Reaction mass of sodium 3-{[3-(diethylamino)propyl]carbamoyl}-2-(dodecylamino)propanoate and sodium 3-{[3-(diethylamino)propyl]carbamoyl}-3-(dodecylamino)propanoate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Adequacy of study:

other information

Applicant's summary and conclusion

Executive summary:

There is no reliable and relevant information source in which the toxicokinetic properties (absorption, distribution, metabolism, elimination) of thesubmission substancewere investigated. The expected toxicokinetic behaviour is derived from the physicochemical properties and the results from the available toxicological data following the guide given in the REACH guidance document R.7c.

CHIMEXANE HB is a substance composed of constituents having a molecular weight in the 379-519 g/mol range. It is a pasty solid with an estimated water solubility above 158.4 mg/L at 20°C. Vapour pressure was determined to be 0.0085 Pa at 20°C and it has lipophilic properties (3<log K_ow<4.5 for the main constituents, extrapolated log K_ow= 4 for the submission substance). The surface tension is 30.08 mN/m at 20°C at 1000 mg/L. More details regarding these data can be found in the section 4 of CHIMEXANE HB IUCLID dossier.

Absorption:

In anacute oral toxicity study, the major clinical signs observed in animals dosed 2000 mg/kg bw were hypoactivity, piloerection and dyspnea. Lower body weight gain was observed in the surviving animal dosed 2000 mg/kg bw and in 1/5 females dosed 300 mg/kg bw. The systemic toxicity effects observed at 2000 mg/kg bw indicate that thesubmission substance is absorbed when administered orally at high doses.

In anacute dermal toxicity study, no systemic effects were observed at 2000 mg/kg bw CHIMEXANE HB. However, the submission substance has a molecular weight < 500 and is a lipophilic substance (log Kow = 4) and has moderate water solubility: dermal absorption is therefore expected. Also, as the substance has also corrosive properties, damage to the skin surface may enhance penetration.

In a90-day repeated dose toxicity study, tubular necrosis with clinical chemistry changes were observed in animals dosed 450 mg/kg bw/day CHIMEXANE HB. These effects indicate that the submission substance is absorbed when administered orally at moderately high doses.

Thus, indications of oral and dermal uptake of CHIMEXANE HB/the submission are given. Therefore the bioavailability of CHIMEXANE HB/the submission substance can be considered to be existent but maybe limited.

Distribution:

Available physico-chemical data (low molecular weight, lipophilicity and moderate water solubility) indicate that the submission substancecould be distributed to many tissues and, due to its lipophilicity, may have a particular affinity for fatty tissues.

Metabolism:

No data are available but differences in cytotoxicity were observed with and without the use of a metabolic activation system in differentin vitrogenotoxicity studies (HPRT,chromosome aberration assay). This indicates that the submission substance may be metabolised by hepatic microsomal fractions.

Excretion:

As nephrotoxicity was observed in the 90-day repeated dose toxicity study, it can be considered that the submission substance and its metabolites are excreted in urine. 

Accumulative potential:

Based on some toxicological studies that provide indications on CHIMEXANE HB absorption and metabolism (repeated dose toxicity study and genotoxicity studies) and on physico-chemical information (molecular weights < 500 and log Kow =4), it is concluded that CHIMEXANE HB is partially bioavailable, it is also likely to be metabolized by hepatic enzymes and excreted. Therefore, the potential for bioaccumulation is expected to be low.