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 151 g/mol.

The substance has a moderate log Octanol/Water partition coefficient (log Pow 3.5) and is water soluble (115 mg/L).

There was mortality observed in an acute oral toxicity study, but only at dose levels of 3150 mg/kg bw/day and above.

There was no signs of toxicity in an acute inhalation study.

Oral repeated dose studies, showed some possible evidence of absorption but no significant toxicity.

The substance is not a skin irritant or skin sensitiser.

The substance was non-mutagenic in in-vitro and in-vivo 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 readily soluble in water and has a moderate log Octanol: Water partition coefficient (log Pow 3.5). 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 results of the acute oral toxicity study showed mortality only at very high concentrations (> 2000 mg/kg bodyweight). Repeated dose toxicity studies found that oral administration of the test substance to rats for a period of ninety consecutive days at dose levels of 10, 30, 100 and 300 mg/kg/day resulted in treatment-related effects in animals of either sex treated with 300 and 100 mg/kg/day. No such changes were demonstrated at 30 or 10 mg/kg/day. The 'No Observed Effect Level' (NOEL) was, therefore considered to be 30 mg/kg/day. 300 mg/kg/day may be regarded as a "No Observed Adverse Effect Level" (NOAEL). At 300 and 100 mg/kg/day effects were seen in haemoglobin, mean cell volume and neutrophils and decrease in lymphocyte count was found at 300 mg/kg/day only. In the absence of any supporting data in the bone marrow to suggest an effect of treatment the intergroup differences were considered of no toxicological significance. Minor effects were seen in blood chemistry including an increase in total protein in females treated at 300 mg/kg/day and an increase in albumin in males. Males also showed a reduction in alanine aminotransferase at all doses. In the absence of a dose-related response or supporting data to suggest an effect of treatment these intergroup differences were considered of no toxicological importance. Animals treated with 300 mg/kg/day showed an increase in liver weight, which was also seen in males treated with 100 mg/kg/day. Males treated with 100 and 30 mg/kg/day showed a statistically significant increase in heart and females treated with 300 mg/kg/day showed an increase in adrenal and kidney weight. The majority of individual values were within the normal range for rats of the strain and age used and in the absence of any histological correlates the intergroup differences were considered not to be of any toxicologically significant. In the liver marginal centrilobular hepatocyte enlargement was observed at 300 mg/kg/day. Three instances of centrilobular hepatocyte enlargement were seen at 100 mg/kg/day. In the bone marrow a higher incidence of lower grades of severity of adipose infiltration of the marrow, indicative of increased marrow cellularity, was seen for females only treated with 300 mg/kg/day but not at any other treatment level. This was considered to be a marginal effect that did not attain statistical significance.

A one-generation reproductive toxicity study at dose levels of 75, 200 and 500 mg/kg/day found increased incidences of excess salivation and/or ungroomed coat occurred in P generation male and/or female rats in the 500 mg/kg/day dosage group. However, these clinical signs were not considered an adverse effect of the test item. At 500 mg/kg/day, sporadic reductions in body weight gains occurred in male rats prior to cohabitation, followed by persistent reductions in weight gain through the end of the study. Non-reproductive organ weights were affected in both sexes at the end of the dosage period, as well as terminal body weights. Increased brain and spleen weights occurred in male rats treated with 500 mg/kg/day test item, while increased liver and kidney weights occurred in both sexes in this same dosage group. The toxicological significance of the increased organ weights was unable to be determined because there were no microscopic findings that could be correlated with the changes in organ weights.

These results would suggest that there is some potential absorption of the test item following oral administration, but no evidence of significant toxicity

Some limited passage across the dermal barrier may be possible as the substance is a liquid and the Log P value and water solubility favours moderate dermal absorption. Skin absorption was predicted to be ≤ 80% by a Skin Absorption Model (SAM), based on a calculated Jmax value. The substance is not a skin irritant and so dermal penetration would not be enhanced by damage to the skin surface. Skin irritation and sensitisation studies report no systemic effects, and so are not suggestive of high dermal uptake.

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 is favourable for absorption directly across the respiratory tract epithelium by passive diffusion. In an acute inhalation study clinical observations included aqueous discharge from noses, salivation, reddened ears and limbs. No mortality was observed and no abnormalities reported at pathology, suggesting adsorption is limited.

 

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. The lack of skin sensitization response would suggest the material does not bind to circulatory proteins. The limited fat solubility suggests the material is unlikely to accumulate in body fat.

Metabolism

The results of the 90-day repeat dose toxicity study found an increase in liver weight in both sexes and marginal centrilobular hepatocyte enlargement was observed among animals of either sex treated with 300 mg/kg/day, p<0.05). Two instances of centrilobular hepatocyte enlargement were seen among males and one female treated with 100 mg/kg/day. This may suggest enhanced hepatic metabolism. However, the fact that the material is already freely water soluble suggests that metabolism may not be required to enhance excretion.

Genotoxicity studiesin vitroshow 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 studies give 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 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 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.