Registration Dossier

Administrative data

Description of key information

A combined repeated dose and reproductive/developmental screening study was performed with read across substance CAS No. 90268-36-3 (Butanedioic acid, sulfo-, 1-C12-18-alkyl esters, disodium salts) according to OECD guideline 422, showed NOAEL-levels of 60 mg/kg bw for paternal/maternal toxicity, 120 mg/kg bw for reproductive toxicity and 120 mg/kg bw for developmental toxicity. A 90-day study was also available for the read across substance CAS No. 37294 -49 -8 (Disodium C-isodecyl sulphonatosuccinate) in the mono-ester subgroup, given to rats at 0.25, 1 and 4% in the diet. This study showed a NOAEL of 1% in the diet, corresponding with 750 mg/kg bw.  For risk assessment, the lowest NOAEL of 60 mg/kg bw  in the OECD 422 study was selected as this approach was considered most conservative. 

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
60 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Klimisch 1

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

Subacute toxicity

No data were available for the registered substance, but read across data were available from subgroup member CAS No. 90268-36-3 (Butanedioic acid, sulfo-, 1-C12-18-alkyl esters, disodium salts):

- A key study for subacute toxicity was performed by means of an oral combined repeated dose and reproduction/development screening study according to OECD guideline 422 (Hansen, 2013a). The test item was a solid formulation (containing >93% active ingredient) which was administered as a watery solution orally by gavage to rats at dose levels of 60, 120 and 300 mg act. ingr./kg bw/day for at least 28 days in male rats up to 54 days in female rats. One of 10 male and one of 10 female animals at 300 mg/kg bw/day died prematurely on test day 33 or on gestation day 9. Slight to moderate salivation was noted in a few male and female animals at 120 mg/kg bw/day; at 300 mg/kg bw/day, piloerection and a slight to extreme salivation was noted for several to all male and female animals on several days. Reduced body weight was noted for the male animals at 120 mg/kg bw/day and for both sexes at 300 mg/kg bw/day. Increases in ALAT, aP and ASAT and decreases in globulin, cholesterol, chloride and potassium concentrations were noted for the male and/or female animals of the intermediate and/or the high dose group (120 and/or 300 mg/kg bw/day). Several organ weights were seen in males and females dosed at 120 and 300 mg/kg bw/day, most remarkably for the thymus and liver weights of the animals of the high dose group. Macroscopic inspection revealed changes in the stomach of male animals dosed at 300 mg/kg bw/day and female animals dosed at 120 and 300 mg/kg bw/day. Histopathological examination revealed changes in the liver (hepatocellular hypertrophy and macrovesicular vacuolation) and the non-glandular stomach (squamous cell hyperplasia) of male and female animals dosed at 300 mg/kg bw/day. These latter changes are considered to be related to a local activity of the test item. As humans lack a forestomach, the relevance of these changes for humans is questionable.

NOAEL-levels were as follows: 60 mg/kg bw for paternal/maternal toxicity and 120 mg/kg bw for reproductive and developmental toxicity (see Section 7.8.1 and 7.8.2). The reproductive and developmental changes were seen at paternal/maternal toxic doses, and were considered to be secondary to that toxicity.

- A supporting 14-day dose-range-finding study (Hansen, 2013b) was conducted with test item containing >95 % active ingredient to select the dose levels for a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test of the test item in rats. The animals were treated once daily with100, 300 and 1000 mg act. ingr./kg bw/day by oral administration. Four of 5 males and all (5) females treated orally with 1000 mg/kg bw/day died prematurely. Oral treatment with 1000 mg/kg bw/day caused signs of systemic toxicity in form of pilo-erection, reduced motility, pultaeous faeces/diarrhoea, salivation, increased drinking water consumption, ataxia or decreased body temperature in the male and/or female rats. A decrease in body weight, body weight at autopsy and food consumption was noted for the male and female rats treated with the intermediate and the high dose. At necropsy, whitish deposits on the stomach mucosa were observed in the male rats treated orally with 300 mg/kg bw/day. The high dose of 1000 mg/kg bw/day led to further changes in the gastro-intestinal tract in both sexes such as inflation or discolourations. The examination of organ weights revealed a dose-related increase of liver weights. The dose of 300 mg/kg bw was considered as NOAEL, and dose levels selected for the repeated dose and reproduction/developmental toxicity screening test were 60, 120 and 360 mg/kg bw/day.

- In conclusion, NOAEL-levels of 60 mg/kg bw for paternal/maternal toxicity, 60 mg/kg bw for reproductive toxicity and 120 mg/kg bw for developmental toxicity were obtained in a combined repeated dose and reproductive/developmental screening study which was performed with registered substance according to OECD guideline 422. Therefore, no classification is needed.

 

Subchronic toxicity

A 90 -day study was not available for the registered substance, however read across data were available from a category member, CAS No. 37294-49-8 (Disodium C-isodecyl sulphonatosuccinate).

- For this read across substance, a 14 -day dose rang finding study was also conducted as supporting study (Hansen, 2013c). Rats were treated once daily with a test item (47% purity) at100, 300 and 1000mgact. ingr./kg bw/day by oral gavage administration. None of the animals died prematurely. The body weight of the male rats treated orally at 1000 mg/kg bw/day was slightly decreased on test days 8 and 15 compared to the control group. Body weight gain and body weight at autopsy changed accordingly. None of the male and female rats treated orally at 100, 300 or 1000 mg/kg bw/day revealed any test item-related changes in behaviour, external appearance or faeces. No changes in the relative food consumption were noted at any of the tested dose levels. At macroscopic inspection at necropsy, test item-related changes in the stomach (detachment of mucosa, haemorrhagic foci, mucosa thickened/swollen, ulcer and cardia thickened) were noted for the animals treated with 1000 mg /kg bw/day. Further, the absolute kidney weights of the high dosed animals were decreased. In conclusion, 300 mg/kg body weight can be considered as NOAEL. This was comparable to the registered substance, therefore read across was considered valid.

- A 90-day toxicity study was performed in rats with this read across test item containing ca. 50% active ingredient (Tegeris and Underwood, 1975a) at 0.25%, 1.00% and 4.00% in the diet (corresponding to mean calculated test article intake of 188, 750 and 3000 mg act.ingr./kg bw/day). At the highest dose levels, it caused a significant difference in body weight gain, most probably related to an effect by the compound during absorption from the gastro-intestinal tract. There was one mortality in the high dosed females. Haematology and serum analysis also indicated toxicity at the high dose, whereas at the medium dose, only some organ-to-body weight changes were observed (e.g. liver weight increases in both sexes). Other organ-to-body weight changes were also observed at the high dose group (e.g. slightly decreased gonad weights in males; decreased gonad weight in females); increased relative kidney weights were observed in all female dose groups. Chronic renal disease (mild) was observed in 1/20 males and 6/20 females of the high dose groups. The high dose was considered to be toxic, whereas the changes of the medium dose may be considered adaptive. Therefore 1% (750 mg/kg bw/day) may be considered as NOAEL.

- A 90 -day toxicity study in dogs was performed with test item containing ca. 50% active ingredient (Tegeris and Underwood, 1975b) at 0.12%, 0.50% and 2.00% in the diet (corresponding to mean calculated test article intake of 30, 125 and 500 mg act. ingr. /kg bw/day). There was a decreased feed consumption, feed efficiency and corresponding weight loss in the high dose (2.00%) group of dogs. Also testicular atrophy and hepatic fatty infiltration were observed in the same group without functional impairment of the liver. These observations were not considered to be direct toxic manifestations of the test item, as disturbed fat absorption is known as a physiological action of the sulfosuccinate class of compounds. Effects at the highest dose were considered to be secondary manifestations to disturbed fat absorption at these high multiples of human intake. The dose of 500 mg/kg bw (2% in the diet) was considered NOAEL.

- The dog species was considered to be less appropriate due to the disturbed fat absorption, by which systemic effects could not be correctly interpreted. The NOAEL of 750 mg/kg bw/day in rats was selected as main endpoint; this was also consistent with the selection of the rat as main species and NOAELs from the Di-ester substances.

- In conclusion for the subchronic toxicity a NOAEL of 1% in the diet, corresponding with 750 mg/kg bw, was obtained in a 90 -day study with read across substance CAS No. 37294 -49 -8.

 

Conclusion

- For risk characterisation, the paternal/maternal NOAEL of 60 mg/kg bw in the OECD 422 study with subgroup member CAS No. 90268-36-3 was selected as most conservative value.

- Further information supporting the safety of the test substance is provided in the read across justification for the Mono-ester subgroup, (justification with data matrix separately attached in Section 13).


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Key study for the 28-day study. Note however that there is also a key study for the 90-day oral toxicity with a read across substance.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver; digestive: stomach; urogenital: kidneys

Justification for classification or non-classification

As there were no relevant findings below classification threshold of 100 mg/kg bw, classification for repeated dose toxicity is not warranted according to the EC Directive (No.93/21/EEC) and CLP (No. 1272/2008 of 16 December 2008).