Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

% of Radioactive Dose Absorbed Dermally - 0.040% in 6 hrs to 0.159% in 120 hrs
oral systemic absorption is very low (0.55 to 1.30% of total radioactive dose administered).

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
0.55
Absorption rate - dermal (%):
0.159

Additional information

The registered substance has been studied in extensive absorption, distribution, metabolism and excretion (ADME) studies.

The data from the dermal study clearly indicate that absorption of radioactivity into systemic circulation (blood) following dermal exposure to [14C]-132983 -41 -6 for 6 hours is extremely low. The low dermal systemic bioavailability was also evidenced by the low blood concentrations (close to limit of detection) observed. Definitive toxicokinetic analysis was very limited because of low blood concentrations observed. Based on comparison with an oral absorption ADME study carried out separately and comparison of their AUCs, dermal absorption occurs even to a lesser extent (at least one order to two orders of magnitude less) than oral absorption at the same 100 mg/kg dose range. Due to the low systemic absorption, distribution to the individual tissues was very low (<0.001%) and not expected to pose any bioaccumulation potential via the dermal route. Overall, systemic absorption of the registered substance by the skin is extremely low and these findings would not be expected to cause systemic exposure concerns since so little material was absorbed via this route. It is believed that the high molecular weight MW 599, average), low water solubility (<0.01 mg/L) and high log Kow (>10) physico-chemical characteristics of the test material may be the main contributing factors limiting its dermal absorption [see references, Roberts and Walters (2008); U.S. EPA (1992); Bronaugh and Maibach (1989); Flynn (1990)]. The radiolabelled ADME experiments showed that oral systemic absorption of the registered substance is very low (0.55 to 1.30% of total radioactive dose administered).and is not expected to cause systemic exposure concerns given the very low systemic oral bioavailability and the fact that systemic toxicity has not been reported for the test material in rats. In addition, the very poor oral absorption findings are consistent with the inherently high molecular weight (MW 599 average) and low water solubility of the registered substance (<0.01 mg/L). The remainder of the total radioactive dose was found recovered as unabsorbed test material in the faeces. Although the test material was distributed to the tissues after oral absorption, the amounts remaining in most tissues were extremely low at the end of 144 hours and were not considered to pose any health safety effect concern. The registered substance has not been reported to cause any specific target tissue toxicity or adverse effects. Metabolism of the registered substance is likely to be occurring in the liver since polar water-soluble metabolites including sulphate or glucuronide conjugates have been detected in the plasma and in the urine. The exact chemical identity of the metabolites have not been fully characterized owing to the lack of available metabolite reference standards for comparison as well the confounding issue that the registered substance is a complex mixture which may contain many different isomeric components making structural assignment challenging. However, based on read-across analogy with structurally related alkylated naphthalenes (Kojima et al 1982 and Hoke et al 1998), the metabolic pathways taking place most likely involve oxidative metabolism of the “tetradecyl“ side alkyl side-chain group in the registered substance to form the corresponding alcohol or subsequent further oxidized carboxylic acid metabolite (and their conjugates). Metabolites formed via oxidation of the tetradecyl “alkyl side-chain pathway” are believed to lead to detoxified, water-soluble conjugates that are readily excreted in the urine and are believed to account for the relatively non-toxicity reported for structurally analogous alkylated naphthalenes (see review by Hoke et al 1998). Finally, the toxicokinetics blood data reported for the registered substance in this study were found to fit a two-compartment oral absorption model. Using the WinNonlin v6.3 modeling software program, key kinetic rate constants and parameters such as Cmax, tmax, absorption and elimination rate constants and half-lives, clearance, volume of distribution, AUC, etc. were calculated to provide a comprehensive toxicokinetic information profile for the registered substance in accordance with OECD 417 guidance. Taken together, the available studies support that the registered substance