Hexanoic acid, 3,5,5-trimethyl-, 2,2,6,6-tetramethyl-1-[2-[(3,5,5-trimethyl-1-oxohexyl)oxy]ethyl]-4-piperidinyl ester

Endpoint summary

Description of key information

In regard to the results of the OECD 422 guideline study and the assessment of toxicokinetics and metabolism the test item is not expected have a bioaccumulation potential or to provoke delayed systemic toxic effects. The test compound is most likely systemically available after oral administration, however, there are strong indications for phase I and II metabolism and subsequent biliary excretion.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

There are no studies available in which the toxicokinetic properties of the test substance were investigated. Assessment of absorption, metabolism and excretion based on single and repeated dose studies.

 

Chemistry

The test substance (molecular weight of 482 Da) is a yellowish liquid with a water solubility (deionised water) of < 0.0004 mg/l. Based on individual solubilities in water and octanol the logPow is calculated to be > 9.4, measured by HPLC logPow is > 6.5. Examination of the vapour pressure was carried by effusion method, extrapolated to 25 ° VP is < 0.000001 hPa. In regard to the molecular structure of the substance and the poor solubility in water hydrolysis is not likely.

 

Absorption

In an acute oral and dermal toxicity study, rats were administered to the test substance. No mortalities or clinical signs of toxicity were observed at the limit dose of 2000 mg/kg bw, indicating primarily a very low level of oral and dermal toxicity.

Based on a calculation according to the model of Fitzpatrick the substance is expected to be of moderate skin permeability (Fitzpatrick, et al., 2004).

In an acute oral toxicity study, rats were administered to the test substance. No mortalities or clinical signs of toxicity were observed at the limit dose of 2000 mg/kg bw, indicating primarily a very low level of oral toxicity. The NOAEL in male and female rats in an OECD 422 study is considered to be 150 mg/kg bw, the maximum dose level applied. Mortality or toxicological effects were not observed in this study. However, the decrease of the total bilirubin level as well as the accumulation of α2u-globulin in high dose males indicates that the substance is systemically available after oral administration.

The substance is expected to be stable at physiological pH levels even in an acidic (gastric juice) or basic environment (pancreatic secretion). Hydrolysis of the ester bond requires high pH level, i.e. presence of NaOH, and leads to formation of 4-Hydroxy-1-(2-hydroxyethyl)-tetra methyl piperidine (HEHTPM) and trimethyl hexanoic acid. Hydroxylation of the methyl groups of the hexanoic acid side chains and subsequent formation of keto- or secondary carbonic acid-groups in turn is more likely. In a second step these metabolites can be conjugated with e.g. UDP-glucuronic acid and thereafter excreted via the biliary route. The supposed induction of phase II enzymes would correlate with the decrease in bilirubin (substrate if UGT1A1) observed high dose males.

In case the UDP-glucuronic acid is eliminated afterwards by intestinal enzymes, the previously introduced modifications by phase I enzymes should be adequate for biliary or renal excretion.

 

Conclusion on potential bioavailability and delayed systemic effects

In regard to the results of the OECD 422 guideline study and the assessment of toxicokinetics and metabolism the test item is not expected have a bioaccumulation potential or to provoke delayed systemic toxic effects. The test compound is most likely systemically available after oral administration however there are strong indications for phase I and II metabolism and subsequent biliary excretion.

 

 

Used references:

 

Fitzpatrick, D., et al. (2004). "Modelling skin permeability in risk assessment-the future." Chemosphere 55 (10): 1309-14.