Registration Dossier

Administrative data

Description of key information

Rats received 1,3-butylene glycol in the diet at levels of 1.0, 3.0, and 10%, for two years (500, 1500 and 5000 mg/kg/d). The control group was fed the basal laboratory diet. The physical appearance and behavior of the test rats generally was comparable with those of the corresponding controls. Organ weights and ratios were comparable with the controls. None of the test rats showed any sign of compound related effect.

 

Dogs received 1,3-butylene glycol in the diet at levels of 0.5, 1.0, and 3.0%, for two years (125, 250 and 750 mg/kg/d). The control group was fed the basal laboratory diet. The physical appearance and behavior of the test dogs generally was comparable with those of the corresponding controls. Organ weights and ratios were comparable with the controls. None of the test dogs showed any sign of compound related effect.

 

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 will be without deleterious effect at the highest levels fed to experimental animals, namely, 10% (5000 mg/kg/d) in the diet of rats and 3% (750 mg/kg/d) in the diet of dogs.

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.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: oral
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.
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 5 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: calculated (10% source substance in diet, food factor 0.05; see ECHA Guidance on Information requirements R.8)
Key result
Critical effects observed:
no

Mean Survival Time and Body Weight of Rats receiving Various Dietary Concentrations of (R/S)-1,3-Butanediol

Criterion

Controls

Dietary concentration of 1,3-butanediol

1.0%

3.0%

10%

Male

Female

Male

Female

Male

Female

Male

Female

Mean body weight (g)

Initial

90

81

89

80

91

80

88

80

4 weeks

270

192

266

190

269

192

255

159

20 weeks

511

299

515

293

500

298

524

306

52 weeks

565

347

560

320

511

347

578

370

Survival (a)

Initial

60/60

60/60

30/30

30/30

30/30

30/30

30/30

30/30

4 weeks

60/60

60/60

30/30

30/30

30/30

30/30

30/30

30/30

20 weeks

59/60

60/60

30/30

30/30

30/30

30/30

29/30

30/30

52 weeks

46/60

54/60

27/30

26/30

26/30

27/30

24/30

29/30

104 weeks

12/55

14/55

2/25

3/25

2/25

8/25

8/25

4/25

Mean survival time

(days) (b)

521

521

511

521

513

553

553

587

(a) Survival is expressed as the ratio of the number of animals alive at the indicated time from beginning of the study, divided by the number with which the study commenced. The denominator at 104 weeks is adjusted to reflect the sacrifice of 5 animals at one year.

(b) Adjusted to compensate for interval sacrifice at one year.

Conclusions:
On the basis of this study, 1,3-butanediol is considered to be without deleterious effect at the highest levels fed to experimental animals for 2 years, namely, 10% (5000 mg/kg/d) in the diet of rats. 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 will be without deleterious effect at the highest levels fed to experimental animals, namely, 10% (5000 mg/kg/d) in the diet of rats.
Executive summary:

Rats received 1,3-butylene glycol in the diet at levels of 1.0, 3.0, and 10%, for two years (500, 1500 and 5000 mg/kg/d). The control group was fed the basal laboratory diet. The physical appearance and behavior of the test rats generally was comparable with those of the corresponding controls. Organ weights and ratios were comparable with the controls. None of the test rats showed any sign of compound related effect.

 

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 will be without deleterious effect at the highest levels fed to experimental animals, namely, 10% (5000 mg/kg/d) in the diet of rats.

Endpoint conclusion
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.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

Additional information

Justification for classification or non-classification

Rats received 1,3-butylene glycol in the diet at levels of 1.0, 3.0, and 10%, for two years (500, 1500 and 5000 mg/kg/d). None of the test rats showed any sign of compound effect.

 

Dogs received 1,3-butylene glycol in the diet at levels of 0.5, 1.0, and 3.0%, for two years (125, 250 and 750 mg/kg/d).  None of the test dogs showed any sign of compound effect.

 

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 will be without deleterious effect at the highest levels fed to experimental animals, namely, 10% (5000 mg/kg/d) in the diet of rats and 3% (750 mg/kg/d) in the diet of dogs.

 

Based on the information summarized above, (R)-(-)-butane-1,3-diol does not meet the criteria for classification as a specific target organ toxicity — repeated exposure hazard according to section 3.9. of the European CLP (Regulation (EC) No 1272/2008 as amended).