Diisopropyl adipate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from a publication.

Data source

Reference

Reference Type:

publication

Title:

Embryonic-Fetal Toxicity and Teratogenic Effects of Adipic Acid Esters in Rats

Author:

Singh, A .R ., Lawrence, W .H ., and Autian, J

Year:

1973

Bibliographic source:

Journal of Pharmaceutical Sciences. VoL 62, No. 10 October 1973:1596-1600

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:

Embryonic-fetal toxicity and teratogenic study of the test chemical in rats

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Diisopropyl adipate

EC Number:

230-072-0

EC Name:

Diisopropyl adipate

Cas Number:

6938-94-9

Molecular formula:

C12H22O4

IUPAC Name:

1,6-bis(propan-2-yl) hexanedioate

Details on test material:

- Name of test material (as cited in study report):dipropyl adipate
- Molecular formula (if other than submission substance):C12H22O4
- Molecular weight (if other than submission substance): 230.302 g/mol
- Substance type:organic
- Physical state: liquid

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Sprague-Dawley Inc., Madison, WI
- Age at study initiation: No data available
- Weight at study initiation: 175-225 g
- Fasting period before study:No data available
- Housing: Females were housed individually after confirmed pregnancy.
- Diet (e.g. ad libitum): Purina laboratory chow, ad libitum
- Water (e.g. ad libitum): Tap water, ad libitum
- Acclimation period: Female rats were selected for experimentation only after observation of at least two complete 4- or 5-day estrus cycles.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-27°C
- Humidity (%): No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available

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

Administration / exposure

Route of administration:

intraperitoneal

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No Data Available

Details on mating procedure:

- Impregnation procedure: Cohoused
- If cohoused: Yes
- M/F ratio per cage: 1 male/5 females
- Length of cohabitation: Until confirmed pregnancy
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.N/A
- Further matings after two unsuccessful attempts: N/A
- Verification of same strain and source of both sexes: [yes / no (explain)]
- Proof of pregnancy: Presence of sperm in the vaginal smear, being Day 0 of gestation.
- After successful mating each pregnant female was caged (how): Individually and was kept undisturbed except for specified injections.
- Any other deviations from standard protocol: N/A

Duration of treatment / exposure:

Upto day 20 of gestation

Frequency of treatment:

On 5th, 10th, and 15th days of gestation

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 119.89, 359.67, 719.34 or 1198.805 mg/kg
Basis:

No. of animals per sex per dose:

Blunt needle (injection): 5 pregnant female rats
Distilled water: : 5 pregnant female rats
Normal saline: : 5 pregnant female rats
Cottonseed oil: : 5 pregnant female rats
Dipropyl adipate :
119. 89 mg/Kg: 5 pregnant female rats
359.67 mg/Kg: 5 pregnant female rats
719.34 mg/Kg: 5 pregnant female rats
1198.805 mg/Kg: 5 pregnant female rats

Control animals:

other: Blunt end needle

Details on study design:

No Data Available

Examinations

Maternal examinations:

No Data Available

Ovaries and uterine content:

On the 20th day of gestation, 1 day prior to expected parturition, the rats were sacrificed by ether inhalation. The uterine horns and ovaries were surgically exposed to permit counting and recording of the numbers of corpora lutea, resorption sites, and viable and dead fetuses.

Fetal examinations:

Body weight : Mean fetal weights in the mid- and high-dose groups were significantly lower than in the control group.
Gross pathology: There was a significant increase of gross fetal abnormalities was noted in the mid and high dosed groups as compared to control.
Skeletal abnormalities: SSkeletal abnormalities occurred at only at higher dose i.e 5.3% .
Visceral abnormalities No changes were observed

Statistics:

Acute LD50 values, 95% confidence limits, and slopes were calculated by Cornfield and Mantel’s modification of Karber’s method.

Indices:

No data available

Historical control data:

No data available

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Only one resorption site was ohserved in the test chemical group. No other gross pathological effects were observed in the test chemical treated group.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Details on results:

Only one resorption site was ohserved in the test chemical group. No other gross pathological effects were observed in the test chemical treated group.

Maternal developmental toxicity

Number of abortions:

not specified

Pre- and post-implantation loss:

not specified

Total litter losses by resorption:

effects observed, non-treatment-related

Description (incidence and severity):

Only one resorption site was ohserved in the test chemical group. No other gross pathological effects were observed in the test chemical treated group.

Early or late resorptions:

effects observed, non-treatment-related

Description (incidence and severity):

Only one resorption site was ohserved in the test chemical group. No other gross pathological effects were observed in the test chemical treated group.

Dead fetuses:

not specified

Changes in pregnancy duration:

not specified

Changes in number of pregnant:

not specified

Other effects:

not specified

Details on maternal toxic effects:

Only one resorption site was ohserved in the test chemical group. No other gross pathological effects were observed in the test chemical treated group.

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

119.89 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

early or late resorptions

gross pathology

maternal abnormalities

total litter losses by resorption

Remarks on result:

other: Not Specified

Maternal abnormalities

Abnormalities:

not specified

Results (fetuses)

Fetal body weight changes:

no effects observed

Reduction in number of live offspring:

not specified

Changes in sex ratio:

not specified

Changes in litter size and weights:

not specified

Changes in postnatal survival:

not specified

External malformations:

effects observed, non-treatment-related

Description (incidence and severity):

High cases of external malformations were observed at 719.34 or 1198.805 mg/kg.

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

High cases of skeletal malformations were observed at 719.34 or 1198.805 mg/kg.

Visceral malformations:

effects observed, non-treatment-related

Description (incidence and severity):

High cases of Visceral malformations were observed at 719.34 or 1198.805 mg/kg.

Other effects:

not specified

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Effect levels (fetuses)

1

Dose descriptor:

NOAEL

Effect level:

119.89 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: teratogenicity

2

Dose descriptor:

LOAEL

Effect level:

359.67 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Treatment related:

not specified

Applicant's summary and conclusion

Conclusions:

The no observed adverse effect level (NOAEL) value of the test chemical was found to be 119.89 mg/kg bw/day.

Executive summary:

A study was performed to evaluate and assess the effect of the test chemical on the maternal animals and on the fetus of the treated maternal animals. In this study, the test chemical was administered to the test animals via the intraperitoneal route at doses of 0, 119.89, 359.67, 719.34 or 1198.805 mg/kg/day on Day 5, 10 and 15 days of gestation with the test chemical. Female rats were selected for experimentation only after observation of at least two complete 4- or 5-day estrus cycles. Occurrence of estrus was determined by daily vaginal smears, obtained by introducing 0.2 ml. of fresh, clean tap water into the vagina with a smooth. clean. sterile medicine dropper, withdrawing a part of the liquid, and transferring it to a clean slide. The slide was examined microscopically while fresh, and the stage of estrus (proestrus, metstrus, or diestrus) was determined according to cell types found in the vaginal smear. Test animals were adult, virgin female, Sprague-Dawley rats, weighing 175-225 g. Adult, male rats of this strain were utilized as the “stud pool.” Five female rats were housed with one male in a large cage at room temperature (22-27“) with foods and fresh tap water provided ad libitum. The onset of gestation was established by the presence of sperm in the vaginal smear and was designated as Day 0. with the following day being Day 1 of the gestation period. At this time, the female rats were moved to individual cages, where they were kept undisturbed except for specified injections. There were 31 groups, each composed of five female rats. All treatments were administered by intraperitoneal injection on the 5th, 10th, and 15th days of gestation. On the 20th day of gestation, 1 day prior to expected parturition, the rats were sacrificed by ether inhalation. The uterine horns and ovaries were surgically exposed to permit counting and recording of the numbers of corpora lutea, resorption sites, and viable and dead fetuses.The parameters resorptions, number of corpora lutea, fetal survival, mean fetal weight and gross, skeletal and visceral abnormalities were analysed. No increased level of fetal deaths was noted and no effect of teratogenicity was observed. Slight increase in gross and skeletal abnormalities was observed at concentrations above 119.89 mg/kg/day of the test chemical. The no observed adverse effect level (NOAEL) value of diisopropyl adipate was found at dose level of 119.89 mg/kg/day since at this dose no effects were observed on rat fetuses.