Reaction products of 3-aminomethyl-3,5,5-trimethylcyclohexylamine and m-phenylenebis(methylamine) 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:

2010-02-02

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert Statement, no study available

Data source

Reference

Reference Type:

other: An expert statement

Title:

Unnamed

Year:

2010

Report date:

2010

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

Reaction products of benzene-1,3-diyldimethanamine and 3-aminomethyl-3,5,5-trimethylcyclohexanamine with oligomerisation products of 4,4'-propane-2,2-diyldiphenol with 2-(chloromethyl)oxirane

EC Number:

700-128-3

Molecular formula:

Not applicable (UVCB substance)

IUPAC Name:

Reaction products of benzene-1,3-diyldimethanamine and 3-aminomethyl-3,5,5-trimethylcyclohexanamine with oligomerisation products of 4,4'-propane-2,2-diyldiphenol with 2-(chloromethyl)oxirane

Details on test material:

NA

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

Statistics:

Not applicable

Results and discussion

Preliminary studies:

Not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:

BADGE with IPDA/MXDA is a hard viscous mass at room temperature with a molecular weight of 647 g/mol on an average. Vapour pressure is 0.0707 Pa at 20 °C. The partition coefficient (logPow =< 2.3) was determined using the HPLC-method. The substances water solubility was determined to be 72.8 ± 11.8 mg/l at 20 ± 1 °C.

As the substance is a solid, vapour pressure is extremely low and the boiling point is at 253 °C at 98 kPa (>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 BADGE with IPDA/MXDA 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, BADGE with IPDA/MXDA 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 BADGE with IPDA/MXDA 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 BADGE with IPDA/MXDA will become bioavailable and most of BADGE with IPDA/MXDA ingested will be eliminated through faeces. Respectively, toxicity to orally administered BADGE with IPDA/MXDA is low, as shown in acute and subacute toxicity tests. The compounds estimated log BCF-value of 3.84 (EPIWIN v4.00) indicates that BADGE with IPDA/MXDA is not likely to bioaccumulate, if becoming bioavailable. Low amounts of bioavailable BADGE with IPDA/MXDA, after e.g. ingestion, are likely to be metabolised and parent compound and degradation products are expected to slowly distribute via systemic circulation.

Details on excretion:

Low amounts of bioavailable BADGE with IPDA/MXDA, 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 BADGE with IPDA/MXDA 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.

Metabolite characterisation studies

Metabolites identified:

not specified

Details on metabolites:

No data

Applicant's summary and conclusion

Conclusions:

Based on the substance structure and associated physical – chemical characteristics, very low to low amounts of Reaction Product of Bisphenol A diglycidylether (BADGE) with IPDA and MXDA will become bioavailable through inhalation, upon contact to skin or following oral ingestion. The substance is expected to be excreted via faeces (high molecular weight forms, unchanged substance) and if bioavailable, the substance or its metabolites are expected to be excreted via urine or bile (polar conjugated forms, breakdown products). Bioaccumulation is unlikely.

Executive summary:

Toxicokinetic Analysis of Reaction Product of Bisphenol A (BADGE) with IPDA and MXDA

BADGE with IPDA/MXDA is a hard viscous mass at room temperature with a molecular weight of 647 g/mol on an average. Vapour pressure is 0.0707 Pa at 25 °C. The partition coefficient (logPow = 2.3) was determined using the HPLC-method. The substances water solubility was determined to be 72.8 ± 11.8 mg/L at 20 ± 1 °C.

As the substance is a solid, vapour pressure is extremely low and the boiling point is at 253 °C at 98 kPa ( > 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 BADGE with IPDA/MXDA 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, BADGE with IPDA/MXDA 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 BADGE with IPDA/MXDA 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 BADGE with IPDA/MXDA will become bioavailable and most of BADGE with IPDA/MXDA ingested will be eliminated through faeces. Respectively, toxicity to orally administered BADGE with IPDA/MXDA is low, as shown in acute and subacute toxicity tests. The compounds estimated log BCF-value of 3.84 (EPIWIN v4.00) indicates that BADGE with IPDA/MXDA is not likely to bioaccumulate, if becoming bioavailable.

Low amounts of bioavailable BADGE with IPDA/MXDA, 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 BADGE with IPDA/MXDA 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.

Administered orally, BADGE with IPDA/MXDA 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 BADGE with IPDA/MXDA 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 BADGE with IPDA/MXDA will become bioavailable and most of BADGE with IPDA/MXDA ingested will be eliminated through faeces. Respectively, toxicity to orally administered BADGE with IPDA/MXDA is low, as shown in acute and subacute toxicity tests. The compounds estimated log BCF-value of 3.84 (EPIWIN v4.00) indicates that BADGE with IPDA/MXDA is not likely to bioaccumulate, if becoming bioavailable.

Low amounts of bioavailable BADGE with IPDA/MXDA, 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 BADGE with IPDA/MXDA 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.