3,4,5,6-tetrachloro-N-[2-(4,5,6,7-tetrachloro-2,3-dihydro-1,3-dioxo-1H-inden-2-yl)-8-quinolyl]phthalimide

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Reason / purpose for cross-reference:

reference to other study

Description of key information

There are no studies available in which the toxicokinetic properties of the test substance were investigated. Based on the large molecular size, the absence of adverse findings in toxicity studies, and the presence of functional groups for metabolism, a potential for bioaccumulation is unlikely. Further details for this assessment are given below (please refer to "Additional information").

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Chemistry

The test substance (molecular weight of 694 g/mol) is a yellow solid. The water solubility (deionised water) is below 0.05 mg/L and its fat solubility between 0.23 and 0.5 mg/L. The calculated log Pow is therefore 1.03. The melting point is above 300 °C, which excludes vaporization of the test material. Examination of the particle size distribution revealed that 99.5 % are <100 µm, 42.9% <10 µm and 10.4% <4 µm.

 

Absorption

In regard to the poor water solubility and the absence of hydrolysable groups, the test substance cannot undergo pH-dependent hydrolysis in the stomach. Due to the high molecular weight (>500 g/mol) gastrointestinal absorption is very limited. As it does not bear resemblance to fatty acids, uptake via micelles with bile acids is unlikely. In line with this, no mortalities or clinical signs of toxicity were observed in doses up to 10000 mg/kg bw in an acute oral toxicity study, indicating primarily a very low level of oral toxicity. The NOAEL in male and female rats in a subacute oral repeated dose study is considered to be at the limit dose of 1000 mg/kg bw.

 

Based on the large molecular size, dermal uptake is unlikely. Skin penetration is expected to be marginally based on a model calculation (Fitzpatrick et al., 2004). However, the reliability of the calculation is limited for nanomaterials since it is based on molecular weight and log Kow and the log Kow is not determinable for nanomaterials. However, in an acute dermal toxicity study, rats were administered up to 2500 mg/kg bw of the test substance. No mortalities or clinical signs of toxicity were observed, indicating a very low level of dermal toxicity.

 

The test substance has a very low vapor pressure. This indicates that absorption of the substance via vapor inhalation is not relevant. As the substance is a powder, inhalation of particles is possible. Inhalation exposure of male Wistar rats to dust-aerosols at concentrations of 5, 20, 60 mg/m³ of the test substance for 5 consecutive days did not cause any treatment-related systemic adverse effects. The systemic no observed adverse effect concentration (NOAEC) is therefore set above 60 mg/m³. The NOAEC for local effects is 20 mg/m³, based on increased total cell counts, absolute neutrophil, lymphocyte, monocyte, bronchial epithelial cells, total protein levels as well as γ-glutamyl transferase (GGT), lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) activities, monocyte chemoattractant protein-1 (MCP-1) and cytokine-induced neutrophil chemoattractant-1 (CINC-1/IL-8) levels in BAL; increased histiocytes with intracytoplasmic yellow particles, hypertrophy/ hyperplasia of terminal bronchioles and infiltration of neutrophiles. Data from lavage and histology were consistent with the above mentioned effects. However, all effects were reversible after a 3-week recovery period. The local pulmonary effects observed are considered to appear at lung overload causing concentrations. Since no systemic toxicity was observed, no conclusion on respiratory absorption can be drawn.

 

Metabolism

No indication of uptake or reactivity was observed in any study, including acute studies, irritation, sensitization, genotoxicity and repeated dose toxicity studies.

Tests on biosolubility (static) and on dissolution kinetics (dynamic) in phagolysosomal simulant fluids were performed with the test substance to determine the persistence after uptake in cells, e.g. alveolar macrophages. These assays showed that the substance is not soluble in a static system. High biopersistence due to no dissolution (k<1ng/cm²/h) and no significant transformation in a dynamic system was seen as well, indicating that the substance is not dissolved or degraded after uptake, e.g. by alveolar macrophages.

In the unlikely case of uptake, potential metabolism might involve hydroxylation of keto-groups and phase-II reaction, i.e. substitution of chlorine by GSH.

  

Excretion 

As mentioned above, observations of yellowish stained feces in oral acute and repeated dose toxicity studies indicate that the substance is excreted unchanged via the feces. In case of gastrointestinal uptake and metabolism through hydroxylation and phase-II substitution of chlorine, it is expected that the test substance might be excreted predominantly via the urine. Overall, the test substance is not expected to accumulate in the body.

 

Used references:

Fitzpatrick, D., et al. (2004). "Modelling skin permeability in risk assessment-the future." Chemosphere 55 (10): 1309-14.