Alkanes, C14-17, chloro

Endpoint summary

Additional information

The absorption, tissue distribution and elimination of a¹⁴C-labelled C14 -17 chlorinated paraffin (52% chlorinated) after a single oral gavage administration at a dose level of 525 mg/kg bw was investigated in male rats. Radioactivity in blood and plasma, urine and faeces, selected tissues (but not gastrointestinal tract) and residual carcass was determined for up to 89 days post dosing. In animals kept in metabolism cages until termination, the average total recovery of radioactivity from urine, faeces and those tissues and organs sampled was 83.6% of the administered dose. Approximately 70% of the dose was recovered in the faeces and approximately 6% in the urine in the first 4 days after administration. This suggests that only about 30% of the orally administered dose was absorbed by day 4. Radioactivity was still detectable in urine and faeces at the end of the study, suggesting mobilization and excretion from tissue depots. Distribution of radioactivity into the liver and kidney was rapid, with highest levels (1.6 and 0.07% of the dose respectively) seen 24 hours after dosing; whereas distribution into fat and skin-and-fur was slower with the highest levels (2.5 and 3.7% respectively) seen on day 12 post-dosing. After reaching a peak, elimination of radioactivity from the tissues occurred with a half-life of approximately 2-5 days (well perfused tissues such as the liver and kidneys) or approximately 2 weeks (poorly perfused tissues such as white adipose tissue). On completion of the study (88 days) approximately 2% of the administered radioactivity remained in the tissues, primarily in the skin and fur (Elcombe, 2005a).

In a limited study, the analysis of urine samples from a group of four bile-duct cannulated female rats intravenously administered 5-6 mg/kg bw of uniformerly labelled polychlorinated hexadecane (65% chlorination) indicated metabolites that were tentatively identified as mercapturic acids and methylated mercapturic acids, indicating conjugation of the MCCP components with glutathione. Similarly, analysis of the biliary metabolites suggested the presence of a mercapturic acid of the MCCPs (Ahlmen et al. 1986). According to the draft RAR (EU, 2008), quite extensive metabolism of MCCPs to CO2 occurs following oral administration of MCCPs of lower chlorination, but is much more limited with MCCPs of higher (e.g. 69%) chlorination.

A recent OECD-compliant in vitro study using human skin (Johnson, 2005) showed that after 24 hours, approximately 0.7% of Cereclor S52 (a C14-17 chlorinated paraffin; 52% chlorination) was absorbed. The overall skin absorption determined by this study (0.7%) is likely to be an overestimate, as the study was designed to measure skin penetration under the most conservative conditions.

 

There is no specific information for the inhalation route of exposure. However, given that the data indicate about 30% absorption by the oral route and less than 1% by the dermal route, and in view of the very high log Pow and the very low water solubility of MCCPs, it is reasonable to assume that inhalation absorption is also likely to be low (maximum of 50%). The data available do not allow any conclusions to be drawn regarding the way in which the degree of chlorination of these substances may affect the extent of absorption following oral administration (or any other route).

In rats, transmission of a C14 -17 chlorinated paraffin (34% chlorination) or its metabolites via the mother to the developing fetus in utero was evident although it is not clear if this occurs with all forms of MCCPs (EU, 2008).

The only human data (summarised in IUCLID chapter 7.10.5) relates to information on the presence of chlorinated paraffins in human breast milk, indicating the potential for excretion via this route (Thomas and Jones, 2002; Thomas et al. 2006). In the published study (Thomas et al. 2006), all 25 samples analysed (from 18 women) contained very low concentrations of MCCPs, ranging from 0.0062 (detection limit) to 0.32 µg/g fat, with a median value of 0.021 µg/g fat. The two recent studies which investigate the clearance and pharmacokinetics of radio-labelled vitamin K, administered either by intraperitoneal injection (Powrie, 2010a) or gavage (Powrie, 2010b) to female rats pretreated with Cereclor S52 (by stomach tube) for 14 days, are summarised in the repeated dose toxicity section (Mechanisms of internal haemorrhages; IUCLID Chapter 7.5). 

References (of studies for which no ESR has been created - move to reference list in CSR):

Ahlmen M et al. (1986). Chlorinated paraffins: formation of sulphur-containing metabolites of polychlorohexadecane in rats. Xenobiotica, 16, 225-232 (cited in EU, 2008).