Benzoic acid, 2,3,4,5-tetrachloro-6-cyano-, methyl ester, reaction products with 2-methyl-1,3-benzenediamine and sodium methoxide

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional 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 assessments are given below.

 

Chemistry

The test substance (molecular weight of 656 Da) is a yellow powder those water solubility (deionised water) is < 32 µg/l. The solubility in different organic solvents is low to very low (< 10 mg/100ml), the logPow is calculated to be 0.5. The melting point is above 400°C which excludes vaporisation of the test material. Examination of the particle size distribution revealed a MMD of 2.5 µm (D10 1.27 µm, D90 26.95 µm). With regard to the molecular structure of the substance and the poor solubility in water, hydrolysis is not likely.

 

Absorption

In an acute oral and inhalation toxicity study (analogue substance), rats were administered to the test substance. No mortalities or clinical signs of toxicity were observed at doses of 5000 mg/kg bw and 1.04 mg/l air, respectively, indicating primarily a very low level of oral and inhalation toxicity. The NOAEL in male and female rats in a subacute oral repeated dose study on a structural analogue is 1000 mg/kg bw/day. With 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.

Skin penetration can be excluded based on model calculation (Fitzpatrick, et al., 2004).

The test substance has a comparably very low vapour pressure. This indicates that absorption of the substance via vapour inhalation is not relevant.

 

Metabolism

Single oral application of the test item to male and female rats did not provoke any effect than yellow stained feces. Oral administration of an analogue substance to Wistar rats at doses of 100, 300 and 1000 mg/kg bw/day, for 28 days resulted in no test item-related effects and no differences in food consumption or body weight development. The hematology, clinical biochemistry and urinalysis parameters did not show test item-related differences when compared with those of the controls. Organ weights of test item-treated animals were unaffected, and macroscopical/microscopical findings were of no toxicological relevance.

Based on the results of this study, 1000 mg/kg bw/day was considered to be the no observed- adverse-effect-level (NOAEL).

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

In case the substance is absorbed via the gastrointestinal system, the material will be transported to the liver. Possible degradation by metabolising enzymes may cause formation of benzenendiamine. Benzenediamine is highly toxic, irritating and a strong sensitizer. Single or double oral application of the test item at high concentrations (acute oral toxicity testing, micronucleus assay) did not reveal mortality or signs of toxicity. Instead, excretion of yellow or orange stained feces was observed indicating a lack of enzymatic or bacterial degradation. Rather than formation of benzenediamine, substitution of chlorine by glutathion and subsequent excretion of the conjugated metabolite via urine is possible.

  

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.