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Key value for chemical safety assessment

Additional information

Valid experimental data were available to assess the genetic toxicity in vitro (A detailed justification document has been provided in IUCLID chapter 13):

 

Gene mutation in bacteria

1,6-hexanedioldiacrylate was not mutagenic in a standard plate test and in a pre-incubation Ames test with and without metabolic

activation, tested up to 5000 μg/plate in Salmonellatyphimurium TA1535, TA 1537, TA 98 and TA 100; S9 fraction was from the

liver of male Sprague-Dawley rats, treated with a single dose of 500 mg/kg bw Aroclor 1254 five days before sacrifice and mixed

with a series of cofactors (comp. OECD 471; BASF AG 1989). Cytotoxicity was observed >500 µg/plate and higher, depending on

test strain.

In another standard plate Ames test with and without metabolic activation (tested up to 5000 μg/plate in Salmonella typhimurium

TA1535, TA 1537, TA 98, TA 100 and TA 1538 metabolic activation, 1,6-hexanedioldiacrylate was not mutagenic. Metabolic

activation was from S9 fraction from the liver of male rats, treated with a single dose of Aroclor 1254 seven days before sacrifice and

mixed with a series of cofactors (comp. OECD 471; TNO 1979). Cytotoxicity was observed at concentrations of > 500 µg/plate

and higher, depending on test strain, without S9-mix in Salmonella typhimurium TA1535, TA 1537, TA 98 and TA 100 and in

Salmonella typhimurium TA1538 at concentrations >=1000 µg/plate and higher, with or without S9-mix.

 

Gene mutation in mammalian cells

The test substance was also negative for genotoxicity in a mouse lymphoma assay using L5178Y cells at levels up to 0.0125 µl/ml

without metabolic activation and up to 0.0250 µl/ml with metabolic activation (comp. OECD 476; Litton Bionetics Inc., 1976).

Cytotoxicity was observed at doses > 0.0094 µl/ml without metabolic activation.

 

Genetic toxicity in vivo

There are no valid data available to assess the genetic toxicity of 1,6-hexanedioldiacrylate in-vivo.

However, there are valid data available which assessed the genetic toxicity toxicity of the structurally related tripropylene glycol

diacrylate (Cas No. 42978-66-5) in-vivo. These data were adopted to 1,6 -hexanedioldiacrylate by read-across:

Tripropylene glycol diacrylateshowed no mutagenic activity in in-vivo assays with rodents. In a mouse micronucleus assay on polychromatic erythrocytes, tripropylene glycol diacrylate led to a negative result after single oral administration of 87.5, 175, 350 mg/kg bw. Sampling times were 24 and 48 h (BASF AG 2004, Val. 1). As a negative control, male mice were administered merely the vehicle, olive oil,by the same route, which gave frequencies of micronucleated polychromatic erythrocytes within the historical control range. Both of the positive control chemicals, i.e. cyclophosphamide for clastogenicity and vincristine for spindle poison effects, led to the expected increase in the rate of polychromatic erythrocytes containing small or large micronuclei. Animals which were administered the vehicle or the positive control substances cyclophosphamide or vincristine did not show any clinical signs of toxicity. The administration of the test substance led to clinical signs. According to the results of the present study, the single intraperitoneal administration of tripropylene glycol diacrylate did not lead to any increase in the number of polychromatic erythrocytes containing either small or large micronuclei. The rate of micronuclei was always close to the range as that of the concurrent negative control in all dose groups and at all sacrifice intervals and within the range of the historical control data. A dose-dependent inhibition of erythropoiesis determined from the ratio of polychromatic to normochromatic erythrocytes was detected from about of 87.5 mg/kg body weight onward

Another in vivo micronucleus test was also negative after oral administration of tripropylene glycol diacrylate. In this test doses of 2000, 1000 and 500 mg/kg bw were administered. Sampling time was 24 and 48 h after administration. 5 males per dose and harvest time point were used (Covance 2007, Val. 1). All animals in all the dose groups and controls appeared normal immediately after dosing and remained healthy until the appropriate harvest timepoint. TPGDA did not induce statistically significant increases in micronucleated PCEs at any test article dose examined (500, 1000, or 2000 mg/kg). TPGDA was not cytotoxic to the bone marrow (i.e., no statistically significant decreases in the PCE:NCE ratios) at any dose of the test article analyzed. The vehicle control group had approximately0.09% micronucleated PCEs and the group mean was within the historical control range. The positive control, cyclophosphamide, induced a statistically significant increase in micronucleated PCEs as compared to that of the vehicle control.

In another study the test substance was applied dermally to Tg.AC mice (3 times a week for 20 weeks). Peripheral blood leukocytes were evaluated for DNA damage (single-strand breaks, alkali labile sites, DNA crosslinking) at weeks 4, 8, 12, 16, and 20 by using the alkaline (pH > 13) single cell gel (SCG) assay. Peripheral blood polychromatic erythrocytes (PCE) and normochromatic erythrocytes (NCE) were evaluated for the presence of micronuclei at week 20 (Tice 1997, Val. 2). The extent of DNA migration in leukocytes of mice treated by dermal application with TPGDA at 1, 5, or 10 μmol per mouse was not significantly different, either by trend test analysis or by a pairwise comparison of each treatment dose against the concurrent vehicle control, at any sample time. TPA (0.002 μmol per mouse), the positive control for the tumorigenicity studies, also failed to significantly alter the extent of DNA migration or its intercellular dispersion in leukocytes of mice treated by dermal application.After 20 weeks of treatment, the frequency of micronucleated PCE and NCE in blood were not increased in the mice treated with TPGDA or TPA. The percentage of PCE was increased in mice treated with TPGDA. This increase was highly significant. By a pairwise comparison, the lowest effective dose of TPGDA inducing a significant increase in percentage of PCE was 10 μmol per mouse. TPA, at 0.002 μmol per mouse also induced a marginally nonsignificant increase in the percentage of PCE. This observed increase in the rate of erythropoiesis may reflect bone marrow/blood toxicity, a homeostatic mechanism in response to the treatment-induced tumor burden, and/or a hematopoietic response to epidermal keratinocyte cytokines induced by tissue injury.

Read across justification:

 

HDDA (CAS # 13048-33-4), DPGDA (CAS#57472-68-1) and TPGDA (CAS # 42978-66-5) are suitable for read across among each other as they are all structurally similar Difunctional Acrylates with comparable toxicological properties (all are sensitizing and have irritating effects on skin and eyes).


Short description of key information:
GENETIC TOXICITY IN VITRO:
Gene mutation in bacteria
- S. typhimurium TA 1535, TA 1537, TA 98 and TA 100, with and without metabolic activation (Ames test): negative (comp. OECD 471; BASF AG 1989)
- S typhimurium TA1535, TA 1537, TA 98, TA 100 and TA 1538, with and without metabolic activation (Ames test): negative (comp. OECD 471; TNO 1979

Gene mutation in mammalian cells
Mouse L5178Y cells with and without metabolic activation (Mouse Lymphoma Assay): negative (comp. OECD 476; Litton Bionetics 1976)

GENETIC TOXICITY IN VIVO:
- Mouse, MNT in-vivo: negative (acc. OECD 474, BASF AG 2004); Read-across to tripropylene glycol diacrylate (Cas No. 42978-66-5)
- Mouse, MNT in-vivo: negative (acc. OECD 474, Covance 2007); Read-across to tripropylene glycol diacrylate (Cas No. 42978-66-5)
- Mouse, Single cell gel assay and micronucleus assay: negative (Tice 1997, Val. 2); Read-across to tripropylene glycol diacrylate (Cas No. 42978-66-5)

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

The test substance was not genotoxic in in vitro experiments using mammalian and bacterial cells. There are currently no data available to classify 1,6-hexanedioldiacrylate for causing genotoxicity in-vivo; however, results obtained for the structurally similar tripropylene glycol diacrylate (Cas No. 42978-66-5), which were adopted to 1,6 -hexanedioldiacrylate by read-across, were negative for genotoxic effects in vivo.