Update on labeling convention for products containing indoxacarb

11 July 2019

Indoxacarb is an insecticide that was first approved and registered in Australia in the early 2000s. Indoxacarb exists in two enantiomeric forms (S and R) with an optically active (asymmetric) carbon atom at the bridgehead of the oxadiazine ring. Only the S-enantiomer has insecticidal activity, however, from a human toxicological and residues perspective, both the S- and R-enantiomers are significant.

The ISO common name ‘indoxacarb’ refers specifically to the active S-enantiomer, methyl (4aS)-7-chloro-2-{(methoxycarbonyl)[4-(trifluoromethoxy)phenyl]carbamoyl}-2,5-dihydroindeno[1,2-e][1,3,4]oxadiazine-4a(3H)-carboxylate.

Both the S- and R-enantiomers contribute to human toxicology and the entry for indoxacarb in the Poison Standard covers both enantiomers. Similarly, the residue definition for indoxacarb includes both enantiomers, and routine analytical methods used for residues analysis (ie non-chiral methods) do not distinguish between the S- and R-enantiomers.

There has been confusion with regard to the terminology for indoxacarb in active constituent statements on product labels, with some labels referring to the total content of S- and R-enantiomers and others just to the content of the active S-enantiomer. To provide clear information on both the content of the active S-enantiomer (the active constituent), and the content of the R enantiomers, which is important for toxicological and residues purposes, the APVMA is proposing a new standard form of expression of indoxacarb in active constituent statements:

• [X] g/L (g/kg) indoxacarb (S:R) (equivalent to [Y] g/L (g/kg) active S-isomer)

Where X is the concentration of the sum of S and R enantiomers, Y is the concentration of the S-enantiomer, and S:R gives the ratio of S to R isomers, as fractions of 100 (eg 75:25).

An example of this is:

• 400 g/kg indoxacarb (75:25) (equivalent to 300 g/kg active S-isomer)

The enantiomeric composition of commercially available indoxacarb active constituent has evolved over time with improvements in the manufacturing process allowing enantioselective synthesis. Initially a technical material containing equal concentrations of the S- and R-enantiomers was developed. Later developments in the manufacturing process allowed the production of S-enantiomer enriched indoxacarb, with active constituent with a 3:1 S/R enantiomer ratio, and later still, material with ≥ 9:1 S/R. Currently, technical active constituent with a minimum purity (ie S-enantiomer content) of ≥ 900 g/kg, and a manufacturing concentrate (technical concentrate), with a minimum of 467 g/kg, are commercially available.

There are proposed changes to the active constituent standards for indoxacarb to create a standard for technical indoxacarb with a purity ≥ 900 g/kg and to make minor modifications to the existing standard which applies to manufacturing concentrates.

Currently, there are 15 approvals for indoxacarb active constituent, which are not all clearly identified as technical active or manufacturing concentrate. APVMA is proposing to amend these approvals to clearly identify them as either technical active or manufacturing concentrate, and to indicate the S:R isomer ratio. Affected holders will be notified in writing and sent an amended approval notice.

When selecting or changing a source of indoxcarb active constituent in a formulated product, registrants and formulators need to be mindful of the isomeric composition and purity of the source. In the case of changing to a source of active with a different isomeric ratio, or to a manufacturing concentrate from a technical active (or vice versa), this is likely to have an impact on the formulation and may necessitate an item 14 application with appropriate supporting data (eg Chemistry, efficacy).

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