Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics, other
Remarks:
expert statement
Type of information:
other: expert statement
Adequacy of study:
supporting study

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion

Conclusions:
Due to lack of quantitative data, absorption rates of 100% are indicated for all three routes. This basically indicates that, although the absorption is probably low, there is likely no significant difference expected in absorption between oral, dermal and inhalation route. Available studies (readily biodegradable, low log kow 1.2) do not indicate a concern for bioaccumulation.
 
Low bioaccumulation potential
Absorption: 100% by all three routes
Executive summary:

 1. Physical-chemical properties

The test substance, cyclohexanone peroxide CAS 12262-58-7 is a multi-constituent (equilibrium mixture of cyclohexyl based organic peroxides: 2408-01-7, monoperoxy monomer; 2407-94-5, monoperoxy dimer; 78-18-2, diperoxy dimer; 2699-12-9, triperoxy dimer; 2699-11-8, diperoxy monomer) and has a molecular weight range of 132.2 – 262.3 g/mole. It is a clear liquid.

The substance is classified as Organic peroxide type D; liquid, Division 5.2; UN 3105.

Organic peroxides are thermally unstable substances, which may undergo self-accelerating decomposition. The self-accelerating decomposition temperature (SADT) is 55°C. The maximum storage temperature is 25°C and the minimum is -10°C.

The major thermal decomposition products are: carbon dioxide, cyclohexanone and water.

 

The substance has no melting point or boiling point due to the SADT. The vapour pressure is 1.90 KPa at 20°C which is in the low range.

The octanol-water partition coefficient is low at is 1.2 and the water solubility is 9.3 g/L.

 

2. Data from acute toxicity studies and irritation studies

The oral LD50 forcyclohexanone peroxideis 1242 mg/kg bw. The inhalation LD50 >5ppm and there is no acute dermal study. Further acute toxicity testing is not possible due the corrosive nature of the substance. Since dermal absorption is not quantitatively evaluated, 100% is assumed as worst case assumption.

 

3. Data from repeated dose toxicity studies

Oral:

In an OECD422 the test item was administered by gavage to three groups, each of twelve male and twelve female Wistar Han™:RccHan™:WIST strain rats, for approximately six weeks to males and up to eight weeks to females including a two week pre-pairing phase, pairing, gestation and early lactation, at dose levels of 30, 100 or 200 mg/kg bw/day. A control group of twelve males and twelve females was dosed with vehicle alone (Polyethylene glycol 400).

There were no unscheduled deaths considered to be related to the systemic toxicity of the test item. There were four premature decedents during the course of the study, two each from the 100 or 200 mg/kg bw/day dose groups; one female from either dose group was found dead whilst the other was killedin extremis. Three of these animals showed clinical signs of respiratory distress which correlated with microscopic changes in the trachea with the change considered to have been a major factor in the death of one female from each dose group; these clinical signs and microscopic changes and, thus the deaths, were considered likely to be due to an irritant nature of the test item and not an indication of its systemic toxicity. Microscopic examination of the tissues from the remaining female treated with 200 mg/kg bw/day showed marked inflammatory change in the reproductive tract and secondary lymphoid/cellular depletion and it was deemed likely that these changes were a result of parturition and unrelated to administration of the test item.

 At 200 mg/kg bw/day, individual animals of either sex surviving to the scheduled necropsy showed a few instances of noisy respiration mainly during the latter half of the treatment period with one of the males also showing noisy/laboured respiration and decreased respiratory rate on Day 35. These were deemed likely to be due to an irritant nature of the test item and not an indication of its systemic toxicity. Of the four premature decedent animals, three showed inflammatory changes in the trachea with the change considered to have been a major factor in the premature death of two of the animals. These changes are unusual, correlated with the respiratory clinical sign noted and may be indicative of reflux after gavage dosing and thus related to test item irritancy rather than its toxicity.

 

No other treatment-related effects were detected in animals of either sex at any dose level.

 

Based on the available data, the premature deaths of three females were considered likely due to an irritant nature of the test item rather than an indication of its systemic toxicity and, as such the ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity, was considered to be 200 mg/kg bw/day within the confines of this study.

 

There was no effect of treatment on mating performance, fertility, gestation length or any of the maternal and offspring parameters measured and The ‘No Observed Effect Level’ (NOEL) for reproductive toxicity, within the confines of this screening study, was considered to be 200 mg/kg bw/day. 

 

Inhalation:

There are no data from repeated dose studies via the inhalation route. One acute inhalation study is available in which a low concentration, based on vapor formation at ambient temperature, was tested. LD50 is >5.0 ppm (based on the vapor, >0.029 mg/l). No irritation was observed in this study. The substance is corrosive to skin and eyes and further testing is not foreseen. The substance is a liquid with a low vapour pressure (1.90 KPa at 20°C).

 

Dermal:

No data from repeated dose studies via dermal route. The substance is corrosive to skin and eyes and further testing is not foreseen.

 

3. Absorption, distribution, metabolism, excretion

 

No adme data are is available and therefore 100% adsorption is assumed for all routes.Available studies (readily biodegradable, low log kow 1.2) do not indicate a concern for bioaccumulation.