Propanoic acid, 2-(4-chloro-2-methylphenoxy)-, 2-ethylhexyl ester, (2R)-

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

11 July 1994 - 6 May 1997

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1997

Report date:

1997

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

according to guideline

Guideline:

EPA OPP 85-1 (Metabolism and Pharmacokinetics)

Version / remarks:

November 1984

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

2-Ethylhexyl (R)-2-(2-methyl-4chlorophenoxy)propionate

EC Number:

630-324-3

Cas Number:

861229-15-4

Molecular formula:

C18H27ClO3

IUPAC Name:

2-Ethylhexyl (R)-2-(2-methyl-4chlorophenoxy)propionate

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material (radiolabelled): 443-11
- Source and lot/batch No.of test material (non-labelled): NHL/11/93

RADIOLABELLING INFORMATION
- Radiochemical purity: 99.5%
- Specific activity: 4.43 µCi/g (164 kBq/g)
- Locations of the label: 14C

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material (radiolabelled): ca. -20°C
- Storage condition of test material (non-labelled): 4°C in the dark

Radiolabelling:

yes

Remarks:

14C

Test animals

Species:

rat

Strain:

Wistar

Remarks:

Crl: (WI)BR

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK9 Ltd., Margate, Kent, UK
- Age at study initiation: 7 to 11 weeks
- Weight at study initiation: 190-350 g
- Housing: in groups of up to 5 per cage in wire floor polypropylene cages suspended over polypropylene dirt trays containing soft white wood sawdust
- Diet: ad libitum, pellet diet, SQC Rat and mouse Maintenance Diet No.1, Expanded
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23
- Humidity (%): 40-70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 hours/12 hours

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

1%

Duration and frequency of treatment / exposure:

single administration

Doses / concentrations

Dose / conc.:

5 other: mg/kg

Remarks:

corresounding to a nominal dose of 15 µCi/animal (0.555 MBq)

No. of animals per sex per dose / concentration:

pharmacokinetic study: 5 males
excretion balance: 5 males

Control animals:

no

Details on study design:

Study duration 168 h

Details on dosing and sampling:

TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood, plasma, serum, expired air, adrenals, residual carcass, brain, fat (abdominal), spleen, stomach (minus contents), kidney, liver, gross lesions, muscle (quadriceps), bone (femur), skin (dorso-lumbar), stomach contents, gonads, heart, thyroids, lungs
- Time and frequency of sampling:
Blood: 0 (pre dose), 0.5, 1.5, 3, 6, 9,12, 24, 48, 72, 120, and 168 h
Urine: 6,12, 24, 48, 72, 96, 120,144 and 168 h post-dose
Faeces: 24, 48, 72, 96, 120, 144 and 168 h post-dose
Expired air: 12, 24, and 48 h post dose

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, faeces
- Time and frequency of sampling: 0 to 6, 6 to 12, 12 to 24, and 24 to 48 h (urine); 0to24, and 24 to 48 h (faeces)
- From how many animals: samples pooled
- Method type for identification: HPLC-MS, TLC

OTHER
- An additional experiment was carried out using LC-MS (MRM) to confirm the presence and concentration of carboxy-Mecoprop-P in urine. Carboxy-Mecoprop-P is a known plant metabolite.

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Rapid absorption after oral exposure.

Main ADME results 2

Type:

distribution

Results:

Distribution throughout the body water.

Main ADME results 3

Type:

metabolism

Results:

Predominantly hydrolysis of the ester to the corresponding acid. No evidence of the presence of the unchanged ester.

Main ADME results 4

Type:

excretion

Results:

Predominantly and fast via urine.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Following oral administration of [14C]-MCCP-P 2-EHE, radioactivity was rapidly absorbed.

Details on distribution in tissues:

Distribution throughout the body water.

Details on excretion:

Excretion predominately in urine. No radioactivity was detected in expired air and there was no accumulation of radioactivity in any of the tissues excised after the 168 h study period or in the carcass from either dose group.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

LC-MS analysis of urine and faeces samples showed that the radiolabelled ester was excreted predominantly as its corresponding acid. In addition, there were at least five minor components which together accounted for less than 5% of the urinary radioactivity. There was no evidence of the presence of the unchanged MCPP-P 2 EHE. The presence of Carboxy-mecoprop-P could not be confirmed.

Any other information on results incl. tables

Pharmacokinetic studies (Dose groups A and B) - mean data, n=5

The following pharmacokinetic parameters were determined for plasma after a single oral dose of [14C]-MCPP-P 2-EHE and [14C]-MCPP-P DMA at nominal dose level of 5 mg/kg body weight:

Plasma	[14C]-MCPP-P 2-EHE (Group A)	[14C]-MCPP-P DMA (Group B)
Cmax (μg equiv./g)	19.98	26.85
Tmax (h)	3.6	2.0
T 1/2 elim (h)	8.36	6.61
AUC(0-t) (μg equiv.h/g)	187.6	276.2
AUC(0 -∞ ) (μg equiv.h/g)	188.5	277.0

Excretion balance studies (Dose groups C and D) –mean data, n=5

The excretion and tissue retention of radioactivity was determined after a single oral dose of [14C]-MCPP-P 2-EHE and [14C]-MCPP-P-DMA at a nominal dose level of 5 mg/kg body weight. The results are summarised below expressed as percentage of administered radioactivity in each sample type:

	[14C]-MCPP-P 2-EHE  (Group C)		[14C]-MCPP-P DMA  (Group D)
		Normalized to 100%		Normalized to 100%
Urine	71.09	81.99	86.43	84.90
Faeces	3.29	3.79	4.68	4.60
Cage wash	12.17	14.04	10.68	10.49
CO2 trap 1	ND	ND	ND	ND
CO2 trap 2	ND	ND	ND	ND
Cage debris	0.15	0.17	0.06	0.06
Final cage	0.01	0.01	< 0.01	< 0.01
Total	86.71	100	101.80	100

ND = None detected

Following a single oral dose of [14C]-MCPP-P 2-EHE, 86.7 % of the administered radioactivity was recovered. This recovery is lower than would normally be expected, however, there was no evidence of accumulation in any of the tissue samples excised after the 168 h period or in the carcass. The ester is insoluble in water and these consistently low recoveries were probably due to a lack of homogeneity in the suspended test article. This observation appears to be a general feature of ester forms of this class of compound.

Radioactivity was rapidly absorbed and excreted predominately in urine. For dose groups C and D where the distribution and excretion balance was investigated, 95.5 % and 96.3 % of the total urinary radioactivity respectively was recovered within 24 h.

No radioactivity was detected in expired air and there was no accumulation of radioactivity in any of the tissues excised after the 168 h study period or in the carcass from either dose group.

Characterization of metabolites

LC-MS analysis of urine and faeces samples (Group C) showed that [14C]-MCPP-P 2-EHE was excreted predominately as MCPP-P acid (53.9 % of the administered dose) and a hydroxylated metabolite (almost certainly the 2-hydroxymethyl derivative) (17.30 % of the administered dose). There were at least five additional minor components but together these metabolites accounted for less than 5 % of the urinary radioactivity. There was no evidence for the presence of the unchanged ester.

Dose group D samples were not analysed as the DMA salt is chromatographically identical to MCPP-P acid.

The presence of carboxy-Mecoprop-P was not confirmed in urine. However, in a MCPP-P acid ADME study (HE study no. 1149/3), using a semi-quantitative LC-MS (NRM) method, the presence of this metabolite was confirmed, levels of radioactivity accounting for up to 0.07 % of the administered dose.

Applicant's summary and conclusion

Conclusions:

MCPP-P 2-EHE was rapidly absorbed and distributed throughout the body water and no bioaccumulation was observed. Hydrolysis to MCPP-P acid occurred rapidly and excretion of this metabolite was predominantly via urine.

Executive summary:

An OCED TG 417 study was performed to assess the toxicokinetics of MCPP-P 2-EHE in male rats. Following oral administration of 5 mg/kg bw [14C]-labeled test item, radioactivity is rapidly absorbed and excreted predominantly in urine. There was no accumulation of radioactivity in any tissue or organ after 168 hours. LC-MS analysis of urine and faeces samples showed that MCPP-p 2 EHE was excreted predominantly as MCPP-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. The data clearly show that MCPP-P 2-EHE is metabolised through MCPP-P acid, which is then metabolized by the scheme described for MCPP-P acid.