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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
1989
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Test procedure according to national guidelines and standards (TSCA Guidelines) including GLP
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1989
Report Date:
1989

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: EPA regulations, TSCA (40 CFR Part 798.4700, September 1985, and revised edition May 1987)
GLP compliance:
yes
Remarks:
Springborn Laboratories, Inc., Mammalian Toxicology Division, 553 North Broadway, Spencerville, Ohio 45887, USA
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Oleylamine

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazelton Research Products, Inc., Denver, Pennsylvania, USA
- Age at study initiation: ~6 months
- Weight at study initiation: 3.0 to 5.0 kg
- Housing: Animals were housed individually during acclimation and while on study in suspended stainless steel cages.
- Diet (ad libitum): Purina Certified Rabbit Chow #5322
- Water (ad libitum): deionized tap water
- Acclimation period: 34 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): ~21
- Humidity (%): 55 ± 15
- Photoperiod (hrs dark / hrs light): 12 / 12


IN-LIFE DATES: From: 1989-08-22 To: 1989-09-22

Administration / exposure

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

Analytical verification of doses or concentrations:
yes
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.
Details on mating procedure:
Artificial insemination:
Semen was collected from New Zealand White males. Semen will be collected in an artificial vagina and evaluated for volume, motility and concentration. Prior to insemination, the semen will be diluted with 0.9% physiological saline and maintained in a water bath at 37 °C during the insemination procedure. Approximately 0.5 mL of the diluted semen will be introduced in the doe´s vagina. Semen from one male will be used to inseminate an equal number of females in each group every day. Immediately following the insemination, the female rabbits will receive human chorionic gonadotropin 100 IU/doe administered intravenously (via marginal ear vein).
Duration of treatment / exposure:
from gestation day 6 through 18
Frequency of treatment:
single daily doses
Duration of test:
13 days
No. of animals per sex per dose:
22
Control animals:
yes, concurrent vehicle
Details on study design:
Range-finding study: 5, 25, 50, 100, 150 mg/kg/day. Mortality occurred in the 50, 100 and 150 mg/kg/day groups. Outward clinical signs of toxicity were observed at the 5 mg/kg/day level and above. Body weight losses occurred in the 25, 50, 100, 150 mg/kg/day groups. A dose level of 50 mg/kg/day was considered to be excessive for a high dose level of the definitive teratology study due to the induced mortality. Conversely, 25 mg/kg/day did not produce sufficient maternal toxicity to be considered suitable as a high dose level. Thus, 30 mg/kg/day was selected in anticipation of producing sufficient maternal toxicity. Graduated doses of 10 and 3 mg/kg/day were selected as mid and low dose levels, respectively. A dose level of 10 mg/kg/day was expected to induce minimal maternal toxicity while the 3 mg/kg/day dose level was selected to determine a no-effect level of maternal and developmental toxicity.

Examinations

Maternal examinations:
Animals were examined daily. Clinical signs of toxicity including physical or behavioral abnormalities were recorded. Mortality checks were performedtwice daily (morning and afternoon). During the dosing period, animals were observed for toxic effects between on-half hour and two hours postdosing.

Body weights were recorded on GD 0, 6, 9, 12, 15, 19, 24 and 29. BWC was recorded for GD 0-6. 6-9, 9-12, 12-15, 15-19, 19-24, 24-29, 6-19 and 0-29.

Food consumption was measured daily during gestation. Food consumption was calculated as g/kg/day and g/animal/day for the following gestationintervals: 0-6, 6-9, 9-12, 12-15, 15-19, 19-24, 0-29 and 6-19.
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:
Fetal morphological examination: external (each fetus), visceral (all viable and nonviable fetus was dissected and examined), skeletal (each fetus will be eviscerated, skinned and fixed) abnormalities
Statistics:
Analyses were performed by a digital VAX 11/730 computer. Two-tailed tests were utilized unless otherwise indicated. Group comparisons were performed using Dunnett´s test. Count data were analyzed using Chi-square Test for fetal sex ratios, Mann-Whitney U-Test for resorptions, and Fisher´sExact Test for the number of fetal variations and malformations using the litter as the experimental unit.
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:
Treatment-related adult female mortalities occurred in the 30 mg/kg/day group. Clinical signs of toxicity and irritation of the lips and chin were observed at the 10 and 30 mg/kg/day levels. Salient clinical signs included labored breathing and rales. Dose-dependent body weight losses or reduced weight gain, along with a corresponding reduction in food consumption occurred during the treatment period in the 10 and 30 mg/kg/day groups. Gross necropsy evaluation of the gastrointestinal tracts from females sacrificed on GD 18 revealed no other irritative effects.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
3 mg/kg bw/day (nominal)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
> 30 mg/kg bw/day (nominal)
Basis for effect level:
other: developmental toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
No treatment-related changes were apparent at any level tested concerning necropsy observations, cesarean section data or fetal morphological examinations.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
> 30 mg/kg bw/day (nominal)
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The oral administration of 10 and 30 mg/kg/day of Oleylamine to pregnant New Zealand White rabbits induced frank, dose dependent maternal toxicity exhibited by clinical signs, body weight losses and reduced food consumption. Treatment-related mortalities occurred only in the 30 mg/kg/day group. A dosage level of 3 mg/kg/day was determined to be a no-effect level for maternal toxicity. Oleylamine was neither developmentally toxic nor teratogenic at dosage levels of 3, 10, 30 mg/kg/day. A NOAEL for maternal toxicity of 3 mg/kg body weight per day and a NOAEL for developmental toxicity of > =30 mg/kg body weight per day is derived from this study.
Executive summary:

A guideline conform teratology study in New Zealand rabbits with Oleylamine as test substance has been performed. Prior to initiation of the main study, a range-finding study at dose levels of 5, 25, 50, 100 and 150 mg/kg bw/d had been conducted. During the range finding-study, treatment-related deaths had occurred in the 50, 100, and 150 mg/kg bw/d groups. Outward clinical signs of toxicity were observed at the 5 mg/kg bw/d dose level and above. Body weight losses occurred in the 25, 50, 100 and 150 mg/kg bw/d dose groups. A dose level of 50 mg/kg bw/d was considered to be excessive for a high dose level for the main study. Conversely, 25 mg/kg bw/d did not produce sufficient maternal toxicity to be considered suitable as a high dose level. Thus 30 mg/kg bw/d as top dose level was selected for the main study in anticipation of producing sufficient maternal toxicity.

In the main study groups of 22 inseminated females were treated orally (gavage) with dosages of 3, 10, and 30 mg/kg bw/d or with the vehicle (Mazola corn oil) during gestation days 6 to 18. During the study animals were examined daily. Any clinical signs of toxicity including physical or behavioural abnormalities were recorded. Individual body weights were recorded on gestation days 0, 6, 9, 12, 1, 19, 24 and 29. Individual food consumption was measured daily. Two animals in each group were selected to be sacrificed and necropsied after treatment on gestation day 18 to determine the appearance and severity of gastrointestinal tract irritation. On gestation day 29 caesarean section was performed on all surviving animals. The numbers of viable fetuses, early and late resorptions as well as the number of corpora lutea were recorded. Fetuses were examined for external, visceral and skeletal abnormalities.

As result of the study, treatment-related mortality occurred as two females died in the 30 mg/kg bw/d group, one on gestation day 9 and the other on gestation day 25. In addition, one female each at the 3, 10, and 30 mg/kg bw/d levels aborted prior to scheduled sacrifice. Outward clinical signs of toxicity were observed at the 10 and 30 mg/kg bw/d levels. In the 10 mg/kg bw/d dose group, rales and laboured breathing were noted. Additional findings in the 30 mg/kg bw/d level included few or no feces and emaciation. Irritation of the mouth area also developed in females in this group. The irritation was characterised by swollen raised white areas, scab-like lesions and /or sloughing of the skin of the lips and the chin. No other signs of treatment-related gastrointestinal irritation or internal changes were observed at gross necropsy at gestation days 18 and 29. Dose-dependent body weight loss (gestation days 6-9, respectively 6-19) or reduced weight gain, along with a corresponding reduction in food consumption occurred during the treatment period in the 10 and 30 mg/kg bw/d groups. Net body weight gain (adjusted for gravid uterine weight) was also lower. Following cessation of treatment, weight gain increased in the 30 mg/kg bw/d group. No such effects were observed in the dose group treated with 3 mg/kg bw/d. Caesarean section data obtained from the treated groups did not reveal any meaningful differences (concerning number of corpora lutea, implantation sites, viable fetuses, implantation loss, fetal sex and fetal weight) when compared with the controls. Fetal evaluations of type and frequency of malformations and variations did not reveal any indications for a treatment related teratogenic effect. In summary, oral administration of octadecenylamine to pregnant rabbits produced dose-dependent maternal toxicity in the 10 and 30 mg/kg bw/d dose groups. No indications of an embryotoxic, fetotoxic or teratogenic effect was observed at any tested level. A NOAEL/maternal toxicity of 3 mg/kg bw/d and a NOAEL/developmental toxicity of>30 mg/kg bw/d can be derived from the study.