1-isoctyloxycarbonyl ethylated 2,4,6 tris (2,4- hydroxyphenyl) -1,3,5 triazine derivatives

Endpoint summary

Description of key information

Repeated dose toxicity was evaluated in a GLP-conform 28d study according OECD guideline 407. The test item was administered daily by oral gavage to SPF-bred Wistar rats of both sexes at dose levels of 50, 200 and 800 mg/kg body weight/day. After 14d post observation period animals were sacrificed. Pathology revealed fatty changes in different treatment groups at different organs. These changes were no longer present after 14d treatment-free period. Decreased locomotor activity was observed at the high dose group.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

800 mg/kg bw/day

Study duration:

subacute

Species:

rat

Additional information

Performance and observations

In a subacute toxicity study (CIBA 2002c), the test item was administered daily by oral gavage to SPF-bred Wistar rats of both sexes at dose levels of 50, 200 and 800 mg/kg body weight/day for a period of 28 days. The groups comprised 5 animals per sex which were sacrificed after 28 days of treatment. Additional 5 rats per sex and group were used at 0 and 800 mg/kg. These animals were treated for 28 days and then allowed a 14-day treatment-free recovery period after which they were sacrificed.

All animals survived until scheduled necropsy. Treatment related clinical signs were not observed. Body weight gain and food consumption was unaffected by the treatment. Haematology, clinical biochemistry and urinalysis revealed no abnormalities. Also examination of organ weight and pathology were without any findings.

No test item related differences in fore- or hindlimb grip strength were evident. The observed decreased mean locomotor activity in males and females, treated with 800 mg/kg/day, recorded from 0 to 15 minutes was considered to be a test item related effect.

In the liver of females a slight increase of fatty change at doses of 800 mg/kg/day and in the adrenals of males a slight increase of cortical fatty change at doses of 200 and 800 mg/kg/day at the end of treatment were observed. After 14-day treatment-free recovery period, no test item-related changes were determined.

Discussion

Histopathological examination revealed development of fatty changes in liver and adrenal glands. A certain amount of fat storage is a normal physiological condition and, as long there is no further sign of liver injury like necrosis, apoptosis or fibrosis, this effects is not considered as an adverse effects but as an adaptive biochemical response for increased amounts. The adrenal cortex produces mineralo- and glucocorticoids using cholesterol as a scaffold substance. Therefore, certain amount of fat vacuoles in the zona fasciculata (place of biochemical synthesis) is physiological. Under some occasions the amount of fat may increase, i.e. all stress factors due to an increased need for corticosteroid precursors.

Moreover, a short-term decrease in mean locomotor activity of the high dose group was determined. The activity was measured four times within 1h during the fourth week of treatment. Diminished activity was recorded in the first quarter only, thereafter, locomotor activity was comparable to control. The deviation from control was statistical significant but not dose-dependent. Thus, toxicological relevance is not clear and a treatment related effect not likely.

Repeated dose studies via dermal or inhalative route were not performed.The molecular weight of the test item is much higher than 500 g/mol and the substance has a logPow > 6. Thus, the test item is not well absorbed via skin. Additionally, the results of other dermal tests to acute toxicity, irritation and sensitization show that the substance does not cause any reaction to skin. Therefore, toxic effects upon repeated dermal application are unlikely.

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available studies are considered reliable and suitable for classification purposes under 67/548/EEC. As a result the substance is notconsidered to be classified for repeated dose toxicity under Directive 67/548/EEC, as amended for the 30th time in Directive 2008/58/EC.

 

 

Classification, Labeling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is not considered to be classified for repeated dose toxicity under Regulation (EC) No. 1272/2008, as amended for the second time in Directive (EC 286/2011).