10G and 12G). Notable necropsy observations included non-dose related pathologic observations in the lungs for all groups, but were otherwise not remarkable. Evaluation of uterine contents showed a slight, but not statistically significant, increase in resorptions in the 1000 mg/kg dose group, but no notable differences in other parameters. Fetal evaluations showed no notable differences between treated and control groups for body weight or crown-rump distances. Petal external exams revealed one malformation (apparent micrognathia) in the 500 mg/kg group and one (no tail) in the 1000 mg/kg group. Visceral examinations revealed no frank malformations. Skeletal malformations were slightly elevated for the 1000 mg/kg group. Head sectioning revealed 2 fetuses from 2 litters (1000 mg/kg) with dilated cerebral ventricles, a finding unique to this group.

 

There was no statistically significant effect on the mean number of malformed fetuses per litter. The mean fraction of fetuses with malformations and the incidence of litters with at least one malformed fetus were statistically different among the dose groups.

 

Within the framework of the experimental methods, oxo-octyl acetate appeared to increase the resorptions and structural aberrations of fetuses, but only at a dose which was maternally toxic.