N-(4-amino-9,10-dihydro-3-methoxy-9,10-dioxo-1-anthryl)benzenesulphonamide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

calculation (if not (Q)SAR)

Adequacy of study:

supporting study

Study period:

2016

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Calculation/prediction method

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2016

Report date:

2016

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

The absorption, distribution, metabolism and excretion of FAT 36034/H TE have been predicted in the absence of toxicokinetic studies.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

N-(4-amino-9,10-dihydro-3-methoxy-9,10-dioxo-1-anthryl)benzenesulphonamide

EC Number:

274-040-4

EC Name:

N-(4-amino-9,10-dihydro-3-methoxy-9,10-dioxo-1-anthryl)benzenesulphonamide

Cas Number:

69563-51-5

Molecular formula:

C21H16N2O5S

IUPAC Name:

N-(4-amino-3-methoxy-9,10-dioxo-9,10-dihydroanthracen-1-yl)benzenesulfonamide

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

None

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 12-45

Radiolabelling:

no

Results and discussion

Any other information on results incl. tables

Absorption

Neither the physico-chemical properties nor the available toxicological information provide any indication of a route of absorption. The low water solubility will not enhance absorption across the gut wall by normal diffusion therefore; there is less likelihood of significant absorption. However, a combined repeated dose oral toxicity study with reproduction/developmental toxicity screening performed for a similar chemical structured test substance produced by the study sponsor indicated test item and or metabolite bioavailability and that in all probability the gastro-intestinal tract provides the primary route of absorption; subsequently entering the circulatory systemviathe blood. The test item was shown to be a skin sensitizer therefore damage to the skin barrier may permit increased test item penetration. However, the lack of evidence of any form of irritation from the topical dermal and ocular irritation studies together with absence of any convincing evidence of systemic toxicity from the single dose oral toxicity (LD50 >2000 mg/kg) substantiate that from the data available for studies conducted with FAT 36034/H TE that this test substance has minimal toxic potential whether absorbed through the dermis or gastro-intestinal routes. Furthermore, low water solubility would not enhance absorption across the gut wall by normal diffusion therefore; there is less likelihood of significant absorption. A low octanol/water partition coefficient also suggest passage across biological membranes would be limited.

 

Distribution

There is minimal information available relating to the distribution of FAT 36034/H TE; however, neither the physico-chemical properties nor the available toxicological information provide any clear indication of a mechanism for distribution.

 

Metabolism

The test item was found to be mutagenic in bacteria albeit no information was provided to indicate whether this was in the absence or presence of metabolic activation; nevertheless, rat S9 fraction does not necessarily reflect human metabolism. Furthermore, there was no evidence to suggest that the test substance may be metabolised, although no studies have yet been conducted to identify metabolites.

 

Excretion

Poor water-soluble products are not favourable for urinary excretion and therefore excretion of unabsorbed test material is most likely to be via the faeces.

Applicant's summary and conclusion

Conclusions:

The studies conducted for FAT 36034/H provided no evidence to indicate absorption, distribution or clearance of the test substance, however; based on supporting toxicological information performed for a similar chemical structured test substance the most likely route of excretion of FAT 36034/H following oral exposure is indicated to be via the gastro intestinal tract in the faeces.

Executive summary:

The absorption, distribution, metabolism and excretion of FAT 36034/H have been predicted in the absence of toxicokinetic studies. For FAT 36034/H no absorption was indicated via a single oral gavage administration or from topical application to intact skin nor ocular routes of exposure, hence dermal absorption is expected to be low. However, the available data confirmed the test item can cause skin sensitisation therefore low levels of dermal absorption may occur through damaged skin. Repeated dose oral toxicity data derived from a similar chemical substance produced by the study sponsor indicated absorption of the test substance and or metabolites will take place in the gastro-intestinal track following oral gavage administration. No uptake via inhalation is anticipated on the basis that the inhalable particle size fraction was determined to be 15.0% at <100 μm indicating almost all inhaled particles will be cleared in the oral/nasal region and subsequently swallowed with the mucus. FAT 36034/H and/or its predicted metabolites have the potential for systemic distribution. Repeated dose oral toxicity data derived from a similar chemical substance produced by the study sponsor indicated FAT 36034/H and/or its predicted metabolites could potentially be distributed throughout the body, as indicated from the effects seen from the “read-across” product in which treatment related effects were identified in the spleen and bone marrow. The studies conducted for FAT 36034/H provided no evidence to indicate absorption, distribution or clearance of the test substance, however; based on supporting toxicological information performed for a similar chemical structured test substance the most likely route of excretion of FAT 36034/H following oral exposure is indicated to be via the gastro intestinal tract in the faeces.