Derivation of an oral toxicity reference value for nickel

•Oral TRVs were developed for adults, toddlers, and nickel-sensitized people.•The TRVs for toddlers and adults (chronic exposure) are both 20 μg Ni/kg-day.•The adult TRV is based on post-implantation/perinatal mortality in rats.•The toddler TRV is based on decreased body weight in young rats.•The oral TRV for dermally-sensitized to Ni is 4 μg Ni/kg added to diet.

Nickel (Ni) is in the earth's crust and can be found in environmental compartments such as water, soil, and air, as well as food. This paper presents an assessment of the oral nickel toxicity data in support of non-cancer health-based oral exposure limits or toxicity reference values (TRVs). This paper derives TRVs for three populations of interest: adults, toddlers, and people who have been dermally sensitized to nickel. The adult/lifetime TRV of 20 μg Ni/kg-day is based on post-implantation loss/perinatal mortality in a 2-generation reproductive study in rats. Several recent assessments by regulatory agencies have used the same study and endpoint, but the dose-response modeling conducted here was more appropriate for the study design. Toxicokinetic data from rats and humans indicate that the applied uncertainty factors are very conservative. Because the endpoint relates to fetal exposure and is not relevant to toddlers, a toddler TRV was derived based on decreased body weight in young rats; this TRV was also 20 μg Ni/kg-day. A separate TRV of 4 μg Ni/kg in addition to Ni in food was derived for protection of nickel-sensitized populations from flare-up of dermatitis, based on studies of single exposures in humans under conditions that maximize oral absorption.