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Increased Information Requirements for Human Health
Most important, several new testing requirements are under consideration for Annex VII, mostly based on ‘NAM’ (New Approach Methodologies i.e., alternatives to in-vivo studies):
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In vitro cytotoxicity
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Toxicokinetics & ADME (Absorption, Distribution, Metabolism, and Excretion)
- in chemico protein binding (e.g. fraction unbound in human plasma)
- in vitro human hepatic clearance (e.g. isolated human hepatocytes)
- in vitro intracellular bioaccumulation (e.g. in Caco-2 cells)
- in vitro intestinal absorption (e.g. Caco-2 permeability)
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Endocrine Disruption (ED) In-vitro mechanistic information (relevant for both human health and environment)
- Estrogen receptor transactivation assay (OECD TG 455)
- Androgen receptor transactivation assay (OECD TG 458)
- H295R steroidogenesis assay (OECD TG 456)
- Aromatase assay (OPPTS 890.1200)
For substances that raise concerns, triggering testing for repeated dose toxicity and screening for reproductive/developmental toxicity (OECD TG 422) and in-vivo tests on endocrine disruption would be considered. Inter alia, the following options for triggers are under discussion: Trigger based on biological half-life predicted from log Kow (>3) or trigger based on in-vitro toxicokinetics data (to be generated only after this revision).
The triggers/waivers are still under discussion.
The proposed additional requirements if there is a concern for ED are: Uterotrophic Bioassay in Rodents (OECD TG 440) and Hershberger Bioassay in Rats (OECD TG 441).
To update the requirements to scientific progress and to balance the additional requirements at low tonnages and for EDs, the following studies are proposed to be deleted:
- acute oral toxicity in rats (Annex VII)
- acute dermal & inhalation toxicity in rats (Annex VIII)
- skin corrosion/irritation (Annex VIII)
- serious eye damage/eye irritation (Annex VIII)
- assessment of the toxicokinetic behaviour to the extent that can be derived from the relevant available information (Annex VIII)
- further studies beyond the 90-day study (Annex IX column 2)
- pre-natal developmental toxicity study 2nd species (Annex X and trigger in Annex IX)
- long-term repeated toxicity study (≥ 12 months) (Annex X)
- tentatively: carcinogenicity study (Annex X)?
The scope of studies that may be deleted and the conditions for deletion are under discussion.
Increased Information Requirements for Environment
For the environmental data requirements, the following proposals were presented:
- Replacing short-term fish toxicity test and bioaccumulation in fish with in vitro tests
- Long-term toxicity testing on invertebrates (Daphnia): move them from Annex IX to Annex VII
- Triggers/waivers: are under discussion
- Additional requirements for ED identification: are under discussion
The overview presentation about the entire scope of envisaged changes in the context of the REACH revision can be found here:
CARACAL presentation.
