CORE QUESTION

Did the study adequately characterize exposure to the chemical of interest and the exposure administration methods?

PROMPTING QUESTIONS

For each study:

Does the study report the source and purity and/or composition (e.g., identity and percent distribution of different isomers) of the chemical? If not, can the purity and/or composition be obtained from the supplier (e.g., as reported on the website)
Was independent analytical verification of the test article purity and composition performed?
Did the authors take steps to ensure the reported exposure levels were accurate?
For inhalation studies: were target concentrations confirmed using reliable analytical measurements in chamber air?
For oral studies: if necessary based on consideration of chemical-specific knowledge (e.g., instability in solution; volatility) and/or exposure design (e.g., the frequency and duration of exposure), were chemical concentrations in the dosing solutions or diet analytically confirmed?

Are there concerns about the methods used to administer the chemical (e.g., inhalation chamber type, gavage volume, etc.)?

NOTE: Consideration of the appropriateness of the route of exposure is not evaluated at the individual study level. Relevance and utility of the routes of exposure are considered in the PECO criteria for study inclusion and during evidence synthesis.

BASIC CONSIDERATIONS

It is essential that these criteria are considered, and potentially refined, by assessment teams, as the specific variables of concern can vary by chemical (e.g., stability may be an issue for one chemical but not another).

A judgment and rationale for this domain should be given for each cohort or experiment in the study.

Good: Chemical administration and characterization is complete (i.e., source, purity, and analytical verification of the test article are provided). There are no concerns about the composition, stability, or purity of the administered chemical, or the specific methods of administration. For inhalation studies, chemical concentrations in the exposure chambers are verified using reliable analytical methods.

Adequate: Some uncertainties in the chemical administration and characterization are identified but these are expected to have minimal impact on interpretation of the results (e.g., source and vendor- reported purity are presented, but not independently verified; purity of the test article is sub-optimal but not concerning; For inhalation studies, actual exposure concentrations are missing or verified with less reliable methods).

Deficient: Uncertainties in the exposure characterization are identified and expected to substantially impact the results (e.g., source of the test article is not reported; levels of impurities are substantial or concerning; deficient administration methods, such as use of static inhalation chambers or a gavage volume considered too large for the species and/or lifestage at exposure).

Critically Deficient: Uncertainties in the exposure characterization are identified and there is reasonable certainty that the results are largely attributable to factors other than exposure to the chemical of interest (e.g., identified impurities are expected to be a primary driver of the results).

EXAMPLE RATINGS

Oral study - Good - Source (3M) and purity (98%) are described, and the authors provided verification using analytical methods (GC/MS). Addressing concerns about known instability in solution for this chemical, the authors verified the dosing solutions twice weekly over the course of the experiment. Animals were exposed via gavage with all dose groups receiving the same volume.

Inhalation study - Good - Source (3M) and purity (98%) of the test article are described. All animals were transferred to dynamic inhalation exposure chambers for the exposures. The concentration of the test chemical in the air was continuously monitored from the animals' breathing zone throughout the 6-hour exposure periods and mean daily average concentrations and variability were reported.

Follow link to see attachments that contain example answers to the animal study evaluation domains.

ECHA, 2023, 11363018