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EC number: 247-891-4 | CAS number: 26658-19-5
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Comparable to guideline study (analytical purity of test substance not specified, number of animals with implantation sites per group was below 16, limited documentation, only organogenesis covered (days 6-18 of gestation)).
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 974
- Report date:
- 1974
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- yes
- Remarks:
- (analytical purity of test substance not specified, number of animals with implantation sites per group was below 16, limited documentation)
- GLP compliance:
- no
- Limit test:
- no
Test material
- Reference substance name:
- D-glucitol
- EC Number:
- 200-061-5
- EC Name:
- D-glucitol
- Cas Number:
- 50-70-4
- Molecular formula:
- C6H14O6
- IUPAC Name:
- D-glucitol
- Details on test material:
- - Name of test material (as cited in study report): FDA 71-31, sorbitol
- Physical state: fine white crystalline material
Constituent 1
Test animals
- Species:
- rabbit
- Strain:
- Dutch
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Weight at study initiation: 2.07-2.51 kg
- Housing: singly
- Diet (ad libitum)
- Water (ad libitum): tap water
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- VEHICLE
- Amount of vehicle (if gavage): 1, 2, 3, 4, 5, 6, 6.4 for the respective 2.5, 16, 74.3, 345, 1600 mg/kg bw/day dose group - Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- - Impregnation procedure: [artificial insemination]
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 hous later, each doe was inseminated artificically with 0.3 mL of diluted semen from a proven donor buck using approximately 20000000 motile sperm according to the procedure described by Vogin et al. (Pharmacologist 11, 282 (1969)). - Duration of treatment / exposure:
- day 6-18 of gestation
- Frequency of treatment:
- daily
- Duration of test:
- 29 days
Doses / concentrations
- Remarks:
- Doses / Concentrations:
16, 74.3, 345, 1600 mg/kg bw/day
Basis:
actual ingested
- No. of animals per sex per dose:
- 13 (control group, 1600 mg/kg bw/day)
10 (2.5 mg/kg 6-aminonicotinamide)
12 (16, 74.3, 345 mg/kg bw/day) - Control animals:
- yes, sham-exposed
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
BODY WEIGHT: Yes
- Time schedule for examinations: on days 0, 6, 12, 18, and 29 of gestation
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- daily observation, but no recording
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29 (caesarean section under surgical anesthesia) - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes - Fetal examinations:
- - External examinations: Yes: [all pups per litter]
- Soft tissue examinations: Yes: [all pups per litter]
- Skeletal examinations: Yes: [all pups per litter], cleared in potassium hydroxide, stained with alizarin red dye and examined)
- Head examinations: Yes: [all pups per litter]
After detailed gross examination for the presence of external congenital abnormalities, the live fetuses of each litter were placed in an incubator for 24 hours for the evalutation of neonatal survival. All survivng pups were then sacrificed and examined for visceral and skeletal abnormalities.
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 600 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:
The following soft tissue abnormalities were found:
Control group: 1 pup with medial rotation of hind limbs.
Positive control group: Several pups of different dams showed treatment-related anopia, medial rotation of hind limbs, harelip, and/or short tails.
74.3 mg/kg bw dose group: 1 pup with microcephaly was observed. This effect was assumed to be a chance finding.
Partial resorptions increased with the dose, but at the highest administered dose a value of 25% was evaluated which was similar to controls (23%). The total number of live fetuses and the average number of live fetuses/dam decreased with the dose. The toxicological relevance is questionable and effects in other species have also to be taken into account.
Effect levels (fetuses)
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 600 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: teratogenicity
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Any other information on results incl. tables
Table 1: Average maternal body weights (in kg)
|
Day |
||||
|
0 |
6 |
12 |
18 |
29 |
Dose group |
|
|
|
|
|
Sham |
2.28 |
2.37 |
2.42 |
2.57 |
2.65 (13) |
Positive Control |
2.51 |
2.58 |
2.64 (10) |
2.8 (8) |
2.71 (10) |
16 mg/kg bw TS |
2.14 |
2.30 |
2.29 |
2.37 |
2.55 (12) |
74.3 mg/kg bw TS |
2.07 |
2.14 |
2.2 |
2.29 |
2.45 (12) |
345 mg/kg bw TS |
2.14 |
2.22 |
2.24 |
2.32 |
2.41 (12) |
1600 mg/kg bw TS |
2.15 |
2.26 |
2.3 |
2.39 |
2.4 (12) |
- TS: test substance
- number of surviving dams in parentheses
Table 2: Litter response (caesarean section data)
Dose group |
Sham |
Positive Control |
16 mg/kg bw TS |
74.3 mg/kg bw TS |
345 mg/kg bw TS |
1600 mg/kg bw TS |
Pregnancies |
|
|
|
|
|
|
Total No. |
13 |
10 |
12 |
12 |
12 |
13 |
Died or aborted (before day 29) |
0 |
0 |
0 |
0 |
0 |
1 |
To term (on day 29) |
13 |
10 |
12 |
12 |
12 |
12 |
Corpora lutea |
|
|
|
|
|
|
Total No. |
152 |
145 |
161 |
195 |
150 |
176 |
Average/dam mated |
10.1 |
13.2 |
10.7 |
13.9 |
10.7 |
11 |
Live litters |
|
|
|
|
|
|
Total No. |
13 |
8 |
12 |
12 |
12 |
9 |
Implant Sites |
|
|
|
|
|
|
Total No. |
85 |
70 |
73 |
80 |
64 |
66 |
Average/dam |
6.54 |
7 |
6.08 |
6.67 |
5.33 |
5.5 |
Resorptions |
|
|
|
|
|
|
Total No. |
5 |
6 |
2 |
1 |
2 |
6 |
Dams with 1 or more sites resorbed |
3 |
3 |
1 |
1 |
2 |
3 |
Dams with all sites resorbed |
-- |
1 |
-- |
-- |
-- |
2 |
% partial resorptions |
23.1 |
30 |
8.33 |
8.33 |
16.7 |
25 |
% complete resorptions |
-- |
10 |
-- |
-- |
-- |
16.7 |
Live fetuses |
|
|
|
|
|
|
Total No. |
80 |
56 |
71 |
79 |
62 |
54 |
Average/dam |
6.15 |
5.6 |
5.92 |
6.58 |
5.17 |
4.5 |
Sex ratio (M/F) |
1.05 |
1 |
1.22 |
1.11 |
1.22 |
1.52 |
Dead Fetuses |
|
|
|
|
|
|
Total No. |
-- |
8 |
-- |
-- |
-- |
6 |
Dams with 1 or more dead |
-- |
1 |
-- |
-- |
-- |
1 |
Dams with all dead |
-- |
1 |
-- |
-- |
-- |
1 |
% partial dead |
-- |
10 |
-- |
-- |
-- |
8.33 |
% all dead |
-- |
10 |
-- |
-- |
-- |
8.33 |
Average fetus weight (g) |
36.7 |
36.1 |
38.9 |
36.8 |
38.2 |
39.4 |
Table 3: Summar of skeletal findings
Dose group |
Sham |
Positive Control |
16 mg/kg bw TS |
74.3 mg/kg bw TS |
345 mg/kg bw TS |
1600 mg/kg bw TS |
Live Fetuses (at term) |
80/13 |
56/8 |
71/12 |
79/12 |
62/12 |
54/9 |
Sternebrae |
|
|
|
|
|
|
Incomplete oss. |
-- |
3/2 |
1/1 |
1/1 |
3/3 |
2/2 |
Scrambled |
-- |
-- |
-- |
-- |
-- |
-- |
Bipartite |
-- |
-- |
-- |
1/1 |
1/1 |
1/1 |
Fused |
1/1 |
1/1 |
1/1 |
2/1 |
1/1 |
1/1 |
Extra |
-- |
2/2 |
1/1 |
3/1 |
1/1 |
1/1 |
Missing |
1/1 |
2/2 |
-- |
1/1 |
-- |
1/1 |
Other |
-- |
-- |
-- |
-- |
-- |
-- |
Ribs |
-- |
-- |
-- |
-- |
-- |
-- |
Incomplete oss. |
-- |
-- |
-- |
-- |
-- |
-- |
Fused/Split |
-- |
7/4 |
-- |
-- |
-- |
-- |
Wavy |
-- |
-- |
-- |
-- |
-- |
-- |
Less than 12 |
-- |
-- |
-- |
-- |
-- |
-- |
More than13 |
-- |
-- |
-- |
-- |
-- |
-- |
Other |
-- |
-- |
-- |
-- |
-- |
-- |
Vertebrae |
-- |
-- |
-- |
-- |
-- |
-- |
Incomplete oss. |
-- |
-- |
-- |
-- |
-- |
-- |
Scrambled |
1/1 |
7/4 |
-- |
-- |
-- |
1/1 |
Fused |
-- |
-- |
-- |
-- |
-- |
-- |
Extra ctrs. oss. |
-- |
-- |
-- |
-- |
-- |
-- |
Scoliosis |
-- |
1/1 |
-- |
-- |
-- |
-- |
Other |
-- |
31/5 |
-- |
-- |
-- |
-- |
Applicant's summary and conclusion
- Conclusions:
- The test substance had no effect on intrauterine development.
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