4-[(4-chloro-6-{[(3 or 4)-sulfophenyl]amino}-1,3,5-triazin-2-yl)amino]-2-{[1-ethyl-2-hydroxy-4-methyl-6-oxo-5-(sulfonatomethyl)-1,6-dihydropyridin-3-yl]diazenyl}benzenesulfonic acid, lithium sodium salts

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert assessment

Adequacy of study:

key study

Study period:

2017-03-13

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The assessment is based on the test results of the test substance. Meets generally accepted scientific standards, well documented and acceptable for assessment.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Assessment based on test data. No ADME studies are available.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

4-[(4-chloro-6-{[(3 or 4)-sulfophenyl]amino}-1,3,5-triazin-2-yl)amino]-2-{[1-ethyl-2-hydroxy-4-methyl-6-oxo-5-(sulfonatomethyl)-1,6-dihydropyridin-3-yl]diazenyl}benzenesulfonic acid, lithium sodium salts

EC Number:

942-795-5

Molecular formula:

Not applicable; this UVCB substance contains: C24H20ClN8O11S3.xLi.yNa, (x + y) = 3; 0 < (x,y) < 3 with 748.9 < MW < 797.0 g/mol (UVCB substance), C24H21N8O12S3.xLi.yNa, (x + y) = 3; 0 < (x,y) < 3 with 730.4 < MW < 778.6 g/mol (UVCB substance), C18H15Cl2N7O8S2.xLi.yNa, (x + y) = 2; 0 < (x,y) < 2 with 606.2 < MW < 638.3 g/mol (UVCB substance), C21H17N8O9S3.xLi.yNa, (x + y) = 3; 0 < (x,y) < 3 with 642.4 < MW < 690.5 g/mol (UVCB substance), C30H25N9O14S4.xLi.yNa, (x + y) = 4; 0 < (x,y) < 4 with 891.5 < MW < 955.7 g/mol (UVCB substnace), and traces of NaCl and Na2SO4.

IUPAC Name:

4-[(4-chloro-6-{[(3 or 4)-sulfophenyl]amino}-1,3,5-triazin-2-yl)amino]-2-{[1-ethyl-2-hydroxy-4-methyl-6-oxo-5-(sulfonatomethyl)-1,6-dihydropyridin-3-yl]diazenyl}benzenesulfonic acid, lithium sodium salts

Test material form:

solid: particulate/powder

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Based on the physio-chemical properties, CJ301 does not seem to have the potential to be absorbed through biological membranes.

Oral
The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 are favourable for oral absorption. Solids have to dissolve before they can be absorbed. Only marginal absorption after oral ingestion is expected due to the molecular weight of >606.2 g/mol and when the “Lipinski Rule of Five” is applied to the registered substance as two of the rules are not fulfilled (the molecular weight and the log Pow).
Based on the high water solubility of 483.06 g/L, the substance has the potential to readily dissolve into the gastrointestinal fluids. Thereafter, absorption across the biological membrane by passive diffusion will be limited based on the log Pow of -3.79. Additionally, there are experimental data available on the acute oral toxicity of CJ301. No mortality was observed and no signs of toxicity occurred. Furthermore, no test substance- related effects were noted in the gross pathological examination. These results support the assumption that the test substance will have very low potential to be absorbed by the oral route. Nevertheless, there is publically available data to suggest that sulfonated azo dyes are absorbed after ingestion and there are many publications relating to possible metabolic processes. Discolouration of whole animals has been reported in oral repeated dose toxicity studies with sulfonated azo dyes suggesting absorption and distribution. Hence, it can be concluded that CJ301 may have a low potential to be absorbed via the oral route.
In summary, absorption after ingestion of CJ301 is expected to be low.

Inhalation
CJ301 has a vapour pressure of < 10E-6 kPa at 25 °C and therefore is off negligible volatility. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapours, gases, or mists is not expected to be significant.
CJ301 has a mass median diameter (MMAD) of 59 μm. The particle size indicates the presence of inhalable/respirable particles. In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract. Considering the MMAD of CJ301 is not below 50 μm, if inhaled as an aerosol, it is unlikely to reach the thoracic region to be absorbed via the inhalation route but is likely to be retained in the mucus and transported out of the respiratory tract by the mucociliary mechanism and swallowed.
In conclusion, the substance is a non-volatile solid and absorption via the inhalation route is expected to be very low.

Dermal
The smaller the molecule, the more easily it may be taken up. In general, a molecular weight below 100 favours dermal absorption, above 500 g/mol the molecule may be too large for dermal absorption. Log Pow values between 1 and 4 favour dermal absorption particularly if water solubility is high. Since CJ301 has a water solubility of 483.06 g/L, molecular weight of > 606.2 g/mol and a log Pow of -3.79, dermal absorption of the substance is likely to be low. The substance may be too hydrophilic to cross the lipid-rich environment of the stratum corneum.
Additionally, QSAR prediction for the skin absorption potential of CJ301 resulted in a very low dermal absorption potential of about 1%.
Moreover, acute dermal toxicity studies on similar sulfonated azo dyes showed none to be acutely toxic or no evidence of dermal absorption. In the available guinea pig maximisation test with CJ301, no evidence of adverse systemic effects was observed, but CJ301 caused extreme sensitisation reaction in guinea pigs. Hence, it could be concluded that CJ301 will have potential to be absorbed via the dermal route.
In summary, dermal absorption of CJ301 is likely to be low.

Details on distribution in tissues:

Distribution within the body depends on the molecular weight, the lipophilic character and water solubility of the substance. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. Due to the molecular weight of > 606.2 g/mol and log Pow of -3.79, distribution of the substance in the body is considered to be very limited. Since the substance is very hydrophilic, distribution particularly in fat cells is unlikely.

Details on excretion:

As CJ301 is considered to have a low potential to be absorbed after ingestion, it is expected that the unabsorbed substance will be excreted via faeces.

Metabolite characterisation studies

Details on metabolites:

There are no data regarding the enzymatic metabolism of CJ301. The available bacterial reverse mutation assay showed no observable difference in effects with and without metabolic activation for CJ301.

Applicant's summary and conclusion

Conclusions:

Adsorption
Based on the physio-chemical properties, CJ301 does not seem to have the potential to be absorbed through biological membranes.

Distribution
Due to the molecular weight of > 606.2 g/mol and log Pow of -3.79, distribution of the substance in the body is considered to be very limited. Since the substance is very hydrophilic, distribution particularly in fat cells is unlikely.

Excretion
As CJ301 is considered to have a low potential to be absorbed after ingestion, it is expected that the unabsorbed substance will be excreted via faeces.

Metabolism
There are no data regarding the enzymatic metabolism of CJ301. The available bacterial reverse mutation assay showed no observable difference in effects with and without metabolic activation for CJ301.