Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Twenty-five animals of both sexes were fed either control diet or diet supplemented with (R/S)-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 all but one group of dams and pups. The pregnancy rate of F1A rats decreased during five successive mating cycles (likely secondary to parental toxicity and stress): no pups were obtained at the high-dose level group of the fifth series of litters (F2E generation). However, the added stress of a highly ketogenic, semi-synthetic diet may have contributed significantly to this effect. A significant increase in the concentration of ketone bodies in blood, urine and liver tissues was noted in rats fed diets contain (R/S)-1,3-butanediol at the levels of 20 or 25% (study referenced in journal article). Therefore, physiological stress may be associated with increased ingestion of (R/S)-1,3-butanediol.

 

Excluding the F2E 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.

 

Documentation of this well-planned study is insufficient: Exposure duration is not clearly stated, purity of the test item is not given. Examination of the parental generation is insufficient; test results were not evaluated statistically. Despite these shortcomings the study was judged to be reliable with restrictions as it indicates that fertility is not impaired through (R/S)-1,3 -butylene glycol exposure up to 10% in diet (5000 mg/kg bw/d).

 

Values generated on the source substance will represent a very similar or slightly worse case than the target substance. It is predicted that (R)-(-)-1,3-butanediol will not influence fertility in concentrations up to 10% in the diet (5000 mg/kg bw/d).

HYPOTHESIS FOR THE ANALOGUE APPROACH

Data for butane-1,3-diol (CAS No. 107-88-0) was used to address the toxicological data requirements for (R)-(-)-butane-1,3-diol (CAS No. 6290-03-5) in an analogue read-across approach. The basis for this read-across approach is the extreme structural similarity of the source and target substances, in that the source substance is a racemic mixture of a pair of enantiomers, whereas the target substance is solely the R-enantiomer of that source pair. Two compounds that are enantiomers of each other have the same physical properties, except for the direction in which they rotate polarized light and how they interact with different optical isomers of other compounds (ECHA, 2008). Passive absorption of a substance into a test species and distribution through its tissues are governed by the physical-chemical properties of the substance, particularly its molecular size, log P, and water solubility (ECHA, 2014), and are therefore expected to be exactly the same for both enantiomers. The R-enantiomer half of the source substance and all of the target substance have been shown to metabolise in a mammalian system to a physiological ketone body, whereas the S-enantiomer of that ketone body derived from the other half of the source substance has been shown to metabolise into a compound that is not naturally present, but which can still be utilized by a less direct pathway (Desrochers et al., 1992). On the premise that a less direct metabolic pathway must be more energy-expensive, and therefore may be more likely to perturb the system and potentially produce an adverse effect, toxicity data on the source substance will represent a very similar or slightly worse case than, and provide a sound basis for a slightly conservative assessment of, the toxicity of the target substance.

Link to relevant study records
Reference
Endpoint:
multi-generation reproductive toxicity
Remarks:
four generation study with embedded continuous breeding study
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Data for butane-1,3-diol (CAS No. 107-88-0) was used to address the toxicological data requirements for (R)-(-)-butane-1,3-diol (CAS No. 6290-03-5) in an analogue read-across approach. The basis for this read-across approach is the extreme structural similarity of the source and target substances, in that the source substance is a racemic mixture of a pair of enantiomers, whereas the target substance is solely the R-enantiomer of that source pair. Two compounds that are enantiomers of each other have the same physical properties, except for the direction in which they rotate polarized light and how they interact with different optical isomers of other compounds (ECHA, 2008). Passive absorption of a substance into a test species and distribution through its tissues are governed by the physical-chemical properties of the substance, particularly its molecular size, log P, and water solubility (ECHA, 2014), and are therefore expected to be exactly the same for both enantiomers. The R-enantiomer half of the source substance and all of the target substance have been shown to metabolise in a mammalian system to a physiological ketone body, whereas the S-enantiomer of that ketone body derived from the other half of the source substance has been shown to metabolise into a compound that is not naturally present, but which can still be utilized by a less direct pathway (Desrochers et al., 1992). On the premise that a less direct metabolic pathway must be more energy-expensive, and therefore may be more likely to perturb the system and potentially produce an adverse effect, toxicity data on the source substance will represent a very similar or slightly worse case than, and provide a sound basis for a slightly conservative assessment of, the toxicity of the target substance.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Target Chemical: (R)-(-)-butane-1,3-diol (228-532-0; 6290-03-5)
Source Chemical: butane-1,3-diol (203-529-7; 107-88-0)
For further details refer to attached Justification For Read-Across Of Toxicity Data

The target substance is known to be of high purity (≥99 % w/w), so the low levels of impurities it could contain are not expected to substantially affect its physical-chemical properties. The purities of the samples of source material that were tested are not specifically known, but it is assumed that they would not have been sufficiently impure as to substantially affect the study results. On this basis, the applicability of the data on the source substance to the target substance is not expected to be compromised by the presence of impurities in either substance.

3. ANALOGUE APPROACH JUSTIFICATION
The basis for this read-across approach is the extreme structural similarity of the source and target substances. Specifically, the source substance is a racemic mixture of a pair of enantiomers, whereas the target substance is solely the R-enantiomer of that source pair. The source substance is therefore nominally comprised 50% of the target substance itself (the R-enantiomer), and 50% of its mirror image (the S-enantiomer), which differs from the target substance only in the chirality of one carbon atom. The selection of this source substance is justified on the basis that there is no other source substance that could possess a greater degree of structural similarity to the target substance.

Enantiomers are two stereoisomers that are related to each other by a reflection: they are mirror images of each other. Every stereocentre in one has the opposite configuration in the other. Two compounds that are enantiomers of each other have the same physical properties, except for the direction in which they rotate polarized light and how they interact with different optical isomers of other compounds (ECHA, 2008). Passive absorption of a substance into a test species and distribution through its tissues are governed by the physical-chemical properties of the substance, particularly its molecular size, log P, and water solubility (ECHA, 2014), and are therefore expected to be exactly the same for both enantiomers.

In a mammalian system, both enantiomers have been shown to be taken up by the liver and converted to their respective 3-hydroxybutyrate (beta-hydroxybutyrate; BHB) at identical rates. The target substance and one half of the source substance are converted into R-BHB, and the other half of the source substance is converted into S-BHB. R-BHB is a physiological ketone body, whereas S-BHB is not naturally present, but can still be utilized by a less direct pathway (Desrochers et al., 1992). On the premise that a less direct metabolic pathway is more energy-expensive, and may therefore be more likely to perturb the system and potentially produce an adverse effect, toxicity data on the source substance will represent a very similar or slightly worse case than, and provide a sound basis for a slightly conservative assessment of, the toxicity of the target substance.

4. CONCLUSION
Values generated on the source substance will represent a very similar or slightly worse case than the target substance

REFERENCES
Desrochers S, David F, Garneau M, Jetté M, Brunengraber H (1992). Metabolism of R- and S-1,3-butanediol in perfused livers from meal-fed and starved rats. Biochem J 285:647-653.

ECHA (2008). Guidance on information requirements and chemical safety assessment. Chapter R.6: QSARs and grouping of chemicals. May 2008. Available at: https://echa.europa.eu/documents/10162/13632/information_requirements_r6_en.pdf

ECHA (2014). Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. Volume 2.0, November 2014. Available at: https://echa.europa.eu/documents/10162/13632/information_requirements_r7c_en.pdf/e2e23a98-adb2-4573-b450-cc0dfa7988e5
Reason / purpose:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across: supporting information
Related information:
Composition 1
Reason / purpose:
read-across: supporting information
Related information:
Composition 1
Test material information:
Composition 1
Specific details on test material used for the study:
(R)-(-)-Butane-1,3-diol value is read-across from supporting (R/S)-butane-1,3-diol (203-529-7; 107-88-0) data.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Female animals showed no significant abnormal growth rates. Body weight gains of male rats in all four generations were slightly depressed with an apparent dose relationship. The efficiency of food utilization through 10 weeks of post-weaning remained constant for all generations of both sexes and was not affected by (R/S)-1,3-butanediol treatment.

No significant treatment-related differences were noted on histopathologic examination of testes or ovaries and pituitary glands.

Values generated on the source substance will represent a very similar or slightly worse case than the target substance.
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 12 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No treatment related effects in F0 generation
Remarks on result:
other:
Remarks:
24% in diet, food factor 0.05 according to Guidance on Information Requirements R.8; Values generated on the source substance will represent a very similar or slightly worse case than the target substance.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Female animals showed no significant abnormal growth rates. Body weight gains of male rats in all four generations were slightly depressed with an apparent dose relationship. The efficiency of food utilization through 10 weeks of post-weaning remained constant for all generations of both sexes and was not affected by (R/S)-1,3-butanediol 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 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.

Values generated on the source substance will represent a very similar or slightly worse case than the target substance
Key result
Dose descriptor:
LOAEL
Generation:
other: F1A, F1B
Effect level:
ca. 12 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
Remarks on result:
other:
Remarks:
all generations (F1A, F1B, F2A, F3A) except F0; Values generated on the source substance will represent a very similar or slightly worse case than the target substance
Key result
Dose descriptor:
NOAEL
Generation:
other: F1A, F1B
Effect level:
ca. 12 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: no treatment related effects
Remarks on result:
other:
Remarks:
calculated (24% in diet, food factor 0.05 according to Guidance on Information Requirements R.8); Values generated on the source substance will represent a very similar or slightly worse case than the target substance
Key result
Dose descriptor:
NOAEL
Generation:
other: F1A, F1B
Effect level:
ca. 5 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
Remarks on result:
other:
Remarks:
calculated (10% in diet, food factor 0.05 according to Guidance on Information Requirements R.8); Values generated on the source substance will represent a very similar or slightly worse case than the target substance
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Female animals showed no significant abnormal growth rates. Body weight gains of male rats in all four generations were slightly depressed with an apparent dose relationship. The efficiency of food utilization through 10 weeks of post-weaning remained constant for all generations of both sexes and was not affected by (R/S)-1,3-butanediol 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 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.

Values generated on the source substance will represent a very similar or slightly worse case than the target substance
Key result
Dose descriptor:
LOAEL
Generation:
other: F2A, F3A
Effect level:
ca. 12 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
Remarks on result:
other:
Remarks:
calculated (24% in diet, food factor 0.05 according to Guidance on Information Requirements R.8); Values generated on the source substance will represent a very similar or slightly worse case than the target substance
Key result
Dose descriptor:
LOAEL
Generation:
other: F2E
Effect level:
ca. 12 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: no pregnant females to produce the F2E generation; reduced number of females in former litters of the F2 generation
Remarks on result:
other:
Remarks:
calculated (24% in diet, food factor 0.05 according to Guidance on Information Requirements R.8); Values generated on the source substance will represent a very similar or slightly worse case than the target substance
Key result
Dose descriptor:
NOAEL
Generation:
other: FE2
Effect level:
ca. 5 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: no pregnant females to produce the F2E generation; reduced number of females in former litters of the F2 generation
Remarks on result:
other:
Remarks:
calculated (10% in diet, food factor 0.05 according to Guidance on Information Requirements R.8); Values generated on the source substance will represent a very similar or slightly worse case than the target substance
Key result
Dose descriptor:
NOAEL
Generation:
other: F2A, F3A
Effect level:
5 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
Remarks on result:
other:
Remarks:
(10% in diet, food factor 0.05 according to Guidance on Information Requirements R.8); Values generated on the source substance will represent a very similar or slightly worse case than the target substance
Reproductive effects observed:
not specified

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

0

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

 

Values generated on the source substance will represent a very similar or slightly worse case than the target substance

Conclusions:
(R/S)-1,3-butylene glycol did not influence fertility in a four 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 (likely secondary to parental toxicity and stress). Values generated on the source substance will represent a very similar or slightly worse case than the target substance. It is predicted that (R)-(-)-1,3-butanediol will not influence fertility in concentrations up to 10% in the diet (5000 mg/kg bw/d).
Executive summary:

Twenty five animals of both sexes were fed either control diet or diet supplemented with (R/S)-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 all but one group of dams and pups. The pregnancy rate of F1A rats decreased during five successive mating cycles (likely secondary to parental toxicity and stress): no pups were obtained at the high-dose level group of the fifth series of litters (F2E generation). However, the added stress of a highly ketogenic, semi-synthetic diet may have contributed significantly to this effect. A significant increase in the concentration of ketone bodies in blood, urine and liver tissues was noted in rats fed diets contain (R/S)-1,3-butanediol at the levels of 20 or 25% (study referenced in journal article). Therefore, physiological stress may be associated with increased ingestion of (R/S) 1,3-butanediol.

Excluding the F2E 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.

 

Documentation of this well-planned study is insufficient: Exposure duration is not clearly stated, purity of the test item is not given. Examination of the parental generation is insufficient (e.g.no histopathological examination of sexual organs), test results were not evaluated statistically. Despite these shortcomings the study was judged to be reliable with restrictions as it indicates that fertility is not impaired through (R/S)-1,3 -butylene glycol exposure up to 10% in diet (5000 mg/kg bw/d).

Values generated on the source substance will represent a very similar or slightly worse case than the target substance. It is predicted that (R)-(-)-1,3-butanediol will not influence fertility in concentrations up to 10% in the diet (5000 mg/kg bw/d).

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
5 000 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
The available information meets the tonnage driven data requirements of REACH, and there is acceptable reliability and consistency across the different studies.

Effects on developmental toxicity

Description of key information

Teratogenic effects of (R/S)-1,3-butylene glycol were investigated as part of a multi-generation study in rats receiving 0, 5, 10 and 24% (R/S)-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 (R/S)-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 (R/S)-1,3-butylene glycol in the diet. Values generated on the source substance will represent a very similar or slightly worse case than the target substance. The NOAEL for fetotoxicity of (R)-1,3-butylene glycol in the diet is predicted to be approximately 2500 mg/kg bw/d.

HYPOTHESIS FOR THE ANALOGUE APPROACH

Data for butane-1,3-diol (CAS No. 107-88-0) was used to address the toxicological data requirements for (R)-(-)-butane-1,3-diol (CAS No. 6290-03-5) in an analogue read-across approach. The basis for this read-across approach is the extreme structural similarity of the source and target substances, in that the source substance is a racemic mixture of a pair of enantiomers, whereas the target substance is solely the R-enantiomer of that source pair. Two compounds that are enantiomers of each other have the same physical properties, except for the direction in which they rotate polarized light and how they interact with different optical isomers of other compounds (ECHA, 2008). Passive absorption of a substance into a test species and distribution through its tissues are governed by the physical-chemical properties of the substance, particularly its molecular size, log P, and water solubility (ECHA, 2014), and are therefore expected to be exactly the same for both enantiomers. The R-enantiomer half of the source substance and all of the target substance have been shown to metabolise in a mammalian system to a physiological ketone body, whereas the S-enantiomer of that ketone body derived from the other half of the source substance has been shown to metabolise into a compound that is not naturally present, but which can still be utilized by a less direct pathway (Desrochers et al., 1992). On the premise that a less direct metabolic pathway must be more energy-expensive, and therefore may be more likely to perturb the system and potentially produce an adverse effect, toxicity data on the source substance will represent a very similar or slightly worse case than, and provide a sound basis for a slightly conservative assessment of, the toxicity of the target substance.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Data for butane-1,3-diol (CAS No. 107-88-0) was used to address the toxicological data requirements for (R)-(-)-butane-1,3-diol (CAS No. 6290-03-5) in an analogue read-across approach. The basis for this read-across approach is the extreme structural similarity of the source and target substances, in that the source substance is a racemic mixture of a pair of enantiomers, whereas the target substance is solely the R-enantiomer of that source pair. Two compounds that are enantiomers of each other have the same physical properties, except for the direction in which they rotate polarized light and how they interact with different optical isomers of other compounds (ECHA, 2008). Passive absorption of a substance into a test species and distribution through its tissues are governed by the physical-chemical properties of the substance, particularly its molecular size, log P, and water solubility (ECHA, 2014), and are therefore expected to be exactly the same for both enantiomers. The R-enantiomer half of the source substance and all of the target substance have been shown to metabolise in a mammalian system to a physiological ketone body, whereas the S-enantiomer of that ketone body derived from the other half of the source substance has been shown to metabolise into a compound that is not naturally present, but which can still be utilized by a less direct pathway (Desrochers et al., 1992). On the premise that a less direct metabolic pathway must be more energy-expensive, and therefore may be more likely to perturb the system and potentially produce an adverse effect, toxicity data on the source substance will represent a very similar or slightly worse case than, and provide a sound basis for a slightly conservative assessment of, the toxicity of the target substance.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Target Chemical: (R)-(-)-butane-1,3-diol (228-532-0; 6290-03-5)
Source Chemical: butane-1,3-diol (203-529-7; 107-88-0)
For further details refer to attached Justification For Read-Across Of Toxicity Data

The target substance is known to be of high purity (≥99 % w/w), so the low levels of impurities it could contain are not expected to substantially affect its physical-chemical properties. The purities of the samples of source material that were tested are not specifically known, but it is assumed that they would not have been sufficiently impure as to substantially affect the study results. On this basis, the applicability of the data on the source substance to the target substance is not expected to be compromised by the presence of impurities in either substance.

3. ANALOGUE APPROACH JUSTIFICATION
The basis for this read-across approach is the extreme structural similarity of the source and target substances. Specifically, the source substance is a racemic mixture of a pair of enantiomers, whereas the target substance is solely the R-enantiomer of that source pair. The source substance is therefore nominally comprised 50% of the target substance itself (the R-enantiomer), and 50% of its mirror image (the S-enantiomer), which differs from the target substance only in the chirality of one carbon atom. The selection of this source substance is justified on the basis that there is no other source substance that could possess a greater degree of structural similarity to the target substance.

Enantiomers are two stereoisomers that are related to each other by a reflection: they are mirror images of each other. Every stereocentre in one has the opposite configuration in the other. Two compounds that are enantiomers of each other have the same physical properties, except for the direction in which they rotate polarized light and how they interact with different optical isomers of other compounds (ECHA, 2008). Passive absorption of a substance into a test species and distribution through its tissues are governed by the physical-chemical properties of the substance, particularly its molecular size, log P, and water solubility (ECHA, 2014), and are therefore expected to be exactly the same for both enantiomers.

In a mammalian system, both enantiomers have been shown to be taken up by the liver and converted to their respective 3-hydroxybutyrate (beta-hydroxybutyrate; BHB) at identical rates. The target substance and one half of the source substance are converted into R-BHB, and the other half of the source substance is converted into S-BHB. R-BHB is a physiological ketone body, whereas S-BHB is not naturally present, but can still be utilized by a less direct pathway (Desrochers et al., 1992). On the premise that a less direct metabolic pathway is more energy-expensive, and may therefore be more likely to perturb the system and potentially produce an adverse effect, toxicity data on the source substance will represent a very similar or slightly worse case than, and provide a sound basis for a slightly conservative assessment of, the toxicity of the target substance.

4. CONCLUSION
Values generated on the source substance will represent a very similar or slightly worse case than the target substance

REFERENCES
Desrochers S, David F, Garneau M, Jetté M, Brunengraber H (1992). Metabolism of R- and S-1,3-butanediol in perfused livers from meal-fed and starved rats. Biochem J 285:647-653.

ECHA (2008). Guidance on information requirements and chemical safety assessment. Chapter R.6: QSARs and grouping of chemicals. May 2008. Available at: https://echa.europa.eu/documents/10162/13632/information_requirements_r6_en.pdf

ECHA (2014). Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. Volume 2.0, November 2014. Available at: https://echa.europa.eu/documents/10162/13632/information_requirements_r7c_en.pdf/e2e23a98-adb2-4573-b450-cc0dfa7988e5
Reason / purpose:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across: supporting information
Related information:
Composition 1
Reason / purpose:
read-across: supporting information
Related information:
Composition 1
Principles of method if other than guideline:
study on teratogenicity
GLP compliance:
not specified
Limit test:
no
Test material information:
Composition 1
Specific details on test material used for the study:
(R)-(-)-Butane-1,3-diol value is read-across from supporting (R/S)-butane-1,3-diol (203-529-7; 107-88-0) data.
Key result
Dose descriptor:
NOAEL
Effect level:
12 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: No treatment related effects
Remarks on result:
other: calculated (24% in diet, food factor 0.05 according to Guidance on Information Requirements R.8)
Remarks:
Values generated on the source substance will represent a very similar or slightly worse case than the target substance.
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 12 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: teratogenicity
Remarks on result:
other: calculated (24% in diet, food factor 0.05 according to Guidance on Informati on Requirements R.8)
Remarks:
Values generated on the source substance will represent a very similar or slightly worse case than the target substance.
Key result
Dose descriptor:
LOAEL
Effect level:
ca. 5 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: fetotoxicity
Remarks on result:
other: calculated (10% in diet, food factor 0.05 according to Guidance on Informati on Requirements R.8)
Remarks:
Values generated on the source substance will represent a very similar or slightly worse case than the target substance.
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 2 500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: fetotoxicity
Remarks on result:
other: calculated (5% in diet, food factor 0.05 according to Guidance on Information Requirements R.8)
Remarks:
Values generated on the source substance will represent a very similar or slightly worse case than the target substance.
Abnormalities:
not specified
Developmental effects observed:
not specified

Values generated on the source substance will represent a very similar or slightly worse case than the target substance.

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

 

Conclusions:
No teratogenic effects were seen in rats treated with up to 24% (12000 mg/kg bw/d) (R/S)1,3-butylene glycol in the diet. But fetotoxic effects occurred in concentrations at or above 10% (5000 mg/kg bw/d) (R/S)-1,3-butylene glycol in the diet. Values generated on the source substance will represent a very similar or slightly worse case than the target substance.
Executive summary:

Teratogenic effects of (R/S)-1,3-butylene glycol were investigated as part of a multi-generation study in rats receiving 0, 5, 10 and 24% (R/S)-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 (R/S)-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 (likely secondary to parental toxicity and stress). The NOAEL for fetotoxicity was 2500 mg/kg bw/d of (R/S)-1,3-butylene glycol in the diet. Values generated on the source substance will represent a very similar or slightly worse case than the target substance. The NOAEL for fetotoxicity of (R)-1,3-butylene glycol in the diet is predicted to be approximately 2500 mg/kg bw/d.

 

The study was judged to be reliable with some minor restrictions due to some shortcomings of the study (e.g. not according to guideline, missing data on test substance purity, no data on sex distribution of the offspring reported although this endpoint was recorded according to the method section).

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
2 500 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
The available information meets the tonnage driven data requirements of REACH, and there is acceptable reliability and consistency across the different studies.

Justification for classification or non-classification

Reproductive toxicity of (R/S)-1,3-butylene glycol was investigated as part of a multi-generation study in rats receiving 0, 5, 10 and 24% (R/S)-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 (R/S)-1,3-butylene glycol in the diet. The NOAEL for fetotoxicity was 2500 mg/kg bw/d of (R/S)-1,3-butylene glycol in the diet. Treatment with the test item had no influence on reproduction and lactation parameters for all but one group 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). However, the added stress of a highly ketogenic, semi-synthetic diet may have contributed significantly to this effect. A significant increase in the concentration of ketone bodies in blood, urine and liver tissues was noted in rats fed diets contain (R/S)-1,3-butanediol at the levels of 20 or 25% (study referenced in journal article). Therefore, physiological stress may be associated with increased ingestion of (R/S) 1,3-butanediol.

 

Values generated on the source substance will represent a very similar or slightly worse case than the target substance.  Therefore, it is predicted that the target substance (R)-(-)-1,3-butanediol would not have shown any sign of compound effect (reproductive toxicity).

 

Based on the information summarized above, (R)-(-)-butane-1,3-diol does not meet the criteria for classification as a reproductive toxicity hazard according to sections 3.7. of the European CLP (Regulation (EC) No 1272/2008 as amended).