Diisopropyl adipate

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / 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 peer reviewed journal.

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:

other: OECD 414 (PreNatal Developmental Toxicity Screening Test)

Principles of method if other than guideline:

The above experiment 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.

GLP compliance:

not specified

Justification for study design:

No Data Available

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

Test material form:

liquid

Details on test material:

SOURCE OF TEST MATERIAL
- Identification: Di isopropyl adipate (CAS No. - 6938-94-9)
- Source of test material: Sustainability Support Services (Europe) AB
- Appearance: Colourless Liquid
- Batch No.of test material: Lot 1/05
- Manufactured date: Not provided
- Expiration date of the lot/batch: Not provided
- Purity: 99.55%

RADIOLABELLING INFORMATION (not applicable)
- Radiochemical purity: N/A
- Specific activity: N/A
- Locations of the label: N/A
- Expiration date of radiochemical substance: N/A

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Stored in cool place. Kept container tightly closed in a dry and well- ventilated place.
- Stability under test conditions: No data available
- Solubility and stability of the test substance in the solvent/vehicle: No data available
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: No data available

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: No data available
- Preliminary purification step (if any): No data available
- Final dilution of a dissolved solid, stock liquid or gel: No data available
- Final preparation of a solid: No data available

FORM AS APPLIED IN THE TEST (if different from that of starting material): No data available

OTHER SPECIFICS:
- Safety precautions: Avoided contact with skin and eyes. Avoided inhalation of vapour or mist. Normal measures for preventive fire protection were taken. Aprons, caps, mask, gloves and goggles were used to ensure the health and safety of the personnel.
- Disposal: The remaining unused test item was disposed as per internal SOPs of sa-FORD and the same was documented in the raw data.

Specific details on test material used for the study:

- Appearance: Colourless Liquid
- Molcular weight: 230.302 g/mol
- Substance type: Organic

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

No Data Available

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: No Data Available
- Age at study initiation: No Data Available
- Weight at study initiation: Females: 175-225 g.
- Fasting period before study: No Data Available
- Housing: The test animals were housed in the individual cages.
- Use of restrainers for preventing ingestion (if dermal): no
- Diet (e.g. ad libitum): Food was provided ad libitum.
- Water (e.g. ad libitum): Fresh tap was provide ad libitum.
- Acclimation period: No Data Available

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

Administration / exposure

Route of administration:

intraperitoneal

Vehicle:

unchanged (no vehicle)

Details on exposure:

Details on exposure
PREPARATION OF DOSING SOLUTIONS: The test chemical was administered to the animals in at four dosage levels: one-thirtieth, one-tenth, one-fifth, and one-third of their acute LD-50 values.

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

VEHICLE
- Justification for use and choice of vehicle (if other than water): No Data Available
- Concentration in vehicle: No Data Available
- Amount of vehicle (if gavage): No Data Available
- Lot/batch no. (if required): No Data Available
- Purity: No Data Available

Details on mating procedure:

Details of mating
- M/F ratio per cage: (1:5) Five female rats were housed with one male.
- Length of cohabitation: Mating was conducted on 13 days.
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy: 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.
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility. No Data Available
- Further matings after two unsuccessful attempts: [no / yes (explain)] No Data Available
- After successful mating each pregnant female was caged (how): The female rats were moved to individual cages, where they were kept undisturbed except for specified injections.
- Any other deviations from standard protocol: No Data Available

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No Data Available

Duration of treatment / exposure:

No Data Available

Frequency of treatment:

No Data Available

Details on study schedule:

No Data Available

Doses / concentrations

Remarks:

0.1262, 0.3786, 0.7572 and 1.2619 ml/kg bw intraperitoneally

No. of animals per sex per dose:

There were 31 groups, each composed of five female rats.

Control animals:

not specified

Details on study design:

No Data Available

Positive control:

No Data Available

Examinations

Parental animals: Observations and examinations:

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.

Oestrous cyclicity (parental animals):

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, metestrus, or diestrus) was determined according to cell types found in the vaginal smear.

Sperm parameters (parental animals):

No Data Available

Litter observations:

The following parameters of adverse effects were investigated:
(a) embryonic-fetal toxicity, as evidenced by resorptions and stillbirths,
(b) gross (external) malformations of fetuses,
(c) skeletal malformations.
(d) visceral abnormalities, and
(e) fetal size (weight).

In all evaluations. both viable and nonviable fetuses were considered

Postmortem examinations (parental animals):

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.

Postmortem examinations (offspring):

(b) gross (external) malformations of fetuses,
(c) skeletal malformations.
(d) visceral abnormalities were observed.

Statistics:

No Data Available

Reproductive indices:

Implantation Index, Resorption Index, Uterine Index.

Offspring viability indices:

Fetal viability index.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

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

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: 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)

The number of resorptions observed in the animals were sporadic and thus were not considered as treatment related.

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

1.262 other: ml/Kg

Based on:

test mat.

Sex:

female

Basis for effect level:

gross pathology

reproductive performance

Remarks on result:

other: Not Specified

Target system / organ toxicity (P0)

Critical effects observed:

not specified

System:

other: Not Specified

Results: F1 generation

General toxicity (F1)

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

no mortality observed

Description (incidence and severity):

No mortality was observed at any treated dose levels of the tes chemical.

Body weight and weight changes:

no effects observed

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

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

No significant effects on gross abnormalities except some sporadic cases of skeletal and visceral malformations were observed in the fetus treated with the test chemical.

Histopathological findings:

not specified

Other effects:

not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):

not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:

not specified

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

1.127 other: ml/Kg

Based on:

test mat.

Sex:

male/female

Basis for effect level:

viability

mortality

body weight and weight gain

gross pathology

Remarks on result:

other: Not Specified

Target system / organ toxicity (F1)

Critical effects observed:

not specified

System:

other: Not Specified

Overall reproductive toxicity

Reproductive effects observed:

not specified

Treatment related:

not specified

Applicant's summary and conclusion

Conclusions:

Based on all the observations and results, it was concluded that the NOAEL for the test chemical was 1.269 ml/Kg bw.

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 0.1262, 0.3786, 0.7572 and 1.2619 ml/kg bw. 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 following parameters of adverse effects were investigated, embryonic-fetal toxicity, as evidenced by resorptions and stillbirths, gross (external) malformations of fetuses, skeletal malformations, visceral abnormalities, and fetal size (weight). In all evaluations. both viable and nonviable fetuses were considered. After treatment it was observed that, only one resorption site was ohserved in the test chemical group. No other gross pathological effects were observed in the test chemical treated group. No effects on the estrous cyclicity of the maternal animals was observed. Also, no effects on the reproductive parameters was observed. In fetal examinations, no effects on the body weights and the viability of the fetus was observed. Also, no significant effects on gross abnormalities except some sporadic cases of skeletal and visceral malformations were observed in the fetus treated with the test chemical.  Thus, based on all the observations and results, it was concluded that the NOAEL for the test chemical was 1.269 ml/Kg bw.