Reaction mass of Chromate(1-), [N-[7-hydroxy-8-[(2-hydroxy-5-nitrophenyl)azo]-1-naphthalenyl]acetamidato(2-)][1-[(2-hydroxy-5-nitrophenyl)azo]-2-naphthalenolato(2-)]-, hydrogen, compd. with N-cyclohexylcyclohexanamine (1:1) and hydrogen bis[1-[(2-hydroxy-5-nitrophenyl)azo]-2-naphtholato(2-)]chromate(1-) , compound with dicyclohexylamine (1:1) and hydrogen bis[N-[7-hydroxy-8-[(2-hydroxy-5-nitrophenyl)azo]-1-naphthyl]acetamidato(2-)]chromate(1-) , compound with dicyclohexylamine (1:1)

Endpoint summary

Description of key information

The test item does not indicate a potential for bioaccumulation based on its physical-chemical properties and available experimental data.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

Toxicokinetic analysis of Reaction mass of Chromate(1-), [N-[7-hydroxy-8-[(2-hydroxy-5-nitrophenyl)azo]-1-naphthalenyl]acetamidato(2-)][1-[(2-hydroxy-5-nitrophenyl)azo]-2-naphthalenolato(2-)]-, hydrogen, compd. with N-cyclohexylcyclohexanamine (1:1) and hydrogen bis[1-[(2-hydroxy-5-nitrophenyl)azo]-2-naphtholato(2-)]chromate(1-) , compound with dicyclohexylamine (1:1) and hydrogen bis[N-[7-hydroxy-8-[(2-hydroxy-5-nitrophenyl)azo]-1-naphthyl]acetamidato(2-)]chromate(1-) , compound with dicyclohexylamine (1:1)

(EC 926-865-0)

 

There are no studies available that investigate the toxicokinetic behaviour of the test item. Based on the molecular structure of the constituents and physicochemical properties a toxicokinetic assessment can be performed.

 

The test item is an organometallic multi-constituent substance appearing as black fine powder at ambient conditions. The molecular weight of the test item ranges between 848.84 and 964.94 g/mol with a relative density of 1.374 at 20 °C. Melting point of the substance could not be determined since the substance decomposes before melting at temperatures > 200 °C. Boiling point was therefore considered to be > 300 °C. Consequently, determination of vapour pressure was technically not feasible, however, vapour pressure can be anticipated to be < 10^-6 Pa. The test item is moderately soluble in water as indicated by solubilities of 6.1 to 46 mg/L with an experimental loading rate of 0.1 and 1.0 g/L, respectively. However, solubility is dependent on the loading rate and may thus become even greater than 46 mg/L with application of a corresponding greater loading rate. Correspondingly, the n-octanol/water partition coefficient ranges between 3.3 and 4.2 at 20 °C. The particle size distribution was experimentally determined as follows: <4 µm= 2.1%; <10 µm= 5.2%; <100µm= 46%.

 

Absorption

Uptake of the target substance in the intestine is based on the low water solubility and relatively large molecular weight of the undissociated complex, expected to be limited (ECHA guidance R7c Table R.7.12-1). The logPow being 3.3- 4.2 is within the favourable range for passive diffusion. Altogether, the ingested fraction is likely to partially pass the intestine unchanged and to be excreted directly via faeces. The chromium complexes present in the test item are anticipated to (at least partly) dissociate in the gastric environment, leading to the release of chromium (III) and the corresponding ligands, which are also strongly colored. The dissociation of the complex is expected to be identical for all constituents, due to the common molecular structures.
The direct excretion of the unchanged substance or ligands is experimentally supported by the observed dark coloration of the faeces in the acute oral toxicity study with a structural analogue (Ciba-Geigy Ltd, 1972a, please also refer to read-across justification attached to IUCLID Section 13), the 14-day dose range finder with the test item (BASF 2017c) as well as the Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test according to OECD 422 (BASF, 2018). In the dose range finder as well as in the OECD 422 additionally systemic effects were observed, which indicates that the test item becomes at least partially bioavailable. Further, there is experimental indication that the test item or its dissociation products passes the placental barrier and reaches the developing fetus. Grey discoloration of skin, liver, thymus and kidneys was observed in pups, as well as developmental abnormalities of the caudal vertebra. These findings are considered to be caused by test item treatment of the dams.

Even though the logPow is within the optimal domain for dermal absorption, absorption via the skin of neat test item is unlikely due to its physical state, molecular weight of the constituents, and the low water solubility (ECHA guidance R7c Table R.7.12-3). Nevertheless, based on the LLNA study, in which solubilized substance was dermally administered, absorption is suggested due to the observed black discoloration of faeces in all dose groups (BASF 2017a). Exposure via the inhalation route is expected to be limited since the substance decomposes before melting, indicating that evaporation will not occur. Based on the particle size, ca. half of the volume of the test item has the potential to be inhaled (46 % are smaller than 100 μm). A smaller fraction of these particles may also reach the thoracic region (applicable for sizes < 50 μm (ECHA guidance R7c Table R.7.12-2)). Further, 5.2 % of the particles are < 10 µm indicating that those could also reach the alveolar region of the respiratory tract. Based on these considerations, exposure to the substance via the inhalation route may be possible in terms of dust inhalation.

Distribution

The (dissociated) substance is expected to be widely distributed through the body based on the observed discoloration during the gross pathology in the 14-day dose range finder (BASF 2017c) and the main OECD 422 study (BASF, 2018). Since the logPow of the test item does not exceed 4 bioaccumulation is not anticipated (ECHA guidance R7c).

Metabolism

As mentioned above, the chromium complexes in the substance may dissociate partly in the gastrointestinal tract, releasing the ligands and chromium (III). However, a certain amount of the complex is absorbed unchanged indicated by the presens and persistens of the black discoloration (dissociation of the complex would result in decolorization of the dye). Upon absorption, oxidation reactions on the phenyl groups and alkyl chain might be expected by Cytochrome P450 enzymes. Resulting hydroxy or epoxide groups are potential substrates for phase II conjugation reactions such as glucuronidation of glutathione conjugation. Reduction of azo bonds might also be catalysed by enzymatic processes, for example in the liver or by the microflora in the intestine (Levine, 1991).

Excretion

The observed coloration of faeces indicates that the substance (or at least the ligands of the chromium complexes) is excreted in the faeces. The excretion in the faeces might be direct (e.g. without intestinal absorption) or via biliary excretion which might occur after metabolic conversion of the substance. Although smaller degradation products may be excreted via the urinary tracts as well, there are no experimental indications that this route of excretion applies to the test item (e.g. no discoloration of urine or effects on the kidneys).

Uncertainties regarding toxicokinetics

Although no toxicokinetic data are available on the test item, there are no remaining uncertainties. Based on physico-chemical properties supported by experimental observations, the test item is expected to be absorbed via the oral and dermal route to some extent uptake via inhalation route cannot completely be excluded. Upon ingestion a part of the material might be directly excreted via the faeces or after dissociation of the chromium complexes. From observations in the acute oral toxicity on a structural analogue substance, a 14- day dose range finder and a corresponding OECD 422 main study with the test item it is concluded that at least a fraction is absorbed via the oral route. The observed discoloration (gross pathology) indicates a wide distribution of the components throughout the body probably also passing the placental barrier. Coloration of the faeces indicates the excretion of substance directly in the faeces or via the biliary route, with the azo bond still (partially) intact. Several metabolic reactions on the chromium complexes are to be expected which might enhance excretion.

Conclusion on toxicokinetics

Based on the available data it can be concluded that the test item becomes bioavailable via the oral and dermal route at least to some extend most likely in its dissociated form. It is further readily distributed among body compartments likely crossing placental barriers, too. Metabolic conversion is expected by Phase I and Phase II enzymes. Excretion is mainly accomplished via the faeces. The test item does not indicate a potential for bioaccumulation based on its physical-chemical properties and available experimental data.