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Administrative data

Description of key information

The acute oral toxicity data generated on the source substance [(R/S)-butane-1,3-diol (203-529-7; 107-88-0)] will represent a very similar or slightly worse case than the target substance [(R)-(-)-Butane-1,3-diol]. Non-fasted rats were given single oral doses. The LD50 (observation period: 14 days) of (R/S)-butane-1,3-diol was 22800 mg/kg bw. The acute oral toxicity of (R)-(-)-Butane-1,3-diol is predicted to be LD50 of approximately 22800 mg/kg bw.

 

The acute inhalation toxicity data generated on the source substance [(R/S)-butane-1,3-diol (203-529-7; 107-88-0)] will represent a very similar or slightly worse case than the target substance [(R)-(-)-Butane-1,3-diol]. No lethal effects were observed in rats after a single 8-hours exposure to a (R/S)-butane-1,3-diol saturated vapour. The acute inhalation toxicity of (R)-(-)-Butane-1,3-diol is predicted to be 8-hour LC50 greater than the saturated vapour concentration.

 

The work of this group pre-dates range finding toxicity guidelines and provided much of the basis for their development. Their results are cited by many subsequent authoritative review bodies and are often found in SIDS and SIAR documents via secondary references. Therefore, these results are deemed reliable.

 

Testing by the dermal route does not need to be conducted as the substance does not meet the criteria for classification as acute toxicity or STOT SE by the oral route and no systemic effects after dermal exposure are predicted on the basis of non-testing approaches (e.g. read-across).

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

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute 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
Sex:
male
Dose descriptor:
LD50
Effect level:
ca. 22 800 mg/kg bw
Based on:
test mat.
Interpretation of results:
GHS criteria not met
Conclusions:
The acute oral toxicity data generated on the source substance [(R/S)-butane-1,3-diol (203-529-7; 107-88-0)] will be directly applicable to the target substance [(R)-(-)-Butane-1,3-diol]. The predicted acute oral toxicity is low (LD50: 22800 mg/kg bw).
Executive summary:

The work of this group pre-dates range finding toxicity guidelines and provided much of the basis for their development. Their results are cited by many subsequent authoritative review bodies and are often found in SIDS and SIAR documents via secondary references. Therefore, these results are deemed reliable.

 

The acute oral toxicity data generated on the source substance [(R/S)-butane-1,3-diol (203-529-7; 107-88-0)] will represent a very similar or slightly worse case than the target substance [(R)-(-)-Butane-1,3-diol]. Non-fasted rats were given single oral doses. The LD50 (observation period: 14 days) of (R/S)-butane-1,3-diol was 22800 mg/kg bw. The acute oral toxicity of (R)-(-)-Butane-1,3-diol is predicted to be LD50 of approximately 22800 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
22 800 mg/kg bw
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.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
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
Sex:
male
Dose descriptor:
LC0
Based on:
test mat.
Exp. duration:
8 h
Remarks on result:
not determinable due to absence of adverse toxic effects
Remarks:
No deaths were reported following exposure to a saturated vapour
Interpretation of results:
GHS criteria not met
Conclusions:
The acute inhalation toxicity data generated on the source substance [(R/S)-butane-1,3-diol (203-529-7; 107-88-0)] will be directly applicable to the target substance [(R)-(-)-Butane-1,3-diol]. The predicted acute inhalation toxicity is low (8-hour LC50 > saturated vapour concentration).
Executive summary:

The work of this group pre-dates range finding toxicity guidelines and provided much of the basis for their development. Their results are cited by many subsequent authoritative review bodies and are often found in SIDS and SIAR documents via secondary references. Therefore, these results are deemed reliable.

 

The acute inhalation toxicity data generated on the source substance [(R/S)-butane-1,3-diol (203-529-7; 107-88-0)] will represent a very similar or slightly worse case than the target substance [(R)-(-)-Butane-1,3-diol]. No lethal effects were observed in rats after a single 8-hours exposure to a (R/S)-butane-1,3-diol saturated vapour. The acute inhalation toxicity of (R)-(-)-Butane-1,3-diol is predicted to be 8-hour LC50 greater than the saturated vapour concentration.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
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.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Reason / purpose:
read-across: supporting information
Related information:
Composition 1
Endpoint conclusion
Endpoint conclusion:
no study available
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.

Additional information

Justification for classification or non-classification

The acute oral toxicity of (R)-(-)-butane-1,3-diol is predicted to be LD50 of approximately 22800 mg/kg bw; this is in excess of the classification cut-off of 2000 mg/kg bw.

The acute inhalation toxicity of (R)-(-)-butane-1,3-diol is predicted to be 8-hour LC50 greater than the saturated vaopur concentration. As no deaths were reported at the saturated vapour concentration, the substance does not meet the criteria for classification as an acute inhalation toxicity hazard.

Testing by the dermal route does not need to be conducted as the substance does not meet the criteria for classification as acute toxicity or STOT SE by the oral route and no systemic effects after dermal exposure are predicted on the basis of non-testing approaches (e.g. read-across). By extension, the substance does not meet the criteria for classification as an acute dermal toxicity hazard.

 

Based on the information summarized above, (R)-(-)-butane-1,3-diol does not meet the criteria for classification as an acute toxicity hazard by oral, dermal or inhalation exposure according to section 3.1. of the European CLP (Regulation (EC) No 1272/2008 as amended).