Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

In a five generation study with embedded continuous breeding study no effects on fertility were observed in 4 generations up to the highest concentration tested (24% in diet; 12000 mg/kg bw/d). The pregnancy rate of F1A rats decreased during 5 successive mating cycles, no pubs were obtained at the highest concentration of the fifth series of litters (F2E). Therefore, the mid dose group (10% in diet; 5000 mg/kg bw/d) was selected as NOAEL. No effects on fertility were observed in additional studies of lower reliability at comparable dose-levels.

Link to relevant study records
Reference
Endpoint:
toxicity to reproduction
Remarks:
other: five generation study with embedded continuous breeding study
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: publication with some shortcomings in documentation (purity of test substance not stated, exposure duration not clearly stated, no statistical evaluation)
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Principles of method if other than guideline:
five generation study with embedded continuous breeding study
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals 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


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



Details on mating procedure:
- M/F ratio per cage: one male/ one female
- Length of cohabitation: 7 days
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
- After 7 days of unsuccessful pairing replacement of first male by another male.
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged individually.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
F0 rats were treated 4 weeks before the mating period. Female rats of the F0 were fed diets containing 1,3-butanediol throughout the mating, gestation and lactating period. After 11 weeks of feeding, 25 males and 25 females from each dosage group of F1A animals were randomly selected and paired to produce the F2 generation (no further information).
Frequency of treatment:
daily
Details on study schedule:
At 1-2 weeks after weaning of the first litters (F1A), each female of the F0 generation was mated with a different male and a second series of litters was produced (F1B).
All animals of the F1B generation were discarded at weaning except for ten males per group, which were reared to sexual maturity and used in a dominant lethal test. Pubs of the F1A were reared to maturity. After 11 weeks of feeding, 25 males and 25 females from each dosage group of F1A animals were randomly selected and paired to produce the F2 generation. Five successive mating cycles were achieved with the F1A rats within a period of 77 weeks (F2A, F2B, F2C, F2D, F2E).
The F2B, F2C, F2D and F2E were examined and sacrificed as part of the continuous breeding phase of the study, while the F2A litter was mated to produce the F3A and F3B litters. The F3A litter was used for the cytogenetic portion of the study and was mated to produce the F4A and F4B litter, which are indicated by the chart in the orginal paper to be part of the cytogenicity study.
The pregnant dams of the F2A litters (producing the F3B) were divided in two groups: 1/4 were allowed to give birth normally and 3/4 were used for teratological examination on day 19 of gestation.
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:
25 rats per sex per dose group in the F0, F1A, F1B, F2A, F3A
Control animals:
yes, plain diet
Positive control:
none
Parental animals: Observations and examinations:
After 4 weeks of feeding of the F0 the respective diets, blood samples were collected from ten rats per sex per group for determination of alkaline phosphatase, glucose, hematocrit, hemoglobin and total and differential leucocyte counts. Urine analysis of the same animals provided measurements of albumin, glucose, ketones, occult blood, pH, specific gravity and microscopic examination. For F1A rats which survived at least 66 weeks, the gonads and pituitary glands were examined microscopically. During the eleventh week of feeding of F1A animals blood and urine samples were collected from ten rats per sex per group and evaluated as mentioned above.

Body weight: yes

Reproductive performance: yes
Litter observations:
viability, mean pub weight at day 4 and 21 post partum
Postmortem examinations (parental animals):
histopathologic examination of the testes or ovaries and pituitary glands of the F1A
Reproductive indices:
fertility (percent matings resulting in pregnancies) and gestation indices (percent pregnancies resulting in litters cast alive)
Offspring viability indices:
- percent pubs cast alive that survived to 4 days
- percent pups alive at 4 days that survived to 21 days
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
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: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Female animals showed no significant abnormal growth rates. Except the P0-Generation, body weight gains of male rats in all four consecutive generations were slightly depressed with an apparent dose relationship (for details see below). The efficiency of food utilization through 10 weeks of post-wening remained constant for all generations of both sexes and was not affected by 1,3-BD treatment.

CLINICAL STUDIES
Hematology, blood chemistry and urinalysis showed no trend associated with treatment for F0, F1, F2 and F3 generation animals

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
During five successive mating cycles of F1A rats, a gradual decrease in the pregnancy rate was seen. Both the number of pregnant females and the fertility index appeared to be dose-related for several series of F2 litters, especially F2D and F2E. For the fifth series of litters, no pups were obtained in the highest-dose group. However, the gestation, viability and lactation indexes, as well as the mean pup body weights at 4 and 21 days showed no significant differences between specific litter series or between control and test groups (excluding high-dose animals of the fifth series of litters). No significant treatment-related differences were noted on histopathologic examination of testes or ovaries and pituitary glands as a possible explanation of the observed reproductive failure during the fifth cycle.
For the other three generations of dams and pups, no significant dose-related trends were observed for the reproduction and lactation parameters, as described above.

Key result
Dose descriptor:
NOAEL
Effect level:
12 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: absence of adverse effects
Remarks on result:
other: dose calculated (24% in diet, food factor 0.05 according to Guidance on Information Requirements R.8)
Key result
Dose descriptor:
NOAEL
Effect level:
12 000 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: absence of effects on reproduction
Remarks on result:
other: dose calculated (24% in diet, food factor 0.05 according to Guidance on Information Requirements R.8)
Key result
Critical effects observed:
no
Lowest effective dose / conc.:
12 000 mg/kg bw/day (nominal)
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
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: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
effects observed, treatment-related
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Female animals showed no significant abnormal growth rates. Body weight gains of adult male rats in four F1 generations were slightly depressed with an apparent dose relationship (for details see bel
ow). The efficiency of food utilization through 10 weeks of post-wening remained constant for all generations of both sexes and was not affected by treatment.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
During five successive mating cycles of F1A rats, a gradual decrease in the pregnancy rate was seen
. Both the number of pregnant females and the fertility index appeared to be dose-related for several
series of F2 litters, especially F2D and F2E. For the fifth series of litters, no pups were obtained in t
he highest-dose group. However, the gestation, viability and lactation indexes, as well as the mean
pup body weights at 4 and 21 days showed no significant differences between specific litter series or
between control and test groups (excluding high-dose animals of the fifth series of litters). No signifi
cant treatment-related differences were noted on histopathologic examination of testes or ovaries and
pituitary glands as a possible explanation of the observed reproductive failure during the fifth cycle.
For the other three generations of dams and pups, no significant dose-related trends were observed
for the reproduction and lactation parameters, as described above.
Key result
Dose descriptor:
LOAEL
Effect level:
12 000 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
Remarks on result:
other: dose calculated (24% in diet, food factor 0.05 according to Guidance on Information Requirements R.8)
Key result
Dose descriptor:
LOAEL
Effect level:
12 000 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
reproductive performance
Remarks on result:
other: dose calculated (24% in diet, food factor 0.05 according to Guidance on Information Requirements R.8)
Key result
Dose descriptor:
NOAEL
Effect level:
5 000 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
Remarks on result:
other: dose calculated (24% in diet, food factor 0.05 according to Guidance on Information Requirements R.8)
Key result
Dose descriptor:
NOAEL
Effect level:
5 000 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
reproductive performance
Remarks on result:
other: dose calculated (24% in diet, food factor 0.05 according to Guidance on Information Requirements R.8)
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
12 000 mg/kg bw/day (nominal)
System:
other: unspecific effects
Organ:
other: body weight gain
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
12 000 mg/kg bw/day (nominal)
System:
female reproductive system
Organ:
other: reduced fertility
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
- no treatment related effects in F1 offspring (details for the effects of P1 generation (F2 litters) are presented above and in the attached document)
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
12 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no developmental toxicity
Remarks on result:
other: maternal dose calculated (24% in diet, food factor 0.05 according to Guidance on Information Requirements R.8)
Key result
Critical effects observed:
no
Lowest effective dose / conc.:
12 000 mg/kg bw/day (nominal)
System:
other: no developmental effects observed
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Key result
Dose descriptor:
NOAEL
Generation:
other: F2A-F2E
Effect level:
12 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no developmental effects
Remarks on result:
other: maternal dose calculated (24% in diet, food factor 0.05 according to Guidance on Information Requirements R.8)
Key result
Critical effects observed:
no
Lowest effective dose / conc.:
12 000 mg/kg bw/day (nominal)
System:
other: no developmental effects observed
Key result
Reproductive effects observed:
yes
Lowest effective dose / conc.:
12 000 mg/kg bw/day
Treatment related:
yes
Relation to other toxic effects:
reproductive effects in the absence of other toxic effects
Dose response relationship:
yes
Relevant for humans:
yes

Body weight gain of male rats is presented in the following table:

 Generation  Dietary level (%)  Weeks  Mean weight gain (g)
 F0  0  23  153
   5  23  149
   10  23  141
   24  23  149
 F1A  77  481
   5  77  429
   10  77  410
   24  77  383
 F1B  0  11  298
   5  11  278
   10  11  263
   24  11  257
 F2A  0  11  305
   5  11  282
   10  11  278
   24  11  272
 F3A  0  9  296
   5  9  270
   10  9  263
   24  9  222
Conclusions:
1,3-butylene glycol did not influence fertility in a five generation study with an embedded continuous breeding study in concentrations up to 10% in the diet (5000 mg/kg bw/d). In the highest concentration tested (24%, 12000 mg/kg bw/d) no offspring in the fifth litter of the F2 generation were produced.
Executive summary:

Twenty five animals of both sexes were fed either control diet or diet supplemented with 1,3-butylene glycol at dose levels of 5, 10 or 24% of the diet (2500, 5000 or 12000 mg/kg bw/d). Treatment with the test item had no influence on reproduction and lactation parameters for four of five generations of dams and pups. The pregnancy rate of F1A rats decreased during five successive mating cycles: no pups were obtained at the high-dose level group of the fifth series of litters (F2E generation). Excluding this group, the viability of F2 generation pups revealed no significant differences between litters or between control and test groups. Body weight gains of male rats in all four generations were slightly depressed with an apparent dose relationship. Body weight gain of females was not affected (Hess et al., 1981).

The study indicates that fertility is not impaired through 1,3 -butylene glycol exposure up to 10% in diet (5000 mg/kg bw/d).

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
5 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
sufficient for evaluation
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Effects on fertility were investigated in rats which received up to 24% 1,3 -butylene glycol in the diet (12000 mg/kg bw/d). No effects were observed in 4 generations of a five generation study. But the pregnancy rate of F1A rats decreased during 5 successive mating cycles and no pubs were obtained at the highest concentration of the fifth series of litters (2FE). Additionally, in this study a dose dependent influence of the test item on the body weight gain of male rats was observed (Hess et al., 1981). The highest dose (24%, 12000 mg/kg bw/d) was therefore regarded as LOAEL and the mid dose (10% in diet, about 5000 mg/kg bw/d) as NOAEL. Instead of some shortcomings in the documentation, this well planned and performed study was judged to be reliable and was selected as key study for this endpoint.

The findings of the key study are supported by the data from two other multigeneration studies, which did not report an impairment of fertility by 1,3 -butylene glycol concentrations of 20% or 24% in diet (10000 or 12000 mg/kg bw/d, respectively; Dymsza and Adams, 1969; Celanese, 1974). However, due to their incomplete documentation these studies were judged to be of lower reliability (RL3). In a multigeneration study in rats which received about 5000 mg 1,3 -BD/kg bw on two days per week no impairment of fertility or reproductive disturbances were observed (Meyer, 1951).

Taking into account all information available for 1,3 -butylene glycol there is only single evidence from the continuous breeding study in rats which revealed adverse effects on fertility in the fifth litter of the F1 in the highest dose group. As the effects were only observed under extreme conditions (continuous breeding) in the highest dose group at a dose which is irrelevant under normal use conditions and far (about ten times) above the limit dose usually used for such kind of studies these data are regarded as irrelevant with respect to a possible classification. This conclusion is supported by the data on reproductive toxicity available for the structurally closely related 1,2- and 1,4 -butylene glycol for which there is also no evidence of adverse effects on fertility (see read-across document in section 13) as well as by data from additional studies on fertility of 1,3 -butylene glycol, which did not observe adverse effects on fertility at comparable dose levels. Therefore, it is concluded that no classification of 1,3 -butylene glycol for effects on fertility is required.

Effects on developmental toxicity

Description of key information
No teratogenic effects were observed in the presence of 1,3-butylene glycol. Fetotoxic effects in the presence of 1,3-butylene glycol were decreased birthweights (NOAEL 4236 mg/kg bw/d), or missing or incomplete ossificated sternebrae (NOAEL 2500 mg/kg bw/d).
Link to relevant study records
Reference
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)
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Principles of method if other than guideline:
study on developmental toxicity
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Wistar
Details on test animals 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




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
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
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
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
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
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined
Changes in number of pregnant:
no effects observed
Details on maternal toxic effects:
no effects observed
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)
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): 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
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)
Key result
Abnormalities:
effects observed, treatment-related
Localisation:
skeletal: sternum
Description (incidence and severity):
missing and incomplete ossification of sternebrae
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

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
  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
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).

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
2 500 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
sufficient for evaluation
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

No teratogenic effects were observed in two studies on developmental toxicity. In a nearly guideline conform test a NOAEL for fetotoxic effects (decreased birthweight) of 4236 mg/kg bw/d was observed (Mankes et al., 1986). Additionally, in this study a number of minor, growth-related structural variations were observed in pups, which were in accordance with the findings of the key study. In the study which was selected as key study (Hess et al., 1981) fetotoxic effects (missing sternebrae, incomplete ossification of sternebrae) were recorded at concentrations of 10% and 24% 1,3-butylene glycol in the diet (5000 and 12000 mg/kg bw/d). The NOAEL was 5% 1,3 -butylene glycol in the diet (2500 mg/kg bw/d).

The effects observed in fetuses, especially the effects on sternebrae, are regarded as substance related and adverse. However, as these effects were only observed at doses which clearly exceed the limit values recommended in current guidelines and as no such effects were observed in investigations with the structural closely related compounds 1,2- and 1,4 -butylene glycol they are not regarded as relevant for classification. Therefore it is concluded that no classification for effects on development is required for 1,3 -butylene glycol.

Mode of Action Analysis / Human Relevance Framework

In the absence of information on species specific effects or metabolism the results are regarded as relevant for humans.

Justification for classification or non-classification

Based on the available data it is concluded that 1,3 -butylene glycol has not to be classified for toxicity on reproduction according to Regulation (EC) No 1272/2008.