Reaction mass of 5-[[4-[benzylmethylamino]phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium methyl sulphate and 3-[[4-[benzylmethylamino]phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium methyl sulphate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: Assessment based on physicochemical properties and available toxicological data

Adequacy of study:

weight of evidence

Study period:

September 2018

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2018

Report date:

2018

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

toxicokinetics

Principles of method if other than guideline:

Assessment based on physicochemical properties and available toxicological data as suggested in the ECHA document R.7c

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Diethyl sulphate, compound with N-methyl-N-[4-[(1-methyl-1H-1,2,4-triazol-5-yl)azo]phenyl]benzylamine (1:1)

EC Number:

263-444-6

EC Name:

Diethyl sulphate, compound with N-methyl-N-[4-[(1-methyl-1H-1,2,4-triazol-5-yl)azo]phenyl]benzylamine (1:1)

Cas Number:

62163-53-5

Molecular formula:

C17H18N6.C2H6O4S

IUPAC Name:

diethyl sulfate - N-benzyl-N-methyl-4-[(1-methyl-1H-1,2,4-triazol-5-yl)diazenyl]aniline (1:1)

Test material form:

solid: crystalline

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The test item has a moderately high molecular weight (432.5 g/mol) which is likely to inhibit absorption and distribution. The low Octanol: water partition coefficient suggests that passage across biological membranes will not be facilitated by active absorption processes. The test item is, however, freely soluble in water and so some distribution in the water compartment may take place. The results of the repeated dose toxicity studies, including dose range finding indicate that the primary effects were associated with the gastro-intestinal tract. It is possible to suggest that the toxic changes observed are more to do with direct contact with the test item following oral ingestion rather than due to systemic toxicity per se. The test item is known to be an irritant from the results of an Eye Irritation test with a 36 % solution of the test item and therefore irritation of any type of mucous-type membrane (such as that seen in rat forestomach) may be possible when such a test item is in direct contact with this type of membrane. An acute oral toxicity study also indicated that this single exposure at high dose levels also induced a response that is likely to reflect damage to mucosal membranes of the stomach. The clinical observation of animals displaying curved body shape is often associated with abdominal discomfort, which in itself may be linked with administration of an irritant material and its effect on the stomach.
Although no dermal toxicity is available and a lack of dermal irritation to either intact or abraded skin following exposure with a 36% solution of the test item suggests that dermal exposure is unlikely to elicit the same response as that seen following oral ingestion and therefore the dermal route of exposure may be less significant than oral ingestion. If dermal absorption were to take place then it would be expected that the degree of absorption would be more limited than via oral ingestion due to the physical structure of the skin barrier and the chemical characteristics of the test item that show the limitations of absorption seen with passage across the membranes of the gut.
The test item is predicted to be non-volatile as based on the thermal decomposition data and therefore exposure to the test item via inhalation is not expected. These physical characteristics together with those characteristics that demonstrate that passage of test item across the gut mucosal membranes are limited would suggest that any absorption from inhalation of test item is unlikely to achieve higher systemic concentrations than that seen via oral ingestion.

Details on distribution in tissues:

For any test item that is absorbed following oral ingestion, the high water solubility should facilitate the distribution of the test substance throughout the body in the water compartment of circulatory systems. The chemical structure of the test item, with its lack of significant reactive groups on the molecule suggest that the test item will not bind to proteins within the circulatory system.
Accumulation of the test substance in body fat is not expected due to the high water solubility and low Octanol: water partition coefficient value. The passage of test item across specialized biological membranes such as the blood/brain, blood testis or blood/placental barrier will be subject to the same physical limitations (high molecular weight and low octanol: water partition coefficient) as with absorption from the gastro-intestinal tract and may therefore suggest that biological distribution will be inhibited across such biological structures. This suggestion may be supported by the lack of test item stained cellular structures such as brain and testis identified from histopathological assessment of treated animals from the repeated dose toxicity study.

Details on excretion:

High water-soluble products are favourable for urinary excretion. Elimination of any non-absorbed test item following oral ingestion may occur via the faeces. The presence of stained bedding for treated animals indicates some test item excretion but it is not clear as to whether this was from faeces or urine.

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

Metabolism

The available studies have not indicated any active metabolism of the test item. There is no evidence of enhanced hepatic metabolism of test item from the histopathological examination of livers of animals from the repeated dose toxicity/reproduction study. Water soluble products such as this test item may not need to be metabolised prior to urinary excretion as the dye and its counter-ion will be readily dissolved in their ionic form (if absorbed) and will then be able to be excreted in this state without the need for further metabolic change.

Applicant's summary and conclusion

Conclusions:

The studies conducted provided limited evidence to indicate absorption and systemic distribution of the test substance. If absorbed and systemically distributed, this would be a result of the high water solubility of the test item but this absorption/distribution would be limited by the molecular size of the test item. There was no obvious evidence of hepatic metabolism of the test item. The most likely route of excretion of water soluble products such as the test item, following oral ingestion and absorption, was via the urine. Elimination of the non-absorbed fractions may occur via the faeces. The presence of test item-stained animal bedding on the repeated dose toxicity study suggests that some excretion has taken place but it could not be confirmed as to what the nature of the excreta that it related to.

Executive summary:

The absorption, distribution, metabolism and excretion of FAT 31016/T TE have been predicted in the absence of toxicokinetic studies.

 

FAT 31016/T TE absorption was not convincingly indicated via the oral route of administration although the water solubility of the test item would facilitate absorption but the molecular weight may well inhibit such absorption to any great extent. No evidence of test item staining of organs or tissues was reported for acute or repeated dose toxicity studies thereby supporting a lack of absorption of the test item.

 

Inhalation of volatile products is unlikely based on the predicted non-volatility of the test item FAT 31016/T TE.

 

FAT 31016/T TE is expected to have low dermal absorption based on dermal irritation values from a study with a 36 % solution of the test item. No systemic toxicity was reported from the skin irritation study and no specific discolouration of subcutaneous tissue was reported. Discolouration that was reported to the application site was likely to be from test item in direct contact with the epidermis.

 

FAT 31016/T TE is likely to be distributed throughout the body in the water compartment whereas accumulation in body fat is considered unlikely. The test item is unlikely to require hepatic metabolism prior to excretion. No discoloration of the liver was reported from the repeated dose toxicity studies and histopathology failed to show any changes to indicate exposure to the test item.

 

Excretion of FAT 31016/T TE is expected to be via the urine after absorption although biliary excretion may occur but due to the water solubility of the test item, elimination via the kidney seems the most obvious route of excretion. Elimination of the non-absorbed fraction may occur via the faeces although no specific recording of stained faeces was reported for the repeated dose toxicity studies. However, staining of bedding was reported for animals on the repeated dose toxicity study which may indicate some elimination of test item from either urine or faeces.