Registration Dossier

Administrative data

dermal absorption
Adequacy of study:
key study

Data source

Reference Type:
other: Assessment of toxicokinetic behaviour
Report Date:

Materials and methods

Test guideline
no guideline followed
Principles of method if other than guideline:
review based on the current knowledge of the substance: Molecular weight, vapour pressure, octanol/water partition coefficient, water solubility. The available acute oral (Bradshaw, 2011 - report No. 41101792) and eye irritation (Bradshaw, 2011 - report No. 41102090) studies, the twenty-eight day study (Dhinsa, 2012 - 41101789). The mutagenicity studies (Thompson, 2011 - report No. 41102091, Lacey, 2011 - report no. 41101786), Flander, 2012 - report no. 41101787, Flander, 2012 - report no. 41202876) and the skin sensitising study (Bradshaw, 2011 - report No. 41102091). For further details on all the studies listed, refer to the current dossier in the relevant sections.
GLP compliance:
Not applicable

Test material

Test material form:
solid: particulate/powder
migrated information: powder
Details on test material:
Toxicokinetic Assessment based on the structure of the molecule of the substance (refer to the reference substance of the current dossier)
and the following criteria:
* Molecular Weight: 458.38 g/mol
* Water Solubility: 0.326 mg/L
* Vapour Pressure: 5.4 x10-13 Pa at 25°C
* Partition Coefficient: log Pow 2.36
* Acute Oral Toxicity: LD50 > 2000 mg/kg bw
* Acute Dermal (Limit Test): LD50 > 2000 mg/kg bw
* Acute Dermal irritation: Non irritant to rabbit skin
* Acute Eye Irritation: Mild irritant (classified)
* Skin Sensitization: Negative
* 28 Day Repeated dose
NOAEL Systemic toxicity - 1000 mg/kg bw/day
NOEL Systemic toxicity - 30 mg/kg bw/day
NOEL Neurotoxicity - 1000 mg/kg bw/day
* Ames test: Negative
* Chromosomal Aberration Test: Negative

Test animals

Details on test animals and environmental conditions:
Not applicable

Administration / exposure

Duration of exposure:
Not applicable
Not applicable
No. of animals per group:
Not applicable
Details on study design:
Not applicable
Details on in vitro test system (if applicable):
Not applicable

Results and discussion

Absorption in different matrices:
* Absorption
Although the test item is moderately lipophilic in nature the relative small molecular size of the substance should also allow absorption through passive diffusion. Results of the twenty-eight day repeated dose study in rats showed evidence to support the gastric absorption of the test item (Dhinsa, 2012). This would suggest that the gastro-intestinal tract provides a route of absorption, following oral administration, before entering the circulatory system via the blood. Limited absorption may also take place via the skin due to the relative small molecular size.
The low vapour pressure value (5.4 x 10-13 Pa at 25°C) shows that the substance is not available as a vapour therefore inhalation is not a significant route of exposure.

* Distribution
Systemic distribution is evident from the twenty-eight day repeated dose study (Dhinsa, 2012) as a result of the organ changes observed. The lack of evidence to suggest the test item is a skin sensitizer suggests that it does not bind to carrier proteins in the circulatory system (Bradshaw, 2011). The moderately lipophilic nature of the test item suggests that bioaccumulation in body fat is unlikely.

* Metabolism
The results of the twenty-eight day repeated dose study showed evidence of an adaptive response in the liver in rats (Dhinsa, 2012); which is normally associated with enhanced metabolism. The test item was non-mutagenic and results of the genotoxicity assays have shown that genotoxicity is neither enhanced nor diminished in the presence of the S9 metabolising system (Thompson, 2011).

* Excretion
Poor water-soluble products are not favourable for urinary excretion and therefore biliary excretion may well be a significant route for this material. However as there is evidence of hepatic metabolism which suggests urinary excretion cannot be ruled out. The results of the twenty-eight day repeated dose study did show evidence of this as a potential route of excretion. The main reason for xenobiotic metabolism is to render the product more water soluble thereby allowing urinary excretion. Any test item that is not absorbed from the gut will be excreted in the faeces.

Applicant's summary and conclusion

Based on the data currently available for the test item, it is suggested that absorption of the test substance from the gastrointestinal tract can take place. Some absorption may also take place via the skin. Once absorbed, the substance would be distributed in the serum. Biliary excretion may well be a significant route for the substance however urinary excretion may also be possible.