Benzenamine, N-phenyl-, styrenated

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
According to REACH Annex VIII column 1 (8.6.1), the following study for repeated dose toxicity is required: Short-term repeated dose toxicity study (28 days), one species, male and female, most appropriate route of administration, having regard to the likely route of human exposure.
There is a suitable Klimisch 1 GLP OECD 407 guideline study available, assessing the toxicological properties of 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin after oral gavage over 28 days. In general, the oral route is the most suitable one to assess systemic effects in humans, which is the main aim of this endpoint. The dermal or inhalative route is only scientifically relevant in case of considerable exposure, any route-specific toxicological mode of action or local effects, whereas sufficient information on the latter can be gained via irritation tests (REACH No. 8.1. or 8.2). According to REACH Annex VIII column 2 (8.6.1), the appropriate route shall be chosen on the following basis: Testing by the dermal route is appropriate if:
(1) inhalation of the substance is unlikely; and
(2) skin contact in production and/or use is likely; and
(3) the physicochemical and toxicological properties suggest potential for a significant rate of absorption through the skin. Although inhalation of styrenated diphenylamine to any toxicologically relevant amount is unlikely, the latter conditions do not apply. Due to the inherent rather low toxicity of styrenated diphenylamine, a very high exposure to the substance would be required, which is excluded due to the taken workplace safety precautions. Even if exposure arises, exposition of workers would be magnitudes below any possible dose levels which could reveal any effects in animal models. Based on the current knowledge, the substance is not classified for human-relevant endpoints, and any theoretical exposure which could lead to any effects in humans, even with applying appropriate uncertainty factors, would be magnitudes below the actual one.
Further, the physicochemical and toxicological properties do not suggest potential for a significant rate of absorption through the skin. Skin absorption is influenced by several factors, i.a.:
- Molecular weight: Less than 100 favors dermal uptake. Above 500 the molecule may be too large.
The substance is an UVCB substance, so no absolute molecular weight can be given. The substance consists mainly of Isomers (o-, m- and p-substitution) of di-styrenated diphenylamines and Isomers (o-, m- and p-substitution) of mono-styrenated diphenylamines, to a lesser extent of Isomers (o-, m- and p-substitution) of tri-styrenated diphenylamines. These isomers have molecular weights of 273, 377, and 481 g/mol. With those molecular weights, absorption is in theory possible, but not highly favoured, especially with increasing numbers of styrene moieties. Mono-substituted isomers are generally more likely to be absorbed than tri-substituted ones.
- LogPow: for substances having a logPow above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself may be slow.
The experimental determination gave a result of logPow = 4.62 (styrenated diphenylamine, UVCB), EpiSuite estimation revealed the following results for the single constituents:
p-mono-styrenated diphenylamine: Log Kow = 5.4482
p,p‘-di-styrenated diphenylamine: Log Kow = 7.6051
o,p,p‘-tri--styrenated diphenylamine: Log Kow = 9.7620
Taking into account the rather high logPow values, dermal absorption may practically not occur.
- Water solubility: The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore, if the water solubility is below 1 mg/L, dermal uptake is likely to be low. With a water solubility of 20.6 µg/l, the substance was found to be virtually insoluble in water. Also here, dermal absorption may practically not occur.
- Skin irritation / corrosion: If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration. Styrenated diphenylamine is not classified as irritant to the skin. Also no pathological changes on the treated skin of male and female rats were found in an acute dermal toxicity test at a dose of 2000 mg/kg. Further, the substance does not need to be classified as irritating to the eye, which is in general considered to be more sensitive than the skin. Therefore, no additional penetration enhancement must be considered. In consequence, the available OECD 407 and 422 studies (oral exposure route) is sufficient to cover this endpoint, no repeated dose testing via dermal route needs to be performed and can consequently be waived due to animal welfare.