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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
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.

There is a substantial data base on triethanolamine (TEA) online available. TEA is not listed in Annex VI of directive 1272/2008. In addition the effects of TEA on human health were assessed by the OECD in the SIDS initial assessment Report [3]. Despite of some local signs of irritation TEA gives no rise to concern of adverse effects on human health. Therefore a contribution of TEA to the effects on human health is considered to be negligible when assessing human health effects of C8-14AS TEA (CAS 85665-45-8). Therefore, read across to alkyl sulfates with other counter ions is considered to be valid and reliable. This approach was also followed by the OECD in the SIDS initial assessment profile [1] and by the voluntary industry programme carrying out Human and Environmental Risk Assessments (HERA [2]).

There is no 2-generation toxicity study with alkyl sulfates available. Nevertheless, this endpoint is sufficiently covered as data on the reproductive organs after subchronic treatment are available. Subchronic repeated oral toxicity studies with C12-15AS Na (CAS 68890-70-0), C16-18AS Na (CAS 68955-20-4) and C13-15AS Na (CAS 86014-79-1) gave no indication of adverse effects on reproductive organs (Munday et al., 1976, 1977a, 1977b). At very high doses (around or above 1000 mg/kg bw/day) increases in relative (but not absolute) testes weights were noted. This effect was not considered as adverse but was attributed to a decreased body fat/body weight ratio. There were also no adverse histopathological findings at necropsy. The primary effect after application via gavage but not after application via the diet was gastrointestinal irritation, particularly of the forestomach. Moreover it was impossible to differentiate between systemic effects as a consequence of the local irritation or due to specific substance properties. After dietary application the liver was the only target organ identified. Adaptive effects on this organ included an increase in liver weight, enlargement of liver cells and elevated levels of liver enzymes. Liver effects were more apparent in dietary studies, partly because these allowed administration of higher doses of the test material with less GI tract injury (cf. chapter on repeated dose toxicity for details on study conduct and results).

As confirmed by literature (Mangelsdorf et al. 2003, Ulbrich and Palmer 1995, Janer et al. 2007, Dent 2007, Sanbuissho et al. 2009) histopathological examinations of reproductive tissues in repeated dose toxicity studies on rodents are of high value and high sensitivity for evaluation of reproductive toxicity in males and females. Moreover, histopathological changes on the reproductive organs in repeated dose toxicity studies are indicative of effects on fertility. Since histological examinations of the reproductive organs are covered in the studies described above, these repeated dose toxicity studies should be considered as sensitive and sufficient enough to evaluate toxicity on fertility. With additional respect to animal welfare, conducting of a two-generation reproductive toxicity study appears scientifically not of high priority. This assumption is further supported by the results of a study during which whole body radiography on rats after i.p. injection of 35S-C10AS K, C12 AS K and C18 AS K was performed. The aim was to follow the distribution of the labeled alkyl sulfates and/or their metabolites within the body with time. For all compounds the only organs, where radioactivity was detected, were the liver and the kidney. The levels (not quantified) were highest 1 h after application (cf. chapter on toxicokinetics for details). Thus, within this study the alkyl sulfates did not reach the reproductive organs. This could explain why the only relevant effects after dietary application in the repeated dose toxicity studies were observed in the liver and why no treatment related effects on the reproductive organs were observed.

Summary of in vivo data

Within the repeated dose studies no histopathological findings on reproductive organs were observed. In addition it is questionable if alkyl sulfates reach the reproductive organs. Therefore, no effects on fertility are expected and conducting a 2-generation study is not needed.

 

Further considerations

However, a reproductive toxicity study on a structurally similar surfactant material, alpha olefin sulfonate (AOS) was conducted. The 2-generation reproductive study (Lion Co., 1980: AOS-Mg: Effects upon the reproductive performance of rats treated continuously throughout two successive generations; unpublished report no. 80/LIF044/508) on the alpha olefin sulfonate mixture showed a complete absence of treatment-related effects on reproductive capacity or systemic organ pathology at systemic doses ranging from approximately 250-1000 mg/kg bw/day based on food intake, similar to the NOAELs in repeated dose studies on AS. The lack of reproductive organ toxicity in dietary, repeated dose studies on various AS surfactants, even at doses in excess of the NOAELs, provides further corroboration for the absence of specific, surfactant-mediated effects on the reproductive organs. The comparable toxicokinetic and metabolic profiles, as well as their toxicological similarities for this and other toxicological endpoints, support the conclusion that insights from the reproductive toxicity study on AOS are applicable to AS.

With regard to animal welfare this read across should be considered to close the data gap in case that waiving of this endpoint seems not sufficient. A more detailed rationale for a read across from AOS to AS would be handed in subsequently.

REFERENCES

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

[2] (HERA Draft report, 2002);
http://www.heraproject.com/files/3-HH-04-%20HERA%20AS%20HH%20web%20wd.pdf

[3] SIDS initial assessment report, (1995);

http://webnet.oecd.org/HPV/UI/SIDS_Details.aspx?Key=5ca67317-5fcc-41ea-a429-53d1267be383&idx=0


Short description of key information:
Waived

Effects on developmental toxicity

Description of key information
OECD 414, rat, developmental toxicity, oral: not teratogenic
Maternal: NOEL = 250 mg/kg bw/day; LOEL > 250 mg/kg bw/day
Developmental: NOEL = 250 mg/kg bw/day; LOEL > 250 mg/kg bw/day
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
250 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
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.

There is a substantial data base on triethanolamine (TEA) online available. TEA is not listed in Annex VI of directive 1272/2008. In addition the effects of TEA on human health were assessed by the OECD in the SIDS initial assessment Report [3]. Despite of some local signs of irritation TEA gives no rise to concern of adverse effects on human health. Therefore a contribution of TEA to the effects on human health is considered to be negligible when assessing human health effects of C8-14AS TEA (CAS 85665-45-8). Therefore, read across to alkyl sulfates with other counter ions is considered to be valid and reliable. This approach was also followed by the OECD in the SIDS initial assessment profile [1] and by the voluntary industry programme carrying out Human and Environmental Risk Assessments (HERA [2]).

In the developmental toxicity study which was chosen as key study C12-14AS Na (CAS 85586-07-8) was administered orally by gavage to pregnant Wistar rats at dose levels of 0, 63, 125, 250 and 500 mg/kg bw/day once daily from Day 6 to 15 of gestation (Cambridge, 1987). In summary, C12-14AS Na (CAS 85586-07-8) induced maternal toxicity, indicated by body weight decrease, diarrhoea and increased mortality, when administered at doses of 500 mg/kg bw/day. Developmental toxicity could be seen by an increased number of intrauterine deaths, a decreased live foetal body weight and toxic retardation with delayed ossification and increased incidence of supernumerary cervical ribs and shortened thoracic rib at 500 mg/kg bw/day. Based on the available information the NOEL for maternal toxicity and developmental toxicity is set at 250 mg/kg bw/day.

The purpose of the study conducted by Palmer (1975) was to assess the effects of orally administered C12AS Na (CAS 151-21-3) on embryonic and foetal development in pregnant CD-rats and NZW-rabbits. In this study, C12AS Na (CAS 151-21-3) was administered orally by gavage at dose levels of 0, 0.2, 2, 300 and 600 mg/kg bw/day once daily from Day 6 to Day 15 (rat) / Day 19 (rabbit) of gestation. In summary, the results of the study showed that repeated oral administration of C12AS Na (CAS 151-21-3) to pregnant rats and rabbits did not cause symptoms of cumulative maternal toxicity up to a dose level of 300 mg/kg bw/day. There were no treatment-related foetal abnormalities at necropsy and no treatment-related effects in the reproduction data. Thus, based on the available information, the NOAEL for teratogenicity and developmental toxicity are assessed to be greater than 600 mg/kg bw/day.

The effect of C12AS Na (CAS 151-21-3) on embryonic and foetal development was as well assessed by Unilever (1976) in Wistar rats. The test substance was administered by gavage at dose levels of 0, 63, 125, 250 and 500 mg/kg bw/day once daily from Day 6 to 15 of gestation. No cumulative maternal toxicity was seen up to a dose level of 250 mg/kg bw/day. At 500 mg/kg bw/day dams showed significant decreased body weight and food consumption together with corresponding clinical signs like diarrhoea. No treatment-related foetal abnormalities or effects in the reproduction data were observed at 500 mg/kg bw/day. Thus, the NOAEL for teratogenicity and developmental toxicity are assessed to be greater than 500 mg/kg bw/day.

Finally, embryonic and foetal development was examined after administration of C16-18AS Na (CAS 68955-20-4; Unilever, 1978). The alkyl sulfate was administered by gavage at dose levels of 0, 112, 225, 450 and 675 mg/kg bw/day once daily from Day 6 to 15 of gestation. At 450 mg/kg bw/day and higher dams showed significant decreased body weight gain together with diarrhoea. No treatment-related foetal abnormalities or effects in the reproduction data were observed at 675 mg/kg bw/day. Thus, the NOAEL for teratogenicity and developmental toxicity are assessed to be greater than 675 mg/kg bw/day.

Conclusion

In the repeated dose studies it was observed that the primary effect after application via gavage is gastrointestinal irritation. This is consistent with the primary irritant properties of the AS and the bolus effect after application by gavage. Moreover, it was impossible to differentiate between systemic effects as a consequence of the local irritation or due to specific substance properties.

In the developmental toxicity study where teratogenic effects were observed, these occured at the highest dose level after oral gavage. However at this dose level signs of marked maternal toxicity, i.e. increased mortality was observed. At dose levels inducing no maternal toxicity no teratogenicity was observed.Thus, AS are not teratogenic.

REFERENCES

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

[2] (HERA Draft report, 2002);
http://www.heraproject.com/files/3-HH-04-%20HERA%20AS%20HH%20web%20wd.pdf

[3] SIDS initial assessment report, (1995);

http://webnet.oecd.org/HPV/UI/SIDS_Details.aspx?Key=5ca67317-5fcc-41ea-a429-53d1267be383&idx=0

Justification for classification or non-classification

The available data on reproductive toxicity 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.