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Toxicity Summary

 

Acute oral toxicity:

In a recent study (2005), performed according to actual guidelines, an LD50 of >2000 mg/kg bw was determined. The test substance was administered in CMC/Tween 80). There were no adverse effects noted in the animals and no systemic effects were observed.

 

Acute dermal toxicity:

In a recent study, performed according to actual guidelines, the LD50 was >2000 mg/kg bw and no adverse effects were noted in the animals. No indication for a dermal absorption was obtained from this study.

 

Repeated dose toxicity:

Results of a 28-Day toxicity study and of a 90-Day toxicity study demonstrate an absorption of the test substance in the gastrointestinal tract and a distribution in the body. The test substance induced mild hepatic alterations, notable as hepatocellular vacuoles and by some clinical-chemical parameters. A decrease in the number of platelets in the blood and some organ weight changes were noted in addition.

All test substance related findings were present only in a low grade of severity and never became life-threatening.

The presence of hepatocellular vacuoles is attributed to the test substance, but, in the absence of clear signs of toxicity, they are interpreted rather as adaptive changes.

None of the test substance related effects persisted until the end of the recovery period. There was no pronounced sex difference in the response to the test substance.

The No-observed-adverse-effect-level (NOAEL) of "Resin 835 A" was at 316 mg per kg body weight and day in both sexes, based on possible adverse effects in the high dosed group. No severe toxic effects were noted even at a dose of 1000 mg/kg.

In a Prenatal Developmental Toxicity Study (gavage) 250 mg/kg bw/day was associated with decrease in food consumption and lower maternal body weights during the initial phase of treatment (Day 5 -8). At 1000 mg/kg bw/day there was a reduction in maternal body weights gains during the treatment period GD 5 to 20 (-15.7%) and in food consumption during the treatment period GD 5 to 20 (-17.3%) and throughout gestation period 0 to 20 (-13.4 %).

At 1000 mg/kg/day, the male and female fetal weights (-8.9% and -7.3%, respectively) were significantly lower and were considered to be treatment-related. Fetal skeletal examination revealed significant increase in minor anomalies such as Extra, Accessory and Rudimentary rib No.14 at 1000 mg/kg/day and this finding was attributed to maternal stress due to treatment as evidenced by decrease in maternal body weight / body weight gain, and food consumption.

Based on the above findings, it is concluded that, No Observed Adverse Effect Level (NOAEL) for Maternal toxicity and Fetal developmental toxicity is 250 mg/kg/day

 

Reproductive toxicity

In a Prenatal Developmental Toxicity Study (gavage) 250 mg/kg bw/day was associated with decrease in food consumption and lower maternal body weights during the initial phase of treatment (Day 5 -8). At 1000 mg/kg bw/day there was a reduction in maternal body weights gains during the treatment period GD 5 to 20 (-15.7%) and in food consumption during the treatment period GD 5 to 20 (-17.3%) and throughout gestation period 0 to 20 (-13.4 %).

At 1000 mg/kg/day, the male and female fetal weights (-8.9% and -7.3%, respectively) were significantly lower and were considered to be treatment-related. Fetal skeletal examination revealed significant increase in minor anomalies such as Extra, Accessory and Rudimentary rib No.14 at 1000 mg/kg/day and this finding was attributed to maternal stress due to treatment as evidenced by decrease in maternal body weight / body weight gain, and food consumption.

 

Genetic toxicity

The test item gave negative results in one bacterial gene mutation test, in one mammalian gene mutation test and in one mammalian cytogenetic study, regardless whether tested without or with the addition of metabolizing enzymes. All studies were performed under GLP and according to current guidelines. The test item was non-mutagenic in all three assays.

 

Toxicokinetic summary

 

Absorption / distribution

Absorption of the test substance in the gastrointestinal tract and a distribution in the body was demonstrated by two oral repeated dose toxicity studies and a prenatal developmental toxicity study with the test item. No systemic effects were noted after single oral administration (acute oral toxicity).

No systemic effects were noted after single dermal exposure to the test substance (acute dermal toxicity study). The high partition coefficient n-octanol/water (ca. 6.5) and the low water solubility (<1 mg/L) might however enable a penetration of the test item through biological membranes. A potential for bioaccumulation might also exist, based on the high partition coefficient.

 

Metabolism

No relevant differences occurred in the three mutagenicity studies with and without the addition of a metabolising system. Therefore no indication of the importance of the metabolism of the test item was obtained from these studies.

 

Excretion

No information is available on excretion of the test item.