Speciality Chemicals Magazine JUL / AUG 2025 | Page 32

Figure 2- Derivation of a human-relevant‘ safe’ dose by application of uncertainty factors to a critical point of departure

Guidance in the pharmaceutical sector provides different factors for different animals, considering the varying lifespans of the typical species used in pre-clinical testing. When a study lasts for at least one half of a lifetime or is a developmental study covering the whole period of organogenesis, no factor is required.

Factors of 2, 5 or 10 are used for six-month, three-month or shorter studies in rodents or 3.5-year, two-year or shorter studies in nonrodents. Pharmaceutical guidance for mutagenic impurities also introduces the concept of‘ less-than-lifetime’ administration, with staggered thresholds depending on duration of dosing. Care should be taken in the application of these thresholds and the ratios between them in health risk assessment of potential genotoxic carcinogens. 6

The less-than-lifetime concept does not really apply in the food industry, where dietary intake is essentially considered to be constant. EFSA guidance includes a factor of 2 to extrapolate from a sub-chronic study to a lifetime ADI, but does not suggest any further adjustments.

Extrapolation between routes of administration can be extremely complex. Ideally, it requires knowledge of the specific toxicokinetic behaviour of a chemical – especially the extent to which it is absorbed by the different routes.

The vast majority of standard toxicological data were generated by the oral route, so the extrapolation is almost always from an oral study to a potential route of exposure – inhalation of a chemical in the workplace, for example, or direct systemic exposure( e. g. via intravenous administration) from a medical device. However, in the absence of specific data, there are default adjustments that can be made.

In general, it is only necessary to add an uncertainty factor when the route of likely human exposure has a greater potential absorption than the route of administration in the key study. For medical devices, for example, factors of up to 100 are applied to oral data on compounds with low bioavailability when converting to a parenteral TI. Extrapolating to inhalation exposures has to take into account the standard respiratory volumes of the animals and humans, as well as the different levels of absorption in the different species.

There is little general ICH guidance for pharmaceuticals on this matter, though oral absorption is the driving factor in their derivation of PDEs for elemental impurities. For organics, there is also a need to consider the effects of first-pass metabolism in the liver. After oral administration, a significant proportion of any dose will pass through the liver and be subject to metabolism before the substance reaches the systemic circulation.

In a recent draft reflection paper, the European Medicines Agency proposed that oral absorption is key and that, for organics lacking oral bioavailability data, a parenteral PDE can be extrapolated by dividing the oral PDE by 100.

32 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981