Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: Based on available physico-chemical properties and toxicological data of the substance
Adequacy of study:
key study
Study period:
July 31, 2015
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-GLP assessment based on physico-chemical properties and toxicological data of the substance

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2015
Report date:
2015

Materials and methods

Objective of study:
other: Toxicokinetic assessment
Principles of method if other than guideline:
An expert assessment was made based on physical chemical properties such as solubility in various solvents and log Pow and toxicity data available.
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-Propenenitrile, reaction products with 3-amino-1,5,5-trimethylcyclohexanemethanamine
EC Number:
292-053-3
EC Name:
2-Propenenitrile, reaction products with 3-amino-1,5,5-trimethylcyclohexanemethanamine
Cas Number:
90530-15-7
Molecular formula:
C10 H22 N2 . C3 H3 N1
IUPAC Name:
2-Propenenitrile, reaction products with 3-amino-1,5,5-trimethylcyclohexanemethanamine

Administration / exposure

Details on study design:
The assessment of the toxicokinetic properties of the test substance was performed based on the results obtained for toxicological end-points and physico-chemical data such as solubility, plus other reports and MSDS data.

Results and discussion

Any other information on results incl. tables

- ABSORPTION by the dermal route:

The pure test substance is corrosive to skin, which would indicate that local dermal damage could result in a high potential for systemic absorption from dermal exposure. The skin sensitisation study was positive at concentrations of over 1% (EC3 of 1.4%) indicating a relatively good skin penetration even at low concentrations.

- ABSORPTION by the oral route:

Examination of the data from the repeat dose oral studies gave an indication of there being good evidence for oral bioavailability by the oral route for the test substance. The high water solubility and low LogP suggests relatively high rates of intestinal bioavailability. The biological effects (at dose levels above 300 mg/kg bw/day) following administration of an aqueous solution of test substance confirms the bioavailability.

- ABSORPTION by the inhalation route:

The relatively low volatility suggests a low risk of inhalation exposure. The physicochemistry suggests any test substance in the vapour phase would probably be absorbed, but the low concentrations in air from the test substance at room temperature would not be expected to be of any concern.

- Other Biological Assays:

High water solubility indicates ready absorption by aquatic organisms.

- Potential for Bioavailability and Bioaccumulation:

The studies performed and the available physicochemical data are consistent with an organic molecule with a high bioavailability with no indication or evidence for potential for bioaccumulation. The low LogP, the high water solubility and the mammalian toxicity after oral doses at high levels supports the concept of high bioavailability. Low melting point and surface activity would also facilitate high bioavailability. Evidence from in vitro cytotoxicity shows reduced toxicity in the presence of S9 liver enzymes; also rats given >28 d of a daily dose of approximately 30% of a dose that can be lethal after a few days exposure, had no major toxic effects; this indicates a lack of bioaccumulation. The physicochemical and biological

data suggests that absorbed chemical would be eliminated by excretion in urine, and/or metabolised to non-toxic metabolites.

The repeat dose mammalian studies showed clear toxicity with mortality after a few days treatment at 300 mg/kg bw/day and above, but little systemic toxicity at 100 mg/kg bw/da administered daily for well over 28 d. This data shows that there was no indication of cumulative toxicity. A lack of cumulative toxicity for a chemical with known toxicity supports the concept of rapid elimination of the chemicals. There were no studies that showed any evidence of bioaccumulation.

- Potential for Distribution and Metabolism:

There were no studies performed to specifically study distribution or metabolism. However, the high water solubility and low LogP suggest this type of chemistry would be in equilibrium with the water phase in animals, and would not tend to partition onto lipid tissues. The high water solubility would allow rapid excretion in urine. The evidence from in vitro assays indicated lower toxicity in the presence of liver enzymes (S9); also the repeat

dose rodent studies of >28 d showed no major toxicity at a dose level relatively close to a dose that can be lethal after a few administrations. These data support the concept of a chemical which is probably detoxified in biological systems. Hence the chemicals in test substance are considered to be rapidly distributed in mammals, but eliminated by excretion and/or metabolism, with the test substance chemicals and metabolites expected to be mainly eliminated in urine.

The biodegradation study with sewage sludge did not show rapid biodegradation, there was no significant hydrolysis at temperatures of <50°C, and the high Koc suggests a low mobility in soil. These data suggest the chemical may not be eliminated rapidly in the environment, but the low toxicity to fish and Daphnia, and the very high water solubility (allowing rapid dilution in the environment) suggest there is not a high risk in environmental exposure scenarios.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
The physicochemical and biological data on the test substance suggests that it is readily bioavailable. The test substance would be distributed systemically in the water phase, but would not tend to partition into lipid tissues, it appears to be metabolised and eliminated relatively rapidly.
Executive summary:

A toxicokinetic assessment was conducted based on available physico-chemical properties and toxicological data of the test substance.Data from dermal irritation and skin sensitization indicates relatively good skin penetration even at low concentrations. Examination of the data from the repeat dose oral studies gave an indication of there being good evidence for oral bioavailability by the oral route for the test substance. The high water solubility and low Log Kow suggests relatively high rates of intestinal bioavailability. The biological effects (at dose levels above 300 mg/kg bw/day) following administration of an aqueous solution of test substance confirms the bioavailability. The relatively low volatility suggests a low risk of inhalation exposure. The low vapour pressure suggests low concentrations in air at room temperature which would not be expected to be of any concern. The studies performed and the available physico-chemical data are consistent with an organic molecule with a high bioavailability with no indication or evidence for potential for bioaccumulation. The low Log Kow, the high water solubility and the mammalian toxicity after oral doses at high levels supports the concept of high bioavailability. Low melting point and surface activity would also facilitate high bioavailability. A lack of cumulative toxicity for a chemical with known toxicity supports the concept of rapid elimination of the chemicals. Again, the high water solubility and low Log Kow suggest equilibrium with the water phase in animals, and would not tend to partition onto lipid tissues. The high water solubility would allow rapid excretion in urine. The low toxicity to fish and Daphnia, and the very high water solubility (allowing rapid dilution in the environment) suggest there is not a high risk in environmental exposure scenarios. Based on the above information, the physico-chemical and biological data on the test substance suggests that it is readily bioavailable. The test substance would be distributed systemically in the water phase, but would not tend to partition into lipid tissues, it appears to be metabolised and eliminated relatively rapidly (Esdaile DJ, 2015).