Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
According to REACH Annex VIII column 2, 8.5.2. Testing by the inhalation route is appropriate if exposure of humans via inhalation is likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size.
The substance melts at 299°C, the boiling point could not be determined with the most sensitive method, i.e. vapour pressure measurement by effusion method, weight loss, according to OECD Guideline for the Testing of Chemicals 104. It could not be determined because the vapour pressure is too low. The vapour pressure itself was determined as very low, i.e. 1 * 10exp(-7) hPa at 25°C (calculated using the Modified Watson Correlation, OECD 104, GLP). So, the exposure to 1,3-dimethyl-4-aminouracil via inhalation of vapour can be disregarded as no vapour will be formed during handling. Also, the substance is a solid, so the formation of inhalable droplets or aerosols can furthermore be excluded.
The particles of 1,3-Dimethyl-4-aminouracil form various size agglomerates. The measurement of the single particles was not possible. The amount of test item with a particle size below 250 µm was only about 2 %. This amount is too small and not relevant for the particle size distribution. The main agglomerate size was found in the range of 250 µm to 2000 µm. 50 % of the test item agglomerates exceeded 500 µm. 0.00% were < 75µm. According to ECHA’s guidance on data requirements Chapter R.7c, In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract. As obvious, only less than 2% of the particles in general have the potential to be inhaled, and none of the particles have the potential to reach the part of the lung in which no ciliary clearance occurs. Also, direct dust exposure is excluded during handling, hence not fulfilling the above-mentioned criteria for the necessity of testing.
Furthermore, testing is scientifically not necessary and would not reveal any additional information which cannot be derived from other available acute toxicity data, so that testing can be omitted due to animal welfare:
According to ECHA’s guidance, Moderate log P values (between -1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. The log Pow of the test item 1,3-dimethyl-4-aminouracil was determined to be -0.4 at 20°C and pH 6.2-6.9 (flask method, OECD 107). Hence, this value may indicate a certain potential for absorption. With a water solubility of 5.46 g/L at 20°C, absorption here can also not be excluded, in case any particle reaches the respiratory tract. Further, there are no signs of toxicity obvious via the oral or dermal route.
There is no study available (and required) for the acute inhalation toxicity of 1,3-dimethyl-4-aminouracil; however, there are LD50 values via other application routes available:
Oral: LD50 > 5000 mg/kg, LD0 ≥ 5000 mg/kg (similar to OECD 401)
Dermal LD50 > 2000 mg/kg, LD0 ≥ 2000 mg/kg (OECD 402, GLP)
The obtained values are consistent and can be hence considered as reliable, and may be so used for further considerations:
According to OECD guideline 403 (Acute inhalation toxicity), the concentration of respirable particles for limit testing is 5 mg/L over 4 h. Taking into account for rats a standard respiratory volume of 0.2 l/min and average body weight of 250 g (Guidance on information and requirements and chemical safety assessment, chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012, ECHA, http://echa.europa.eu/web/guest/guidance-documents/guidance-on-information-requirements-and-chemical-safety-assessment), a total respiratory volume of 48 litre over 4 h can be assumed. This would result in a total dose of 240 mg per rat, which is equivalent to 960 mg/kg bw.
Assuming in a worst-case scenario that this total dose will be absorbed to 100%, and assuming furthermore that the orally applied amount is only absorbed to 50%, this dose would correspond to an oral dose of 1920 mg/kg bw. This value is below the relevant determined LD50 and even LD0 via the oral and dermal route, i.e. 2000 mg/kg bw. Hence, it can be reasonably assumed that an additional acute toxicity test via the inhalation route would reveal an LC50inhalation >5 mg/l, most likely even a LC0inhalation ≥5 mg/l. This is supported by the reasonably assumable hindered absorption via the inhalatory route compared to the oral one due to the particle size and tendency of the particles to form agglomerates.
Furthermore, during the investigation of the acute dermal toxicity, no alterations of the skin were detected, and 1,3-dimethyl-4-aminouracil is neither a skin nor eye irritant nor a dermal sensitizer. So it can be additionally concluded, that no local effects during inhalation toxicity testing are likely occur and need to be regarded.
In consequence, the available oral and dermal acute toxicity studies are sufficient to cover this endpoint, no acute toxicity testing via inhalation route needs to be performed and can consequently be waived due to animal welfare.

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion