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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
Not stated
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
This endpoint study record is part of a Weight of Evidence approach comprising of read-across from two analogue source substance studies. The results of the read-across studies agree as to the toxicity to reproduction potential and are sufficient to fulfil the information requirements as further explained in the provided toxicity to reproduction endpoint summary.

Data source

Reference
Reference Type:
publication
Title:
Teratologic Evaluation of FDA 71-89 (Glycerol: Glycerine) in Mice, Rats and Rabbits
Author:
Food and Drug Research Laboratories, Inc.
Year:
1974
Bibliographic source:
FDRL (1974). Teratologic Evaluation of FDA 71-89 (Glycerol: Glycerine) in Mice, Rats and Rabbits. (PB-234 876; Contract Number: FDA-71-260). Prepared by Waverly (NY): Food and Drug Research Laboratories, Inc. (FDRL) for U.S. FDA.

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
Study follows intent of OECD 414 study design. Test material was administered by oral gavage to rats on days 6-15 of gestation. Examination of fetuses: body weight, sex, external abnormalities, visceral (1/3 fetuses) and skeletal (2/3 of fetuses) examination
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Glycerol
EC Number:
200-289-5
EC Name:
Glycerol
Cas Number:
56-81-5
Molecular formula:
C3H8O3
IUPAC Name:
Propane-1,2,3-triol
Details on test material:
GLYCERINE USP grade
Specific details on test material used for the study:
FDA 71-89 (Glycerol; glycerine)
Purity not specified - assumed to meet US FDA requirements

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age: adult
- Mean weight at study initiation (Day 0): 214 - 230 g

Virgin adult female albino rats (Wistar derived stock) were individually housed in mesh bottom cages in temperature- and humidity-controlled quarters with free access to food and fresh tap water. They were mated with young adult males, and observation of the vaginal sperm plug was considered Day 0 of gestation.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Beginning on Day 6 and continuing daily through Day 15 of gestation, the females were dosed by oral intubations. The controls were sham treated with the vehicle (water) at a level equivalent to the group receiving the highest test dose.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Exposure period: daily Days 6 through 15 of gestation inclusive
Frequency of treatment:
Daily
Duration of test:
20 days
Doses / concentrationsopen allclose all
Dose / conc.:
13.1 mg/kg bw/day (actual dose received)
Remarks:
Dosing volume 1 mL/kg bw
Dose / conc.:
60.8 mg/kg bw/day (actual dose received)
Remarks:
Dosing volume 1 mL/kg bw
Dose / conc.:
282 mg/kg bw/day (actual dose received)
Remarks:
Dosing volume 2 mL/kg bw
Dose / conc.:
1 310 mg/kg bw/day (actual dose received)
Remarks:
Dosing volume 6 mL/kg bw
No. of animals per sex per dose:
25 - 28 females/treatment with test item
Control animals:
yes, concurrent vehicle
other: Positive control: Aspirin

Examinations

Maternal examinations:
All animals were observed daily for appearance and behaviour with particular attention to food consumption and weight.
Ovaries and uterine content:
On Day 20 all dams were subjected to Caesarean section under surgical anesthesia, and the number of implantation sites, resorption sites, and live and dead fetuses were recorded. The urogenital tract of each dam was examined in detail for anatomical normality.
Fetal examinations:
The body weights of the live pups were recorded. All fetuses were examined grossly for the presence of external congenital abnormalities. One-third of the fetuses of each litter underwent detailed visceral examinations employing the Wilson technique. The remaining two-thirds were cleared in potassium hydroxide, stained with alizarin red S dye and examined for skeletal defects.
Statistics:
Not indicated

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed

Maternal developmental toxicity

Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
Did not differ from the number occurring spontaneously in the vehicle-treated controls.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
Did not differ from the number occurring spontaneously in the vehicle-treated controls.
Dead fetuses:
no effects observed
Description (incidence and severity):
No dead fetuses were reported in the treatment group or vehicle-treated controls. The positive control (Aspirin) reported dead fetuses.
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Did not differ from the vehicle-treated controls.
Changes in number of pregnant:
no effects observed

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
1 310 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: Did not differ from the vehicle-treated controls.

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
Did not differ from the vehicle-treated controls.
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
Did not differ from the vehicle-treated controls.
External malformations:
no effects observed
Description (incidence and severity):
Did not differ from the number occurring spontaneously in the vehicle-treated controls.
Skeletal malformations:
no effects observed
Description (incidence and severity):
Did not differ from the number occurring spontaneously in the vehicle-treated controls.
Visceral malformations:
no effects observed
Description (incidence and severity):
Did not differ from the number occurring spontaneously in the vehicle-treated controls.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
1 310 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Did not differ from the vehicle-treated controls.

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
There was no effect on developmental toxicity of offspring of female rats dosed with glycerol up to 1310 mg/kg bw/day.
Executive summary:

This study was designed to establish the no-observed-effect level (NOEL) for developmental toxicity of glycerol administered by gavage in rats. Dams were administered 0, 13.1, 60.8, 282, or 1310 mg/kg bw/day glycerol on Gestation Days 6 – 15. On Day 20 all dams were subjected to Caesarean section and the numbers of implantation sites, resorption sites, and live and dead fetuses were recorded. The fetuses were examined grossly for the presence of external congenital abnormalities. One-third of fetuses underwent detailed visceral examinations and the remaining two-thirds were examined for skeletal defects.

There was no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the vehicle-treated controls. Under conditions of this study, there was no effect on developmental toxicity of offspring of female rats dosed with glycerol up to 1310 mg/kg bw/day.