Registration Dossier

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: assessment based on available data
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-GLP assessment report

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2010
Report Date:
2010

Materials and methods

Principles of method if other than guideline:
Method not determined: reference not located

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Any other information on results incl. tables

For the test substance, information on absorption, distribution, metabolism and excretion is available on experimental animals and on human. An overview of the information is given below.

After oral ingestion of the test substance, there is a rapid absorption from the GItract in experimental animals and humans. In humans peak plasma concentration is reached within 1-2 hr. Chemical carboxylic acid compounds can be metabolized via various pathways, with glycineconjugation being a very common route. For the test substance, glycine conjugation is the mainroute of metabolism in many animals species including human. As a result of this route of metabolism, hippuric acid (benzoyl-glycine) is formed and excreted in urine.

The urinary excretion of orally administered 14C-test substance in man and 20 species of animals was examined by Bridges and coworkers, with hippuric acid (benzoyl-glycine) generally being the major urinary metabolite in the species studied. At an oral dose of 50 mg/kg bw, the test substance was excreted by rodents almost entirely as hippuric acid (95-100% of 24hr excretion)b. After ip administration of 14C-test substance (100 μmol/100 g bw or 200 mg/kg bw), 75- 90% of the 14C excreted in 24 hr, of which 99% hippuric acid and trace of benzoyl glucuronide. An oral dose of 2 mg/kg bw 14C-test substance resulted in only 0.04% of the applied dose in urinary benzoylcarnitine. In man at a dose of 1 mg/kg the test substance was excreted entirely as hippuric acid.

The test substance metabolism, as a function of liver mitochondria, depends on the concentrations of ATP, CoA and glycine in the mitochondrial matrix. Although drug metabolism is primarily a liver function, also kidneys have shown to contain appreciable amounts of metabolizing enzymes. The metabolism of the test substance to hippuric acid and glucuronide has been studied in viable hepatocytes and renal tubule fragments from rat, hamster, ferret and dog. Hippuric acid formation was observed in hepatocytes and renal tubules from rat and hamster; a small amount of glucuronidation occurred in hepatocytes of all species tested. However, the liver is quantitatively the most important organ because the renal medulla has only low synthetic activity and the mass of the liver exceeds that of the kidneys.

Based on the observations on excretion of hippuric acid after oral the test substance administration, it can be concluded that the test substance will be absorbed almost completely in the gastro-intestinal tract. For risk assessment purposes the oral absorption of the test substance is set at 100% absorption. Experiments on the distribution and elimination in the rat have shown no accumulation of the test substance in the body.

There is no information available on absorption via inhalation. The relatively low vapourpressure/high boiling point indicate that the test substance will not be available for inhalation as vapour. The particle size distribution of the test substance (1.5% will be present as <425 μm) indicates that there are no inhalable/respirable particles present. Based on these properties, no repiratory exposure and hence no inhalation absorption is to be expected. If however during use of the substance particles between 100 and 10 μm are generated, these will deposit in the nasopharyngeal region and subsequently be coughed or sneezed out of the body or swallowed. Particles below 10 μm might reach the tracheobronchial or pulmonary regions. Based on its water solubility (2.93 g/L) the test substance will dissolve in the mucus lining of the respiratory tract, and can be absorbed throuigh aqueous pores (MW< 200). Following its modest lipophilic character (log Pow =1.88) the test substance has the potential to be absorbed directly across the respiratory tract epithelium. From a worst case scenario basis it is therefore concluded that when the test substance is inhaled (particles< 10 μm only), absorption of the test substance is to be expected and the inhalation absorption of the test substance for risk assessment purposes is therefore set at 100%.

In vitro skin absorption study with hairless guinea pig showed that the metabolism of the test substance during skin absorption is similar qualitatively to that reported for systemic administration. However, only a small percentage of the test substance was converted to hippuric acid in the skin, in contrast to almost complete conjugation after a systemic dose to humans and many animal species. This was also reported by Naseri-Sina and co-workers, who studied in vitro cutaneous metabolism of [carboxyl-14C] the test substance studies in rat and human, and compared this with metabolism in rat hepatocytes. Tissue-specific differences in metabolism was observed, with conjugation in hepatocytes significantly greater (>98% of radioactivity recovered as glycine conjugate) than in keratinocytes (10.9% and 2.1% glycine conjugate in rat and human skin cells, respectively, during 8 hr incubation). These results indicate that rat and human skin possesses low glycine conjugating activity. Human skin is generally recognized as less permeable to chemicals than is animal skin; human skin may also be less capable of biotransforming certain topically applied chemicals.

In vivo data also showed that the test substance is not completely absorbed by the dermal route. In human subjects, 36% dermal absorption in low dose (4 μg/cm2) was observed within 12 hours with a total uptake of 43% within 5 days. Dermal exposure to a high dose (2000 μg/cm2) resulted in 14% dermal absorption within 24h. In vivo dermal studies with experimental animals confirm the results with human. Absorption ranged from 25% in pigs to 89% in rhesus monkeys. For risk assessment purposes, the dermal absorption of the test substance is set at 43%.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study resultsOverall there are signs of systemic absorption via oral and dermal exposures, no evidence of target organs or of excretion. After oral ingestion and dermal absorption, the test substance will be metabolised to hippuric acid. Experiments on the distribution and elimination in the rat have shown no accumulation of the test substance in the body.
Executive summary:

With reviewing the existing data, for the test substance, information on absorption, distribution, metabolism and excretion is available on experimental animals and on human. A toxicokinetic assessment has been performed based on physical chemical properties of the substance and available open literature.

Overall there are signs of systemic absorption via oral and dermal exposures, no evidence of target organs or of excretion. After oral ingestion and dermal absorption, the test substance will be metabolised to hippuric acid. Experiments on the distribution and elimination in the rat have shown no accumulation of the test substance in the body.