2-ethylhexyl (4-chloro-2-methylphenoxy)acetate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

8.09.2006 - 30.11.2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Cross-reference

Reason / purpose for cross-reference:

read-across source

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2006

Report date:

2006

Materials and methods

Objective of study:

metabolism

toxicokinetics

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

(4-chloro-2-methylphenoxy)acetic acid

EC Number:

202-360-6

EC Name:

(4-chloro-2-methylphenoxy)acetic acid

Cas Number:

94-74-6

Molecular formula:

C9H9ClO3

IUPAC Name:

(4-chloro-2-methylphenoxy)acetic acid

impurity 1

Reference substance name:

Water

EC Number:

231-791-2

EC Name:

Water

Cas Number:

7732-18-5

Molecular formula:

H2O

IUPAC Name:

water

impurity 2

Reference substance name:

4-chloro-o-cresol

EC Number:

216-381-3

EC Name:

4-chloro-o-cresol

Cas Number:

1570-64-5

Molecular formula:

C7H7ClO

IUPAC Name:

4-chloro-2-methylphenol

Test material form:

solid

Specific details on test material used for the study:

MCPA technical
Test substance MCPA Technical with a chemical purity of 97.2 %, was produced by Zaklady Chemiczne „Organika-Sarzyna" S.A. The compound was kept at laboratory temperature.

Radiolabeled MCPA:
14C-MCPA (4-chloro-2-methylphenoxy)-[14C] acetic acid) was synthesized with the carbon label at the 1-position of the acetic moiety. It was prepared by Institute of Isotopes Co., Ltd., Budapest, Hungary. [14C]-MCPA had specific activity 2062 mBq/mmol. The radiochemical purity was mm 98 %. The isotope was kept frozen at minus 15°C.

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Wistar

Details on species / strain selection:

The Wistar strain rats were obtained from Velaz ( Praha, Czech Republic). A body weight in quarantine was within the range 140 - 160 g (Protocols No. 17/2006 and 19/2006).

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

ethanol

Details on exposure:

Rats were administered a single oral dose of 14C-MCPA at 5 and 100 mg.kg-1. Suspension of a substance was added in syringe by gavage with metal probe. Mass of 1 mg MCPA (dose 5 mg*kg-1) or 20 mg (dose 100 mg*kg-1) was dissolute in 0.5 ml of 48% ethanol in which was added 14C-MCPA to provide volume of 2.5 ml*kg-1 for both doses.
The nominal radioactive quantity of 14C-MCPA at all test doses was 50 µCi/kg-1, which approximately 10 µCi per 200 mg of body weight is contained in a volume of 0.5 ml of administered solution. Volume of administrated solution in all cases was below 1 ml.

Rats directly before starting of experiment were weighted and applied volume of dose suspension was calculated on a body weight.
Stability: Both low and high doses 14C-MCPA preparations are found to be stable and homogeneous for at least 24 h. All 14C-MCPA doses are administered within approximately 18 h of preparation.

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

MCPA is degraded with elimination half-life 6.5 at low dose and 11 h at high dose.

Main ADME results 2

Type:

distribution

Results:

It has demonstrated that MCPA does not trend to be stored or accumulated in tissues.

Main ADME results 3

Type:

metabolism

Results:

MCPA circulated in blood as unchanged form (RT=6.9 min). It was excreted by urine mainly as parent compound and two metabolites; its 2-hydroxy derivative HMCPA with RT=2.6 mm and unidentified metabolite with RT=6 min.

Main ADME results 4

Type:

excretion

Results:

More than 90% of the initial dose of MCPA was eliminated by urine during 24 h at low dose and 48 h at high dose.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

These results indicate that substance is rapidly absorbed from the gut in rats. Peak plasma concentration was achieved within Tmax. 4 – 6 h. Comparison of the plasma peaks Cmax between two dose levels shows 16-fold increase and 50-fold for AUC0 ∞ at high dose. Despite this, the more than proportional increase of the AUC indicated that excretion of MCPA is retarded at the high dose. It is degraded with elimination half-life 6.5 at low dose and 11 h at high dose.

Details on distribution in tissues:

Target organs were kidney that is associated with a renal excretion route, and skin. All tissue levels were low (< 0.4 % for the low dose and < 0.07 % for the high dose) at 72 h post-dose. It has demonstrated that MCPA does not trend to be stored or accumulated in tissues. Total radioactivity in body was calculated to be approximately 101% AA and below 0.6% AA was found in carcass at the end of experiments for both doses.

Details on excretion:

Results achieved that MCPA is efficiently absorbed and also eliminated. Renal excretion of parent compound and metabolites was a major elimination route. More than 90% of the initial dose was eliminated by urine during 24 h at low dose and 48 h at high dose.

Metabolite characterisation studies

Metabolites identified:

yes

Remarks:

HMCPA

Details on metabolites:

MCPA circulated in blood as unchanged form (RT=6.9 min). It was excreted by urine mainly as parent compound and two metabolites; its 2-hydroxy derivative HMCPA with RT=2.6 mm and unidentified metabolite with RT=6 min.