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Administrative data

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

An in vitro gene mutation study in bacteria and an in vitro gene mutation study in mammalian cells do not need to be conducted because adequate data from a reliable in vivo mammalian gene mutation test are available – [study scientifically not necessary].

 

An in vitro cytogenicity study in mammalian cells or in vitro micronucleus study does not need to be conducted because adequate data from an in vivo cytogenicity test are available – [study scientifically not necessary].

Link to relevant study records

Referenceopen allclose all

Endpoint:
in vitro cytogenicity / micronucleus study
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
an in vitro cytogenicity study in mammalian cells or in vitro micronucleus study does not need to be conducted because adequate data from an in vivo cytogenicity test are available
Reason / purpose:
data waiving: supporting information
Related information:
Composition 1
Endpoint:
in vitro gene mutation study in bacteria
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Reason / purpose:
data waiving: supporting information
Related information:
Composition 1
Endpoint:
in vitro gene mutation study in mammalian cells
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
an in vitro gene mutation study in mammalian cells does not need to be conducted because adequate data from a reliable in vivo mammalian gene mutation test are available
Reason / purpose:
data waiving: supporting information
Related information:
Composition 1
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Genetic toxicity in vivo

Description of key information

Rats were fed butane-1,3-diol in concentrations up to 24% of the diet and paired to produce F1A, F2A and F3A litters. Analysis of the femur bone marrow of at least two animals per sex and dose of these litters revealed no increase in chromosomal aberrations. Males of the F1B generation were used to examine dominant lethal effects after mating them with virgin females. The exposure did not cause a significant effect with respect to fertility, viable fetuses per implantation sites and percentage of resorption per implantation sites (mutagenic index). A dose-related trend was not evident.

 

This study was well performed with doses high enough to cause a reduced body weight gain. Despite some conceptional deficiencies as well as incomplete data reporting this study is judged to be reliable and sensitive, due to the repeated application of high doses over long time periods and several generations.

 

Values generated on the source substance will represent a very similar or slightly worse case than the target substance. Therefore, it is predicted that consumption of the target substance (R)-1,3-butanediol would not result in an increase in chromosomal aberrations and would not induce dominant lethal effects.

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.

Link to relevant study records

Referenceopen allclose all

Endpoint:
in vivo mammalian somatic cell study: cytogenicity / bone marrow chromosome aberration
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
Principles of method if other than guideline:
genotoxicity test in vivo after subchronic oral exposure over 3 generations
Type of assay:
other: chromosome aberration assay
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/female
Genotoxicity:
negative
Toxicity:
no effects
Remarks:
only slight depression of body weight gain
Vehicle controls valid:
not applicable
Negative controls valid:
yes
Positive controls valid:
not applicable
Remarks on result:
other:
Remarks:
Values generated on the source substance will represent a very similar or slightly worse case than the target substance
Additional information on results:
Dietary concentrations of 5, 10 and 24% (R/S)-1,3-butanediol correspond with body doses of 2000, 4000 and 9600 mg/kg bw for males and 2500, 5000 and 12000 mg/kg bw for females (based on a daily food consumption of 40 and 50 g/kg bw for males and females, respectively, according to the Guidance on Information Requirements R.8).

The number of abnormal cells was not increased with respect to the normal range of aberrant cells in untreated F1A, F2A and F3A animals. No specific abnormalities were observed in the treated animals and no dose-related effects were noted. Values generated on the source substance will represent a very similar or slightly worse case than the target substance.

Conclusions:
The test substance (R/S)-1,3-butanediol did not induce chromosomal aberrations after subchronic oral exposure of rats over 3 generations with dietary concentrations of up to 24%. Values generated on the source substance will represent a very similar or slightly worse case than the target substance.
Executive summary:

Rats were fed butane-1,3-diol in concentrations up to 24% of the diet and paired to produce F1A, F2A and F3A litters. Analysis of the femur bone marrow of at least two animals per sex and dose of these litters revealed no increase in chromosomal aberrations.

Values generated on the source substance will represent a vey similar or slightly worse case than the target substance. Therefore, it is predicted that consumption of the target substance (R)-1,3 -butanediol would not result in an increase in chromosomal aberrations.

This study was well performed with doses high enough to cause a reduced body weight gain. Despite some conceptional deficiencies (no positive controls, low numbers of cells per dose group examined) as well as incomplete data reporting (e.g. with respect to substance purity, time point of examination, statistical analysis of the results) this study is judged to be reliable and sensitive, due to the repeated application of high doses over long time periods and several generations.

Endpoint:
in vivo mammalian somatic cell study: gene mutation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
This endpoint study record is the experimental source record for the registered target substance.
Reason / purpose:
reference to same study
Related information:
Composition 1
Reason / purpose:
reference to same study
Related information:
Composition 1
Reason / purpose:
reference to same study
Related information:
Composition 1
Reference:
Composition 0
Principles of method if other than guideline:
genotoxicity test in vivo after subchronic oral exposure
GLP compliance:
not specified
Type of assay:
rodent dominant lethal assay
Test material information:
Composition 1
Specific details on test material used for the study:
The test compound, 1,3-butanediol, was obtained from the Celanese Chemical Company, New York
Species:
rat
Strain:
Wistar
Details on species / strain selection:
Wistar rats (FDRL-stock)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 14-15 weeks
- Housing: individually
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2 °C
- Photoperiod: 12 h dark / 12 h light
Route of administration:
oral: feed
Details on exposure:
SEMIPURIFIED DIET
20% casein
8% refined corn oil
4% salt mix
1% vitamin mix
33.5% corn starch
33.5% dextrose

DIET PREPARATION
- test diets were prepared by substituting 1,3-butanediol for equal amounts by weight of corn starch and dextrose
Duration of treatment / exposure:
Rats were treated 4 weeks before the mating period. Female rats of the F0 were fed diets containing 1,3-butanediol throughout the mating, gestation and lactating period of the F1A generation. At 1-2 weeks after weaning of the F1A litter, F0 females were mated with different males and the F1B generation was produced. Ten males per dose group of F1B generation were used for the dominant lethal test. They were housed individually in mating cages and fed the same diet concentrations as the F0 generation. For 8 consecutive weeks, 2 virgin females (100 days old) were introduced each and remained for 7 days. Afterwards the females were kept individually for another 7 days and then examined.
Frequency of treatment:
daily
Post exposure period:
none
Dose / conc.:
0 other: % Basis: nominal in diet
Dose / conc.:
5 other: % Basis: nominal in diet
Dose / conc.:
10 other: % Basis: nominal in diet
Dose / conc.:
24 other: % Basis: nominal in diet
No. of animals per sex per dose:
ten males of the F1B generation
Control animals:
yes, concurrent no treatment
Positive control(s):
None
Tissues and cell types examined:
The reproductive tract of the mated females was examined with respect to the number of implantates, resorption sites, viable and dead fetuses
Evaluation criteria:
The mutagenic index (% resorptions/implantation sites) was calculated according to a method of Epstein and Schaffer.
Statistics:
Statistical analysis was performed, but not stated in detail
Sex:
male/female
Genotoxicity:
negative
Toxicity:
no effects
Remarks:
only slight depression of body weight gain
Vehicle controls valid:
not applicable
Negative controls valid:
yes
Positive controls valid:
not applicable
Additional information on results:
Dietary concentrations of 5, 10 and 24% correspond with body doses of 2000, 4000 and 9600 mg/kg bw for males and 2500, 5000 and 12000 mg/kg bw for females (based on a daily food consumption of 40 and 50 g/kg bw for males and females, respectively, according to the Guidance on Information Requirements R.8).

The percentage of pregnancies as well as the percentage of viable fetuses per implantation site were not significantly different between treatment and control groups. The mutagenic index did not show a trend with increasing doses

 

Control

5%

10%

24%

No. pregnancies total

106

97

130

117

% Pregnancies (20 matings)

66.3

60.6

81.3

73.1

Implant sites

1165

1024

1452

1310

Viable fetuses total

1101

962

1389

1269

% Viable fetuses/implant sites

94.5

94.0

95.7

96.9

Resorptions total

64

62

63

41

% Resorptions/implant sites*

5.5

6.1

4.3

3.1

*: mutagenic index

Conclusions:
The test substance did not induce dominant lethal effects after oral exposure of rats with dietary concentrations of up to 24%.
Executive summary:

Rats were fed butane-1,3-diol in concentrations up to 24% of the diet and paired to produce F1A and F1B litters. Males of the F1B generation were used to examine dominant lethal effects after mating them with virgin females. The exposure did not cause a significant effect with respect to fertility, viable fetuses per implantation sites and percentage of resorption per implantation sites (mutagenic index). A dose-related trend was not evident.

 

This study was performed at high doses, which produced body weight gain. Deficiencies of this study are the incomplete data reporting (e.g. with respect to substance purity, statistical analysis of the results). In summary, this study is judged to be reliable with restrictions.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Additional information

Justification for classification or non-classification

Rats were fed butane-1,3-diol in concentrations up to 24% of the diet and paired to produce F1A, F2A and F3A litters. Analysis of the femur bone marrow of at least two animals per sex and dose of these litters revealed no increase in chromosomal aberrations. Males of the F1B generation were used to examine dominant lethal effects. The exposure did not cause a significant effect with respect to fertility, viable fetuses per implantation sites and percentage of resorption per implantation sites (mutagenic index). A dose-related trend was not evident.

 

Values generated on the source substance will represent a very similar or slightly worse case than the target substance. Therefore, it is predicted that consumption of the target substance (R)-1,3-butanediol would not result in an increase in chromosomal aberrations and would not induce dominant lethal effects.

 

Based on the information summarized above, (R)-(-)-1,3-butanediol does not meet the criteria for classification as a germ cell mutagenicity hazard according to section 3.5 of the European CLP (Regulation (EC) No 1272/2008 as amended).