Reaction product of 1-chloro-2,3-expoxypropane, sodium hydroxide, sodium carbonate and water

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

Not stated

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: This study was conducted prior to GLP and test guidelines, but sufficient data is available for interpretation of results

Data source

Reference

Reference Type:

publication

Title:

Teratological evaluation of glycerin in mice, rats and rabbits.

Author:

N.T.I.S. US Department of Commerce.

Year:

1974

Bibliographic source:

Report No. PB-234876

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Study follows intent of OECD 414 study design. Test material was administered by oral gavage to rabbits on days 6-18 of gestation. Examination of fetuses: body weight, sex, external abnormalities, visceral (1/3 of fetuses) and skeletal (2/3 of fetuses) examination

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Glycerol

EC Number:

200-289-5

EC Name:

Glycerol

Cas Number:

56-81-5

Molecular formula:

C3H8O3

IUPAC Name:

glycerol

Test material form:

not specified

Details on test material:

FDA 71-89. purity not specified but since the material is identified as FDA, it probably met FDA requirements.

Test animals

Species:

rabbit

Strain:

Dutch

Details on test animals or test system and environmental conditions:

TEST ORGANISMS
- Age: adult
- Mean weight at study initiation (Day 0: 2.09-2.38 kg
- Number of animals: 15-20 females/treatment

Virgin, adult, Dutch-belted female rabbits were individually housed in mesh bottom cages in temperature and humidity controlled quarters with free access to food and fresh tap-water.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on exposure:

ADMINISTRATION / EXPOSURE
- Test duration: 20 days
- Exposure period: day 6-18 of gestation inclusive
- Definition of day 0: observation of vaginal sperm plug
- Route of administration: oral (gavage)
- Doses: 11.8, 54.8, 254.5 and 1180 mg/kg bw (dosing volume <6 mL/kg)
- Vehicle: water

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data.

Details on mating procedure:

On Day 0, each doe was given an injection of 0.4 ml of human chorionic gonadotropin (400 IU) via the marginal ear vein. Three hours later, each doe was inseminated artificially with 0.3 ml of diluted semen from a proven donor buck using approximately 20 x 10 (6) motile sperm according to the procedure described by Vogin et al (Pharmacologist 11, 282 (1969).

Duration of treatment / exposure:

Exposure period: day 6-18 of gestation inclusive

Frequency of treatment:

Daily

Duration of test:

Test material was administered on days 6-18 of gestation. Animals were sacrificed on day 29 of gestation

No. of animals per sex per dose:

15-20 females/treatment

Control animals:

yes, concurrent vehicle

other: positive control: 6-aminonicotinamide

Details on study design:

PARAMETERS ASSESSED DURING STUDY:
- Mortality/clinical observations: daily
- Body weight: on day 0, 6, 11, 15 and 20
- Food consumption: daily
- Examination of uterine content: no. of implantation sites, resorptions and live and dead fetuses
- Examination of fetuses: body weight, sex, external abnormalities, visceral (1/3 of fetuses) and skeletal (2/3 of fetuses) examination

ORGANS EXAMINED AT NECROPSY: urogenital tract

Examinations

Maternal examinations:

PARAMETERS ASSESSED DURING STUDY:
- Mortality/clinical observations: daily
- Body weight: on day 0, 6, 12, 18 and 29
- Food consumption: daily

Ovaries and uterine content:

Examination of uterine content: no. of corpora lutea, implantation sites, resorptions and live and dead fetuses

Fetal examinations:

Examination of fetuses: body weight, sex, external abnormalities on day 29, neonatal survival (live fetuses of each litter were placed in an incubator for 24 hours for the evaluation of neonatal survival), visceral (by dissection) and skeletal examination (fetuses were cleared in potassium hydroxide, stained with alizarin red S dye and examined for skeletal effects) on day 30

Statistics:

Not indicated

Indices:

No additional information available.

Historical control data:

No additional information available.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
MATERNAL TOXIC EFFECTS BY DOSE LEVEL:
- Mortality: 1 animal at 54.8 mg/kg bw, 2 at 254.5 mg/kg bw and 1 at 1180 mg/kg bw
- Body weight: no treatment related effects, significant decrease only at 254.5 mg/kg bw (14%) compared to controls.
- Food consumption: no data
- Clinical signs: not reported
- Number pregnant per dose level: 14/15, 12/15, 10/18, 13/20 and 13/15 for 0, 11.8, 54.8, 254.5 and 1180 mg/kg bw
- Number aborting: 2 at 254.5 mg/kg bw
- Number of corpora lutea: 9.7, 11.7, 5.6, 8.2 and 11.2 for controls and at 11.8, 54.8, 254.5 and 1180 mg/kg bw
- Number of implantations: 6.1, 5.1, 5.4, 7.3 and 6.4 for controls and at 11.8, 54.8, 254.5 and 1180 mg/kg bw
- Number of resorptions (no of dams involved): 5, 2, 4, 2 and 6 for controls and at 11.8, 54.8, 254.5 and 1180 mg/kg bw

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

1 180 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

Details on embryotoxic / teratogenic effects:
FETAL DATA:
- Litter size: No treatment related effects
- Fetal weight: decreased(14%) at 254.5 mg/kg bw compared to controls.
- Number viable: 5.1, 4.7, 4.8, 5.9 and 5.5 per litter for 0, 11.8, 54.8, 254.5 and 1180 mg/kg bw mg/kg bw
- Sex ratio: no treatment related effects
- External abnormalities: none reported
- Visceral abnormalities: no treatment related effects
- Skeletal abnormalities: delayed ossification increased at 254.5 mg/kg bw (without relationship to treatment)

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

1 180 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: No effects were observed in offspring of dams dosed with glycerin.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Table 1 Partial listing of skeletal findings in rabbits

Dose (mg/kg)	control	6 -AN	11.8	54.8	254.5	1180
live fetuses examined (at term)	71/13	49/10	56/12	43/8	65/9	72/12
sternebrae incomplete ossification	1/1	ND	1/1	1/1	8/5	6/2

number of fetuses affected/number of litters affected

6 -AN = 6 -aminonicotinamide

Applicant's summary and conclusion

Conclusions:

There was no effect on developmental toxicity of offspring of female rabbits dosed with glycerin.

Executive summary:

A developmental toxicity study was conducted in rabbits. There was no effect on developmental toxicity of offspring of female rabbits dosed with glycerin at doses as high as 1180 mg/kg/day.