Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: predictions from Basic Data set
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: A qualitative assessment of the toxicokinetics of the substance has been performed, based upon its physical properties and the results of toxicological studies.

Data source

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7c: Endpoint specific guidance Version 2.0 November 2014
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Radiolabelling:
no

Results and discussion

Metabolite characterisation studies

Metabolites identified:
not specified

Bioaccessibility

Bioaccessibility testing results:
key physical properties:

Molecular weight: 363.87
Water solubility: 16.3 g/L
Partition co-efficient log Pow: -0.77
Particle size distribution: 90% (<182 µm), 50% (<96.87 µm), 10% (<47 µm)
Dissociation constant: not determined
pH (10% suspension ): 2.8
Hydrolysis: t1/2 >1 year
Structural alerts- tertiary amine group.

Any other information on results incl. tables

acute oral toxicity: discriminating dose 2000 mg/kg; lethargy noted in males 2 hours post dosing.

Reproductive Toxicity Screen (OECD422): No toxicologically significant effects on fertility, reproductive performance or pup development were noted up to the maximum dose tested (500 mg/kg bw/day), however at the highest dose tested day there was a higher incidence of offspring showing clinical signs concentrated in only a few isolated litters.

28 day repeat dose oral toxicity (OECD422) : Significant systemic effects (clonic convulsions leading to termination) were noted when animals were treated with 750 or 1000 mg/kg bw /day in the initial stages of the study. The following clinical signs were noted in animals treated with 300 mg/kg bw/day: piloerection, hunched posture, lethargy, decreased respiratory rate, pallor of the extremities and diarrhoea.

skin exposure: no irritant effects were noted in in vivo studies with guinea pigs and also the acute dermal toxicity study in rats. these results are equivocal for the potential for the substance to penetrate the stratum corneum.

eye exposure: when tested in the BCOP test system the substance did not induce severe eye damage, and does not significantly increase corneal permeability.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
oral: clinical signs witnessed in the repeat dose oral toxicity study indicates that the substance is absorbed following administration in polyethylene glycol with systemic effects noted: clinical chemistry,thyroid, liver and kidney following exposure to all dose levels. NO toxicologically significant effects were observed on reproductive or developmental parameters in the exposed animals.
The water solubility, partition coefficient and molecular mass all indicate that this substance will be bioavailable via the oral route.

Inhalation: The particle size distribution indicates that there is limited potential for exposure by this route.

Dermal absorption: the physical parameters of the substance: molecular weight and log Pow, indicate that the substance may penetrate the stratum corneum and be systemically available from dermal exposure.

Metabolism: There is significant evidence from the 28 day study to indicate that the substance is undergoing extensive hepatic metabolism (adaptive hepatic hypertrophy at all dose levels with diffuse midzonal/centilobular hypertrophy; increases in serum cholesterol and ALAT).


Excretion: There is limited evidence from the oral toxicity studies conducted ( significant increases in calcium and inorganic phosphorus, presence of hylaine droplets and increases in absolute and relative kidney weights in both sexes in repeat dose studies) that the substance may interact with the kidneys.