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EC number: 225-590-9
CAS number: 4948-15-6
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 density of 1.415 g/cm³ at 20°C and a molecular weight of 599 g/mol. The test article has a low vapor pressure of < 0.000001 hPa at 20°C and is characterized by very low solubility in both water (1.4 µg/l at 20°C) and organic solvents (n-octanol: 1.9 µg/L). The log Pow of 0.13 could only be calculated (based on the low solubility). 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 see 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 ten female albino rats were treated with the test article at 15,000 mg/kg bw by single oral dose (gavage) followed by a 7-day observation period (Hoechst AG, 1967). None of the animals died during the exposure period. No abnormal clinical observations were observed; the pigment was excreted via the feces. In another study ten female Wistar rats were treated with the test article at 5000 mg/kg bw by single oral dose (gavage) followed by a 14-day observation period (Hoechst AG, 1982). None of the animals died during the exposure period. No abnormal clinical observations were observed; the pigment was excreted via the feces. A normal weight gain was observed, and no abnormal findings were made at necropsy. The subchronic toxicity of the test substance was tested in crossbred albino rats in a 90-day feeding trial. Three groups Sprague-Dawley rats (15/sex/dose) were administered the test article at 0 (group III), 10,000 (group II) and 50,000 ppm (group I) in the diet (Hoechst AG, 1967). The general behavior in groups I and II was normal throughout the entire trial period and did not differ from that of the control animals. None of the experimental animals showed signs of a toxic effect. The test article was excreted via the feces. The food consumption and the weight gains of the treated rats were normal and did not differ from that of the control rats. The hematological investigations revealed no pathological findings. Investigation of the urine showed no pathological findings which could be attributed to the test article administered. Macroscopic and microscopic examination revealed no pathological organ damage. The lack of systemic toxicity in these studies suggests poor absorption resulting in low or no bioavailability upon oral ingestion. 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 a dermal toxicity study performed with a structural 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. In an inhalation toxicity study according to OECD guideline 403, Wistar rats (5/sex) were exposed to the test article as dust for 4 hours at a measured concentration of 5.2 mg/L followed by a 14-day observation period (BASF AG, 1989). None of the animals died during the study period. Clinical signs included irregular, accelerated and/or intermittent respiration, flight behavior and discolored fur. From day 7 of the observation period onward, no abnormalities, except discolored fur, were detected in the animals. The body weight gain of male and female rats in the test group, compared with a historical control collective, was not affected by the substance over the total observation period. No pathologic findings were noted during gross pathology. Cascade impactor measurements performed during this inhalation study resulted in a particle size distribution with a mass median aerodynamic diameter (MMAD) of 3 µm (GSD: 3.6), which is well within the respirable range. An additional particle size distribution analysis showed that 99.3% of the analyzed material was smaller than 100 µm and 14.9% of the substance was found in particles smaller than 10 µm. These data demonstrate that the test substance can be inspired and may reach the alveolar region upon dust inhalation. However, since the test article is neither soluble in water nor soluble in fat, absorption and systemic availability after inhalation is not expected. This is additionally confirmed by experimental studies for other category members including 5 and 90 d inhalation exposure where no treatment-related systemic effects could be observed. 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 of the test article. 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. The substance was tested negative in genotoxicity tests (Ames tests, Hoechst, 1982 and BASF, 1998), 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 observations made during toxicity tests (colored feces). Overall, accumulation of test material within the body is not expected.
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