Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics, other
Remarks:
Expert statement
Type of information:
other: Expert statement
Adequacy of study:
key study
Study period:
2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Expert statement, no study available

Data source

Reference
Reference Type:
other: Expert statement
Title:
Unnamed
Year:
2020
Report date:
2020

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Expert statement
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid

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
Doses / concentrations
Remarks:
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

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Generally, oral absorption is limited for molecular weights above 500 g/mol. Due to the lipophilic properties and the low water solubility of ditetradecyl peroxydicarbonate, dissolution in the gastro-intestinal fluids is limited and absorption through the mucosal surface is estimated to be slow. On the other hand, absorption of ditetradecyl peroxydicarbonate may be facilitated following micellular solubilisation by bile salts. Micelles enter the systemic circulation via the lymphatic system, bypassing the liver.
No systemic effects were observed after single and repeated administration of ditetradecyl peroxydicarbonate on rats leading to the following discussion points:
On the one hand, the potential to induce toxic effects of ditetradecyl peroxydicarbonate might be low as the potential decomposition products, myristyl alcohol and carbon dioxide, occur physiologically. On the other hand, no observed effects could be a result of no absorption. In conclusion, bioavailability after oral administration is expected to be low.
As ditetradecyl peroxydicarbonate is a solid at room temperature, it might reach the respiratory tract in its dust state. However, due to the particle size of 1000 to 4000 µm the respirable airborne fraction is negligible. Particles might deposit in the nasal region and would be sneezed out or coughed up. No absorption through the respiratory tract epithelium is expected as dissolution in the mucus is limited by the lipophilic properties and low water solubility of ditetradecyl peroxydicarbonate. Since no specific effects of systemic toxicity were observed after oral administration systemic availability is unlikely also after inhalation exposure.
Similarly, based on physico-chemical properties of ditetradecyl peroxydicarbonate the substance is not likely to penetrate through the skin to a large extent as the high log Pow value and the low water solubility do not favour dermal penetration. It is generally accepted that if a compound’s water solubility is < 1 mg/L, absorption can be anticipated to be low. Moreover, for substances with a log Pow above 6, the rate of penetration is limited by both uptake into the stratum corneum and transfer into the epidermis. However, as ditetradecyl peroxydicarbonate has been identified as a skin sensitiser in a LLNA study, penetration through the skin must have occurred although only to a small fraction of the applied dose.
Details on distribution in tissues:
Assuming that a small fraction of ditetradecyl peroxydicarbonate is absorbed into the body following oral intake, it may be distributed mainly via the lymphatic system. The volume of distribution is estimated to be low and diffusion across cell membranes is limited by the molecular weight and lipophilic properties of the substance.
The potential decomposition product, myristyl alcohol and rather its oxidised form, myristic acid, were shown to bind to serum albumin to facilitate circulation via the bloodstream (Curry, S. et al, 1999).
Based on the BCF value of ditetradecyl peroxydicarbonate and the physiologically occurrence of its potential decomposition products bioaccumulation of the substance in the body can be excluded.
Details on excretion:
As discussed above, absorption of ditetradecyl peroxydicarbonate is limited by the compound’s high lipophilicity and low water solubility. Therefore, ditetradecyl peroxydicarbonate might be directly excreted from the gastro-intestinal tract via faeces.
Once absorbed and transported to the liver, ditetradecyl peroxydicarbonate is expected to be biliary excreted due to its high molecular weight. In case of the decomposition product of ditetradecyl peroxydicarbonate, myristyl alcohol, degradation to carbon dioxide and excretion via the exhaled air is assumed.

Metabolite characterisation studies

Details on metabolites:
Based on the structure of the molecule, decomposition to myristyl alcohol and carbon dioxide might occur to a little extent. Myristyl alcohol is expected to be oxidised to myristic acid which in turn might enter the mitochondrial β-oxidation pathway. Generally, physiologically occurring myristic acid is incorporated in the phospholipid bilayer of the plasma membrane.
Thus, metabolites are not assumed to be more toxic than the parent compound which is further supported by the results obtained in the in vitro mutation and cytogenetic assays in the presence of a metabolic activation system.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:
Physico-chemical properties and experimental data indicate a very low bioavailability of ditetradecyl peroxydicarbonate via oral, dermal and inhalation route.

Applicant's summary and conclusion

Conclusions:
Physico-chemical properties, particularly water solubility and octanol-water partition coefficient and experimental data indicate a very low bioavailability of ditetradecyl peroxydicarbonate via oral, dermal and inhalation route. Assuming that a small fraction of ditetradecyl peroxydicarbonate is absorbed into the body following oral intake, it may be distributed mainly via the lymphatic system. Based on the structure of the molecule, decomposition to myristyl alcohol and carbon dioxide might occur to a little extent. Myristyl alcohol is expected to be oxidised to myristic acid which in turn might enter the mitochondrial β-oxidation pathway. The non-absorbed fraction of ditetradecyl peroxydicarbonate might be directly excreted from the gastro-intestinal tract via faeces. Once absorbed and transported to the liver, ditetradecyl peroxydicarbonate is expected to be biliary excreted due to its high molecular weight. In case of the decomposition product, myristyl alcohol, degradation to carbon dioxide and excretion via the exhaled air is assumed.