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Administrative data

Description of key information

Oral 28-day dietary toxicity with test item containing 35% active ingredient was tested in rats at systemic dose levels of 0.05, 0.25 and 1.25%  in the diet (as solids), corresponding to 48, 254 and 1225 mg act.ingr./kg bw/day. There were no adverse effects observed, therefore the dose of  1225 mg/kg bw/day can be considered as NOAEL.
Oral 90-day dietary toxicity studies with test item (containing 35% active ingredient) were performed in rats at systemic dose levels of 0.5, 2 and 8 (reduced to 4) g act. ingr./kg bw/day and in dogs at 0.062, 0.250 and 1 g act. ingr. /kg bw/day. In rats, 2 and 8 (4) g act.ingr./kg bw/day were toxic, as demonstrated by decreased body weight and food consumption, serum changes, organ-to-body weight decreases and renal disease; the dose of 500 mg/kg bw/day can be considered as NOAEL. The dog study was considered to be less appropriate as the animals were very young and sensitive to gastro-intestinal irritation, although the study did not show systemic toxicity up to 1000 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
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
High quality (Klimish 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

Subacute toxicity

- In a subacute 28 day toxicity study, liquid test item containing 35% act.ingr. of registered test item was added to the basic diet of 4 groups of 10 young male albino rats at dietary levels of 0 (control), 0.05, 0.25 and 1.25% active ingredient (Tusing, 1955). There were no mortalities and no adverse effects on growth or food consumption and autopsies revealed no gross pathology that could be attributed to the dietary feeding of the compound. A NOAEL of 1250 mg act.ingr./kg bw/day was determined, however not all parameters were studied (e.g. haematology, clinical biochemistry and histopathology were missing). The study was considered to be supporting, and no further 28 -day study was needed based on availability of 90-day toxicity data.

- Further, a 14-day dose-range-finding was recently conducted with the same test item used for other toxicity studies (irritation & corrosion; genotoxicity), containing 34.4% active ingredient (Hansen, 2013b). 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. The study confirmed the results of the existing subacute toxicity study, therefore a new repeated dose toxicity study was not deemed necessary.

- In conclusion, subacute toxicity testing was perormed, although these were supporting data. As 90-day studies were available, no further subacute testing was deemed necessary.

Subchronic toxicity

- 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 liver enzymes (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 0.5g 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.

- In conclusion, NOAEL-level of 500 mg/kg bw was considered as the most appropriate value for further risk characterisation.

Conclusion

- For risk characterisation, NOAEL of 500 mg/kg bw in the 90 -day rat repeated dose toxicity study with registered substancewas selected.

- 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

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

Justification for classification or non-classification

Available data suggest values that warrant no classification for repeated dose toxicity under Regulation 1272/2008 (CLP) nor under Directive 67/548/EC (DSD).