Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics, other
Type of information:
other: In accordance with REACH Annex VIII (8.8) an assessment of toxicokinetic behavior has been conducted to the extent that can be derived from the relevant available information.
Adequacy of study:
key study
Study period:
The assessment was conducted in March 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Relevant studies were reviewed by a qualified toxicologist with a view to fulfilling the requirements of Annex VIII (8.8).

Data source

Reference
Reference Type:
other: Review of available data
Title:
Unnamed
Year:
2018

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline required
Principles of method if other than guideline:
In accordance with REACH Annex VIII (8.8) an assessment of toxicokinetic behaviour has been conducted to the extent that can be derived from the relevant available information. The assessment is based on the Guidance on information requirements and chemical safety assessment R.7c: Endpoint specific guidance (ECHA, November 2014)
GLP compliance:
no
Remarks:
Not relevant for assessment

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Any other information on results incl. tables

TOXICOKINETIC BEHAVIOUR

The substance is a liquid with a molecular weight of 194 mg/L.

The substance has a relatively low vapour pressure and is non-volatile and therefore inhalation is not considered to be a significant route of exposure.

The substance has a moderate log octanol/water partition coefficient (log Pow 4.1) and is relatively water soluble (59 mg/L).

There were moderate signs of toxicity in an acute oral toxicity study but no signs of toxicity in a dermal toxicity study.

A repeated dose toxicity study (on a read-across substance) showed some evidence of absorption.

The substance is a skin irritant.

A read-across substance was non-mutagenic and non-clastogenic in in-vitro genotoxicity studies, in either the presence or absence of an auxiliary metabolising system.

 

 Absorption

The test item is a relatively low molecular weight liquid that is fairly soluble in water and has a moderate log Octanol: Water partition coefficient. This suggests that the test item has the potential to cross biological membranes, via diffusion, such as those of the gastro-intestinal tract following oral ingestion. The test item may also have some potential for uptake via micellular solubilisation. The results of the acute oral toxicity study showed moderate signs of systemic toxicity and mortality at a high dose (5000 mg/kg bodyweight). The repeated dose toxicity study (based on read across from (2E)-2-ethyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-buten-1-ol) shows signs of systemic toxicity (adverse effects) and 4 females treated at the highest dose (1000 mg/kg bw/day) were killed prior to scheduled termination for humane reasons related to effects of treatment with the test item. These results suggest that there is some absorption of the test item.

Some more limited passage across the dermal barrier may be possible as the substance is a liquid and the Log P value and water solubility favours low to moderate dermal absorption. Skin absorption was predicted to be ≤ 40% by a Skin Absorption Model (SAM), based on a calculated Jmax value. The substance is a skin irritant, and therefore damage to the skin surface may enhance penetration. The substance is not a skin sensitiser and the acute dermal toxicity study found no signs of systemic toxicity, suggesting dermal uptake is limited.

As the material does not exist as particulates and the material has low volatility (vapour pressure < 0.5kPa), exposure via the inhalation route is limited. The Log P value may be favourable for absorption directly across the respiratory tract epithelium by passive diffusion, and may also have some potential for uptake via micellular solubilisation. The systemic toxicity observed in oral toxicity studies that indicates the potential for absorption following ingestion, also indicates that the substance may also be absorbed if it is inhaled.

 

Distribution

As the test item is of low molecular weight and is water soluble, it can be assumed that any absorbed test item can be readily distributed in the water fraction of circulatory fluids.This may be supported by effects observed in the repeated dose toxicity study.

The lack of skin sensitization response would suggest the material does not bind to circulatory proteins.

The partition coefficient (Log Kow 4.082) may suggest that the test item has some limited potential to accumulate in body fat.

 

Metabolism

The results of the repeat dose toxicity study (based on read across from (2E)-2-ethyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-buten-1-ol) found bodyweight adjusted liver weights were higher than control in males and females after five weeks dosing at 300 or 1000 mg/kg/day. Enlarged livers were observed in females receiving 1000 mg/kg/day and centrilobular hepatocyte hypertrophy was seen in the liver of 2 females receiving 1000 mg/kg/day with enlarged livers. Biochemical changes were seen in females at 1000 mg/kg/day, such as increased levels of enzymes associated with liver function, cholesterol and bilirubin levels. This may suggest enhanced hepatic metabolism. However, the fact that the material is already fairly water soluble suggests that metabolism may not be required to enhance excretion.

Genotoxicity studiesin vitro(based on read across from 2-ethyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-buten-1-ol)show that the genotoxic potential of the test item is neither enhanced nor diminished in the presence of S9 microsomal metabolising system.

 

Excretion

Low molecular weight test items that are water soluble are most likely to be excreted via the kidney although the repeat dose toxicity/reproduction screening study gives no indication of route of excretion. Following oral ingestion, any test item that is not absorbed is likely to be excreted in the faeces

Applicant's summary and conclusion

Conclusions:
The test item is a low molecular weight liquid that is fairly water soluble. Any oral ingestion of the test item may lead to absorption and systemic distribution, there may also be some limited adsorption via the dermal and inhalation routes. Changes in the liver indicate that the test item may be metabolised, but due to the water solubility, metabolism is probably not required for excretion via the kidney, which is the most likely route of excretion for test item.
Executive summary:

The test item is a low molecular weight liquid that is fairly water soluble. Any oral ingestion of the test item may lead to absorption and systemic distribution, there may also be some limited adsorption via the dermal and inhalation routes. Changes in the liver indicate that the test item may be metabolised, but due to the water solubility, metabolism is probably not required for excretion via the kidney, which is the most likely route of excretion for test item.