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Link to relevant study record(s)

Reference
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
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
Statistics:
Not applicable
Preliminary studies:
Not applicable
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.
Metabolites identified:
not specified
Details on metabolites:
No data
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.

Description of key information

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.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

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

1. General

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

2. Toxicological Profile of Reaction Product of Bisphenol A (BADGE) with IPDA and MXDA

The asymmetrical epoxy amine adduct Reaction Product of Bisphenol A diglycidylether (BADGE) with IPDA and MXDA was not tested for acute toxicological properties.

A read across approach was applied to assess oral and dermal acute toxicity, using data from the symmetrical epoxy amine adducts Reaction products of IPDA with bisphenol A diglycidylether (BADGE) and Reaction products of MXDA with bisphenol A diglycidylether (BADGE), as these substances show similar toxicological properties. 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 BADGE with IPDA and MXDA 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 Reaction products of IPDA with bisphenol A diglycidylether (BADGE) 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. In a reproduction/developmental toxicity screening test with Reaction products of MXDA with bisphenol A diglycidylether (BADGE) in CRL:(WI) BR rats the NOAEL for parental effects was 150 mg/kg bw/day. For reproduction and litter effects, the NOAEL was 150 mg/kg bw/day.

3. 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 was estimated to be 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.

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 v4.11) 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 v4.11) 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.

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.

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