Changes of Toxicological Equivalence Criteria

Key points in the latest 2012 revision of EU Sanco 10597/2003 Technical Equivalence Tier II data requirement are as below:

1. For ≥0.1% – <1% new or increased impurities: Ames study;

2. For 2. ≥1% new or increased impurities, 3 in vitro genotoxicity studies, and consider:

a) Acute oral;

b) Sensitization;

c) Developmental study;

d) Neurotoxicity study;

3. For ≥5% new or increased impurities, consider 28 or 90 days repeat dosage bridging study or other studies;

FAO Specification Manual Technical Equivalence Tier II data requirement was revised in 2018 with the below key points:

1. With the implementation of new OECD test guideline and GHS classification, acute oral and dermal studies usually give a result of range rather than numbers. In this situation, it may be not useful for comparison of acute toxicity value between the reference and the new technical material. For example, the comparison is not possible in case that the reference acuteoral LD₅₀ is 87mg/kg bw while the new technical material LD₅₀ is 50-300mg/kg bw.

2. In case that the impurity does not present acute or shot term toxicity, it may be overlooked in the studies. For example, neurotoxicity of Fluazinam impurity 5 can only present in 28 or 90 days studies;

3. Hence, Tier II toxicological equivalence data requirement is amended as below:

a) Ames;

b) Consider eye irritation, skin irritation, skin sensitization, 28 or 90 days repeat dosage studies;

c) Other genotoxicity besides Ames;

d) And consider reproduction, development, carcinogenicity, neurotoxicity and others;

Key points in Brazilian Anvisa RDC 294/2019 Technical Equivalence Tier II data requirement are as below:

1. For ≥0.1% – 1% new or increased impurity, consider the 3 in vitro genotoxicity studies:

a) Ames;

b) Gene mutation study in vitro in mammalian cells; and

c) Chromosomal damage study in vitro in mammalian cells

2. For ≥1% new or increased impurity, consider:

a) Ames;

b) Gene mutation study in vitro in mammalian cells;

c) Chromosomal damage study in vitro in mammalian cells;

d) In vivo chromosomal damage study insomatic cells;

e) Acute oral toxicity study;

f) Eye corrosion/irritation study;

g) Corrosion/Skin irritation Study; and

h) Skin and respiratory sensitization study.

1. Sanco 10597 asks for 3 in vitro genotoxicity studies when new or increased impurity ≥1%, while Brazilian RDC 294 asks for it when new or increased impurity ≥0.1 – 1%. Whether or not the 3 in vitro genotoxicity studies shall be trigged automatically or considered the need based on the specified impurity case is discussable, and eventually it is upon Brazilian authority decision;

2. Below 3 approaches are recommended to schedule the toxicological studies for equivalence registration:

a) Consider the need of toxicological study only when Tier I evaluationis completed and Tier II toxicological data requirement is given (toxicological study sample representativeness/one batch full analysis is required);

b) Conduct 3 in vitro genotoxicity studies along with 5 batches analysis;

c) Conduct all relevant toxicological studies along with 5 batches analysis;

d) The so-called traditional acute 6 pack plus Ames and in vivo micronucleus studies approach is to be re-considered.