Disodium (Z)-4-(9-octadecenylamino)-4-oxo-2(or 3)-sulphonatobutyrate

Endpoint summary

Description of key information

No subcacute toxicity data were available for the registered substance, however read-across substance Butanoic acid, 4-amino-4-oxo-2(or3)-sulfo-, N-(C16-C18 (even numbered), C18unsaturated alkyl)), disodium salts was tested in a key repeated dose/reproduction and developmental toxicity screening study at oral gavage doses of 60, 120 and 300 mag act.ingr./kg bw. At 300 mg/kg bw/day, clinical signs, decreased body weight and food consumption, haematological changes and organ weights changes of several organs were noted in male and female rats. NOAEL-levels were 120 mg/kg bw for paternal/maternal toxicity; 120 mg/kg bw for reproductive toxicity and 300 mg/kg bw for developmental toxicity.
No subchronic data were available for the registered substance, however subchronic (and subacute) data were available from read-across substance 'Butanoic acid, 4-amino-4-oxosulfo-, N-tallow alkyl derivs., disodium salts' (CAS No. 68988-69-2) at dietary doses of 0.50, 2.00 and 8.00 g act.ingr./kg bw/day, of which the high dose was reduced to 4 g/kg feed/day after 6 weeks. NOEL for the test item in the rat was < 500 mg act. ingr. /kg bw/day. Various changes were seen at the highest dose levels, however the mid dose level could be considered as NOAEL, corresponding with 500 mg/kg bw/day. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Study duration:

subacute

Species:

rat

Quality of whole database:

reliable (Klimisch 2)

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

No data were available for registered substance, however data were available for read-across substances

- 'Butanoic acid, 4-amino-4-oxo-2(or 3)-sulfo-, N-(C16-C18 (even numbered), C18 unsaturated alkyl), disodium salts'
- CAS No. 68988-69-2: 'Butanoic acid, 4-amino-4-oxosulfo-, N-tallow alkyl derivs., disodium salts'.
Justification for read-across with category members is provided in Section 13.

 

Subacute toxicity and combined repeated dose toxicity wiht the reproductive/developmental toxicity screening
- Key data for repeated dose toxicity were available from read-across substance 'Butanoic acid, 4-amino-4-oxo-2(or 3)-sulfo-, N-(C16-C18 (even numbered), C18 unsaturated alkyl), disodium salts' in a combination repeated dose/reproduction and developmental toxicity screening study according to OECD TG 422 (Key study; Hansen, 2013a). The test item was administered orally by gavage as a test item containing 25.5% active ingredient to rats at dose levels of 60, 120 or 300 mg act.ingr./kg bw/day. The application started two weeks before mating on test day one and ended on the day or one day before sacrifice. Day of sacrifice was on test day 37 for the male rats and on lactation day 4 or shortly thereafter for the female rats. One of 10 male and one of 10 female animals both at 120 and 300 mg/kg bw/day) died prematurely. At 300 mg/kg bw/day clinical signs in form of salivation, pilo-erection and/or breathing sounds were noted in a few male and female animals for 1 or 2 test days. A statistically significant reduction in body weight was noted in both sexes at 300 mg/kg bw/day. Accordingly, food consumption and body weight were statistically significantly reduced in both sexes at 300 mg/kg bw/day. Haematology showed statistically significant changes at 300 mg test item/kg bw/day, including increased MCH and decreased aPTT time (male animals) and increased No. white blood cells and lymphocytes (female animals). Changes in the relative or absolute organ weights of several organs were noted for the male animals dosed at 300 mg test item/kg bw/day, most remarkably for the relative liver weight which increased for almost 20%. The macroscopic and microscopic examinations revealed no test item related changes.

NOAEL-levels were as follows: 120 mg/kg bw for paternal/maternal toxicity; 120 mg/kg bw for reproductive toxicity (see Section 7.8.1); 300 mg/kg bw for developmental toxicity (see Section 7.8.2).

- A supporting 14 -day dose range finding study was conducted with ' Butanoic acid, 4-amino-4-oxo-2(or 3)-sulfo-, N-(C16-C18 (even numbered), C18 unsaturated alkyl), disodium salts' in rats given test item containing 25.5% active ingredient; the animals were treated once daily with 100, 300 and 1000 mg act.ingr./kg bw/day by oral administration (Hansen, 2013b). One of 5 male animals dosed at 300 mg/kg bw/day and 3 of 5 male animals and 1 of 5 female animals dosed at 1000 mg /kg bw/day died prematurely. Premortal symptoms in form of pilo-erection, reduced motility, increased respiratory rate, cold to touch, decreased respiratory rate and a reduced drinking water consumption. Pilo-erection, a thickened abdomen, pultaceous faeces, an anus soiled with faeces and breathing sounds were noted for the male and female animals treated with 1000 mg/kg bw/day. The body weight of the male animals dosed at 300 or 1000 mg/kg bw/day and of the female animals treated with 1000 mg/kg bw/day was reduced. Body weight gain and body weight at autopsy were reduced accordingly. A reduced food consumption was noted for male and female animals treated with 1000 mg/kg bw/day. At macroscopic inspection at necropsy, one of 5 male animals treated with 300 mg/kg bw/day showed reddened lungs. Furthermore, changes in the gastrointestinal tract (filled with gas, distended, with liquid content, nearly empty, (mucosa) reddened, soft content, haemorrhagic foci, detachment of mucosa), lungs (reddened), spleen (reduced in size) and external observation (thickened / soft abdomen, anus smeared with faeces, pilo-erection) were noted for the male and female animals (including deceased animals) treated with 1000 mg /kg bw/day. The relative and absolute kidney weights of the animals were decreased starting at 100 mg /kg bw/day for the male animals and at 1000 mg/kg bw/day for the female animals. After consideration of these data, the following dose levels were selected for the combined repeated dose toxicity and reproduction/developmental toxicity screening test: 60, 120 and 300 mg/kg bw/day.

- In conclusion, a (parental) NOAEL of 120 mg/kg bw was found in the conbined repeated/reproductive and developmental toxicity study with structurally similar stubance administered by gavage. Therefore it can also be assumed for reigstered substance.

 

Subchronic toxicity
No subchronic data were available for the registered substance, however subchronic (and subacute) data were available from read-across substance 'Butanoic acid, 4-amino-4-oxosulfo-, N-tallow alkyl derivs., disodium salts' (CAS No. 68988-69-2).

-In a supporting 30 -day subacute oral repeated dose study (Shaffer and Golz, 1956b) the test item containing 35% active ingredient was added to the diet of three groups of young male albino rats (10 animals per group) to give concentrations of 0.25%, 0.50% and 1.00% in terms of solids content (act. ingr.) of the sample. In the course of the study, these dietary levels resulted in mean daily dosages of 0.23 g/kg, 0.46 g/kg and 0.88 g act. ingr./kg, respectively. No deaths occurred as a result of feeding of the product, and there were no characteristic signs of toxicity. However, at the highest dosage level, mean daily food intake was significantly reduced and mean body weight gain for the 30-day period was only about one-half that of the controls. Mean kidney weight at this dose was slightly but significantly reduced. At the 0.50% level, mean body weight gain was significantly lower, but food intake was comparable to that of the controls. At the lowest level, neither food intake, nor weight gain were affected, and appearance and behavior of the animals were normal. All animals were sacrificed at the conclusion of the study and no gross pathology was found at autopsy that could be related to feeding of the material. Mean kidney weight was slightly but significantly decreased at the highest dose level. NOAEL was 230 mg act. ingr./kg bw /day.
- In a key subchronic oral repeated dose study (Tegeris and Underwood, 1976a) the test item containing 35% active ingredient was fed to albino rats for ninety days at doses of 0.50, 2.00 and 8.00 g act.ingr./kg bw/day. The rats were carefully observed for the duration of the experiment, body weight and feed intake /conversion were measured and pertinent haematological and biochemical parameters were conducted after 6 weeks and after termination. At the conclusion of the experiment all rats were necropsied and all organs and/or tissues were examined histologically from ten rats (five male and five female). Due to mortality of 4 rats at 8 g/kg bw/day, dosing was reduced to 4 g/kg feed/day after 6 weeks. These studies have further shown that the test item, when fed to rats under the conditions of this experiment, decreased the rate of body weight gain and food intake, at all levels and caused acute gastro-enteritis and/or acute nephritis within six weeks at 8.00 g/kg/day. When this dose was decreased to 4.00 g/kg/day and given for seven weeks some rats displayed zonal fatty infiltration in the liver. At the lowest dose level, decreases in body weight (gain) and feed intake were minimal (<10%) and were not considered relevant. Decreased organ weights were observed for heart, liver, kidneys, adrenal an thyroid weight at the medium and high doses. From the data presented in this study it appears that the NOEL for the test item in the rat was < 500 mg act. ingr. /kg bw/day. A NOAEL of 500 mg act.ingr./kg bw/day however can be considered.
- In a supporting subchronic oral repeated dose study (Tegeris and Underwood, 1976b) the test item containing 35% active ingredient was fed to purebred beagle dogs for ninety days. Thirty two purebred beagle dogs were dosed at 0.062 ,0.250 g and 1.000 g act. ingr./ kg bw/day thoroughly mixed in the diet. The test material interfered with the feed consumption and feed efficiency and decreased the rate of body weight gain of dogs when fed the compound at 0.250 and 1.000 g/kg bw/day, leading to the decision to decrease the highest dose to 0.500 g/kg bw after 2 weeks and stop dosing in this high dose group after six weeks. There was no biological effect on any parameter at 0.062 g active ingredient/kg of body weight per day. The dog study was not considered adequate due to the young age of the animals at start of dosing (3 -4 months). Decreased body weights and feed intake at the higher doses were attributed to higher sensitivity of the gastro-intestinal tract, by which systemic toxicity could not appropriately be determined.

- In conclusion, a NOAEL of 500 mg/kg bw was observed in the key subchronic toxicity study in the rat wiht structurally related subsance, administered by diet. Therefore it can also be assumed for the registered substance.

 

Conclusion
- The NOAEL of 120 mg act. ingr./kg bw in the OECD 422 study was considered as the most conservative value, therefore this was selected as the descriptor for DNEL calculations with registered substance.

- Further information supporting the safety of the test substance is provided in the read across justification for the N1 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 according to most recent standards

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

Justification for classification or non-classification

As there was no toxicity below classification threshold, classification for repeated dose toxicity is not needed according to the EC Directive (No.93/21/EEC) and CLP (No. 1272/2008 of 16 December 2008).