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Repeated dose toxicity: dermal

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Endpoint:
sub-chronic 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 IX column 1 (8.6.2), the following study for repeated dose toxicity is required: Sub-chronic toxicity study (90-day), one species, rodent, 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 408 guideline study available, assessing the toxicological properties of 1,3-Dimethyl-4-aminouracil after oral application in feed over 90 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 IX column 2 (8.6.2), the appropriate route shall be chosen on the following basis: Testing by the dermal route is appropriate if:
(1) skin contact in production and/or use is likely; and
(2) the physicochemical properties suggest a significant rate of absorption through the skin; and
(3) one of the following conditions is met:
— toxicity is observed in the acute dermal toxicity test at lower doses than in the oral toxicity test, or
— systemic effects or other evidence of absorption is observed in skin and/or eye irritation studies, or
— in vitro tests indicate significant dermal absorption, or
— significant dermal toxicity or dermal penetration is recognised for structurally-related substances.
Although inhalation of 1,3-Dimethyl-4-aminouracil to any toxicologically relevant amount is unlikely, the latter conditions do not apply:
(1) Due to appropriate precautionary measures, skin contact in production and/or use is minimized.
(2) 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. With a molecular weight of 155.15 g/mol, absorption is in theory possible.
- LogPow: In order to cross the skin, a compound must first penetrate into the stratum corneum and may subsequently reach the epidermis, the dermis and the vascular network. The stratum corneum provides its greatest barrier function against hydrophilic compounds, whereas the epidermis is most resistant to penetration by highly lipophilic compounds. logPow values between 1 and 4 hence favour dermal absorption. 1,3-Dimethyl-4-aminouracil has a low logPow, i.e. -0.4 at 20°C and pH 6.2-6.9 (flask method, OECD 107). Hence, it is unlikely that the substance could pass the stratum corneum, and dermal absorption is unlikely to occur.
- Water solubility: with a water solubility of 5.46 g/L at 20°C the substance is slightly lipophilic, and is hence presumably slightly hindered to pass the stratum corneum.
- Skin irritation / corrosion: If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration. 1,3-Dimethyl-4-aminouracil is not classified as irritant to the skin. 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.
So summarizing, absorption cannot be excluded, but a significant rate of absorption is not expected.
(3) None of the following conditions are met:
- Both acute oral toxicity studies were performed as limit test (5000 mg/kg for oral, 2000 mg/kg for dermal testing), and no deaths occurred, no abnormalities were noted. Hence, toxicity in the acute dermal toxicity test at lower doses than in the oral toxicity test can neither be confirmed nor excluded as no toxicity was observed at dose levels relevant for classification.
- no systemic effects or other evidence of absorption were observed in skin the available eye irritation studies
- no data in in vitro absorption tests or structurally related substances is available
In consequence, the available OECD 408 study (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.

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