Registration Dossier

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
Type of information:
other: Desk-based assessment
Adequacy of study:
key study
Study period:
Not applicable
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
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
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Detailed information on the 'test material identity' is provided in the attached document including information on individual constituents.

Test animals

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

Administration / exposure

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

Results and discussion

Preliminary studies:
Desk-based assessment.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The molecular weight of all the constituents is low i.e. < 200 g/mol, with a corresponding n-octanol/water partition coefficient in the range of > 4.17 and < 4.25, water solubility (range) of 1 – 100 mg/L and vapour pressure of 19.62 Pa at 25 °C, are suggestive of favourable absorption via all routes of administration. Oral absorption from the gastro-intestinal tract (GI tract) and respiratory absorption via the respiratory tract epithelium: of the substance is mainly via passive diffusion (paracellular pathway) through the intercellular junction pores into portal circulation. With delivery into the liver ensuring first pass metabolism which means that the concentration of the parent substance is reduced before reaching systemic circulation as demonstrated by the hepatocyte vacuolation and the no observed adverse effects following repeated exposure in rats. Furthermore, the irritation potential of the substance may also aid absorption by causing damage to the membrane resulting in high systemic bioavailability of the substance. The substance is considered volatile based on its vapour pressure, therefore exposure via inhalation route is possible. Depending on the inhaled particle size, larger particles deposited within the upper airways which may be largely cleared via the digestive system whereas particles deposited in the lung may be more likely to dissolve and may be absorbed through the lung. Based on the physicochemical properties of the substance passive diffusion is the main route of absorption into the epithelia cells and potentially entering systemic circulation. The physicochemical properties indicate the substance will demonstrate moderate dermal absorption.
Details on distribution in tissues:
The substance has physicochemical properties which may favour wide distribution depending in the route of exposure. Wide distribution is limited via oral/gastro intestinal absorption since the substance is of small molecular weight and can move through first pass metabolic pathway, meaning that the parent constituents are converted to respective metabolites before distribution and overall systemic circulation. This means that the distribution of the parent compound systemically is reduced and the half-life of the parent compound in blood plasma is also reduced. Pulmonary absorption could potentially result into a wide distribution with the heart as the first point and then general circulatory system and subsequently entering the liver before the parent compound is transformed to its respective metabolites. Although skin absorption is expected, the distribution of the substance is reduced compared with oral absorption and distribution.
Details on excretion:
The observed changes in the liver is indicative of possible hepatic metabolism which correspond with renal elimination. The n-octanol/water partition coefficient partition coefficient in the range of > 4.17 and < 4.25 along with constituent water solubility (range): 1 – 100 mg/L in conjunction to the molecular weight of the substance constituents is suggestive of no (bio)accumulation of this substance in fatty tissues after absorption from the gastro-intestinal tract. The substance enters first past metabolism which means its easily converted to more polar derivative(s), then excreted via urine. Based on the molecular structure and solubility, excretion into urine as conjugated metabolites is considered to be a preferred route of elimination.

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
Metabolism is primarily through reductive and oxidative Phase I enzyme-catalyzed reactions in the liver and epithelia cells (such as Clara cells and alveolar type II cell) as demonstrated by the observed hepatocyte vacuolation which is considered and adoptive response to xenobiotic. The main metabolic enzymes are non-P450 aldehyde reduction enzyme systems alcohol dehydrogenase (ADH), aldo-keto reductase (AKR) and short-chain dehydrogenase/reductase (SDR), and aldehyde oxidation enzyme systems xanthine oxidase (XO), aldehyde oxidase (AOX) and aldehyde dehydrogenase (ALDH). Based on the physiochemical properties of the substance constituents: oxidation pathway is the most common pathway and will result into production of carboxylic acid derivatives. The carboxylic acid derivatives will be further conjugated with glucuronides and sulphate via glucuronsyl transferase and sulphotransferase with subsequent elimination via urine. This is demonstrated as demonstrated by the increase liver weight in male which is considered as an adaptation reaction following exposure to xenobiotic(s).

Applicant's summary and conclusion

Conclusions:
The substance possesses physicochemical properties which are favourable for ADME. Exposure by the oral and inhalation routes is more favourable with more limited bioavailability via dermal route exposure. Absorption of the substance is mainly via passive diffusion (paracellular pathway) through the intercellular junction pores into portal circulation. With delivery into the liver ensuring first pass metabolism which means that the concentration of the parent substance is reduced before reaching systemic circulation. This is supported by the changes in the liver and other observations, plus the lack thereof, in the sub-acute oral toxicity test in rats (OECD TG 422, 2018). This included absence of clinical signs and effects of toxicological importance. Although the dermal irritant properties of the substance is expected to enhance dermal absorption, systemic availability was limited as demonstrated by the low/no systemic toxicity observed in dermal exposure studies. There was no site-specific microscopic evidence of irritation at primary exposure sites such as within the GI tract observed which demonstrates that there is no irritant or local toxicity potential of the substance at these sites. Irritation at the GI tract is not expected to affect absorption. This means that passive absorption is more favourable and therefore first pass metabolism, ensuring rapid biotransformation and elimination. It can be concluded that the basic toxicokinetics of the substance do not pose significant toxicological concern through the evaluation of the 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 by the oral and inhalation routes is more favourable with more limited bioavailability via dermal route exposure. Based on the low n-octanol/water partition coefficient partition coefficient i.e. > 4.17 - < 4.25 and water solubility (range) 1 – 100 mg/L and BCF < 2000, in conjunction with the molecular weight of the substance, (bio)accumulation is not considered to be significant and elimination is expected to be rapid. The lack of significant systemic and local toxicity observed following in vivo skin irritation and sensitisation studies potentially indicates that systemic bioavailability of this substance is limited via dermal exposure. Absorption of the substance is mainly via passive diffusion (paracellular pathway) through the intercellular junction pores into portal circulation. With delivery into the liver ensuring first pass metabolism which means that the concentration of the parent substance is reduced before reaching systemic circulation. The substance is expected to be metabolised, primarily through reductive and oxidative Phase I enzyme-catalyzed reactions in the liver and epithelia cells (such as Clara cells and alveolar type II cell) as demonstrated by the observed hepatocyte vacuolation which is considered an adaptive response. Oxidation pathway is the most common pathway and will result into production of carboxylic acid derivatives. The carboxylic acid derivatives will be further conjugated with glucuronides and sulphate via glucuronsyl transferase and sulphotransferase with subsequent elimination via urine. This is supported by the changes in the liver and other observations, plus the lack thereof significant toxicological findings, in the sub-acute oral toxicity test in rats (OECD TG 422, 2018). The observed changes in the liver is indicative of possible hepatic metabolism which correspond with renal elimination. There was no reports of substance accumulation in fatty tissues or primary site of exposures in all animal studies conducted. The lack of significant clinical signs observed following oral sub-acute exposure support oral absorption of test item and other observations organs such as the liver is 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.