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Developmental toxicity / teratogenicity

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developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guidelineopen allclose all
according to guideline
other: Toxic Substances Control Act (TSCA) Guidelines (40 CFR Part 798.4700, September 1985, and revised edition May 1987)
equivalent or similar to guideline
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Details on test material:
- Name of test material (as cited in study report): Oleylamine
- Physical state: pale yellow cloudy liquid
- Analytical purity: no data
- Lot/batch No.: ODA-FG 11/27/84
- Stability under test conditions: confirmed for 6h
- Storage condition of test material: room temperature under nitrogen blanket

Test animals

Details on test animals or test system and environmental conditions:
- Source: Charles River, Portage, Michigan
- Age at study initiation: females: 14 weeks, males used for pairing: 9-11 months
- Weight at study initiation: females: 229-316g
- Fasting period before study: no
- Housing: individually in stainless steel wire mesh cages
- Diet (e.g. ad libitum): Purina Certified Rodent Meal #5002 ad lib.
- Water (e.g. ad libitum): deionized tap water ad lib.
- Acclimation period: 19 days

- Temperature (°C): 22°C +/- 3°C
- Humidity (%):55% +/- 15%
- Air changes (per hr): 10-12
- Photoperiod (hrs dark / hrs light): 12h/12h

Administration / exposure

Route of administration:
oral: gavage
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Dose solutions were prepared daily. Appropriate amounts of the test article for each dose group were weighed into volumetric flasks. Corn oil was added to achieve the final concentrations. The flasks were inverted several times to ensure adequate mixture. The dosing solutions were stored under a nitrogen blanket at room temperature.

- Justification for use and choice of vehicle (if other than water): solubility
- Concentration in vehicle: 2-16mg/ml
- Dosage volume: 5ml/kg b.w.
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
On the first day of dosing and near the end of the dosing period, a subsample from each dosing solution, including the control, was taken and analyzed for verification of the test article concentration.The average recovery for all dosing solutions was within 10% of the nominal concentrations.
Details on mating procedure:
- Impregnation procedure: cohoused
- Male rats: resident Sprague Dawley Crl:COBS CD BR VAF/PLUS
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
10 days (from gestation days 6 to 15)
Frequency of treatment:
Duration of test:
Animals were sacrificed on gestation day 20.
Doses / concentrations
Doses / Concentrations:
10, 40, 80mg/kg b.w.
actual ingested
No. of animals per sex per dose:
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on a range-finding study using 50, 100, 150, 250 mg/kg/day.
Mortality occurred in the 100, 150 and 250 mg/kg/day groups. Outward clinical signs of toxicity and body weight losses or reduced weight gain occurred at the 50, 100, 150 and 250 mg/kg/day levels. A dose level of 100 mg/kg/day was considered to be excessive for a high dose level of the definitive teratology study due to the induced mortality. Conversely, 50 mg/kg/day did not produce sufficient maternal toxicity to be considered suitable as a high dose level. Thus, 80 mg/kg/day was selected in anticipation of producing sufficient maternal toxicity. Graduated doses of 40 and 10 mg/kg/day were selected as the mid and low dose levels, respectively. A dose level of 40 mg/kg/day was expected to induce minimal maternal toxicity while the 10 mg/kg/day dose level was selected to determine a no effect level for maternal and developmental toxicity.


Maternal examinations:
- Time schedule: daily
- Cage side observations: check for clinical signs, physical or behavioral abnormalities, mortality

- Time schedule for examinations: gestation days 0, 6, 9, 12, 16, 20

- Measured on gestation days 0, 6, 9, 12, 16, and 20.
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

- Sacrifice on gestation day 20 (2 animals per group were sacrificed after end of treatment on gestation day 15 to determine severity of gastrointestinal irritation.)
- Organs examined: The thoraic, abdominal, and pelvic cavities were opened and examined. The uterus was removed, weighed, and opened. Uteri with no macroscopic evidence of implantations were stained with 10% aqueous ammonium sulfate solution.
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
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data
Historical control data:
Cesarean section data, fetal malformation data, fetal variation data were provided.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Clinical signs:
Rats receiving 40 or 80mg/kg b.w. exhibited rales, salivation, soft stools, diarrhea, few and abnormal colored feces, fecal and /or urine stain, and unkempt appearance. At the highest dose, also emaciation, rough coat, and dark red material around the eyes, nose and or mouth was observed.

Body weight:
Maternal body weights were reduced in high dose animals from gestation day 9 until scheduled sacrifice. In the mid dose, body weights were also reduced, but body weight gain returned to normal or even exceeded control values after the end of treatment. Food consumption was reduced in both groups during the entire treatment period.

No substance related findings.

Effect levels (maternal animals)

Dose descriptor:
Effect level:
10 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Effect levels (fetuses)

Dose descriptor:
Effect level:
>= 80 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: teratogenicity

Fetal abnormalities

not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion