Reaction products of 3-aminomethyl-3,5,5-trimethylcyclohexylamine with 2,2'-[(1-methylethylidene)bis(4,1-phenyleneoxymethylene)]bisoxirane

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert statement

Adequacy of study:

key study

Study period:

2009-06-23

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert Statement, no study

Data source

Reference

Reference Type:

other: An expert statement

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

Reaction products of 3-aminomethyl-3,5,5-trimethylcyclohexylamine with 2,2'-[(1-methylethylidene)bis(4,1-phenyleneoxymethylene)]bisoxirane

EC Number:

614-657-1

Cas Number:

68609-08-5

Molecular formula:

C41H68N4O4

IUPAC Name:

Reaction products of 3-aminomethyl-3,5,5-trimethylcyclohexylamine with 2,2'-[(1-methylethylidene)bis(4,1-phenyleneoxymethylene)]bisoxirane

Test animals

Details on test animals or test system and environmental conditions:

Not applicable

Administration / exposure

Details on exposure:

Not applicable

Duration and frequency of treatment / exposure:

Not applicable

No. of animals per sex per dose / concentration:

Not applicable

Positive control reference chemical:

Not applicable

Details on study design:

Not applicable

Details on dosing and sampling:

Not applicable

Results and discussion

Preliminary studies:

Not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The test item is a hard viscous mass at room temperature with a molecular weight of 681.02 g/mol. Vapour pressure was calculated to be 0.131 Pa at 25 °C.The partition coefficient (logPow = 2.36) was determined using the HPLC-method. The substances water solubility was determined to be 13.8 mg/l.

As the substance is a solid, vapour pressure is extremely low and the boiling point is at 249 °C (> 150 °C), little exposure via inhalation is expected. Even though the log Pow indicates that some absorption directly across the respiratory tract epithelium can occur, the high molecular weight indicates that the substance will hardly become bioavailable via the inhalation route. Further, the substance showed low toxicity after oral and dermal administration. Together this indicates low systemic availability after inhalation and if bioavailable, low toxicity via this route of administration.

Based on physical-chemical properties the test item absorption across the skin is likely to be low, especially due to the molecular weight > 500 g/mol and low water solubility. No toxicity, neither local nor systemic, was observed following dermal application of 2000 mg/kg bw up to the limit dose.

Details on distribution in tissues:

Administered orally, the test item is not likely to dissolve in the stomach easily, due to its low water solubility. As only dissolved substance is available for adsorption, the quantity of the test item to become bioavailable via the oral route is expected to be low. The high molecular weight does not favour passive diffusion across the gastrointestinal tract. Most likely very low amounts of the test item will become bioavailable and most of the test item ingested will be eliminated through faeces. Respectively, toxicity to orally administered test item is low, as shown in acute and subacute toxicity tests. The compounds estimated log BCF-value of 3.84 (EPIWIN v4.00) indicates that the test item is not likely to bioaccumulate, if becoming bioavailable.

Low amounts of bioavailable test item, after e.g. ingestion, are likely to be metabolised and parent compound and degradation products are expected to slowly distribute via systemic circulation. Based on molecular weight and water solubility, the substance will most likely be excreted via faeces. Metabolism may transform the test item into more polar degradation products. Likely pathways are reactions such as cytochrome P-450-dependent monooxygenase enzyme mediated oxidative ring opening and/or cleavage at the amide side-chain. Parent compound and metabolites formed in phase I metabolic reactions may be rendered more polar by phase II metabolic activity in subsequent reactions. The parent compound or possible metabolites may undergo conjugation (e.g. with glutathione), before being excreted in urine or bile.

Details on excretion:

It is unlikely that the test item is metabolised to more reactive (toxic) products. This assumption is supported by results obtained in oral and dermal toxicity studies and three in vitro tests. In acute and subacute in vivo studies toxicity was moderate to low. In an Ames test and a chromosome aberration assay no significant increase in toxicity was noted in the presence of a rodent microsomal S9-fraction, when compared to incubation without S9-fraction. Together, this data indicates that formation of reactive metabolites is rather unlikely.

Based on the substance’s structure and associated physical-chemical characteristics, very low to low amounts of the test item will become bioavailable through inhalation, upon contact to skin or following oral ingestion. When bioavailable, the substance or its metabolites are expected to distribute slowly, with excretion via urine or bile (polar conjugated forms) and via faces (high molecular weight forms). Bioaccumulation is not likely.

Metabolite characterisation studies

Metabolites identified:

not specified

Applicant's summary and conclusion

Conclusions:

Based on the substance’s structure and associated physical-chemical characteristics, very low to low amounts of the test item will become bioavailable through inhalation, upon contact to skin or following oral ingestion. When bioavailable, the substance or its metabolites are expected to distribute slowly, with excretion via urine or bile (polar conjugated forms) and via faces (high molecular weight forms). Bioaccumulation is not likely.

Executive summary:

The test item is a hard viscous mass at room temperature with a molecular weight of 681.02 g/mol. Vapour pressure was calculated to be 0.131 Pa at 25 °C. The partition coefficient (logPow = 2.36) was determined using the HPLC-method. The substances water solubility was determined to be 13.8 mg/L.

As the substance is a solid, vapour pressure is extremely low and the boiling point is at 249 °C (> 150 °C), little exposure via inhalation is expected. Even though the log Pow indicates that some absorption directly across the respiratory tract epithelium can occur, the high molecular weight indicates that the substance will hardly become bioavailable via the inhalation route. Further, the substance showed low toxicity after oral and dermal administration. Together this indicates low systemic availability after inhalation and if bioavailable, low toxicity via this route of administration.

Based on physical-chemical properties the test item absorption across the skin is likely to be low, especially due to the molecular weight > 500 g/mol and low water solubility. No toxicity, neither local nor systemic, was observed following dermal application of 2000 mg/kg bw up to the limit dose.

Administered orally, the test item is not likely to dissolve in the stomach easily, due to its low water solubility. As only dissolved substance is available for adsorption, the quantity of the test item to become bioavailable via the oral route is expected to be low. The high molecular weight does not favour passive diffusion across the gastrointestinal tract. Most likely very low amounts of the test item will become bioavailable and most of the test item ingested will be eliminated through faeces. Respectively, toxicity to orally administered BADGE with IPDA is low, as shown in acute and subacute toxicity tests. The compounds estimated log BCF-value of 3.84 (EPIWIN v4.00) indicates that the test item is not likely to bioaccumulate, if becoming bioavailable.

Low amounts of bioavailable test item, after e.g. ingestion, are likely to be metabolised and parent compound and degradation products are expected to slowly distribute via systemic circulation. Based on molecular weight and water solubility, the substance will most likely be excreted via faeces. Metabolism may transform the test item into more polar degradation products. Likely pathways are reactions such as cytochrome P-450-dependent monooxygenase enzyme mediated oxidative ring opening and/or cleavage at the amide side-chain. Parent compound and metabolites formed in phase I metabolic reactions may be rendered more polar by phase II metabolic activity in subsequent reactions. The parent compound or possible metabolites may undergo conjugation (e.g. with glutathione), before being excreted in urine or bile.

It is unlikely that the test item is metabolised to more reactive (toxic) products. This assumption is supported by results obtained in oral and dermal toxicity studies and three in vitro tests. In acute and subacute in vivo studies toxicity was moderate to low. In an Ames test and a chromosome aberration assay no significant increase in toxicity was noted in the presence of a rodent microsomal S9-fraction, when compared to incubation without S9-fraction. Together, this data indicates that formation of reactive metabolites is rather unlikely.

Based on the substance’s structure and associated physical-chemical characteristics, very low to low amounts of the test item will become bioavailable through inhalation, upon contact to skin or following oral ingestion. When bioavailable, the substance or its metabolites are expected to distribute slowly, with excretion via urine or bile (polar conjugated forms) and via faces (high molecular weight forms). Bioaccumulation is not likely.