D-tetramethrin

Endpoint summary

Description of key information

A number of studies have been performed in the rat to address the toxicokinetics of tetramethrins using [1RS, trans]-, [1RS, cis]-, [1R, trans] and [1R, cis]-isomers labelled at their alcohol (phthalimide) or acid (chrysanthemic acid) moiety. From the absence of detectable differences between the 1RS- and the 1R-isomers, it may be concluded that the general toxicokinetic behaviour of the 1R- and the 1S-isomers is similar. Minor differences relating to the relative amount of radiocarbon metabolites excreted via urine and the initial elimination velocity were observed for the trans- and cis-isomers (Kaneko H, Ohkawa H, Miyamoto J, 1981, J. Pesticide Sci. 6 (4): 425-435). Considering the low content of cis-isomers of 20 % and 3 % in technical products of tetramethrin and d-trans-tetramethrin, respectively, these minor differences appear not to be of significant practical relevance.

Radiocarbon absorption after administration of acid- and alcohol-labelled C-14 tetramethrin may be estimated from the relative amount excreted in urine and amounted to 42 - 74 and 9 - 46% of trans- and cis-isomers, respectively, depending on dose and pre-treatment. Considering the prevalence of the trans-isomers in tetramethrin technical products, the oral absorption is estimated to be 50 -100% of C-14 tetramethrin. 

Radioactivity in blood and tissues suggests sustained absorption of orally administered tetramethrin isomers with an estimated absorption half-life of approx. 2 hours. In the body tetramethrin is degraded very rapidly as indicated by a tmax of 1 h for the parent compound compared to 8 h for radiocarbon.

Analysis of blood levels of the parent compound and metabolites following i.v. administration support rapid degradation with a t1/2 of approx. 10 min. When administered orally, the percentage of undegraded a.s. was less than 1% of total radiocarbon in blood as early as 1 hour following administration, although it remained unclear whether the responsible metabolic reactions occurred systemically or pre-systemically (Miyamoto J et al., 1968, Agr. Biol. Chem. 32(5): 628-640). 

Total excretion of orally or subcutaneously administered radiocarbon was generally ≥ 90% after 2 days and ≥ 95% after 1 week. Detectable amounts in exhaled air were reported for acid-labelled tetramethrin only: up to 3% of the orally (but not subcutaneously) administered dose of cis- as well as trans-isomers were exhaled as CO2 (Kaneko H, Ohkawa H, Miyamoto J, 1981, J. Pesticide Sci. 6 (4): 425-435). Remaining radioactive tissue residues 5 - 7 days after dosing were generally low with 0.2 - 0.4% and widely distributed.

Highest residue concentrations were found in blood cells. Residues after administration of acid-labelled tetramethrins were approx. 5 times lower than for alcohol-labelled isomers (Kaneko H, Ohkawa H, Miyamoto J, 1981, J. Pesticide Sci. 6 (4): 425-435). Initial metabolism and elimination of the cis-isomers after subcutaneous administration was 2 - 3 times slower than for the trans-isomers.

Main metabolic reactions include ester hydrolysis yielding chrysanthemic acid (or its corresponding oxidation products, see below) and N-(hydroxymethyl)-3,4,5,6-tetrahydrophthalimide (MTI). MTI decomposed, presumably non-enzymatically (Suzuki T, Miyamoto J, 1974, Pesticide Biochem. Physiol. 4(1): 86-97), into 3,4,5,6-tetrahydrophthalimide (TPI) which was subject to further extensive metabolic reactions, including reduction of the 1,2-double bond, hydroxylation at position 2 and 3, and full or partial hydrolysis of the carboxydimide moiety. Chrysanthemic acid was metabolised primarily by oxidation of the isobutenyl group. Subsequent conjugation reactions were reported for various phase I metabolites.

In vitro studies using rat liver microsomes further demonstrated that oxidation reactions were NADPH-dependent, whereas a paraoxon-sensitive enzyme apparently mediated ester hydrolysis.

As a result of the extensive metabolism of tetramethrin, a large percentage of the resulting products (~50%) remained unknown, unidentified or not extracted. Major labelled species identified at > 5% in urine or faeces include the parent compound (5 - 30% in faeces only), 3-hydroxy-cyclohexane-dicarboximide, 1-sulfo-cyclohexane-dicarboximide, N-(hydroxymethyl)-3-hydroxy-1-sulfo-cyclo-hexane-dicarboximide and three unknown metabolites. The sulfonic acid products were reported almost exclusively in faeces and result chemically from addition of sulfite to the 1,2-unsaturated bond of the tetrahydrophthalimide moiety.

In summary, the studies indicate sustained absorption of tetramethrin isomers from the G.I. tract which is estimated to be 50% at doses in the range of the relevant oral NOAELs. Moreover, a very rapid systemic and/or pre-systemic metabolic degradation by oxidation and ester hydrolysis has been shown which is slower for cis- than for trans-isomers. Hence, the resulting levels of undegraded a.s. in blood and nervous system remain very low after oral administration (below 1% of total C-14 at 1 hour). However, bioavailability and systemic levels of parental compound may be different with other routes of application (inhalative, dermal). Excretion occurs via faeces and urine. Sulfonated metabolites in faeces are suggested to be a product of (intra)intestinal metabolism.

Radiocarbon excretion is almost completed after 2 - 3 days. After 1 week C-14 tissue residues decreased to 0.4% or below. Mechanistically, there is potential for interference of organophosphates (paraoxon) with tetramethrin toxicokinetics.

Percutaneous absorption

According to investigations, cited by BAuA (September 2015), a study on percutaneous absorption of technical products containing d-tetramethrin or tetramethrin has been assessed by the German Authorities. For d-tetramethrin, a total of 12.4 ±9.8 µg/cm², corresponding to 6.2 ±4.9% of the applied dose, was absorbed into and through the skin. 1.1 ±1.3 and 3.5 ±5.3% of the doses were found in tissue layers attributed to stratum corneum and remaining epidermis, respectively. Totals of absorbed and absorbable dose were higher for tetramethrin, with 22.3 ±5.8 µg/cm², corresponding to 11.2 ±2.9% of the applied dose, after 24 h. Apparent residues in the stratum corneum were higher than for d-tetramethrin with 13.8 µg/cm²(6.9%), but lower in the remaining epidermis with 3.5 µg/cm² (1.8%). 

Applying the read-across concept established for d-tetramethrin and tetramethrin, and considering the limitations of the in vitro test system, an overall dermal absorption of 10% is derived for tetramethrin and the technical product.

Inhalative absorption

No experimental data are available for the derivation of internal doses achieved by absorption of inhaled tetramethrin or d-tetramethrin aerosol from the lung. Therefore, physiologically-based default assumptions must be used. As outlined in the corresponding Technical Guidance Document, respirable fractions of the test aerosol were calculated from measured aerodynamic particle sizes and, given the molecular weight of 331 g/mol and a logP of 4.3 - 4.6, 100% of the respirable fraction was assumed to be the absorbable dose (European Commission, EUR 20418 EN/1, 2003).

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100