zinc, 5,5'-azobis-2,4,6(1H,3H,5H)-pyrimidinetrione complexes and melamine

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Assumptions/information on toxicokinetics

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: assumptions/information on toxicokinetics derived from available physico-chemical data and toxicological data

Data source

Reference

Reference Type:

other: assumptions/information on toxicokinetics derived from available physico-chemical data and toxicological data

Title:

Unnamed

Year:

2015

Materials and methods

Objective of study:

toxicokinetics

Principles of method if other than guideline:

Information/assumptions of toxicokinetics derived from available physico-chemical information and toxicological studies

Test material

Test material information

Constituent 1

Reference substance name:

Zinc, 5,5'-azobis-2,4,6(1H,3H,5H)-pyrimidinetrione complexes and melamine

IUPAC Name:

Zinc, 5,5'-azobis-2,4,6(1H,3H,5H)-pyrimidinetrione complexes and melamine

Test material form:

other: brown powder

Details on test material:

content: 100 %

Administration / exposure

Details on exposure:

informations/assumptions of toxicokinetics derived from available physico chemical information and toxicological studies

Duration and frequency of treatment / exposure:

Information/assumptions of toxicokinetics derived from available physico-chemical information and toxicological studies

Details on study design:

informations/assumptions of toxicokinetics derived from available physico chemical information and toxicological studies

Details on dosing and sampling:

informations/assumptions of toxicokinetics derived from available physico chemical information and toxicological studies

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Based on the available data from oral and dermal application absorption might be low. No information is available from absorption via respiratory tract.

Main ADME results 2

Type:

distribution

Results:

Following oral application the distribution is limited because no mortality , no clinical signs and no gross or histological lesions were noted

Main ADME results 3

Type:

metabolism

Results:

Due to the negative result in the available in-vitro genotoxicity studies it is assumed that at least no DNA reactive metabolites will be generated

Main ADME results 4

Type:

excretion

Results:

There is no special study available but from the discolored feces during treatment it can be assumed that this is the preferred excretion route

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Despite the molecular mass of Azo zinc complex pigment – melamine compound of ca. 508 g/mol which is just above the threshold of the molecular mass (500 g/mol) favorable for absorption via gastrointestinal tract and considering the nearly insolubility in water (0.52 mg/l) there is evidence that absorption via gastrointestinal tract might be limited. This assumption is supported by the available acute oral toxicity study in which no mortality and no clinical signs related to substance administration up to 2000 mg/kg bw to rats was noted (Shin Sung-sup 2011). Additionally, also the available repeated dose toxicity study over a period of 28 days supported this view. The oral dosing up to 1000 mg/kg bw/day (limit dose) was tolerated without impairment (Kim Seon-yu 2014). The observed discolored feces at all dose levels in all dosed animals recovered after termination of treatment, and confirms the limited absorption of the compound.

Referring to dermal absorption the low water solubility of 0,52 mg/l and the molecular weight >100 indicate that the rate of transfer between the stratum corneum and epidermis is limited and therefore also dermal absorption into the body. The acute dermal toxicity study in rabbits (limit test at one dose level of 2000 mg/kg bw., 24 h) yielded no mortality, no clinical signs and animals gained weight during the post application period and there were no gross pathological findings at necropsy (Shin Sung-Sup 2013). In acute skin and eye irritation studies in rabbits no irritation and no systemic intolerance reactions have been reported (Oh Dong-min 2012) and no skin sensitizing effect has been identified in the Buehler test with guinea pigs (Park Myeong-kyu2012). These observations are in line with the assumptions by physico-chemical data that dermal absorption is limited.

Regarding inhalation absorption there is no animal orption there is no animal study available using the inhalation route. Therefore, only physico-chemical data can be used for the assumption.
The vapor pressure is estimated to be 2.83 x 10-14 Pa at 25 °C, no boiling point could be detected up to 300°C and water solubility of 0.52 mg/l is rather low. Only about 14 % of a dose show particle size <100 µm. Thus, absorption by inhalation exposure can be assumed to be limited

Details on distribution in tissues:

There is no specific investigation available on distribution of Azo Zinc complex Pigment –Melamine compound in the body of mammals. No realistic assumption can be made due to the lack of systemic symptoms and the lack of relevant gross or histopathological lesions in the acute and repeat dose studies in rats. The only relevant observation is the discolored feces recovering after termination of treatment. This observation leads to the assumption that main parts of the compound are excreted directly probably due to the nearly insolubility in water (0.52 mg/l) and the molecular mass of the compound being just above the threshold of favoured absorption via gastrointestinal tract.

Details on excretion:

There is no specific information available. In general the major routes of excretion of an organic compound from the systemic circulation are the urine and/or feces. According to the discolored feces during treatment period in the available 28-day oral study in rats (Kim Seon-yu 2014), it can be assumed that excretion via feces is the preferred route of excretion.

Metabolite characterisation studies

Metabolites identified:

no

Details on metabolites:

There is no specific information available. Based on the results of the in vitro genotoxicity tests with Azo Zinc complex Pigment – Melamine compound [Bacterial Reverse Mutation Test (Ishikawa 2012) and Chromosome Aberration Test in Mammalian Cells (Yasunaga 2012)] it is concluded that DNA reactive metabolites of the substance will most probably not be generated in mammals in the course of hepatic biotransformation.

Applicant's summary and conclusion

Executive summary:

There are no experimental toxicokinetic data with Reaction Mass of Zinc, 5,5’-azobis-2,4,6 (1H,3H,5H)-pyrimidinetrione Complexes and Melamine (Azo Zinc Complex Pigment – Melamine Compound) available. The following remarks on toxicokinetics of Azo Zinc complex Pigment – Melamine compound are therefore based on the available studies which were compiled in the respective IUCLID database. These assumptions follow the procedure indicated in the “Guidance on information requirements and chemical safety assessment chapter R.7c” of the ECHA guidance document (version 2.0, November 2014).

Based on the avaiable data from oral and dermal application absorption might be low. No information is available from absorption via respiratora tract. Following oral application the distribution is limited because no mortality , no clinical signs and no gross or histological lesions were noted. Due to the negative result in the available in-vitro genotoxicity studies is is assumed that at least no DNA reactive metabolites will be generated. There is no special study available but from the discolered feces during treatment it can be assumed that this is the prefered excretion route.