Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics, other
Remarks:
literature review
Type of information:
other: Paper-based review of known data
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report Date:
2018

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The TKA was conducted in accordance with Annex VIII Section 8.8 of Regulation (EC) No. 1907/2006, also known as REACH. The TKA is also based on the Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2014).
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
solid: flakes
Details on test material:
UVCB, C(16-18) amides of methyl terephthalamate. EC # 934-047-1
Specific details on test material used for the study:
no test material was used for this study
Radiolabelling:
no

Results and discussion

Main ADME results
Type:
absorption
Results:
Gastrointestinal: approx. 50%, dermal: approx. 10%, respiratory <10%

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Little to no water solubility, relatively high log octanol water partition coefficients and relatively high molecular weight polymeric structures would suggest somewhat lower potential for absorption across the skin, gastrointestinal tract and respiratory tract. Pentamid™ KH components would be absorbed by the gastrointestinal tract with an approximate absorption rate of 50%. Absorption across the stratum corneum of the skin may be significant but further partitioning from the stratum corneum to the epidermis is unlikely. Dermal absorption rate is approximated to be 10%. Low volatility, the lack of hydrolysis, and limited solubility do not favor respiratory tract absorption. Inhalation absorption rate is likely < 10%.
Details on distribution in tissues:
Little evidence of systemic target organ toxicity was seen in a chronic repeated dose study in the rat with terephthalic acid by dietary administration. The low water solubility and high estimated partitioning into octanol of indicates that methyl-N-octadecylterephthalamate and the other Pentamid™ KH components may accumulate in body fats and/or breast milk. Individual fatty acids are found in the plasma lipid fraction and will be circulated throughout the body, especially in perfused tissues.
Details on excretion:
Fecal excretion is likely a major route of elimination of unabsorbed and unchanged Pentamid™ KH components. Fecal excretion is also a likely major pathway of elimination of any fatty acid esters. Terephthalic acid, the major metabolite of Pentamid™ KH components, methyl-N-octadecylterephthalamate, methyl-N-(C14-16 alkyl) terephthalamate and dimethylterephthalate are primarily excreted in urine with estimates of 83-95% recovery in urine and 2-16% in feces (Ball et al., 2012).

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Esterases result in any absorbed Pentamid(TM) KH being broken down into terephthalic acid and long-chain amide (N-octadecylamine or N-hexadecylamine).

Applicant's summary and conclusion

Conclusions:
Based on a review of known behaviours in various tests, Pentamid(TM) KH is considered relatively non-toxic, with low absorption via gastrointestinal tract, skin or lung. Absorbed parent material is likely excreted in the feces. Theoretical systemic metabolites include terephthalic acid and C16 and 18 N-aklylamines.