The chlorophenoxy herbicide MCPA: a mechanistic basis for the observed differences in toxicological profile in humans and rats versus dogs

Abstract

1. Metabolism data for MCPA in rat, dog and human shows a single oral dose is quantitatively and rapidly absorbed with evidence of non-linear kinetics at >100 mg/kg bw. The extent of metabolism is low and consistent between rat and human, with substantially higher metabolic conversion in dog. Parent accounts for 50%–67% dose in rat, ∼40% in human and 2%–27% in dog. No dog specific metabolite is apparent.

2. In rat and human, MCPA and metabolites are rapidly eliminated in urine (65%–70% within 24 h) but in dog, excretion is via urine and faeces (20%–30% within 24 h), with renal excretion saturating between 5 and 100 mg/kg bw.

3. The species difference in excretion is reflected in pharmacokinetics. Terminal half-life is similar in rat and human (15–17 h) but higher in dog (47 h). Modelling shows species differences in single dose kinetics profoundly affect systemic exposure following repeat dosing.

4. The difference in renal excretion and systemic exposure of MCPA between dogs and rats has been attributed to species differences in active transporters (OAT1/OAT3). A new in vitro flux study in renal proximal tubules supports this hypothesis with net secretion in rat and human of a similar magnitude but significantly less in dog.

Keywords:

• MCPA
• risk assessment
• mechanism
• toxicokinetics
• renal transporters
• protein binding
• excretion
• human

Disclosure statement

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors Bartels and Bond are paid consultants to the MCPA EU Renewal Task Force. The authors Bowen and Gledhill are employees of ERM Regulatory Services which is funded by MCPA EU Renewal Task Force to act as consultant. The authors Brown, Chung and Pye were employees of Newcells Biotech which was funded by MCPA EU Renewal Task Force to conduct renal transporter experiments.

Additional information

Funding

The manuscript includes a review of existing metabolism and pharmacokinetic studies and new studies measuring MCPA plasma protein binding and renal transporter activity. The review and new studies have been funded by the MCPA EU Renewal Task Force.