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 asseement 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

Objective of study:
toxicokinetics
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

Test animals

Species:
other:

Results and discussion

Bioaccessibility

Bioaccessibility testing results:
key physical properties:

Molecular weight: 458
Water solubility: 0.148 mg/L (pH 4); <0.101 mg/L (pH 7); <0.11O mg/L (pH9) and <0.111 mg.l-1 (Milli-RO Water,)
Partition co-efficient (log Pow): 4.9
Particle size: 94.55% of the test particles were <45µm
Dissociation constant: not determined
Hydrolysis: not determined
Structural alerts- no readily ionisable grooups present

Any other information on results incl. tables

acute oral toxicity: discriminating dose 2000mg/kg bw

28 day repeat dose oral toxicity: Liver effects were noted at 125 and 500 mg/kg in both sexes and at 30 mg/kg in males. This was indicated by increased liver weights (at 125 and 500 mg/kg in males, at 500 mg/kg in females), centrilobular hepatocellular hypertrophy (at all dose levels in males, at 125 and 500 mg/kg in females), and changes in clinical biochemistry values (higher plasma levels of ALAT, ALP, albumin and cholesterol in females at 500 mg/kg). Furthermore, a few animals treated at 500 mg/kg showed macroscopic changes of the liver (enlarged or dark red discolored). Increased liver weight and hepatocellular hypertrophy in absence of degenerative changes is regarded as an adaptive, non-adverse response (Ref. 6) and the magnitude of the changes in clinical biochemistry values was modest. Therefore, these liver findings were considered not to be toxicologically relevant.

One female treated at 500 mg/kg had a degenerative change in the kidneys, namely slight renal tubular basophilia (

bilateral) in combination with minimal tubular degeneration. This was considered to be an adverse, treatment-related change.

Treatment-related renal changes were also noted in males. At 125 and 500 mg/kg the incidence and/or severity of hyaline droplet accumulation were higher than in controls. This finding likely represented alpha2uglobulin, a normal protein in male rats which undergoes re-absorption in the proximal cortical tubules. A range of chemicals is known to increase hyaline droplet formation.

Reproductive toxicity:

skin exposure- non irritant and non-sensitising

eye exposure- non-irritant

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
Oral: evidence presented by the combined 28 day oral toxicity/reproductive toxicity study indicates that the substance is absorbed following administration in aqueous suspension; this is despite of the very low water solubility (0.145 mg/L @pH4) and lipophilic partition co-efficient (4.9). Fetal/embronic effects( decreased weight gain) also indicate that the substance is readily distributed once absorbed.

Inhalation: Particle size (<45µm) would indicate that the substance is respirable- the low water solubility will enhance the penetration to the lower
respiratory tract. Given that oral absorption of the substance has benn demonstrated in the 28 repeat dose study, it can be expected that absorption by the inhalation route is also likely.
Dermal absorption: based upon the physical properties of water solubility and partition coefficient- dermal uptake is expected to be low, the log Pow would indicate that the absorption to the lipophilic stratum corneum would be high, however the transfer into the epidermis will be low.

Metabolism: evidence from the 28 day study showing hepatocyte hypertrophy as an adaptive change to substance exposure would indicate that the substance is undergoing hepatic metabolism, however the identity of chemical species and extent of biotransformaiton is unknown.

Excretion: Evidence from the 28 day study, alpha2µglobulin secretion in male kidney, indicates some degree of excretion of the substance or its metabolites.
Executive summary:

Based upon the results of repeat dose toxicity testing and the physical properties of the substacne, it can be predicted that absorption and distribution can be expected by the oral and inhalation routes. Uptake is unlikely by the dermal route, a default value of 10% is assigned base dupon the physical properties of the substance.

Hepatic and renal effects noted at all dose levels indicate that some degree of metabolism and excretion of the substance is taking place.