4-ethoxy-2,3-difluoro-4'-propyl-1,1'-biphenyl

Endpoint summary

Description of key information

Resorption

Because of the molecular structure, low molecular weight and octanol-water partition coefficient (>5.7), resorption of the test item via the gastrointestinal tract is considered to be likely.

After single treatment of rats with the test item at a dose of 2000 mg/kg bw no signs of toxicity were observed (acute oral: key study).

Daily oral treatment by gavage of 100 and 300 mg/kg bw/d of the test item to rats according to the study design was tolerated whereas 1000/600 mg/kg bw/d was clinically not tolerated and lead to early sacrifice of 4 female animals. All doses (100, 300 and 1000 mg/kg bw/d) were clinically tolerated over a treatment period of 41 days in males. Slight effects were seen on motor activity, mean body weight, mean body weight gain and food consumption. In females 100 and 300 mg/kg bw/d were clinically tolerated over a treatment period of approximately up to 7 weeks. At 300 mg/kg bw/d females showed slight effects on mean body weight, mean body weight gain and food consumption and at 100 mg/kg bw/d females only showed a slight effect on mean body weight gain. In the surviving females of group 4 (1000/600 mg/kg bw/d) the mean body weight gain after dose reduction from 1000 to 600 mg/kg bw/d was strongly reduced body and the mean body weight at the beginning and end of treatment was nearly the same. According to the effects of in-life body weights, decreases terminal body weight were seen in 300 mg/kg bw/d females, 1000 mg/kg bw/d males and in the surviving 1000/600 mg/kg bw/d females at necropsy. In addition, decreases of absolute and relative liver weights were observed in 1000/600 mg/kg bw/d females, most likely as a consequence of the catabolic metabolism status. At histopathology, the following treatment-related and non-adverse alterations were noted in the liver of 1000 mg/kg bw/d males and surviving 1000/600 kg/kg/d females: multifocal hepatocellular necroses (both sexes), multifocal mononuclear infiltrates and reduced hepatocellular glycogen content (both females only). The 1000 mg/kg bw/d females that were prematurely sacrificed showed a decreased cellularity in the bone marrow and lymphoid depletion in the cortex of the thymus. Both findings were considered secondary to the moribund condition of the animals. Regarding reproduction parameters no treatment-related effects were noted at the clinically tolerated doses of 100 and 300 mg/kg bw/d. In conclusion, the no adverse effect level (NOAEL) regarding systemic toxicity and reproduction parameters is considered to be 300 mg/kg bw/d.

From these effects it can be concluded that the test item is resorbed after oral administration.

 

Distribution

Due to the low water solubility and the high octanol/water-coefficient, in combination with the low molecular weight, permeation of membranes is assumed to be possible. The toxicological effects found in the repeat dose toxicity study of the test item (OECD 422) clearly show that this compound is distributed throughout the body after oral uptake and is thus systemically available.

 

Metabolism and Excretion

Specific information on the metabolism and excretion of the substance is not available. From the OECD 422 study metabolism in the liver can be assumed as findings were observed in the liver. Due to the molecular properties, excretion via the kidneys is considered to be the main route of elimination.