Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics, other
Remarks:
An assessment of toxicokinetics, based on available data, in accordance with Annex VIII, Section 8.8.1 of Regulation (EC) No 1907/2006 (REACH).
Type of information:
other: Desk-based assessment and read-across from supporting substance (structural analogue or surrogate).
Adequacy of study:
key study
Study period:
2018
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2018
Report date:
2018

Materials and methods

Objective of study:
toxicokinetics
Principles of method if other than guideline:
An assessment of toxicokinetics, based on available data, in accordance with Annex VIII, Section 8.8.1 of Regulation (EC) No 1907/2006 (REACH)
GLP compliance:
no

Test animals

Details on species / strain selection:
No animals were used in this desk-based assessment.
Details on test animals or test system and environmental conditions:
Not applicable

Administration / exposure

Details on exposure:
No animals were used in this desk-based assessment.
Duration and frequency of treatment / exposure:
No animals were used in this desk-based assessment.
No. of animals per sex per dose / concentration:
No animals were used in this desk-based assessment.
Positive control reference chemical:
No animals were used in this desk-based assessment.
Details on study design:
Not applicable.
Details on dosing and sampling:
Not applicable.
Statistics:
Not applicable.

Results and discussion

Preliminary studies:
Not applicable.
Main ADME resultsopen allclose all
Type:
absorption
Results:
Mainly oral. Minimal dermal absorption, and inhaled absorption not expected.
Type:
distribution
Results:
Chemical properties aid systemic distribution and reduce half-life in blood plasma, resulting in minimal tissue accumulation.
Type:
metabolism
Results:
Mainly through gut. Substance expected to be hydrolysed and decarboxylated to give NH3 and CO2.
Type:
excretion
Results:
Possible hepatic metabolism and renal excretion. No accumulation in fatty tissues expected. Excretion into urine. Carbon possibly exhaled as CO2 and nitrogen atoms integrated into endogenous protein.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The molecular weight of both constituents is low (< 200 g/mol), its n-octanol/water partition coefficient (log Pow) is -3.28 (QPRF, KOWWIN), its water solubility is 1.8 ± 0.2 g/L, and vapour pressure is <0.001 Pa (read across data). These are suggestive of favourable absorption from the GI tract following oral administration. Oral absorption of the substance is mainly via passive diffusion through the epithelial barrier by the bulk passage of water into portal circulation, with delivery into the liver (i.e. first pass metabolism). This is supported by the minor systemic changes observed in repeated dose toxicity study in rat. These physicochemical properties indicate the substance will have limited dermal absorption. The substance is not expected to be surface active, which means transfer between the stratum corneum and the epidermis is restricted, thus overall uptake via this route is limited. This is demonstrated by the lack of significant systemic and local toxicity following dermal exposure studies. Based on the vapour pressure of the test item, volatility is very low, therefore systemic availability via the inhalable route is expected to be very low.
Details on distribution in tissues:
The substance has physio-chemical properties that mean that it can easily pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water into the liver. The n-Octanol/water partition coefficient (log Pow=-3.28), water solubility of 1.8 ± 0.2 g/L and the molecular weight of the substance, will aid the distribution of the parent compound systemically, and reduce the half-life of the parent compound in blood plasma resulting in no accumulation in the tissue.
Details on excretion:
Parameters in the liver, lung and thyroid demonstrate possible hepatic metabolism and renal elimination. The n-Octanol/water partition coefficient (log Pow=-3.28), water solubility of 1.8 ± 0.2 g/L and the molecular weight of the substance are suggestive of no accumulation of this substance in fatty tissues after absorption from gastro-intestinal tract, and that the substance could enter circulation via the lymphatic system. Based on the molecular structure and solubility, and excretion into urine as aminated conjugate, the carbon atom may be exhaled as CO2, while the nitrogen atoms may be integrated into endogenous protein.

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
Metabolism is mainly through the gut, and to a small extent the liver phase I and II enzymes, with the principal alcohol metabolizing enzymes being deaminase and aldehyde dehydrogenase. The breakdown in the gut is presumably due to the action of bacterial urease releasing CO2 and ammonia. Upon systemic uptake into the circulatory system, the substance is expected to be hydrolysed and decarboxylated to give an aminated derivatives, NH3 and CO2.

Applicant's summary and conclusion

Conclusions:
The substance has physico-chemical properties which are favourable for ADME. Exposure from oral route is most favourable with limited bioavailability via dermal and inhalation exposure. Based on the n-Octanol/water partition coefficient (log Pow=-3.28) and water solubility of 1.8 ± 0.2 g/L, bioaccumulation is not expected and elimination is expected to be rapid. The minimal systemic and local toxicity observed following in vivo sensitisation and subacute studies, with no overt toxicity or clinical signs observed following oral sub-acute exposure, support oral absorption of the test item, and are demonstrative of distribution, biotransformation and elimination of the test item. It can be concluded that the toxicokinetic of the test item does not pose significant toxicological concern through evaluation of available data.
Executive summary:

A desk-based assessment of the basic toxicokinetics of the substance, in accordance with Regulation (EC) 1907/2006: Annex VIII - Section 8.8.1. The substance possesses physico-chemical properties which are favourable for ADME. Exposure from oral routes is most favourable with minimal inhalation and dermal exposure. Based on the log Pow of -3.28 and water solubility of 1.8 ± 0.2 g/L, bioaccumulation is not significant and elimination is expected to be rapid. The lack of systemic and local toxicity observed following in vivo sensitisation and subacute studies shows that systemic bioavailability of this substance is limited via dermal and inhalation exposure, and are demonstrative of distribution, biotransformation and elimination of the test item.

It can be concluded that the basic toxicokinetics of the test item does not pose significant toxicological concern through evaluation of available data.