Registration Dossier

Administrative data

Description of key information

NOAEL oral, rat, 2-year feeding: ≥ 195 mg/kg bw/d (males); ≥ 259 mg/kg bw/d (females)

Waiver repeated dose toxicity: dermal

Waiver repeated dose toxicity: inhalation

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
259 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
The available data comprises adequate and reliable (Klimisch score 2) studies. The selected study is thus sufficient to fulfil the standard information requirements set out in Annexes VIII-IX, 8.6 of Regulation (EC) No 1907/2006.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

 There are two data sources available from literature referring to repeated dose toxicity of Sulfonic acids, C14-16 (even numbered)-alkane hydroxy and C14-16 (even numbered)-alkene, sodium salts via the oral route. As key study a 2-year feeding study in rats was chosen (Hunter & Benson, 1976). In this study, no adverse effects related to treatment with the test substance were observed; the only effect observed was a slight depression of body weight gain in the high dose males and females during treatment weeks 14 to 26 and returned to normal levels thereafter. All other effects observed were normal for rats of that strain and age and reflected the normal observations related to ageing. Based on that study a NOAEL of 195 mg/kg bw/d for males and 259 mg/kg bw/d for females was determined, which at the same time was the highest administered dose. The slightly higher NOAEL for females was chosen for the risk assessment, as this reflected the highest dose tested, and differences in dose height compared to the male animals occurred due to differences in food uptake. It is justified to assume that the males would have not shown symptoms of toxicity, either, if dosed with the same amount as taken up by feed by the females. This view is supported by peer-reviewed data reporting NOAELs of 500 and 1000 mg/kg bw/d from subchronic studies.

In the supporting study (Stadler et al., 2008) male rats were treated for 90 days with a single dose of 70 mg/kg bw/d. Here, adverse effects in the nasal turbinates were observed which were considered treatment-related. Therefore, a LOAEL of 70 mg/kg bw/d was adopted in that study. However, as this effect did not occur at higher doses in the 2-year feeding study, and the data of the supporting study was obtained from only 5 rats (this study actually focused on a completely different substance; Sulfonic acids, C14-16 (even numbered)-alkane hydroxy and C14-16 (even numbered)-alkene, sodium salts had only been included as an additional treatment group because it served as surfactant in the vehicle for the actual test substance), these effects should be considered as incidental. Additionally, data from peer-reviewed secondary literature (Little, A.D., 1993) of 90-day feeding studies with NOAELs of 500 and 1000 mg/kg bw/d are available. Although not sufficient for assessment these information support the view that the NOAEL of AOS is to be expected well beyond 70 mg/kg bw/d.

 

The available data on repeated dose toxicity via the dermal route is not acceptable for assessment, only secondary sources without sufficient documentation from a review article are existent (Little, 1993). However, none of the available sources, ranging in durations from 2 to 90 days and performed in either rabbits, rats or mice, demonstrated treatment-related systemic effects. The only observations were local irritant effects of varying grade. Therefore, according to Annex IX, section 8.6.2, column 2 of Regulation (EC) No 1907/2006, the testing of repeated dose toxicity via the dermal route, although being relevant for humans, can be omitted as toxicokinetic data demonstrates that dermal absorption is negligible (0.62% via intact skin), and data from a chronic toxicity study via the oral route is available.

 

No data is available on repeated dose toxicity via the inhalative route. However, the test substance is most frequently marketed in form of an aqueous solution, and vapour pressure is negligibly low. Therefore, inhalation is not the most relevant route of exposure. According to Annex IX, section 8.6.2, column 2 of Regulation (EC) No1907/2006, the testing of repeated dose toxicity via the inhalation route can be omitted as this is not the most relevant route of human exposure, and data from a chronic toxicity study via the oral route is available.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

The selected study is the most adequate and reliable one based on the overall assessment of quality, and with special respect to duration and dose descriptor level (active ingredient content). Systemic effects described in the alternatively available 90-day oral gavage study should have also been observed in the selected chronic Repeated Dose Toxicity Study due to the longer study duration. As no adverse effects were observed in the latter despite longer study duration and a higher active ingredient concentration, the chronic Repeated Dose Toxicity Study was selected as key study, and the corresponding NOAEL of 259 mg/kg bw/d served as basis for hazard assessment.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:

The registered substance is most frequently marketed in form of an aqueous solution, and vapour pressure is negligibly low. Therefore, inhalation is not the most relevant route of exposure. According to Annex IX, section 8.6.2, column 2 of Regulation (EC) No1907/2006, the testing of repeated dose toxicity via the inhalation route can be omitted as this is not the most relevant route of human exposure, and data from a chronic toxicity study via the oral route is available.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:

The registered substance is most frequently marketed in form of an aqueous solution, and vapour pressure is negligibly low. Therefore, inhalation is not the most relevant route of exposure. According to Annex IX, section 8.6.2, column 2 of Regulation (EC) No1907/2006, the testing of repeated dose toxicity via the inhalation route can be omitted as this is not the most relevant route of human exposure, and data from a chronic toxicity study via the oral route is available.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:

The available data on repeated dose toxicity via the dermal route is not acceptable for assessment, only secondary sources without sufficient documentation from a review article are existent (Little, 1993). However, none of the available sources, ranging in durations from 2 to 90 days and performed in either rabbits, rats or mice, demonstrated treatment-related systemic effects. Futhermore, according to Annex IX, section 8.6.2, column 2 of Regulation (EC) No 1907/2006, the testing of repeated dose toxicity via the dermal route, although being relevant for humans, can be omitted as toxicokinetic data demonstrates that dermal absorption is negligible (0.62% via intact skin), and data from a chronic toxicity study via the oral route is available.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:

The available data on repeated dose toxicity via the dermal route is not acceptable for assessment, only secondary sources without sufficient documentation from a review article are existent (Little, 1993). In these studies, local irritant effects of varying grade were observed. However, the registered substance is classified as skin irritant according to the criteria of the EU Directive 67/548/EEC and Regulation (EC) No 1272/2008; therefore, corresponding risk management measures are in force, and the risk of local effects is considered to be sufficiently controlled.

Justification for classification or non-classification

Repeated dose administration of Sulfonic acids, C14-16 (even numbered)-alkane hydroxy and C14-16 (even numbered)-alkene, sodium salts for 104 weeks in the diet revealed a NOAEL of 259 mg/kg bw/d.

Based on this data, Sulfonic acids, C14-16 (even numbered)-alkane hydroxy and C14-16 (even numbered)-alkene, sodium salts does not have to be classified for Specific Target Organ Toxicity - Repeated Exposure according to the criteria of the EU Directive 67/548/EEC and Regulation (EC) No 1272/2008.