Salts of 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthenium chloride and 4-{[1-hydroxy-6-({[5-hydroxy-6-(phenyldiazo)-7-sulfonaphthalen-2-yl]carbamoyl}amino)-3-sulfonaphthalen-2-yl]diazo}benzoic acid (2:1)

Endpoint summary

Additional information

F 213 Red is a solid at room temperature with a molecular weight of 1178.03 g/mol. The melting point was determined > 300 °C. Vapour pressure was assumed to be low (F 213 Red decomposes before reaching liquid phase) and calculated for the reactants Direct Orange 102 and Basic Red 1, with values of 1.36E-34 and ca. 1.27E-09 Pa at 25 °C (Modified Grain method), respectively. The partition coefficient (logPow= 2.94) was determined using the HPLC-method. The substances water solubility was determined to be 0.65 mg/l.

 

As the substance is a solid with a high molecular weight, vapour pressure was assumed to be extremely low and the boiling point was determined > 150 °C, very little exposure via inhalation (as gas) is expected (note: the substance is brought to market and used only in liquid preparation). Even though the log Pow indicates that some absorption directly across the respiratory tract epithelium can occur, the high molecular weight indicates that the substance will hardly become bioavailable via the inhalation route. Further, the substance showed low toxicity after oral and dermal administration. Together this indicates low systemic availability after inhalation and if bioavailable, low toxicity via this route of administration.

 

Based on physical-chemical properties F 213 Red absorption across the skin is likely to be low. The molecular weight > 500 g/mol and water solubility are low. No toxicity, neither local nor systemic, was observed following dermal application of 2000 mg/kg bw up to the limit dose.

 

Administered orally, F 213 Red is not likely to dissolve in the stomach easily, due to its low water solubility (< 1 mg/L). As only dissolved substance is available for adsorption, the quantity of F 213 Red to become bioavailable via the oral route is low. Further, high molecular weight does not favour passive diffusion across the gastrointestinal tract. Therefore, most likely very low amounts of F 213 Red or breakdown products will become bioavailable. Most of F 213 Red ingested and its breakdown products will be eliminated through faeces. Hence, observed gastrointestinal tract colouration and red faeces. Respectively, toxicity to orally administered F 213 Red is low, as shown in acute and subacute toxicity tests (NOAEL = 1000 mg/kg bw/day; limit dose). If bioavailable, F 213 Red is not likely to bioaccumulate, based on its low logPow-value (< 3).

 

After becoming bioavailable after e.g. ingestion, F 213 Redis likely to be metabolised and parent compound and degradation products are expected to distribute via systemic circulation. Based on molecular weight and water solubility, most substance will likely be excreted via faeces. If bioavailable, metabolism may transform F 213 Red into more polar degradation products. Likely pathways are reactions such as cytochrome P-450-dependent monooxygenase enzyme mediated oxidative ring opening and/or cleavage at the amide side-chains. Parent compound and metabolites formed in phase I metabolic reactions may be rendered more polar by phase II metabolic activity in subsequent reactions. The parent compound or possible metabolites may undergo conjugation (e.g. with glutathione), before being excreted in urine or bile. Excretion was demonstrated by red colouration of urine and faeces, but in the absence of any clinical pathology alterations, these colourations were not considered to be an adverse effect.

 

It is unlikely that F 213 Red is metabolised to more reactive (toxic) products. This assumption is supported by results obtained in oral and dermal toxicity studies and three in vitro tests. In acute and subacute in vivo studies toxicity was moderate to low. In an Ames test and a chromosome aberration assay no significant increase in toxicity was noted in the presence of a rodent microsomal S9-fraction, when compared to incubation without S9-fraction. Together, this data indicates that formation of reactive metabolites is rather unlikely.

 

Based on the substance’s structure and associated physical-chemical characteristics, very low to low amounts of F 213 Red will become bioavailable through inhalation, upon contact to skin or following oral ingestion. When bioavailable, the substance or its metabolites are expected to distribute, with excretion via urine or bile (polar conjugated forms, breakdown products) and via faces (high molecular weight forms, unchanged substance). Bioaccumulation is unlikely.