(R)-(-)-butane-1,3-diol

Neurotoxicity

Description of key information

The neuropharmacology of (R/S)-1,3-butylene glycol was compared with that of ethanol. Acute intraperitoneal administration of equimolar doses of (R/S)-1,3-butylene glycol or ethanol to rats impaired the aerial righting reflex, attenuated the suppressive effect of punishment on drinking behaviour, lowered blood pressure, and caused a concomitant reduction in the content of guanosine 3’,5’-monophosphate in the cerebellum. Although test data suggested than ethanol and (R/S)-1,3-butylene glycol were of similar potency, the brain content of (R/S)-1,3-butylene glycol was only 33% of that of ethanol after treatment with equimolar doses, suggesting a greater central nervous system (CNS) potency for (R/S)-1,3-butylene glycol. Chronic administration and withdrawal of (R/S)-1,3-butylene glycol caused CNS hyperexcitability in rats that was characteristic of physical dependence. Despite these similarities, there were clear differences in the actions of ethanol and (R/S)-1,3-butylene glycol. In mice, locomotor stimulation caused by ethanol administration was not observed with (R/S)-1,3 -butylene glycol treatment. Furthermore, while (R/S)-1,3-butylene glycol did not alter the concentration of luteinizing hormone in plasma, equivalent doses of ethanol markedly reduced the concentration of this hormone. These data indicate that like ethanol (R/S)-1,3-butylene glycol depresses CNS activity and induces physical dependence, but has less effect on plasma luteinizing hormone concentration than ethanol.

Values generated on the source substance will represent a very similar or slightly worse case than the target substance (R)-1,3-butylene glycol.

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

Effect on neurotoxicity: via oral route

Link to relevant study records

Reference

Endpoint:

neurotoxicity: acute oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

other information

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 for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across: supporting information

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.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

-Effects on locomotor activity of mice: Administration of (R/S)-1,3-butylene glycol did not alter locomotor activity and decreased locomotor activity when compared with that of saline-treated controls.

-Motor coordination: (R/S)-1,3-butylene glycol depressed motor function and induced signs of ataxia in all test animals following administration.

-Effect of chronic treatment and withdrawal hyperexcitability: No significant impairment was noted during the course of their administration. All treatment groups gained weight during the experiment. After 12 days, 1 hr after withdrawal of (R/S)-1,3-butylene glycol, tremor scores were unaltered relative to dextrose-fed controls. One of nine rats fed (R/S)-1,3-butylene glycol developed seizure. After 7.5 hr of withdrawal, tremor scores were significantly increased for 1,3-BD -treated rats. Audiogenic seizures were developed in 33% (3 of 9) of the rats withdrawn from (R/S)-1,3-butylene glycol. One (R/S)-1,3-butylene glycol-withdrawn rat died due to audiogenic seizure.

Values generated on the source substance will represent a very similar or slightly worse case than the target substance (R)-1,3-butylene glycol..

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

-Effect on plasma LH concentration: Treatment with (R/S)-1,3-butylene glycol did not alter plasma LH concentration.

-Effect on blood and brain concentration after acute administration: Administration of 67 mmol/kg of (R/S)-1,3-butylene glycol reached concentration of approximately 120 umoles/mL in the blood. The increase in concentration was dose-dependent.

-Effect of chronic treatment and withdrawal hyperexcitability: Rats fed (R/S)-1,3-butylene glycol had blood (R/S)-1,3-butylene glycol concentration of 20 μmol/mL at the end of treatment period.

Values generated on the source substance will represent a very similar or slightly worse case than the target substance (R)-1,3-butylene glycol..

Behaviour (functional findings):

effects observed, treatment-related

Description (incidence and severity):

-Effect of chronic treatment: Rats fed (R/S)-1,3-butylene glycol for 12-days consumed 240 mmol/kg by the last day of treatment and had blood (R/S)-1,3-butylene glycol concentrations of 20 µmol/mL at 12 noon on that day. Examination of the aerial righting reflex during the course of the treatment showed that (R/S)-1,3-butylene glycol caused no significant impairment during the course of administration.

-Effect on "conflict behavior": Rats treated 30 minutes earlier with (R/S)-1,3-butylene glycol (11-44 mmol/kg) accepted more shocks than saline-treated controls.

Values generated on the source substance will represent a very similar or slightly worse case than the target substance (R)-1,3-butylene glycol..

Details on results:

-Modification of cerebellar cyclic nucleotide content: Administration of (R/S)-1,3-butylene glycol depressed the content of cGMP in cerebellum but did not significantly change the concentration of cAMP in the cerebellum.

-Effect on blood pressure and blood gas chemistry: 67 mmol/kg of (R/S)-1,3-butylene glycol decreased PaCO2 and in creased PaO2 and reduced blood pH compared to saline-treated control group. Both doses of (R/S)-1,3-butylene glycol significantly decreased blood pressure, the highest dose inducing the greatest change in blood pressure.

Values generated on the source substance will represent a very similar or slightly worse case than the target substance (R)-1,3-butylene glycol..

Conclusions:

These data indicate that like ethanol, (R/S)-1,3-butylene glycol depresses CNS activity and induces physical dependence, but has less effect on plasma luteinizing hormone concentration than ethanol. Values generated on the source substance will represent a very similar or slightly worse case than the target substance (R)-1,3-butylene glycol..

Executive summary:

The neuropharmacology of (R/S)-1,3-butylene glycol was compared with that of ethanol. Acute intraperitoneal administration of equimolar doses of (R/S)-1,3-butylene glycol or ethanol to rats impaired the aerial righting reflex, attenuated the suppressive effect of punishment on drinking behaviour, lowered blood pressure, and caused a concomitant reduction in the content of guanosine 3’,5’-monophosphate in the cerebellum. Although test data suggested than ethanol and (R/S)-1,3-butylene glycol were of similar potency, the brain content of (R/S)-1,3-butylene glycol was only 33% of that of ethanol after treatment with equimolar doses, suggesting a greater central nervous system (CNS) potency for (R/S)-1,3-butylene glycol. Chronic administration and withdrawal of (R/S)-1,3-butylene glycol caused CNS hyperexcitability in rats that was characteristic of physical dependence. Despite these similarities, there were clear differences in the actions of ethanol and (R/S)-1,3-butylene glycol. In mice, locomotor stimulation caused by ethanol administration was not observed with (R/S)-1,3 -butylene glycol treatment. Furthermore, while (R/S)-1,3-butylene glycol did not alter the concentration of luteinizing hormone in plasma, equivalent doses of ethanol markedly reduced the concentration of this hormone. These data indicate that like ethanol (R/S)-1,3-butylene glycol depresses CNS activity and induces physical dependence, but has less effect on plasma luteinizing hormone concentration than ethanol.

Values generated on the source substance will represent a very similar or slightly worse case than the target substance (R)-1,3-butylene glycol..