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Description of key information

Key value for chemical safety assessment

Additional information

There were no studies available in which the toxicokinetic properties of the test substance were investigated. Based on the large molecular size, the absence of adverse findings in toxicity studies, and the presence of functional groups for metabolism, a potential for bioaccumulation is unlikely. Further details for this assessments are given below.

 

Chemistry

The test substance (molecular weight of 511 Da) is a granular solid whose water solubility (deionised water) is below 0.05 mg/l and its fat solubility is 170 -227 g/l. The calculated log Pow is 10.15; the vapour pressure is 0.002 hPa.

 

Absorption

In an acute oral and dermal toxicity study, respectively, rats were administered to the test substance. No mortalities or clinical signs of toxicity were observed in doses of 2000 mg/kg bw, indicating primarily a low level of oral and dermal toxicity (see chapter 7.2.1 acute oral toxicity and 7.2.2 acute dermal toxicity). The NOAEL in male and female rats in a subacute oral repeated dose study is 1000 mg/kg bw (see chapter 7.6.1).

Due to the very low water solubility, hydrolysis of the test material even at very low pH (stomach) is not expected. The high molecular weight indicates limited uptake of the test item by the small intestine. Though, the substance bear some resemblance to fatty acids (octadecanoic acid methyl ester) and uptake via micelles with bile acids is thinkable. However, after single oral application soft faeces as well as stained urine and faeces between day 0 and 1 were observed. The time course of this observation suggests that the test material does not enter the enterohepatic cycle. Regarding soft faeces, the substance might influence the texture of faeces or inhibits transient water resumption in colon leading to diarrhoea.

The piperidine ring esterified with a long chained alkyl residue determines the bulky shape of the molecule. Bulky substances may be taken up via Peyer’s Patches in the small intestine. However, this generally leads to their destruction in the macrophages.

With regard to the molecular weight > 500 Da and a logPow > 4, the uptake via skin is expected to be very low (EC, 2004).

The test substance has a comparably very low vapour pressure. This indicates that absorption of the substance via vapour inhalation is not relevant. In addition, the average particle size was determined to be 4.8 x 3.3 x 4.3 mm diameter; the substance is, therefore not inhalable.

 

Metabolism

Oral administration of the test substance to Wistar rats at doses of 100, 500 and 1000 mg/kg/day, for 28 days resulted in no test item-related effects upon mortality and no differences in food consumption or body weight development. The hematology, clinical biochemistry and urinalysis parameters did not show test item-related differences when compared with those of the controls. Organ weights of test item-treated animals were unaffected, and macroscopical/microscopical findings were of no toxicological relevance.

Based on the results of this study, 1000 mg/kg/day was considered to be the no observed- adverse-effect-level (NOAEL).

No indication of uptake or chemical reactivity was observed in any study, including acute studies, irritation, sensitization and genotoxicity in vitro as well as the above described subacute study.

Single oral administration leads to discoloration of urine and faeces. It is, therefore expected that the substance is either not metabolised or reduction by gastrointestinal bacterial or hepatic enzymes leads to formation of non-toxic metabolites. Staining of the faeces and urine is a hint for a lack of metabolism, because cleavage of the substance into metabolites would not lead to discoloration.

In the unlikely case of uptake, potential metabolism might involve hydroxylation of methyl groups and subsequent phase-II conjugation (glucuronidation or sulfonation) at these hydroxyl groups. The test substance is not expected to accumulate in the body.

 

 

Excretion 

Staining of urine and faeces after single oral application is a hint for unchanged renal and biliary excretion. In the case of uptake and metabolism, glucoronidated metabolites would be egested via faeces whereas sulfonated products are excreted by the renal route.

Overall, the test substance is not expected to accumulate in the body.

 

Used references:

  

Guidance document on dermal absorption, European Commision, 2004

REACH Practical Guide on Exposure Assessment and communication in the Supply Chains, June 2010