Octyl (R)-2-(4-chloro-2-methylphenoxy)propionate

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

A study on toxicokinetics according to OECD TG 417 was conducted with Mecoprop-P n-octyl ester on rats, receiving each orally by gavage a nominal dose of 5 mg/kg. Following substance administration 4 rats were used for determination of pharmacokinetic parameters, 4 rats for excretion balance studies (metabolism cages), and 16 rats for investigation of tissue distribution. Additionally, urine, faeces, plasma, liver and kidney were subjected to metabolite profiling.

As result it was found that absorption of the test substance was rapid, with detectable concentrations of radioactivity in the plasma by 0.25 hours post dose and maximum concentrations achieved within 4.5 hours. The plasma half-life was ca 34 hours. Absorption was extensive at >95% of the dose, calculated from excretion in urine and recovery of radioactivity in carcass and tissues. Radioactivity was distributed into the tissues and organs by 4 hours post dose.

Recovery of radioactivity was quantitative by 168 hours post-dose, with excretion mainly via the urine. The elimination of radioactivity was rapid, with >92% of the administered dose being excreted within 24 hours. Clearance of radioactivity was slow, with concentrations being detected in the majority of sampled tissues at 168 hours post dose.

The greatest concentrations of radioactivity were generally associated with the liver and kidneys, the organs of metabolism and excretion. There was no evidence of accumulation of radioactivity in tissues.

Metabolism of Mecoprop-P n-octyl ester was quantitatively extensive, but limited in scope. There were two major metabolites common to urine, faeces, plasma, liver and kidney. One [Mecoprop-P acid (MCPP-P acid)] was formed by de-alkylation and loss of the octyl side chain, the second metabolite was formed by hydroxylation of the first metabolite.

 

For the purpose of justification of grouping and read-across according to regulation (EC) No 1907/2007 (REACH), Annex XI, toxicokinetic studies of Mecoprop-P acid (MCPP-P acid), which is the hydrolysis product of Mecoprop-P n-octyl ester, and of a structural analogue ester to Mecoprop-P 2-ethylhexyl ester (MCPP-P 2-EHE) are included in this chapter.A comparison of the data shows that the toxicokinetic properties (e.g. rapid and extensive absorption, excretion predominantly via urine, quick distribution throughout the body water) are very similar for the three substances.This is based on the fact, that Mecoprop-P n-octyl ester, and also the analogue Mecoprop-P 2-ethylhexyl ester (MCPP-P 2-EHE) are both rapidly metabolised to Mecoprop-P acid (MCPP-P acid) and the corresponding alcohols, and thus the toxicokinetic properties are finally determined by the same species.

 

A full and elaborated justification for read across is attached to the chapter endpoint summary.

 

For an assessment of toxicokinetics of Mecoprop-P 2-EHE, see Bond A, Tier 2 Summary of Toxicology for Mecoprop-P 2 -EHE, Supplementary data on the active substance according to Annex II of Directive 91/414EEC Document M-II (Tier II), 2006:

"Following oral administration of (14C)-Mecoprop-P 2-EHE, radioactivity is rapidly absorbed and excreted predominantly in urine with approximately 95 % of the urinary radioactivity recovered within 24 hours. There was no accumulation of radioactivity in any tissue or organ after 168 hours whatever the dose administered. LC-MS analysis of urine and faeces samples showed that Mecoprop-P 2-EHE was excreted predominantly as Mecoprop-P [acid] (53.9% of the administered dose) and a hydroxylated metabolite (17.3 % of the administered dose). At least 5 minor components accounted together for less than 5% of the urinary radioactivity. There was no evidence of the presence of the unchanged ester."

Conclusion: "the data summarized above clearly show that Mecoprop-P 2-EHE is metabolised through Mecoprop-P [acid], which is then metabolised by the scheme described for Mecoprop [acid]. ..."

Scheme described for Mecoprop acid (MCPP acid): "Oral administration of (14C)-Mecoprop [acid] is followed by a rapid and extensive absorption in the rat. The substance is quickly distributed throughout the body water. The highest concentration of radioactivity is detected in the kidney. Low levels are found in the nervous system (brain and spinal chord). The elimination rate is notably slower from the fatty tissue than from any other tissue or organ, but the quantity finding its way there is very low. Urine is the most important route of excretion representing an average of 81% of the administered dose within the first 48 hours with elimination peak occurring during the first 24 hours. About 45 % of the administered dose is eliminated as the unchanged parent compound and approximately 40 % as conjugated Mecoprop [acid]."