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

Endpoint summary

Link to relevant study record(s)

Reference

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

Details on test animals or test system and environmental conditions:

Not applicable

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

Preliminary studies:

Not applicable

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.

Metabolites identified:

not specified

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.

Description of key information

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.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Toxicokinetic Assessment of the test item

1. General

The epoxy resin amine adduct is produced by mixing the basic resin Bisphenol-A-Diglycidylether (BADGE) with the amine Isophorondiamine (IPDA). The substance is used as hardener component for epoxy adhesives in industrial applications, such as construction industry, only. When reacted with a curing agent, the test item forms a strong inert coating adhesive.

2. Toxicological Profile of the test item

In an acute oral toxicity study with rats the LD50-value was determined between 300 to 2000 mg/kg bw with a cut-off value of 500 mg/kg bw. An acute dermal toxicity study revealed a LD50-value of > 2000 mg/kg bw (limit dose). In a skin irritation study in rabbits, topical application of the substance was well tolerated and no irritation or corrosion effects were observed. In an eye irritation test in rabbits no irritant effects were observed either. A local lymph node assay revealed skin sensitising properties. In a bacterial mutagenicity test (Ames test), a cytogenetic assay using mammalian cells (chromosome aberration test) and an in vitro mammalian cell gene mutation test (mouse lymphoma assay) no mutagenic, clastogenic or genotoxic effects were noted, in the presence and absence of metabolic activation (rodent microsomal S9-fractions). In a subacute oral toxicity study the test item caused no adverse toxic effects in male or female CRL:(WI) BR rats after 28-day subsequent oral (by gavage) administration of 25 mg/kg bw/day, 80 mg/kg bw/day or 200 mg/kg bw/day. However, a slight statistically significant test item influence was found on the white blood cell picture in male animals at 200 mg/kg bw/day. Changes in the female 200 mg/kg bw/day dose group were comparable, but not statistically significant. Similar changes were also observed in one single female animal at 80 mg/kg bw/day. At 200 mg/kg bw/day, test item related changes in enzyme activity of alanine aminotransferase were also observed. None of the findings were considered adverse. At 25 mg/kg bw/day, there were no test item related effects. The no observed effect level (NOEL) was 25 mg/kg bw/day. The no observed adverse effect level (NOAEL) was 200 mg/kg bw/day. In a reproduction/developmental toxicity screening test with the test item in CRL:(WI) BR rats the NOAEL for parental effects was determined at 80 mg/kg bw/day. For reproduction parameters the NOAEL was 150 mg/kg bw/day. For pup growth rate, the NOAEL was 80 mg/kg bw/day.

3. Toxicokinetic Analysis of the test item

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 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. 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.