2,2-dimethyl-1,3-propanediyl didecanoate

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

Gene mutation in bacteria: in vitro (read-across, equivalent/similar to OECD 471): negative with and without metabolic activation

Chromosome aberration in mammalian cells: in vitro (read-across, according to OECD 473): negative with and without metabolic activation

Gene mutation in mammalian cells: in vitro (read-across, according to OECD 476): negative with and without metabolic activation

Link to relevant study records

Reference

Reference 1

Endpoint:

in vitro gene mutation study in bacteria

Type of information:

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

Remarks:

Summary of available data used for the endpoint assessment of the target substance

Adequacy of study:

weight of evidence

Justification for type of information:

refer to analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Key result

Species / strain:

S. typhimurium TA 1535, TA 1537, TA 98 and TA 100

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity

Vehicle controls validity:

valid

Untreated negative controls validity:

not examined

Positive controls validity:

valid

Key result

Species / strain:

other: WP2P [WP2 (pKM101)] and WP2 uvrA [WP2 uvrA (pKM101)]

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity

Vehicle controls validity:

valid

Untreated negative controls validity:

not examined

Positive controls validity:

valid

Remarks on result:

other: Source: CAS 31335-74-7, Central Toxicology Laboratory, 1996

The two source substances (2,2-dimethyl-1,3-propanediyl dioctanoate (CAS 31335-74-7) and fatty acids, C8-10, mixed esters with neopentyl glycol and trimethylolpropane (CAS 97281-24-8)) did not exhibit mutagenic properties in bacterial cells. The result of Central Toxicology Laboratory (1996) was chosen as representative as test was most reliable compared to the other two reports.

Conclusions:

Two analogue source substances did not exhibit mutagenic properties in bacterial cells as investigated in three independent in vitro studies. As explained in the analogue justification, this result is considered to be valid also for the target substance.

Reference 2

Endpoint:

in vitro cytogenicity / chromosome aberration study in mammalian cells

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

refer to analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Key result

Species / strain:

lymphocytes: human lymphocytes

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

cytotoxicity

Remarks:

In Exp 1, -S9, there was a plateau in toxicity between 50 and 400 µg/mL. In Exp 2 at 400 µg/mL (inhibition 45% of mitotic index).

Vehicle controls validity:

valid

Untreated negative controls validity:

not examined

Positive controls validity:

valid

Remarks on result:

other: Source: CAS 68855-18-5, Harlan, 2013a

Conclusions:

No clastogenic potential was observed in an in vitro study performed with an adequate analogue source substance. As explained in the analogue justification, this result is considered to be valid also for the target substance.

Reference 3

Endpoint:

in vitro gene mutation study in mammalian cells

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

refer to analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Key result

Species / strain:

mouse lymphoma L5178Y cells

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

cytotoxicity

Vehicle controls validity:

valid

Untreated negative controls validity:

not examined

Positive controls validity:

valid

Remarks on result:

other: Source: CAS 68855-18-5, Harlan, 2013b

Conclusions:

No mutagenic potential in mammalian cells was observed in an in vitro study performed with an adequate analogue source substance. As explained in the analogue justification, this result is considered to be valid also for the target substance.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Genetic toxicity in vivo

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

No data regarding in vitro genetic toxicity for the target substance neopentyl glycol dicaprate (CAS 27841-06-1) are available. Therefore, the genetic toxicity endpoints gene mutation in bacteria, chromosome aberration and gene mutation in mammalian cells were assessed based on data from the source substances 2,2-dimethyl-1,3-propanediyl dioctanoate (CAS 31335-74-7), fatty acids, C8-10, mixed esters with neopentyl glycol and trimethylolpropane (CAS 97281-24-8), and heptanoic acid, ester with 2,2-dimethyl-1,3-propanediol (CAS 68855-18-5).

In vitro gene mutation in bacteria

The mutagenic potential of 2,2-dimethyl-1,3-propanediyl dioctanoate (CAS 31335-74-7) was tested in two reverse mutation assays performed according to OECD guideline 471 and under GLP conditions (Central Toxicology Laboratory, 1996 & 1995). While the first study is reported according to the guideline, for the latter study the results were only briefly summarised (no information about toxicity, mean number of revertant colonies per plate, individual plate counts included in the study summary). Salmonella typhimurium strains TA1535, TA1537, TA98, TA100 and E. coli WP2P and WP2 uvrA were used. In the first experiment, tester strains were incubated for 72 h with test material concentrations of 100, 200, 500, 1000, 2500 and 5000 µg/plate dissolved in DMSO with and without the addition of a metabolic activation system (phenobarbitale and beta-naphthoflavone induced rat liver S9 mix) in a plate incorporation test. The repeat experiment in both studies was done with an additional 1 h pre-incubation period. Vehicle and appropriate positive controls were included in the study design. Positive control substances induced statistically significant increases in the frequency of revertant colonies indicating the satisfactory performance of the test and the activity of the metabolising system. No increase in the frequency of revertant colonies compared to concurrent vehicle controls was observed in all strains treated with the test substance in both experiments, neither in the presence nor in the absence of metabolic activation. No cytotoxicity was observed. The test item did not induce point mutations by base-pair changes or frame-shifts in the genome of the strains tested under the conditions of these tests.

The mutagenic potential of fatty acids, C8-10, mixed esters with neopentyl glycol and trimethylolpropane (CAS 97281-24-8) was also tested in a reverse mutation assay equivalent or similar to OECD guideline 471 and under GLP conditions (BASF, 1988). Salmonella typhimurium strains TA1535, TA1537, TA98, TA100 and TA1538 were used. Tester strains were incubated for 72 h with test material dissolved in Tween 80/water at concentrations of 8, 40, 200, 1000 and 5000 µg/plate with and without the addition of a metabolic activation system (Aroclor 1254 induced rat liver S9 mix). Vehicle and appropriate positive controls were included in the study. Positive control materials induced statistically significant increases in the frequency of revertant colonies indicating the satisfactory performance of the test and the activity of the metabolising system. No increase in the frequency of revertant colonies compared with concurrent vehicle controls was observed in the strains treated with the test substance, neither in the presence nor in the absence of metabolic activation. No cytotoxicity was observed. The test substance did not induce point mutations by base-pair changes or frame-shifts in the genome of the strains tested.

In vitro chromosome aberration in mammalian cells

A chromosome aberration test was conducted with heptanoic acid, ester with 2,2-dimethyl-1,3-propanediol (CAS 68855-18-5) according to OECD guideline 473 and under GLP conditions in human lymphocytes. Duplicate cultures of human lymphocytes, treated with the test item, were evaluated for chromosome aberrations at three dose levels, together with vehicle and positive controls. Four treatment conditions were used for the study. In Experiment 1, 4 h in the presence of an induced rat liver homogenate metabolising system (S9), at a 2% final concentration with cell harvest after a 20-h expression period and a 4 h exposure in the absence of metabolic activation (S9) with a 20-h expression period. In Experiment 2, the 4 h exposure with S9 was repeated (using a 1% final S9 concentration), whilst in the absence of metabolic activation the exposure time was increased to 24 h. The dose levels used in the main experiments, selected based on data from a preliminary toxicity test, were 12.5, 25, 50, 100, 200, 400 µg/mL for Experiment 1 and 2. All vehicle (solvent) controls had frequencies of cells with aberrations within the range expected for human lymphocytes. All the positive control substances induced statistically significant increases in the frequency of cells with aberrations indicating the satisfactory performance of the test and the activity of the metabolising system. Cytotoxicity was observed in Experiment 1 without metabolic activation; there was a plateau in cytotoxicity between 50 and 400 µg/mL. In Experiment 2 cytotoxicity was observed at 400 µg/mL. The test substance did not induce any statistically significant increases in the frequency of cells with aberrations, in either the absence or presence of S9, in two separate experiments. In conclusion, the test item was considered to be non-clastogenic to human lymphocytes in vitro.

In vitro gene mutation in mammalian cells

A L5178Y mouse lymphoma assay was conducted according to OECD guideline 476 and under GLP conditions with heptanoic acid, ester with 2,2-dimethyl-1,3-propanediol (CAS 68855-18-5). Two independent experiments were performed. In Experiment 1, L51787Y TK +/- 3.7.3 c mouse lymphoma cells (heterozygous at the thymidine kinase locus) were treated with the test item at eight dose levels, in duplicate, together with vehicle (solvent) and positive controls using 4 h exposure groups both in the absence and the presence of metabolic activation (2% S9). In Experiment 2, the cells were treated with the test item at eight dose levels using a 4 h exposure group in the presence of metabolic activation (1% S9) and a 24 h exposure group in the absence of metabolic activation. The dose range of the test substance was selected following the results of a preliminary toxicity test and was determined to be 1.6 to 102.5 µg/mL in both the absence and presence of metabolic activation in Experiment 1. In Experiment 2 the dose range was 1.6 to 102.5 µg/mL in the absence of metabolic activation, and 3.2 to 205 µg/mL in the presence of metabolic activation. The maximum dose levels used in the test were limited by precipitation and test substance-induced toxicity. A precipitate of the substance was observed at and above 102.5 µg/mL in the mutagenicity test. The vehicle (solvent) controls had acceptable mutant frequency values that were within the normal range for L5178Y cell line at the TK +/- locus. The positive control items induced marked increases in the mutant frequency indicating the satisfactory performance of the test and of the activity of the metabolising system. The test item did not induce any toxicologically significant dose-related increases in the mutant frequency at any dose level, either with or without metabolic activation, in either the first or the second experiment.

Conclusion on genetic toxicity

Several source substances were investigated in vitro for their potential to induce effects related to genetic toxicity. Endpoints investigated include gene mutations by base-pair changes or frame-shifts in bacteria, cytogenicity / chromosome aberrations in mammalian cells and mutagenicity in mammalian cells. No effects of toxicological relevance were observed in any experiment, either with or without metabolic activation. The available data indicated a very low level of genetic toxicity for the source substances. Therefore, no hazard for genetic toxicity was expected for the target substance.

Justification for classification or non-classification

The available data on in vitro genetic toxicity of several analogue source substances do not meet the classification criteria according to the CLP Regulation (EC) No. 1272/2008. Based on read-across, also no classification is warranted for the target substance neopentyl glycol dicaprate (CAS 27841-06-1). Data are, therefore, conclusive but not sufficient for classification.