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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
Study period:
1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Detailed publication with some shortcomings in documentation (purity of test substance not stated, no statistical evaluation for the majority of end points)

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1981
Report date:
1981

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
study on developmental toxicity
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
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

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 / concentrations
Remarks:
0, 5, 10 and 24 % nominal in diet, corresponding to 0, 2500, 5000 and 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:
yes

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).