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Description of key information

Key data  for subacute toxicity  were available from an oral (gavage) OECD 422 study in rats  with registered substance 'Butanedioic acid, 2(or 3)-sulfo-, 4-[2-[(1-oxo(C12-C18(even numbered) and C18unsaturated)alkyl))amino]ethyl]esters, disodium salts',  at dose levels given by oral gavage of 100, 300 and 1000 mg/kg bw/day. No relevant effects were observed at 100 and 300 mg/kg bw. At the dose of 1000 mg/kg bw, decreased body weight, increased serum ALAT and decreased serum albumin were observed as systemic changes, whereas  macroscopic and microscopic stomach changes were observed as local changes, the latter without relevance to humans. NOAEL for paternal/maternal toxicity was 300 mg/kg bw/day. 
Key data for subchronic toxicity were available from an oral (diet) 90-day toxicity study in rats with read-aross substance 'Aspartic acid, N-(3-carboxy-1-oxo-sulfopropyl)-N-(C16-C18 (even numbered), C18unsaturated alkyl) tetrasodium salts' dosed at 0.5, 2 and 8 (reduced to 4) g/kg bw.day. The study showed decreased body weight gain, feed consumption and food efficiency at the mid dose and high dose levels and increased SGOT and SGPT (liver enzymes) at the high dose. Further hematuria was seen in the mid and high dose rats, various organ weights were decreased (e.g. decrease in adrenal and gonadal weight in high dose groups; decrease in pituitary weight in females of high dose group) and lower urinary tract pathology was seen in 2 high dosed rats. It thus appeared that the NOEL in the rat was below 0.50 g/kg/day, however 0.5g act.ingr./kg bw/day can be considered as NOAEL.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
High quality (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

Studies were available for registered substance.

- A key study for repeated dose 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 administered orally by gavage to rats with a liquid formulation containing 41.5% active ingredient at dose levels of 100, 300 and 1000 mg/kg bw/day for at least 28 days in male rats and at least 39 days in females. No test item-related premature death was noted in any treatment group. No signs of clinical toxicity were noted for the male and female rats of the low and intermediate dose groups (100 and 300 mg/kg bw/day), whereas slightly increased salivation was noted in one male rat at 1000 mg/kg bw/day. No observational and functional neurological findings were seen up to the highest dose group. A slight reduction in body weight was noted for the male and female rats dosed at 1000 mg/kg bw/day. The laboratory examinations revealed an increased serum ALAT activity for the male and female rats dosed at 1000 mg/kg bw/day, and a decreased serum albumin concentration for the male rats of the high dose group. No test item-related changes were noted during the macroscopic inspection at autopsy with the exception of changes in the stomach from 2 male animals from the high dose group. Microscopic examination revealed the occurrence of squamous cell hyperplasia in the non-glandular mucosa of the forestomach and acute inflammation in the male and female rats of the high dose group. These changes are considered to be local, and not relevant for humans as humans lack a forestomach. NOAEL for paternal/maternal toxicity was 300 mg/kg bw/day.

- In a supporting 14-day dose-range-finding study (Hansen, 2013b) the dose levels were selected for a combined repeated dose and reproduction/developmental toxicity screening test. 5 Male and 5 female rats were treated once daily with a liquid formulation containing 41.5% active ingredient at dose levels of 100, 300 and 1000 mg act.ingr./kg bw/day by oral gavage administration. None of the animals died prematurely. Salivation was noted for 2 of 5 male animals treated with 1000 mg/kg bw/day starting on day 9 and increased faeces was noted for 3 of 5 male and 2 of 5 female high dosed animals starting on test day 5. The food consumption of the male and female animals treated with 1000 mg/kg bw/day was slightly increased by 9% for the males and by 10% for the females in test week 2. None of the male and female rats treated orally with 100, 300 or 1000 mg/kg bw/day revealed any test item-related changes in body weight, body weight gain as well as relative and absolute organ weights or at macroscopic inspection at necropsy. Maximum tolerated dose was 1000 mg/kg bw.

Subchronic toxicity

Data were available for read across substance 'Aspartic acid, N-(3-carboxy-1-oxo-sulfopropyl)-N-(C16-C18 (even numbered), C18unsaturated alkyl) tetrasodium salts'. Justification for read across within the category of N-containing sulphosuccinates (N2 and N3 subcategories) is documented in a separate document attached in Section 13.

- A supporting 14-day dose-range-finding was conducted with test item containing 34.4% active ingredient (Hansen, 2013c). Male and female rats were treated orally with 100, 300 or 1000 mg act. ing. /kg bw/day. No rats died prematurely nor revealed any test item-related changes in behaviour, external appearance or faeces. No changes in body weight and body weight gain, food and drinking water consumption or for relative and absolute organ weights were noted at any of the tested dose levels. Macroscopic examination revealed no test item-related changes at any of the tested dose levels. Maximum tolerated dose was 1000 mg/kg bw.

- In a key subchronic repeated dose toxicity study, 160 Sprague-Dawley albino rats, 80 of each sex, were fed a control diet, or 0.50, 2.00 or 8.00 g/kg /day of test item mixed in the diet (Tegeris and Underwood, 1976a). The liquid test item contained 35.8% active ingredient, which was taken into account for the dosages. The high dose was reduced to 4.00 g/kg/day mixed in the diet for weeks five through to termination. The study showed decreased body weight gain, feed consumption and food efficiency at the mid dose and high dose levels and increased SGOT and SGPT at the high dose. Further hematuria was seen in the mid and high dose rats, various organ weights were decreased (e.g. decrease in adrenal and gonadal weight in high dose groups; decrease in pituitary weight in females of high dose group) and lower urinary tract pathology was seen in 2 high dosed rats. It thus appeared that the NOEL in the rat was below 0.50 g/kg/day, however 0.5 g (500 mg) act.ingr./kg bw/day can be considered as NOAEL.

- In another subchronic repeated dose toxicity study, test item containing 35.8% active ingredient was given in the diet to purebred beagle dogs for ninety days (Tegeris and Underwood, 1976b). Thirty-two purebred beagle dogs, sixteen of each sex, with an average age of three to four months, were fed the control diet or 0.062, 0.250 or 1.000 g act.ingr. /kg bw/day thoroughly mixed in the diet. The dogs were carefully observed for the duration of the experiment and several hematological and biochemical parameters were conducted while the experiment was in progress. At the conclusion of the experiment all dogs were necropsied and all organs and tissues were examined histologically. These studies have shown that the test substance interfered with the average daily feed consumption of the mid-dose female and high dose test dogs and decreased the rate of bodyweight gain of the high dose test dogs when fed to them under the conditions of this experiment. Otherwise it was harmless up to 1 g/kg bw/day; a NOAEL of 0.250 g/kg bw/day can be considered.

 

Conclusion

- The NOAEL of 300 mg/kg bw in the OECD 422 study with registered substance was considered as the most conservative value, therefore this was selected as the descriptor for DNEL calculations.

- Further information supporting the safety of the test substance is provided in the read across justification for the N2 and N3 subgroups, showing that all substances in these sulfosuccinates subgroups had similar NOAELs (justification with data matrix separately attached in Section 13).


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

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

Justification for classification or non-classification

Based on these results and according to the EC Directive (No.93/21/EEC) and CLP (No. 1272/2008 of 16 December 2008), the test substance does not have to be classified and has no obligatory labelling requirement for repeated dose toxicity.