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Description of key information

Two key studies for the evaluation of repeated dose toxicity of the substance are available. A 28-day oral gavage study in rats according to OECD guidlines 407 and 424 and an oral dietary  2-generation study in rats according to OECD guideline 416. In the latter study histopathology of the target organs of the 28-day study was additionally performed.

In the 28-day study groups of 5 male and 5 female Spraque-Dawley rats received daily doses of 0, 15, 150 and 600 mg of the test substance/kg bw  in olive oil by gavage. Treatment related effects in this study were a significantly increased blood cholesterol level in males and females of the high dose group compared to controls, singificantly increased absolute and relative  liver weights in females of the 150 mg/kg bw/day group (35% and 30% respectively), females of the 600 mg/kg bw/day group (78% and 73% respectively) and in males of the high dose group (52% absolute and 68% relative). An increase in absolute and relative thyroid weight was observed in high dose animals. The absolute thyroid weights were increased by 36% and 58% and the relative weights by 48 and 54% in males and females respectively. A slight hepatocellular hypertrophy was observed in 3 of 5 female rats of the 150 mg/kg bw dose group and findings of slight to marked hepatocellular hypertrophy were reported in all males and females of the high dose group. There was no evidence of nuclear or cytoplasmic degenerative or necrotic changes. Thyroid microscopy revealed follicular cell hypertrophy, decreased diameter of follicular lumen and decreased eosinophilic colloidal contents in all animals of the high dose group. These changes are indicative of an increased thyroid activity. This is frequently observed after liver enzyme induction due to increased thyroid hormone turnover in the liver and can thus be secondary to the liver hypertrophy. A NOAEL of 15 mg/kg bw per day was derived from this study based on liver weight changes and liver histopathology ...

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
15 mg/kg bw/day

Additional information

In a 28-day study oral (gavage) study in Sprague-Dawley rats, significantly greater absolute and relative liver weights were noted in females from the mid dose of 150 mg/kg/day and in males at the highest dose (600 mg/kg/day). A significantly higher mean cholesterol level was detected in the high dose animals. A significant increase in absolute and relative thyroid weight was also noted in the high dose group. The higher liver and thyroid weights were considered treatment-related and correlated with histopathological changes observed in these organs among these animals. A NOAEL of 15 mg/kg/day can be determined from this study based on the absolute and relative liver weight changes and the correlated liver histopathology. The effects in the mid dose group where however mild and can be viewed as adaptive rather than adverse effects. It is noted that the dose spacing in this study was large (10 fold) and therefore, the true NOAEL may actually be higher than 15 mg/kg. The target organs identified in the 28 -day and the 2 -generation study are the same, the doses at which the effects were observed in the target organs and the severity of the effects are comparable between the two studies. Therefore, the NOAEL of 15 mg/kg bw/day from the 28-day study, while conservative, can be considered to be relatively robust and an increase in the duration of exposure (to sub-chronic exposure) does not increase the severity of the effect observed. No data are available on inhalation and dermal repeated dose toxicity.

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

Justification for classification or non-classification

Due to the slight rather adaptive than adverse effects observed in the mid dose groups of both the 28 -day and the 2 -generation study in rats that do not represent a significant toxic effect according to Regulation (EC) No 1272/2008 and EC Dir 67/548 and adaptations. A significant toxic effect or target organ toxicity was not observed at dose levels below 300 mg/kg bw per day in the 28 -day study or 100 mg/kg bw per day in the 2 -generation study. Therefore no classification for specific target organ toxicity after repeated exposure is warranted.

Reference:

European Union Risk Assessment Report "2,2-Bis(chloromethyl)trimethylene bis[bis(2-chloroethyl)phophate]" (V6), CAS 38051-10-4, May 2008