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EC number: 823-920-1 | CAS number: 5341-95-7
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1981
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with national standard methods with acceptable restrictions
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 981
- Report date:
- 1981
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Study on developmental toxicity. Publication with some shortcomings in documentation (purity of test substance not stated, no statistical evaluation for the majority of end points).
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- Butane-1,3-diol
- EC Number:
- 203-529-7
- EC Name:
- Butane-1,3-diol
- Cas Number:
- 107-88-0
- Molecular formula:
- C4H10O2
- IUPAC Name:
- butane-1,3-diol
- Test material form:
- liquid
- Details on test material:
- - Name of test material (as cited in study report): 1,3-butanediol
Test material obtained from Celanese Chemical Company, New York
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: 14-15 weeks
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2°C
- Photoperiod: 12 hrs dark/12 hrs light
Administration / exposure
- Route of administration:
- oral: feed
- Details on exposure:
- SEMIPURIFIED DIET
Casein: 20 %
Refined corn oil: 8%
Salt mix: 4%
Vitamin mix: 1%
Corn starch 33.5%
Dextrose: 33.5%
DIET PREPARATION
- test diets were prepared by substituting 1,3-butanediol for equal amounts by weight of corn starch and dextrose - Analytical verification of doses or concentrations:
- no
- Details on mating procedure:
- Investigation of teratogenicity was performed with part of the second litter of the F3 generation of a multigeneration study.
- Duration of treatment / exposure:
- day 0 to day 19 of gestation, additional to exposure of the parental (F2) and former generations (F0 and F1)
- Frequency of treatment:
- daily
- Duration of test:
- Part of multigeneration study
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 2 500 mg/kg bw/day (nominal)
- Remarks:
- 5% nominal in diet, corresponding to 2500 mg/kg bw/day, calculated with food factor 0.05 according to Guidance on Information Requirements R.8
- Dose / conc.:
- 5 000 mg/kg bw/day (nominal)
- Remarks:
- 10% nominal in diet, corresponding to 5000 mg/kg bw/day, calculated with food factor 0.05 according to Guidance on Information Requirements R.8
- Dose / conc.:
- 12 000 mg/kg bw/day (nominal)
- Remarks:
- 24 % nominal in diet, corresponding to 12000 mg/kg bw/day, calculated with food factor 0.05 according to Guidance on Information Requirements R.8
- No. of animals per sex per dose:
- 14-15 females per dose group
- Control animals:
- yes, plain diet
Examinations
- Maternal examinations:
- - sacrifice at day 19 of gestation
- number of implantations, resorptions, viable and nonviable fetuses - Fetal examinations:
- - data on growth abnormalities, weight and sex of fetuses were recorded
- one third of fetuses were examined for soft tissue abnormalities and remaining fetuses were used for skeletal examinations
- soft tissue examinations: fetuses of each group were fixed in Bouin's solution, sectioned according to the method of Wilson and examined in detail for abnormalities
- skeletal examinations: fetuses were fixed in ethyl alcohol and stained with alizarin red and examined for defects - Statistics:
- Skeletal tissue examinations: evaluated by the approximate chi-square test
- Indices:
- Fertility, gestation, gestation and lactation in remaining pups, not sacrificed for teratological examination
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- not specified
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Neuropathological findings:
- not specified
- Histopathological findings: neoplastic:
- not specified
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
- Details on maternal toxic effects:
- no effects observed
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 12 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Remarks on result:
- other: dose calculated (24% in diet, food factor 0.05 according to Guidance on Information Requirements R.8)
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Skeletal malformations:
- effects observed, treatment-related
- Visceral malformations:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
- viability of pups, number of implantation and resorption sites and the mean fetal weight were unaffected by feeding diets with 1,3-butylene glycol up to 24% (12000 mg/kg bw/d), for details see below
- statistically significant increase of incomplete ossification of sternebrae for the middle and high level fetuses as compared with the control fetuses, and a statistically significant increase of missing sternebrae for high dose fetuses, for details see below
Effect levels (fetuses)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 12 000 mg/kg bw/day (nominal)
- Basis for effect level:
- other: teratogenicity
- Remarks on result:
- other: maternal dose calculated (24% in diet, food factor 0.05 according to Guidance on Information Requirements R.8)
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- 5 000 mg/kg bw/day (nominal)
- Basis for effect level:
- other: fetotoxicity
- Remarks on result:
- other: maternal dose calculated (24% in diet, food factor 0.05 according to Guidance on Information Requirements R.8)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 2 500 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: fetotoxicity
- Remarks on result:
- other: maternal dose calculated (24% in diet, food factor 0.05 according to Guidance on Information Requirements R.8)
Fetal abnormalities
- Key result
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- skeletal: sternum
- Description (incidence and severity):
- missing and incomplete ossification of sternebrae
Overall developmental toxicity
- Key result
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 5 000 mg/kg bw/day
- Treatment related:
- yes
- Relation to maternal toxicity:
- developmental effects in the absence of maternal toxicity effects
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
Any other information on results incl. tables
Conducted as part of reproduction study; no definitive
dose-related teratological findings in either soft or
skeletal tissue. Fetotoxicity(e.g., delayed ossification of
sternebrae) noted at 10% and 24% doses, 5000 and 12000 mg/kg bw/d,
respectively.
Incidence of fetal skeletal abnormalities in F3B generation:
| Dietary level (%) | ||||
| 0 | 5 | 10 | 24 | |
| No. of fetuses examined | 124 | 103 | 120 | 103 |
| Sternebrae | ||||
| Incomplete ossification | 31 | 31 | 48* | 65* |
| Scrambled | 1 | 0 | 0 | 0 |
| Bipartite | 1 | 1 | 0 | 3 |
| Extra | 1 | 0 | 0 | 0 |
| Missing | 10 | 3 | 13 | 37** |
| Ribs | ||||
| More than 13 | 4 | 4 | 1 | 1 |
| Vertebrae | ||||
| Incomplete ossification | 4 | 1 | 1 | 2 |
| Scoliosis | 1 | 0 | 0 | 0 |
| Skull | ||||
| Incomplete closure | 9 | 0 | 3 | 10 |
| Hyoid bone | ||||
| Missing | 2 | 0 | 0 | 2 |
| Reduced | 0 | 0 | 0 | 1 |
*: significantly different from respective control, p </= 0.025
**: significantly different from respective control, p </= 0.01
Resorption and implantation data for F3B generation:
| Mean no. of pups per litter | ||||||
| Dietary level (%) | No. of pregnant females | Viable | Non-viable | Implantations (mean per dam) | Resorptions(mean per dam) | Mean fetal weight (g) |
| 0 | 15 | 11.9 | 0 | 12.5 | 0.6 | 3.5 |
| 5 | 15 | 10.1 | 0 | 10.4 | 0.3 | 4.0 |
| 10 | 14 | 12.1 | 0 | 12.6 | 0.5 | 4.1 |
| 24 | 14 | 10.9 | 0 | 11.4 | 0.5 | 3.4 |
Applicant's summary and conclusion
- Conclusions:
- No teratogenic effects were seen in rats treated with up to 24% (12000 mg/kg bw/d) 1,3-butylene glycol in the diet. But fetotoxic effects occurred in concentrations at or above 10% (5000 mg/kg bw/d) 1,3-butylene glycol in the diet.
- Executive summary:
Teratogenic effects of 1,3-butylene glycol were investigated as part of a multigeneration study in rats receiving 0, 5, 10 and 24% 1,3-butylene glycol in the diet (0, 2500, 5000, 12000 mg/kg bw/d). No conclusive teratogenic effects were seen in pups of the F3B generation at levels up to 12000 mg/kg bw/d 1,3-butylene glycol in the diet. Incomplete sternebral ossification at mid- and high-dose levels and missing sternebrae at high-dose level were noted, probably indicating slight delayed development of fetal skeletal tissue. The NOAEL for fetotoxicity was 2500 mg/kg bw/d of 1,3-butylene glycol in the diet (Hess et al., 1981).
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