N,N'-[6,13-diacetamido-2,9-diethoxy-3,10-triphenodioxazinediyl]bis(benzamide)

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 727 Da) is a solid whose water solubility (deionised water) is < 0.01 mg/l. Based on individual solubilities in water and octanol the logPow is calculated to be > 0.57. The material decomposes before melting which excludes vaporisation of the test material. Examination of the particle size distribution revealed a MMD of 22.3 um (D10 4.94 um, D90 141.4 um). In regard to the molecular structure of the substance and the poor solubility in water hydrolysis is not likely.

 

Absorption

In an acute oral and dermal toxicity study, the test substance was administered to rats. No mortalities or clinical signs of toxicity were observed in doses of 15000 mg/kg bw and 2000 mg/kg bw, respectively, indicating primarily a very low level of oral and dermal toxicity. The NOAEL in male and female rats in an OECD 422 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 (> 5700 g/mol) gastrointestinal absorption is expected to be very limited. This suggestion is supported by black staining of the feces and black contents in the GI tract which were observed in all treated animals.

Based on a calculation according to the model of Fitzpatrick the substance is expected to be marginally skin permeable (Fitzpatrick, et al., 2004).

 

Metabolism

Single oral application of the test item to male and female rats did not provoke any effect than diarrhea and reduction in spontanious motiliy. Mortality was not observed up to the highest dose level . Oral repeated administration of the test substance to Wistar rats at doses of 100, 300 and 1000 mg/kg/day 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. Black staining of the feces and black contents in the GI tract were seen for animals in all treated groups in a dose dependent manner. These were secondary to the color of the test substance and were not considered adverse. Based on the results of this study, 1000 mg/kg/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 gastrointestianl system, the material will be transported to the liver where hydroxylation of ethyl and keto groups may occur. Instead, excretion of black stained feces was observed indicating a lack of ezymatic or bacterial degradation.

  

Excretion 

As mentioned above, the substance is expected to be excreted unchanged via the feces. In case of gastrointestinal uptake and metabolism through hydroxylation the substance remains poorly soluble and has still a MW of more than 700 which supports biliary excretion. 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.