Benzoic acid, 2,3,4,5-tetrachloro-6-cyano-, methyl ester, reaction products with p-phenylenediamine and sodium methoxide

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

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 640.8 g/mol) is a yellow solid. The water solubility (deionised water) is < 0.03 mg/l and its fat solubility is about 0.03 mg/l. The melting point is above 300°C which excludes vaporization of the test material. Examination of the particle size distribution revealed that ca. 17% are <4 µm, ca. 39% <10 µm and ca. 96% <100 µm. With regard to the molecular structure of the substance hydrolysis is not likely.

 

Absorption

In an acute oral toxicity study, rats were administered to the test substance. No mortalities or clinical signs of toxicity were observed in doses of 5000 mg/kg bw, indicating primarily a very low level of oral toxicity. The NOAEL in male and female rats in a subacute oral repeated dose study is 1000 mg/kg bw. 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.

 

Based on the large molecular size, dermal uptake is unlikely. Skin penetration is expected to be marginally based on model calculation. 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. The results of available studies on skin sensitization were negative, and therefore gave no indication on dermal absorption.

 

The test substance has a very low vapor pressure. This indicates that absorption of the substance via vapor inhalation is not relevant. As the test substance is a powder, inhalation of particles is possible. In an acute inhalation toxicity study, 1.04 mg/L air did not cause any signs of toxicity. Furthermore, inhalation exposure of rats to 30 mg/m³ of the test substance on 5 consecutive days did not cause any treatment-related systemic adverse effects either. The systemic no observed adverse effect concentration (NOAEC) is therefore set above 30 mg/m³. The NOAEC for local effects is 10 mg/m³, based on increased absolute and relative neutrophil and monocyte counts as well as IL-8/CINC-1 values in bronchoalveolar lavage. However, there was no histological correlate and all effects were reversible within 3 weeks exposure-free recovery period. The local pulmonary effects observed are considered to appear at lung overload causing concentrations.

 

Metabolism

No indication of uptake or chemical reactivity was observed in any study, including acute studies, irritation, sensitization and genotoxicity in vitro as well as a subacute study.

A test on biosolubility (static) and on dissolution kinetics (dynamic) in phagolysosomal simulant fluids was 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 and is of high biopersistence due to no dissolution (k<1ng/cm²/h) and no significant transformation in a dynamic system, indicating that the substance is not dissolved or degraded after cellular 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, the substance is expected to be 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.