Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The whole data base is conclusive and of high quality.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

General aspects

Subchronic repeated dose oral toxicity studies with C12-15AS Na, C16-18AS Na and C13-15AS Na as well as two combined chronic toxicity/carcinogenicity study with C12-15AS Na gave no indication of adverse effects on reproductive organs (Munday et al., 1976, 1977a, 1977b, 1995a&b). 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). No adverse effect on fertility of male Swiss mice was observed within a feeding study with C12AS Na. 10 males were dosed either with 1 % C12AS Na over 2 weeks and fertility was assessed over the ensuing 3 week period or with 0.1% C12AS Na over 6 weeks and fertility was assessed 1, 2 or 3 weeks after termination of treatment with 6 animals. At the highest dose level body weights were significantly decreased, while the treatment caused no adverse effects on fertility. A NOAEL of 1000 mg/kg bw/d was derived for this endpoint in the OECD SIDS. Although the data are limited and are not sufficient for classification purposes the data support the assumption that fertility is not impaired by treatment with C12AS Na.

The existing prenatal developmental toxicity studies (OECD Guideline 414) did not indicate adverse effects on the development of pups, when females were treated with different alkyl sulfates during pregnancy. This is the only OECD Guideline study gathering information on skeletal and visceral effects in the fetuses, but additionally provides further information on the development of pups. Within the study with C12-14AS Na, besides the common investigations of fetuses upon caesarian section, 5 mated rats from each of the treatment groups were selected by random for natural parturition. The observation period of pups of these litters was 21 days. No effect on litter size, pup weight, mortality and no clinical signs of toxicity in pups were observed. Thus, neither indication on developmental toxicity nor the early development of the pups post parturition (until day 21) was observed.

Based on these data, reproductive toxicity or toxic effects on fertility of C12AS Na is very unlikely. To overcome remaining uncertainties a read-across from the structurally related anionic surfactant C12-14AES Na can be performed.

Read-across justification from structurally related alkyl ether sulfate to C12AS Na

No 2-generation toxicity study is available for the registered substance C12AS Na (CAS 151-21-3) or a structurally related alkyl sulfate. Therefore the toxicological data requirements set out in Annex X of Regulation (EC) No. 1907/2006 are formally not fulfilled. In accordance with Annex XI of Regulation (EC) No. 1907/2006 read-across from a structural analogue substance (C12-14 alkyl ether sulfate sodium salt with 2 ethoxylation units) will be performed to reduce animal testing and fulfil the data requirements. Both substances are linear anionic surfactants. The surfactant properties of both substances are conferred by a hydrophobic carbon chain with a polar sulfate group. The carbon chain of the alkyl ether sulfate is ethoxlyated twice prior the sulfate group.The surfactant properties represent the predominant attribute in mediating effects on mammalian health. Next to the structural similarity the test item C12-14AES Na additionally comprises 20% C12AS Na and approximately 9% C14AS Na. Thus approximately 29% of the test item was similar or even identical to C12AS Na. If alkyl sulfates have a reproduction toxic potential, this considerable amount of alkyl sulfates can be expected to contribute to possible effects of the test substance. Therefore the test item is also suited to assess the toxicity to reproduction of C12AS Na. Despite the structural similarity of the source and the target substance and the amount of alkyl sulfates within the test item, there are further reasons to perform a read-across from alkyl ether sulfates to alkyl sulfates. Both linear anionic surfactants are absorbed readily in the gastrointestinal tract. Within the body, both substances are metabolized via omega and beta-oxidation of the carbon chain. The resulting C2-fragments enter the general C2-Pool of the organism and will be either degraded within the citric acid cycle or used to produce ketone bodies. Short carbon chains linked to the sulfate group in case of alkyl sulfates or linked to the ethoxysulfate group in case of alkyl ether sulfates are rapidly urinary excreted. Thus alkyl sulfates in principle comprise the same or comparable metabolites as alkyl ether sulfates. Based on the known metabolites a low systemic toxicity can be expected for both substances. This was proven by several repeated dose toxicity studies with alkyl sulfates and alkyl ether sulfates, respectively (please refer to the analogue justification attached to this waiving statement). Thus the read-across form C12-14AES (ethoxylation degree of 2) is well suited to close the data gap of C12AS Na. The 2-generation study performed with C12-14AES Na is summarised below.

Summary of the 2-generation toxicity study performed with C12-14AES Na (based on the HERA Report, 2003)

C12-14AES Na (ethoxylation degree of 2) was applied to 30 Sprague Dawley rats of each sex via the drinking water at concentrations of 0.03, 0.1 and 0.3% according to OECD Guideline 416. The doses corresponded to daily doses of approximately 30, 100 and 300 mg/kg bw/day. Slight parental toxicity was observed at the top dose group of 0.3% of the test substance. Reduced triglyceride levels (female) and increased percentage neutrophil counts (males) were observed. Both effects were slight and within the range of the historical control data. The male F0 generation showed a small but significant reduction in relative liver weight, but the corresponding brain related liver weights and the absolute liver weights developed not in a dose dependent way. For the F1 generation where similar results were reported, no dose-response relationship was detected either. No effect on liver weight development was seen in the F2 generation. None of the groups revealed any histopathological or clinical-chemical findings. This led to the conclusion that this untypical liver weight reduction was of no toxicological relevance. This is underlined by the absence of such effects in the studies for subchronic toxicity. Therefore the systemic NOAEL can be established at 0.3% ~ 300 mg/kg bw/d. Within the HERA-Report however a NOAEL of 0.1% for systemic toxicity was established. For the main purpose of the study (toxic effects on reproduction) this parameter does however not influence the overall conclusion.

A slight but significantly reduced straight line velocity (VSL) of the sperm was observed in males of the top dose which was rather significant by chance than to reflect a treatment related effect. This is also supported by available subchronic and chronic toxicity studies on various AES where no adverse effects on the primary sex organs of males and females were observed.

At the top dose an increased time needed for sexual development of the male (not significant) and the female (significant) offspring was observed. This effect was investigated in more detail in a developmental toxicity study with C12-14AES up to 1000 mg/kg bw/day and no effects were noted there. Therefore this finding is considered to be incidental.

Based on the available data the NOAEL for reproduction toxicity can be set to greater than 0.3% ~ 300 m/kg bw/d. This is in agreement with the NOAEL established in the HERA report. The Letter of Access for the main study on reproduction toxicity will be purchased as soon as ECHA agrees to the read-across approach and the dossier will be updated with the respective Robust Study Summary.

Conclusion on reproduction toxicity

Due to structural similarities, common metabolites, identical human hazard profiles and the composition of C12-14AES Na the data achieved with C12-14AES Na reflect also the hazard potential of C12AS Na. Therefore the read-across from C12-14AES Na is well suited and also indicated by the 3R concept to close the data gap of C12AS Na. The absence of any reproduction toxicity of C12AS Na is further supported by the known ubiquity occurring metabolites of C12AS Na, the repeated dose toxicity data of alkyl sulfates investigating reproductive organs and the developmental studies with several alkyl sulfates (both data sets including C12AS Na). In consequence, no hazard for reproduction toxicity is expected for C12AS Na. For reasons of animal well fare the read-across from C12-14 AES can be considered to overcome the last uncertainties which may by present actually.


Short description of key information:
There is a reliable OECD guideline study with the structural related analogue substance C12-14AES Na available. In the following, the study result is summarised. For details refer to the discussion below.
OECD 416, rat, 2-generation, oral: not reprotoxic
NOAELrepro > 300 mg/kg bw/day
NOAELsys > 300 mg/kg bw/day

Justification for selection of Effect on fertility via oral route:
There is a reliable OECD guideline study with the structural related analogue substance C12-14AES Na available.

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
Quality of whole database:
The whole data base is conclusive and of high quality.
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. A detailed justification for grouping of alkyl sulfates into a category is provided separately. Please refer for more details on the read-across also to the document “AS Category Approach Justification” attached in section 13 of IUCLID.

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


Justification for selection of Effect on developmental toxicity: via oral route:
A reliable OECD Guideline study was chosen.

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.