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Description of key information

The target substance (R)-(-)-Bauten-1,3-diol was assessed in a Repeated Insult Patch Test with 59 volunteers (56 continued the study to the end) for skin irritation and skin sensitisation with the target substance appled as aqueous solution in concentrations of 10, 20 and 40%, respectively. None of the volunteers at any of the concentrations applied showed and sensitisation reaction during the challenge phase. Also, no marked skin irritation had been observed.

The following information was considered for this Weight of Evidence prediction:

 

1.         No signs of skin sensitisation were observed in several Human Repeat Insult Patch Test (HRIPT) with the source substance ((R/S)-butane-1,3-diol):

-              Schwartz-Peck prophetic patch test: 104 subjects, formulation with 5%;

-              Draize-Shelanski RIPTs:

·        108 subjects, formulation with 16%;

·        49 subjects, 5% formulation; and

·        108 subjects, formulation with 3%.

 

2.         The Toxtree Module (v.2.6.6): Skin sensitisation reactivity domains determined there are no skin sensitisation reactivity domain alerts.

 

3.         The VEGA Skin Sensitization model (CAESAR) 2.1.6 prediction is NON-Sensitizer, the result appears reliable.

 

Based on the weight of the findings of the Human Repeat Insult Patch Test (HRIPT) with the source substance, and the two QSAR predictions, the source substance (R/S)-butane-1,3-diol is predicted to be non-sensitizing. Values generated on the source substance will represent a very similar or slightly worse case than the target substance; therefore, (R)-(-)-butane-1,3-diol it is predicted to be non-sensitizing. This has been confirmed in the Repeated Insult Patch Tests with the target substance (R)-(-)-butane-1,3-diol in queous mixtures with 10, 20, and 40% concentration, respectively.

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

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
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: supporting information
Related information:
Composition 1
Reason / purpose:
read-across: supporting information
Related information:
Composition 1
Reason / purpose:
read-across: supporting information
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 and QSAR data.
Key result
Reading:
other: Weight of Evidence of HRIPT and QSAR predictions
Clinical observations:
no prediction of skin sensitization
Remarks on result:
not measured/tested
Remarks:
See additional information below
Reading:
other: Not applicable, Weight of Evidence of HRIPT and QSAR
Group:
negative control
Remarks on result:
not determinable because of methodological limitations
Reading:
other: Not applicable, Weight of Evidence of HRIPT and QSAR
Group:
test group
Remarks on result:
not determinable because of methodological limitations
Reading:
other: Not applicable, Weight of Evidence of HRIPT and QSAR
Group:
positive control
Remarks on result:
not determinable because of methodological limitations

The following information was considered for this Weight of Evidence prediction:

 

1.      No signs of skin sensitisation were observed in several Human Repeat Insult Patch Test (HRIPT) with the source substance:

-         Schwartz-Peck prophetic patch test: 104 subjects, formulation with 5%;

-         Draize-Shelanski RIPTs:

o  108 subjects, formulation with 16%;

o  49 subjects, 5% formulation; and

o  108 subjects, formulation with 3%.

 

2.      The Toxtree Module (v.2.6.6): Skin sensitisation reactivity domains determined there are no skin sensitisation reactivity domain alerts.

 

3.      The VEGA Skin Sensitization model (CAESAR) 2.1.6 prediction is NON-Sensitizer, the result appears reliable.

Interpretation of results:
GHS criteria not met
Conclusions:
Based on the weight of the findings of the Human Repeat Insult Patch Test (HRIPT) with the source substance, and the two QSAR predictions, the source substance (R/S)-butane-1,3-diol is predicted to be non-sensitizing. Values generated on the source substance will represent a very similar or slightly worse case than the target substance; therefore, (R)-(-)-butane-1,3-diol it is predicted to be non-sensitizing.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on the weight of the findings of the Human Repeat Insult Patch Test (HRIPT) with the target substance, supported by HRIPT test results of the source substance, and the two QSAR predictions, the source substance (R/S)-butane-1,3-diol is predicted to be non-sensitizing. Values generated on the source substance will represent a very similar or slightly worse case than the target substance; therefore, (R)-(-)-butane-1,3-diol it is predicted to be non-sensitizing.

 

The moderate predicted vapour pressure of greater than 8 to less than 10 Pa at 20 °C suggests that exposure to vapours via inhalation cannot be completely excluded. However, no adverse effects were reported following the acute inhalation exposure.

 

Based on the information summarized above, (R)-(-)-butane-1,3-diol does not meet the criteria for classification as a respiratory or skin sensitisation hazard according to sections 3.4. of the European CLP (Regulation (EC) No 1272/2008 as amended).