Sodium etasulfate

Carcinogenicity

Description of key information

OECD 453, rat, combined chronic toxicity/carcinogenicity, oral: not carcinogenic
NOAEL = 1125 mg/kg bw/day; LOAEL > 1125 mg/kg bw/day

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 125 mg/kg bw/day

Study duration:

chronic

Species:

rat

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The available data on carcinogenicity do not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.

Additional information

The possibility of a read-across to other alkyl sulfates in accordance with Regulation (EC) No 1907/2006 Annex XI 1.5. Grouping of substances and read-across approach was assessed. In Annex XI 1.5 it is given that a read-across approach is possible for substances, whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity. The AS reported within the AS category show structural similarity. The most important common structural feature of the category members is the presence of a predominantly linear aliphatic hydrocarbon chain with a polar sulfate group, neutralized with a counter ion. This structural feature confers the surfactant properties of the alkyl sulfates. The surfactant property of the members of the AS category in turn represent the predominant attribute in mediating effects on mammalian health. Therefore, the AS of the AS category have similar physico-chemical, environmental and toxicological properties, validating the read across approach within the category. The approach of grouping different AS for the evaluation of their effects on human health and the environment was also made by the OECD in the SIDS initial assessment profile [1] and by a voluntary industry programme carrying out Human and Environmental Risk Assessments (HERA [2]), further supporting the read across approach between structurally related AS.

A reliable combined chronic toxicity/carcinogenicity study was conducted with C12 -15AS Na (CAS 68890-70-0). For two combined chronic toxicity/carcinogenicity studies similar to OECD Guideline 453 C12-15AS Na (CAS 68890-70-0) was prepared by two different production methods (high conversion bleached or HCB; and low conversion, unbleached or LCU). The substances of these different production methods differed slightly in chain length distribution, the latter having a slightly higher proportion of the C15AS Na. In both studies, the test material was dosed at 0, 0.015, 0.15 and 1.5% in the diet. There was no increase in tumour incidence, nor any impact on tumour type in either study. For both studies, approximately 70% of animals survived to study termination. Mortality was similar across dosage groups and controls. Animals in the 1.5% dose groups in both studies exhibited reduced food and water consumption, and slower growth rates. Within these high dose groups, there were a decreased number of total tumours and tumour-bearing animals.

Other pathological findings are summarized in the Section Repeated dose toxicity. Increased absolute liver weights and liver to body weight ratios, hypertrophy of the hepatic parenchyma, increased relative testicular weights, reduced incidence and severity of chronic nephropathy and nephrocalcinosis, and reduced arterial medial hypertrophy were among the findings at the higher dose levels.

Alkyl sulfates (AS) show a consistent absence of mutagenic activity when tested in in-vitro and in-vivo tests. Neither AS nor its metabolites possess electrophilic functional groups or functional groups associated with mutagenic activity. Taken together with the results of the carcinogenicity studies, AS are considered as non-carcinogenic.

 

Influence of branched carbon chains on carcinogenicity

The OECD Toolbox gives a structural alert for non-genotoxic carcinogenicity for sodium 2-ethylhexyl sulfate (CAS No 126-92-1) due to the presence of the 2-ethylhexyl moiety. It cites a publication (Kluwe et al., 1985) with experimental data on carcinogenicity of several 2-ethylhexyl containing compounds. Kluwe et al. tested four substances all containing a 2-ethylhexyl moiety [di(2-ethylhexylphthalate (DEHP), di(2-ethylhexyl)adipate (DEHA), tris(2-ethylhexyl)phosphate (TEHP), and 2-ethylhexyl sulfate (EHS)] in 2-year studies in rats and mice. Despite differences in their other functional groups, all four substances were related to increased occurrences of hepatocellular neoplasms, principally carcinomas, in female mice. However the increased incidence of hepatocellular neoplasms in the high dose female mice treated with 2-ethylhexyl sulfate (as sodium salt) was considered to be equivocal due to lack of statistical significance. No other neoplasms were unequivocally related to dosing the four substances in these studies. The authors speculated that the mechanism for the carcinogenicity may relate to metabolic generation of 2-ethylhexanol and subsequent peroxisome proliferation.

However, it is generally viewed that peroxisome proliferation is not a relevant mechanism of carcinogenicity for humans. In addition, a chronic toxicity study subsequently conducted on 2-ethylhexanol (Astill et al., 1996) did not demonstrate a clear carcinogenic effect in rats or mice (not more than a weak or equivocal response in female mice only). Furthermore, 2-ethylhexanol (CAS No 104-76-7) is not classified as a carcinogen in the EU.

It should also be noted that there are also two previous NTP bioassays (NTP-82-63, 22/9/1982) which dosed sodium 2-ethylhexyl sulfate to rats and mice for up to 2 years. The studies suggested some association with an increased incidence of hepatocellular carcinomas in female mice only, however the results were not significant compared to historical controls. Overall the results do not unequivocally demonstrate a clear carcinogenic effect in either rats or mice. These results are essentially supported by the later findings of Kluwe et al.

In conclusion, there is no convincing evidence that the presence of the 2-ethylhexyl moiety alone is sufficient to confer carcinogenic properties in humans. Furthermore, four chronic studies on sodium 2-ethylhexyl sulfate have failed to unequivocally demonstrate a clear carcinogenic effect in either rats or mice.

Structural alerts are identified in the OECD Toolbox for non-genotoxic carcinogenicity relating to the presence of the 2-ethylhexyl moiety in sodium 2-ethylhexyl sulfate. However, the mechanistic basis and experimental evidence for such alerts are equivocal and many substances containing this moiety, including but not limited to 2-ethylhexanol, are not classified for carcinogenicity. Overall, the weight of evidence shows that the 2-ethylhexyl moiety does not confer to carcinogenicity in humans. Therefore, sodium 2-ethylhexyl sulfate (CAS No 126-92-1) is expected to be not carcinogenic.

 

References

[1] Astill, B.B., Glngell, R., Guest, D., Hellwig, J., Hodgson, J. R., Kuettler, K., Mellert, W., Murphy, S. R., Sielken Jr., R. L., Tyler, T.R., (1996); Oncogenicity testing of 2-ethylhexanol in Fischer 344 rats and B6C3F1 mice. Fundamental and applied toxicology, vol. 31, pp. 29 – 41

[2] HERA Draft report, (2002);

http://www.heraproject.com/files/3-HH-04-%20HERA%20AS%20HH%20web%20wd.pdf

[3] Kluwe, W.M., Huff, J.E., Matthews, H.B., Irwin, R., Haseman, J.K., (1985); Comparative chronic toxicities and carcinogenic potentials of 2-ethylhexyl-containing compounds in rats and mice. Carcinogenesis vol.6 (11), pp. 1577-1583

[4] NTP technical report on the carcinogenesis bioassay of sodium 2-ethylhexyl sulfate (CAS No. 126-92-1) in F344/N rats and B6C3Fl mice (feed study) (draft) NTP-82-63, 22/9/1982

[5] SIDS initial assessment profile, (2007); http://www.aciscience.org/docs/Alkyl_Sulfates_Final_SIAP.pdf