Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

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.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
0
Absorption rate - dermal (%):
0
Absorption rate - inhalation (%):
0

Additional information

Assessment of the Toxicokinetic Behavior

The test substance is a brown/red solid dyestuff with a density of 1.6 g/cm3 at 20°C and a molecular weight of 418 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 (5.5 µg/l at 20°C) and organic solvents (n-octanol: 5.1 µg/L). The log Pow of -0.03 could only be calculated (based on the solubilities in water and octanol). 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).

Absorption

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 tested according to OECD guideline 401, Wistar rats (5/sex) were treated with the teat substance at 5000 mg/kg bw by single dose (gavage) followed by a 14-day observation period (Hoechst, 1983). None of the animals died during the exposure period. No abnormal clinical observations were observed; the test substance was excreted via the feces (stained feces observed). A normal weight gain was recorded and no abnormal findings were made at necropsy. In a second study Sprague-Dawley rats (5/sex) were treated with the test substance at 5000 mg/kg bw by single dose (gavage) followed by a 14-day observation period (BASF, 1980). None of the animals died during the exposure period. No abnormal clinical observations were observed; the test substance was excreted via the feces. A normal weight gain was observed and no abnormal findings were made at necropsy. In a further study Sprague-Dawley rats (5/sex) were administered the test article at 2000 mg/kg bw by single dose (gavage) followed by a 14-day observation period (Hazleton Laboratories Europe Ltd., 1978). None of the animals died during the exposure period. No abnormal clinical observations were observed. A normal weight gain was observed and no abnormal findings were made at necropsy. In two more studies rats (n = 5) were treated with the test substance or with a mixture containing the test substance at 10000 mg/kg bw by single dose (gavage) followed by a 7-day observation period (both BASF, 1976). None of the animals died during the exposure period. Clinical signs in each study included apathy and dyspnea, respectively. No abnormal findings were made at necropsy. The results of these 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 a dermal toxicity study performed with the test article 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 two inhalation risk tests, the toxicity of an atmosphere saturated at 20 °C with dust of the test compound (BASF, 1974) or with dust generated from a mixture containing the test article at 18.5% (BASF, 1974) was investigated. Two groups of rats (3/sex/group) were exposed sequentially to the dusts for 8 h. None of the animals died during the exposure period and no abnormal clinical signs were reported in either study. In both studies, body weights and gross pathology were normal. In a supporting inhalation toxicity study comparable to OECD guideline 403, a single maximum concentration of the test material was administered to 20 Sprague-Dawley rats (10/sex) as dust by inhalation (nose only) over a period of 4 hours. The concentration of test material, as measured by gravimetric analysis was 0.41 mg/l. (Hazleton, 1978). No deaths occurred during exposure or during the observation period as a result of exposure to the test material. One male treated rat suffocated as a result of turning around in the restraining tube. The mean body weights of the treated rats were depressed following exposure but raised steadily throughout the observation period. All the control rats and 6 male and 7 female treated rats, sacrificed after the 14 day observation period showed a moderate degree of pulmonary congestion and edema was present in some control rats. A similar degree of congestion was also noted in the female treated rat examined immediately after exposure, but congestion was more severe in the male, which had suffocated. No congestion was noted in the two control rats sacrificed at the same time, and no other abnormalities were noted in any of the control animals. The mass median aerodynamic diameter determined during the study (MMAD) was 0.87 µm, which is well within the respirable range. An additional particle size distribution analysis showed that 66 .2% of the analyzed material was smaller than 100 µm and 7% 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. 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 available acute inhalation toxicity studies and based on the very low solubility, particles are expected to be not absorbed and not bioavailable.

Metabolism

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, 1984, BASF, 1991), i.e. there is no indication of a reactivity of the test substance or its metabolites with biomacromolecules under the chosen test conditions.

Excretion

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.