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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study, performed under GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report date:
2005

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Allyl alcohol
EC Number:
203-470-7
EC Name:
Allyl alcohol
Cas Number:
107-18-6
Molecular formula:
C3H6O
IUPAC Name:
prop-2-en-1-ol
Details on test material:
- Test substance allyl alcohol was received from Aldrich Chemical Company, Allentown, PA.
- Lot no.: 20906MB
- Purity: > 99%

Test animals

Species:
rat
Strain:
other: Crl:CD (SD)IGS BR
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc, Raleigh, North Carolina.
- Weight at study initiation: minimum of 220 grams
- Housing: All rats were individually housed in stainless steel wire-mesh cages and suspended above cage board. The cage-board was changed three times per week. Rats were paired for mating in the cage of the male. Following confirmation of mating, females were returned to individual suspended wire-mesh cages.
- Diet (e.g. ad libitum): PMI Nutrition international LLC, Certified Rodent LabDiet 5002, ad libitum. A supplemental feed (approximately 50/50 mixture of Hills Prescription Diet canine feed and water) was also used as many animals were not consuming sufficient amounts of food. This supplemental feed was provided to all animals that consumed less than 10 g/day beginning on 23/09/04.
- Water (e.g. ad libitum): Reverse osmosis-purified (on-site) drinking water delivered by an automatic watering system, ad libitum.
- Acclimation period: 13 days.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3C
- Humidity (%): 50 +/-20%
- Air changes (per hr): 10/hour
- Photoperiod (hrs dark / hrs light): 12 hour light / 12 hour dark.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: deionized water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Test substance formulations were prepared by measuring the volume of test substance based on its specific gravity to obtain the correct mg/ml concentration. These volumes were placed into a calibrated container. 70% of the vehicle was added to these calibrated containers and mixed with a magnetic stirrer until uniform.

VEHICLE
- Concentration in vehicle: 2, 7, 10 mg/ml
Control and test substance formulations were given via gastric intubation (using a flexible polypropylene-shafter, silicone bulb-shaped dosing cannula) at a volume of 5 ml/kg
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Gas chromatography was used to verify dose concentrations. Stability in dosing vehicle was similarly confirmed.
Details on mating procedure:
- Impregnation procedure: cohoused 1:1
- Proof of mating: observation of vaginal plug or presence of sperm after vaginal lavage, referred to as day 0 of pregnancy
Duration of treatment / exposure:
Dosed on gestation days 6-19.
Frequency of treatment:
Once daily during gestation days 6-19.
Duration of test:
20 days
No. of animals per sex per dose:
25 animals per dose
Control animals:
yes, concurrent vehicle
Details on study design:
Daily observations of maternal clinical effects. Body weights and food consumption noted at appropriate intervals. 25 mated females/group were dosed once daily during gestation days 6-19. Animals dying during this period are necropsied. Laparohysterectomies carried out on gestation day 20 and gravid uterine weights and liver weights were recorded. Foetal weights and morphological examination and visceral dissection was carried out.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Checked for moribundity and mortality.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Individual detailed clinical observations recorded from gestation days 0 through 20.

BODY WEIGHT: Yes
- Time schedule for examinations: Individual maternal body weights were recorded on gestation days 0 and 6-20 (daily).

FOOD CONSUMPTION: 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: liver, uterus, ovaries

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, and distribution
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Placental examination: Yes
Fetal examinations:
Viable foetuses were examined for external abnormalities, weighed and sexed. The following examinations conducted on each foetus included (and any findings recorded): eyes, palate and external orifices. All non-viable foetuses were examined (only if autolysis was minimal or absent) and in addition the crown-rump length measured, weighed and sexed. For late resorptions, crown-rump measurements and degree of autolysis were noted.

All viable foetuses underwent the following examinations:
- Visceral examination (including heart and major blood vessels)
- Internal examination to determine the sex of each foetus
- Foetal kidneys were examined for development of renal papillae
- The heads from half of the foetuses of each litter underwent a soft-tissue examination, the heads of the other half were examined by mid-coronal slice.
- Developmental variations and malformations were recorded
Statistics:
Implant and foetal data were summarised on both group and proportional litter bases
Indices:
Post implantation losses:
- post implantation loss/litter (dead foetuses + resorptions per group/gravid females per group)
- summation/group (sum of post implantation losses per litter/litters per group)

Foetal abnormalities:
- Viable foetuses affected/litter (viable foetuses affected per litter/viable foetuses per litter)
- Summation/group (sum of viable foetuses affected per litter/litters per group)
Historical control data:
Presented in an Appendix within the final report

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
- In the 35 and 50 mg/kg/day groups, one and six females were found dead during gestation days 9-20.
- Clinical observations in all dose groups include: salivation, poor grooming (due to declining health), extremities cool to the touch, rocking, swaying while walking and hypoactivity. One female from the 35 mg/kg/day group also displayed shallow respiration. Two females from the 50 mg/kg/day group also had decreased defecation on days 8 and 10 of the gestation period.
- Necropsies of animals that had died after dosing at 50 mg/kg/day revealed a distended stomach, dark red stomach contents (with dark red areas on stomach lining). One female from the 35 mg/kg/day group had white and yellow patches on the liver and an entirely resorbed litter. Of the surviving females who underwent a scheduled necropsy, yellow/white areas on the liver, liver adhesions and misshapen/mottled livers were seen. In addition females from the 35 and 50 mg/kg/day group had enlarged spleens and females from the 35 mg/kg/day group had thickened pericardium and/or pericardium adhesions. One female from the 10 mg/kg/day group displayed yellow areas on the liver.
- A statistically significant loss in mean body weight gain was observed during days 6-9 of the gestation period in females of the 35 and 50 mg/kg/day group (when compared to the control group). In addition, mean body weights of the 50 mg/kg/day dose group were also significantly lower than the control group on day 8-11 of the gestation period and continued to be reduced for the remainder of the study.
- Group mean liver weights were reduced at 35 and 50 mg/kg/day compared to controls (5.4% and 11.6% respectively, the latter being statistically significant).
- No significant reduction in gravid uterine weights was observed.
- Food consumption was significantly reduced in the 35 and 50 mg/kg/day dose group.
- A significant increase in mean liver weights was seen in the 35 and 50 mg/kg/day group.

Effect levels (maternal animals)

Dose descriptor:
LOAEL
Effect level:
10 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
- Small numbers of malformations observed in the 10 and 35 mg/kg/day dose groups were considered spontaneous in origin (none seen at 50 mg/kg/day).
- There were no soft-tissue malformations or developmental variations which were related to test substance exposure.
- Dose-related increases in post-implantation loss were observed in females of the 35 and 50 mg/kg/day dose groups.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 10 mg/kg bw/day
Basis for effect level:
other: Postimplantation Losses

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
No teratogenic effects were seen in this study. The maternal LOAEL is 10 mg/kg/day and the developmental NOAEL is 10 mg/kg/day.
Executive summary:

In a developmental toxicity study allyl alcohol was administered to 25 female rats (Crl:CD (SD)IGS BR) per dose by oral gavage at dose levels of 10, 35, 50 mg/kg/day from days 6 through 19 of gestation. At the scheduled necropsy on gestation day 20, 11 of the surviving 24 and 12 of the surviving 19 females in the 35 and 50 mg/kg/day groups, respectively, had test article-related liver findings, including yellow and/or white areas on the liver, liver adhesions and/or misshapen or mottled livers.  Mean liver weights were increased in the 35 and 50 mg/kg/day groups. Mean litter proportions of postimplantation loss were increased in the 35 and 50 mg/kg/day groups, primarily as a result of two dams in each group that had totally resorbed litters.

 

The maternal LOAEL is  10  mg/kg/day, based on mortalities, clinical signs, total litter loss/abortion, food consumption and bodyweight gain reduction plus macroscopic liver effects seen at higher dosages. 

 

The developmental NOAEL is 10 mg/kg/day, based on post-implantation losses seen at higher dosages.

 

The developmental toxicity study in the rat is classified acceptable and satisfies the guideline requirement for a developmental toxicity study (OECD 414) in rats (strain: Crl:CD (SD)IGS BR)