Reaction products of 4,4'-methylenebis(cyclohexylamine) and 2,2'-[(1-methylethylidene)bis(4,1-phenyleneoxymethylene)]bisoxirane

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Expert statement

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Assessment of the toxicokinetic behaviour of the substance to the extent that can be derived from the relevant available information.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2010

Report date:

2010

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Review of physico-chemical and other relevant information leading to an understanding of toxicokinetics

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

4,4'-methylenebis(cyclohexylamine)

EC Number:

217-168-8

EC Name:

4,4'-methylenebis(cyclohexylamine)

Cas Number:

1761-71-3

Molecular formula:

C13H26N2

IUPAC Name:

4,4'-methylenedicyclohexanamine

Constituent 2

Reference substance name:

4,4'-Isopropylidenediphenol, oligomeric reaction products with 1-chloro-2,3-epoxypropane, reaction products with 4,4'-methylenebis(cyclohexylamine)

EC Number:

500-103-5

EC Name:

4,4'-Isopropylidenediphenol, oligomeric reaction products with 1-chloro-2,3-epoxypropane, reaction products with 4,4'-methylenebis(cyclohexylamine)

Cas Number:

38294-67-6

Molecular formula:

C

IUPAC Name:

Reaction products of 4,4'-methylenebis(cyclohexylamine) and 2,2'-[(1-methylethylidene)bis(4,1-phenyleneoxymethylene)]bisoxirane

Test material form:

liquid: viscous

Administration / exposure

Statistics:

not applicable

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

For PACM, relatively small molecular weight (210.4), water solubility (12.3 g/L) and LogPow (2.03)or absorption. The polymers of PACM BADGE have higher molecular weights (MW 761-1880) which do not favour passive diffusion. Corrosion may facilitate uptake.

Main ADME results 2

Type:

distribution

Results:

Distribution throughout the body is aasumed for PACM (low molecular weight, moderate water solubility). PACM BADGE polymers have a higher molecular weight which suggest that they would not be dwidely istributed.

Main ADME results 3

Type:

metabolism

Results:

The results of repeated dose studies indicate that the substance or its metabolites are distributed to various organs. Genotoxicity studies with and without metabolic activation do not provide further indications on the metabolic pattern of PACM BADGE.

Main ADME results 4

Type:

excretion

Results:

Low molecular weight and moderate water solubility are favorable for excretion of PACM in urine. The larger MW PACM BADGE polymers are unliley to be excreted in urine.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The relatively small molecular weight (210.4) and the moderately water solubility (12.3 g/L) of PACM favour absorption after oral exposure. In addition, the moderate log Pow value (2.03) favours absorption by passive diffusion, although the potentially ionisable groups of PACM might limit diffusion across biological membranes. The larger polymers of PACM BADGE have higher molecular weights (MW 761-1880) which do not favour passive diffusion, although their higher Log Pow values (6.95 - 10.53) indicate lipophilicity.

For risk assessment purposes oral, dermal and inhalation absorption of PACM -BADGE is set at 100%. As the substance is corrosive, uptake may be facilitated by the destruction of skin and membranes.

The results of the 28-day study on PACM BADGE do not provide reasons to deviate from this proposed oral absorption factor; this study indicate that the substance becomes systemically available.
However it is noted that severe gastric corrosion leading to mortality in high-dose animals may be a major contributing factor due to absorption.

One of the uses of PACM BADGE involves spray applications, therefore it must be anticipated that PACM BADGE could reach the nasopharyncheal region or subsequently the tracheobranchial or pulmonary region after inhalation.
If PACM BADGE reaches the tracheobronchial region, absorption through aqueous pores will be limited, taking the molecular weights of > 200 into account.
However, components of PACM BADGE would into the mucus lining of the respiratory tract and the log Pow (ranging from 2.03 to 10.53) would favout absorption directly across the respiratory tract epithelium by passive diffusion.
Furthermore, due its corrosive potential, it may damage the epithelium lining the respiratory tract, which will further promote systemic uptake of the substance.
Overall, although PACM BADGE would not be expected to reach the tracheobranchial region in a large extent, for risk assessment purposes the inhalation absorption of PACM BADGE is set at 100%.

Once absorbed, the small molecular weight and moderate water solubility of PACM are favorable for distribution throughout the body. Possible ionization, low molecular weight and moderate water solubility are favorable for excretion of PACM in urine.
PACM BADGE is a viscous liquid. PACM has the potential to partition from the stratum corneum into the epidermis. In addition, the log Pow of 2.03 is favorable for penetration into the stratum corneum and hence dermal absorption and the moderate water solubility of PACM will not limited dermal absorption. However, the larger polymers of PACM BADGE are unlikely to penetrate the skin due to their much higher molecular weights (MW 761-1880).
Nevertheless, a Local Lymph Node Assay (LLNA) test on PACM BADGE indicate that it is a skin sensitiser, therefore some degree of skin absorption is occuring, probably due to PACM. However, due to its corrosive properties, skin integrity will be affected leading to fast uptake of the substance.

Details on distribution in tissues:

The results of the 28-day study indicate that PACM BADGE or its metabolites are widely distributed throughout the body. Test-item related changes in surviving animals were normalized by the end of the recovery period.
The potential for bioaccumulation is unclear though it is suggested by the log Pow of individual components (ranging from 2.03 to 10.53), however this may be governed by the large molecular weights, precluding cellular uptake.

Details on excretion:

Possible ionization, low molecular weight and moderate water solubility are favorable for excretion of PACM in urine.

Metabolite characterisation studies

Metabolites identified:

no

Details on metabolites:

The results of the 28-day study indicate that PACM BADGE or its metabolites are widely distributed throughout the body. Test-item related changes in surviving animals were normalized by the end of the recovery period.
The potential for bioaccumulation is unclear though it is suggested by the log Pow of individual components (ranging from 2.03 to 10.53), however this may be governed by the large molecular weights, precluding cellular uptake.
Available data of PACM BADGE (e.g. negative results from in vitro genotoxicity studies with and without metabolic activation) do not give further indications on the metabolic pattern of PACM BADGE. .

Any other information on results incl. tables

Based on the present available data, no additional conclusions can be drawn on the distribution, metabolism and excretion of PACM BADGE after dermal and inhalatory absorption.

Applicant's summary and conclusion

Conclusions:

The relatively small molecular weight (210.4) and the moderately water solubility (12.3 g/L) of PACM favour absorption after oral exposure. In addition, the moderate log Pow value (2.03) favours absorption by passive diffusion, although the potentially ionisable groups of PACM might limit diffusion across biological membranes. The larger polymers of PACM BADGE have higher molecular weights (MW 761-1880) which do not favour passive diffusion, although their higher Log Pow values (6.95 - 10.53) indicate lipophilicity.

For risk assessment purposes oral, dermal and inhalation absorption of PACM -BADGE is set at 100%. As the substance is corrosive, uptake may be facilitated by the destruction of skin and membranes.
The results of the 28-day study on PACM BADGE do not provide reasons to deviate from this proposed oral absorption factor; this study indicate that the substance becomes systemically available.
However it is noted that severe gastric corrosion leading to mortality in high-dose animals may be a major contributing factor due to absorption.

One of the uses of PACM BADGE involves spray applications, therefore it must be anticipated that PACM BADGE could reach the nasopharyncheal region or subsequently the tracheobranchial or pulmonary region after inhalation.
If PACM BADGE reaches the tracheobronchial region, absorption through aqueous pores will be limited, taking the molecular weights of > 200 into account.
However, components of PACM BADGE would into the mucus lining of the respiratory tract and the log Pow (ranging from 2.03 to 10.53) would favout absorption directly across the respiratory tract epithelium by passive diffusion.
Furthermore, due its corrosive potential, it may damage the epithelium lining the respiratory tract, which will further promote systemic uptake of the substance.
Overall, although PACM BADGE would not be expected to reach the tracheobranchial region in a large extent, for risk assessment purposes the inhalation absorption of PACM BADGE is set at 100%.

Once absorbed, the small molecular weight and moderate water solubility of PACM are favorable for distribution throughout the body. Possible ionization, low molecular weight and moderate water solubility are favorable for excretion of PACM in urine.
PACM BADGE is a viscous liquid. PACM has the potential to partition from the stratum corneum into the epidermis. In addition, the log Pow of 2.03 is favorable for penetration into the stratum corneum and hence dermal absorption and the moderate water solubility of PACM will not limited dermal absorption. However, the larger polymers of PACM BADGE are unlikely to penetrate the skin due to their much higher molecular weights (MW 761-1880).
Nevertheless, a Local Lymph Node Assay (LLNA) test on PACM BADGE indicate that it is a skin sensitiser, therefore some degree of skin absorption is occuring, probably due to PACM. However, due to its corrosive properties, skin integrity will be affected leading to fast uptake of the substance.

The results of the 28-day study indicate that PACM BADGE or its metabolites are widely distributed throughout the body. Test-item related changes in surviving animals were normalized by the end of the recovery period.
The potential for bioaccumulation is unclear though it is suggested by the log Pow of individual components (ranging from 2.03 to 10.53), however this may be governed by the large molecular weights, precluding cellular uptake.
Available data of PACM BADGE (e.g. negative results from in vitro genotoxicity studies with and without metabolic activation) do not give further indications on the metabolic pattern of PACM BADGE.

Based on the present available data, no additional conclusions can be drawn on the distribution, metabolism and excretion of PACM BADGE.
For risk assessment purposes oral and dermal absorption of PACM BADGE is set at 100%.