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EC number: 221-264-5
CAS number: 3049-71-6
No expected bioavailability neither orally, dermally nor
inhalative was suggested. No bioaccumulation potential assumed. The test
substance is expected not to be metabolized in the body due to low
solubility in both water and fat. Further, excretion was concluded to
occur via feces. However, no experimental data concerning absorption,
distribution, and metabolism have been conducted.
Assessment of the Toxicokinetic Behavior
The test substance is a red solid dyestuff with a relative density of 1.479 g/cm³ at 20°C and a molecular weight of 750.8 g/mol. The test article has a vapor pressure of < 0.000001 hPa at 20°C and is characterized by very low solubility in both water (< 10 µg/l at 20°C) and organic solvents (n-octanol: < 0.1 mg/L). The log Pow was estimated based on the solubility in water and octanol to be 1.0 at 20°C. No studies are available investigating the toxicokinetic properties of the test substance. The toxicokinetic behavior is therefore assessed based on physic-chemical properties and on available toxicity studies performed with the test article and with other members of the category (for category justification refer to the attached document).
Based on the very low water solubility and the low solubility in n-octanol (i.e. fat), bioavailability of the test substance is generally not expected. This is supported by the available toxicity studies. In an oral toxicity study male and female Sprague-Dawley rats (5/sex) were administered the test substance at a single dose of 5000 mg/kg bw by gavage followed by a 14-day observation period (BASF, 1978). None of the animals died during the exposure period. Besides red stained feces no abnormal clinical findings were made and no abnormal findings were made at necropsy. In a second oral toxicity study rats (5/sex/dose) were administered the test substance at single doses of 200, 1,600 and 6,400 mg/kg bw by gavage followed by a 7-day observation period (BASF, 1966). None of the animals died during the study. Clinical signs were atony, ruffled fur, curved body position dyspnea and jumpy behavior. The feces were stained red. No abnormal findings were made at necropsy. The results of both studies do not indicate any systemic availability of the test substance upon oral ingestion. In addition, various oral toxicity studies with repeated administration have been performed with structural analogues of the same category. None of them revealed any toxicity up to the highest dose levels tested (1000 mg/kg bw and up). These results support the proposed lack of absorbance for the members of this category. As a result an accumulation of the test article in the body is not expected.
Dermal absorption is equally unlikely based on the test compound’s very low solubility properties in both water and fat. In addition, substances with a molecular weight of greater than 500 may be too large for dermal uptake. In a dermal toxicity study performed with a structure analogue no signs of toxicity were observed with the limit dose of 2500 mg/kg, indicating a low systemic availability after dermal exposure. In conclusion, based on the low water solubility together with the results of acute dermal toxicity studies, dermal absorption of the test article is not expected.
No indications for absorption after inhalation are given from the available toxicity data and the physic-chemical properties of the test article. For the test substance a 5 d and 90 d inhalation study were performed. In both studies male and female Wistar rats were exposed to the dust aerosol for 6 h/day on 5 consecutive days. During the study mortality, body weight changes, clinical signs, and ophthalmology (only during 90 d study) were observed. After exposure (and recovery time of the satellite groups), the animals were scarified and subjected to necropsy. Clinical pathology parameters including bronchoalveolar lavage with clinicochemical and cytological evaluation of lavage fluid, organ weights and all histopathological changes were determined. No signs of systemic toxicity were observed at the highest tested dose of 60 mg/³ air (5 d) and 20 mg/m³ (90d). Only local effects after 90 d exposure were observed. The cascade impactor measurement showed comparable MMADs and GSDs in the concentration groups. The calculated mass fractions of particles below 3 µm aerodynamic size ranged between 88.8 and 97.3 %. The generated aerosols were highly respirable for rats. However, since the test article is neither soluble in water nor soluble in fat, absorption and systemic availability after inhalation is not expected. Particles deposited in the nasopharyngeal region will most likely be coughed or sneezed out and particles deposited in the trachea-bronchial region will be cleared by mucocilliary mechanisms and swallowed. Dust particles reaching the alveolar region will mainly be engulfed by alveolar macrophages and cleared via the ciliated airways or the lymphatic drainage. In conclusion, the test article can be inspired in the form of dust, however, as indicated by the acute inhalation toxicity study and based on the very low solubility, particles are expected to be not absorbed and not bioavailable.
Distribution and Accumulation
Since the substances are water-insoluble molecules, they will not diffuse through aqueous channels and pores. Therefore, a distribution into different organs is not assumed. No bioaccumulation hazard is expected based on results of repeated dose toxicity data for different pigments of the category in rats and physicochemical properties.
A test on biosolubility (static) and on dissolution kinetics (dynamic) in phagolysosomal simulant fluids was performed with all pigments of the category, except Pigment Red 224 (CAS 128-69-8), to determine the persistence after uptake in cells, e.g., alveolar macrophages. All substances tested were insoluble in phagolysosomal simulant fluid at pH 4.5 in the static and dynamic dissolution assay.
Considering the chemical structure of the test article, Cytochrome P450 linked oxidations of the aromatic ring systems are possible steps in the metabolism. However, based on the low solubility property in both water and fat, the substance is most likely not absorbed and excreted unchanged. This is supported by the observation of colored feces in toxicity studies. Studies on genotoxicity (Ames assays, BASF, 2011, 2002) were negative, i.e. there is no indication of a reactivity of the test substance or its metabolites with biomacromolecules under the chosen test conditions.
The ability to induce biological oxidative damage in chemico was analyzed using the Ferric Reduction Ability of Serum (FRAS) assay and Electron Paramagnetic Resonance spectroscopy (EPR) for every category member except Pigment Red 224 (CAS 128-69-8). Most substances tested were classified as “passive” in both assays. Pigment Red 149 (CAS 4948-15-6) and 178 (CAS 3049-71-6) were classified in FRAS assay but as active in EPR assay.
Furthermore, none of these substances induced pro-inflammatory effects or cytotoxicity in rat alveolar macrophages according to the classification criteria of Wiemann et al. 2016.). Most substances tested were classified as “passive” in both assays. Pigment Red 149 (CAS 4948-15-6) and 178 (CAS 3049-71-6) were classified in FRAS assay but as active in EPR assay.
Since the test article is not soluble in water and fat, excretion is expected to occur predominantly via the feces. This assumption is strengthened by the observation of colored feces in the toxicity studies. Overall, accumulation of test material within the body is not expected.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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