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

Toxicity to aquatic algae and cyanobacteria

Link to relevant study record(s)

Reference

Endpoint:

toxicity to aquatic algae and cyanobacteria

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) is used to address certain ecotoxicological 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 the algal and microbial test populations used in acute algal toxicity and activated sludge respiration inhibition studies, respectively, will possess a considerably broader range of enzymes than a mammalian system, the minor difference in the rates of metabolism of the two enantiomers observed by Desrochers et al. (1992) is not expected to exist in these studies, and the experimentally determined ecotoxicity values for the source substance are therefore directly applicable to the target substance.

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

PURITY/IMPURITIES
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 the algal and microbial test populations used in acute algal toxicity and activated sludge respiration inhibition studies, respectively, will possess a considerably broader range of enzymes than a mammalian system, the minor difference in the rates of metabolism of the two enantiomers observed by Desrochers et al. (1992) is not expected to exist in these studies, and the experimentally determined ecotoxicity values for the source substance are therefore directly applicable to the target substance.

4. CONCLUSION
For each of the following ecotoxicity endpoints required by Annexes VII and VIII:
9.1.2 growth inhibition study on aquatic plants (algae); and
9.1.4 activated sludge respiration inhibition
values generated on the source substance will be directly applicable to 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.

Duration:

72 h

Dose descriptor:

EC50

Effect conc.:

> 1 070 mg/L

Nominal / measured:

meas. (arithm. mean)

Conc. based on:

test mat.

Basis for effect:

growth rate

Key result

Duration:

72 h

Dose descriptor:

NOEC

Effect conc.:

1 070 mg/L

Nominal / measured:

meas. (arithm. mean)

Conc. based on:

test mat.

Basis for effect:

growth rate

Validity criteria fulfilled:

not specified

Conclusions:

Based on mean measured concentrations of (R/S)-butane-1,3-diol, the 72-h ErC50 is > 1070 mg/L and the 72-h NOErC is ≥ 1070 mg/L. Values generated on the source substance will be directly applicable to the target substance. The predicted values for (R)-(-)-butane-1,3-diol are 72-hour ErC50 of > 1070 mg/L and the 72-hour NOErC equal to 1070 mg/L.

Executive summary:

The algae growth inhibitory effects of (R/S)-1,3 -butanediol were studied on Selenastrum sp. following OECD TG 201. A 72-hour limit test with a control (0 mg/L) and the nominal test concentration of 1000 mg/L was set up. Analytical verification of the test concentrations by GLC revealed a mean measured concentration of 1070 mg/L. Based on mean measured concentrations of (R/S)-butane-1,3-diol, the 72-h ErC50 is > 1070 mg/L and the 72-h NOErC is ≥ 1070 mg/L.  Values generated on the source substance will be directly applicable to the target substance. The predicted values for (R)-(-)-butane-1,3-diol are 72-hour ErC50 of > 1070 mg/L and the 72-hour NOErC equal to 1070 mg/L.

Description of key information

The algae growth inhibitory effects of (R/S)-1,3-butanediol were studied on Selenastrum sp. following OECD TG 201. A 72-hour limit test with a control (0 mg/L) and the nominal test concentration of 1000 mg/L was set up. Analytical verification of the test concentrations by GLC revealed a mean measured concentration of 1070 mg/L. Based on mean measured concentrations of (R/S)-butane-1,3-diol, the 72-h ErC50 is > 1070 mg/L and the 72-h NOErC is ≥ 1070 mg/L.  Values generated on the source substance will be directly applicable to the target substance. The predicted values for (R)-(-)-butane-1,3-diol are 72-hour ErC50 of > 1070 mg/L and the 72-hour NOErC equal to 1070 mg/L.

 

HYPOTHESIS FOR THE ANALOGUE APPROACH

Data for butane-1,3-diol (CAS No. 107-88-0) is used to address certain ecotoxicological 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 the algal and microbial test populations used in acute algal toxicity and activated sludge respiration inhibition studies, respectively, will possess a considerably broader range of enzymes than a mammalian system, the minor difference in the rates of metabolism of the two enantiomers observed by Desrochers et al. (1992) is not expected to exist in these studies, and the experimentally determined ecotoxicity values for the source substance are therefore directly applicable to the target substance.

Key value for chemical safety assessment

EC50 for freshwater algae:

1 070 mg/L

EC10 or NOEC for freshwater algae:

1 070 mg/L