Teflubenzuron

Endpoint summary

Description of key information

Based on the data available, the substance has a low absorption rate of 2-18% via the oral route depending on the dose administered. Inhalation and dermal exposures can also be expected to lead to very low absorption rates. Tissue distribution is low, with the exception of stomach and intestines; none of the organs investigated experimentally showed > 1 % tissue distribution of the substance administered. Excretion is rapid (within few days), the excreted compound was determined to be mainly the unchanged parent compound. Very few metabolites were detected in feces and urine, and their concentrations in both were very low.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

18

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

20

Additional information

Several studies exist with thorough investigation of oral absorption and subsequent distribution, metabolization and excretion of the test substance. This information is corroborated by Koerts et al., Xenobiotica 27, 801-017 (1997).

 

Absorption:

All data available indicate that following oral uptake, the test substance is poorly resorbed in the gastrointestinal tract. Based on experiments with radiolabeled test substance, approximately 85-90 % of the orally administered test substance is excreted unchanged with the feces within eight days following the last administration. The numbers vary slightly between studies and depend on the test setup as well as the dose administered, but all studies unanimously report a high excretion of unchanged test substance.

A bile duct canulation (study not included in IUCLID but RSS can be provided upon request) has shown that the summation of radioactivity in urine, bile and liver indicated a total rate of absorption of 18 % or 2 % of the administered dose at low (25 mg/kg bw) and high (750 mg/kg bw) doses respectively. Therefore, the test substance has an overall rate of gastro-intestinal absorption of less than 20 % of the administered dose.

Based on the data available, the oral absorption is to a certain extent dose-dependent, however no differences between sexes was observed.

 

No experimental data for absorption via the respiratory tract is available. In an acute inhalation study, the test substance did not cause mortality when tested up to limit doses. Nevertheless, some clinical signs of mild distress were observed, such as dyspnea and ruffled fur. Therefore, it is feasible to assume that the substance is absorbed to a low degree. This is further supported by the physical-chemical data available (Log Kow 4.98 and water solubility 0.00005 g/L). In the absence of further information, absorption via the respiratory tract is estimated to be around the same degree as the oral route, based on the clinical signs observed in acute studies. Therefore, absorption via the respiratory tract is assumed to be 20% for risk assessment purposes.

 

Similarly, no experimental data for absorption via the skin is available. In acute dermal toxicity studies, the test substance did not cause mortality or any signs of toxicity when tested up to 2000 mg/kg bw in either rats or rabbits. Therefore, it can be concluded that the test substance is absorbed via the skin only to a very small degree, if at all. This is further supported by the physical-chemical data available (Log Kow 4.98 and water solubility 0.00005 g/L). In the absence of further information, absorption via the skin is estimated to be around half of that observed via the oral route, based on the clinical signs observed in acute studies. Therefore, absorption via the skin is assumed to be 10% for risk assessment purposes.

 

Distribution:

In a toxicokinetic study, radiolabeled test substance was administered to rats via gavage daily for seven days and organ load was monitored following the last administration. In all organs examined (liver, kidney, muscle, fat, stomach, intestine), the amount detected was below 1% of administered dose at all time points (1h, 6h, 24h, 2d, 5d), with the exception of stomach or intestines. In the stomach, the amount of radioactivity detected was calculated to be over 1% of the dose administered at 1h and 6h, while it was below 0.1% for all other time points. In the intestine, a similar kinetic  could be observed, although with a time shift - the amount of radioactivity detected was calculated to represent less than 0.1% of the dose administered starting at the 2d time point. Five days after the last administration, the amount of radioactivity detected suggested ≤ 0.01 % of test substance administered in all organs except the liver where residual levels corresponding to 0.05% of the dose administered could still be detected.

 

Metabolization:

In a metabolism study in rats, the by far greatest portion of extractable fecal residues consists of the unchanged parent substance itself (male rats: 67.4 %, female rats: 71.1 % of the applied radioactivity).

The remaining 12.7 % (males) and 11.8 % (females) of the applied radioactivity contained in the fecal extracts represent a large number (at least 15) of unknown compounds none of which exceeds 1 % of the applied radioactivity. 9.8 % (males) and 10.0 % (females) of the applied radioactivity remain unextractable in the feces. About half of these portions (5.2 % and 5.3 %, respectively) can be solubilized with hydrochloric acid. Most of this additionally released radioactivity (4.0 % and 4.1 %, respectively) represents the parent compound, too.

In the urine of the rats three metabolites could be identified. Two of these compounds are structural isomers formed by hydroxylation of the benzoyl ring (positions 3 and 4). The third product is formed by substitution of one fluorine atom of the aniline ring by hydroxide. None of these products exceeds 1 % of the applied radioactivity.

In conclusion, apart from the parent compound, only small amounts of metabolites are detected, consisting of polar substances. One of them has been identified as 3,5-dichloro-2,4-difluorophenylurea in some feces extracts. The metabolic pathway is via meta-hydroxylation of the benzoyl ring and conjugation. Only a very small amount of radioactivity corresponds to the hydroxylated aniline derivatives. Scission of the benzoyl ureido function represents an additional pathway of degradation.

 

Excretion:

The experimental data available reveal that the substance is excreted completely by both sexes within a short period of time (see also information on distribution).

 

 

Summary:

Based on the data available, the substance has a low absorption rate of 2-18% via the oral route depending on the dose administered. Inhalation and dermal exposures can also be expected to lead to very low absorption rates. Tissue distribution is low, with the exception of stomach and intestines; none of the organs investigated experimentally showed > 1 % tissue distribution of the substance administered. Excretion is rapid (within few days), the excreted compound was determined to be mainly the unchanged parent compound. Very few metabolites were detected in feces and urine, and their concentrations in both were very low.