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Key value for chemical safety assessment

Effects on fertility

Description of key information

A study investigating effects on fertility with the target substance sulfuric acid, mono-C12-14 (even numbered)-alkyl esters, magnesium salts (CAS 90583-23-6) is not required because a pre-natal developmental toxicity study is available. Moreover, no histopathological findings on reproductive organs were observed in relevant repeated dose toxicity studies.

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

Relevant data from repeated dose toxicity studies

No data on reproductive toxicity of the target substance sulfuric acid, mono-C12-14 (even numbered)-alkyl esters, magnesium salts (CAS 90583-23-6) and any other structurl analogue substance are available. In order to assess this endpoint, information from various repeated dose toxicity studies performed with a variety of structural analogue alkyl sulfates (AS) are considered. The possibility of a read-across from 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, neutralised 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 represents the predominant attribute in mediating effects on mammalian health. Therefore, the members of the AS category have similar physicochemical, 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 no Extended-One-Generation Reproductive Toxicity Study with alkyl sulfates (AS) available. Nevertheless, this endpoint is sufficiently covered as data on the reproductive organs after subchronic treatment are available. Subchronic repeated oral toxicity studies with sulfuric acid, mono-C12-15-alkyl esters, sodium salts (CAS 68890-70-0), sulfuric acid, mono-C16-18 (even-numbered)-alkyl esters, sodium salts (CAS 68955-20-4) and sulfuric acid, mono-C13-15-alkyl esters, sodium salts (CAS 86014-79-1) gave no indication of adverse effects on reproductive organs (Unilever 1976a, 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 (refer to section 7.5 '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 can be considered as sensitive and sufficient enough to evaluate toxicity on fertility. With additional respect to animal welfare, conducting additional reproductive toxicity studies appears scientifically not justified. This assumption is further supported by the results of a study during which whole body radiography on rats after i.p. injection of 35S-C10 AS K, C12 AS K and C18 AS K was performed. The aim was to follow the distribution of the labeled alkyl sulfates (AS) and/or their metabolites within the body as a function of 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 (refer to section 7.1 'Toxicokinetics, metabolism and distribution' for details). Thus, within this study the AS did not reach the reproductive organs. This can explain why the only relevant effects after dietary application in the repeated dose toxicity studies referred to above 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 whether AS reach the reproductive organs. Therefore, no effects on fertility are expected and conducting additional reproductive toxicity studies is not needed.

 

Further considerations

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 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 similarities for this and other toxicological endpoints, support the conclusion that insights from the reproductive toxicity study on AOS are also applicable to AS.

 

[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

Mangelsdorf, I., Buschmann, J., Orthen, B., 2003. Some aspects relating to the evaluation of the effects of chemicals on male fertility. Regulatory Toxicology and Pharmacology 37, 356–369

Ulbrich, B. and Palmer, A.K. (1995). Detection of effects on male reproduction: a literature survey. J. Am. College of Toxicology 14, 293–327

Janer G, Hakkert BC, Slob W, Vermeire T, Piersma AH. 2007. A retrospective analysis of the two-generation study: What is the added value of the second generation? Reprod Toxicol 24:97-102.

Dent MP. 2007. Strengths and limitations of using repeat-dose toxicity studies to predict effects on fertility. Regul Toxicol Pharmacol. 2007 Aug; 48(3):241-58. Epub 2007 Apr 12.

Sanbuissho A, Yoshida M, Hisada S, et al., 2009. Collaborative work on evaluation of ovarian toxicity by repeated-dose and fertility studies in female rats. J Toxicol Sci 2009.:SP1-22.

Effects on developmental toxicity

Description of key information

No data are available for the target substance sulfuric acid, mono-C12-14 (even numbered)-alkyl esters, magnesium salts (CAS 90583-23-6). Therefore, read-across from structural analogue substances has been applied.

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

Read-across of key information from source substance sulfuric acid, mono-C12-14-alkyl esters, sodium salts (CAS 85586-07-8) supported by additional studies performed with various structural analogue substances.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
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:
key study
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 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
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Key result
Dose descriptor:
NOEL
Remarks:
systemic
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Basis for effect level:
other: No toxic effects.
Remarks on result:
other: Source, key, 85586-07-8, 1987
Key result
Dose descriptor:
NOEL
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: No toxic effects.
Remarks on result:
other: Source, key, 85586-07-8, 1987
Developmental effects observed:
yes
Lowest effective dose / conc.:
500 mg/kg bw/day (actual dose received)
Treatment related:
yes
Relation to maternal toxicity:
developmental effects as a secondary non-specific consequence of maternal toxicity effects
Conclusions:
Treatment of pregnant rats with the test substance at 500 mg/kg bw/day induced a maternal toxic response and this was reflected in the conception which showed toxic retardation. At 250, 125 and 63 mg/kg bw/day, the test substance did not cause maternal toxicity or foetotoxicity and did not show teratogenic potential.
Executive summary:

The developmental toxicity of the target substance is estimated based on an adequate and reliable prenatal developmental toxicity study of a structural analogue source substance. Treatment of pregnant rats with the test substance at 500 mg/kg bw/day induced a maternal toxic response which was reflected in the conception that showed toxic retardation. At 250, 125 and 63 mg/kg bw/day, the test substance did not cause maternal toxicity or fetotoxicity and did not show teratogenic potential. The results are further supported by additional (supporting) studies on various structural analogue substances. As explained in the category justification, the differences in molecular structure between the target and the source substances are unlikely to lead to differences in developmental toxicity / teratogenicity.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
250 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The available information comprises adequate and reliable (Klimisch score 2) studies from various source substances with similar structures and intrinsic properties. Read-across is justified based on common physico-chemical, ecotoxicological and toxicological properties. The selected studies are thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.
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

No data on developmental toxicity / teratogenicity are available for the target substance sulfuric acid, mono-C12-14 (even numbered)-alkyl esters, magnesium salts (CAS 90583-23-6). Therefore, this endpoint is covered by read-across from structurally related alkyl sulfates (AS). The possibility of a read-across from 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, neutralised 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 represents the predominant attribute in mediating effects on mammalian health. Therefore, the members of the AS category have similar physicochemical, 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.

In the developmental toxicity study which was chosen as key study sulfuric acid, mono-C12-14-alkyl esters, sodium salts (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 (Unilever, 1987). In summary, the test item 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 supporting studies conducted by Palmer (1975a, b) was to assess the effects of orally administered sodium dodecyl sulfate (CAS 151-21-3) on embryonic and foetal development in pregnant CD-rats and NZW-rabbits. In this study, the test item 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 sodium dodecyl sulfate (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 sodium dodecyl sulfate (CAS 151-21-3) on embryonic and foetal development was also assessed by Unilever (1976d) in Wistar rats in another supporting study. 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 sulfuric acid, mono-C16-18-alkyl esters, sodium salts (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 performed with a variety of structural analogue alkyl sulfates (AS) 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 which revealed teratogenic effects (Unilever, 1987), these occurred only at the highest dose level after oral gavage. However, at this dose level signs of marked maternal toxicity, i.e., increased mortality was also observed. It is important to note that not teratogenicity was observed at dose levels inducing no maternal toxicity. Thus, based on the experimental findings, AS substances, including the target substance sulfuric acid, mono-C12-14 (even numbered)-alkyl esters, magnesium salts (CAS 90583-23-6), are not considered to exhibit a teratogenic potential.

 

[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 classification or non-classification

The available data on reproductive and developmental toxicity as well as teratogenicity obtainded with structurally analogue substances do not meet the criteria for classification according to the CLP Regulation (EC) No. 1272/2008 and are, therefore, conclusive but not sufficient for classification. Based on read-across the target substance sulfuric acid, mono-C12-14 (even numbered)-alkyl esters, magnesium salts (CAS 90583-23-6) is also not classified for reproductive toxicity.

Additional information