Registration Dossier

Administrative data

basic toxicokinetics
Type of information:
other: expert statement
Adequacy of study:
key study
Study period:
2 (reliable with restrictions)

Data source

Reference Type:
other: expert statement
Report date:

Materials and methods

Test guideline
no guideline followed
GLP compliance:

Test material

Constituent 1
Chemical structure
Reference substance name:
Reaction mass of 4-methylpentane-2,2-diyl dihydroperoxide and 4-methylpentan-2-one and peroxybis-4-methylpentane-2,2-diyl dihydroperoxide
EC Number:
Cas Number:
Molecular formula:
Reaction mass of C6H14O4 and C12H26O6 and C6H12O
Reaction mass of 4-methylpentane-2,2-diyl dihydroperoxide and 4-methylpentan-2-one and peroxybis-4-methylpentane-2,2-diyl dihydroperoxide
additive 1
Chemical structure
Reference substance name:
Diisobutyl phthalate
EC Number:
EC Name:
Diisobutyl phthalate
Cas Number:
Molecular formula:
diisobutyl phthalate
Test material form:

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Oral absorption is favoured for molecular weights below 500 g/mol which is the case for all three components. The substance is soluble in water. The log Pow values of 1.3 and 1.31 for the monomer and MIBK are favourable for absorption by passive diffusion. The dimer with a log Pow of 4.2 may be taken up by micellular solubilisation. As the substance is water soluble and the molecular weight is low, the test item may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. The test item revealed NOAELs of 150 mg/kg bw/day, 200 and 75 mg/kg bw/day in repeated dose and reproduction toxicity studies. Administered in an acute oral study test item leads to a LD50 of 1575.3 mg/kg bw/day. Therefore, it can be assumed that the substance becomes systemically available and direct absorption across the gastrointestinal tract epithelium will occur when applied orally. When administered orally the test item is expected to rapidly hydrolyze.

The highest vapour pressure of MIBK (2.9E+003) assumed a moderate availability for inhalation as a vapour. The vapour pressure of the two other constituents assumed less availability for inhalation. If the substance reaches the lung, the test item may be absorbed. The test item showed toxic effects after inhalation administration, in an acute inhalation toxicity study (LC50 = 1500 mg/m3). Together, this indicates systemic availability after inhalation and if bioavailable, acute toxicity via this route of administration.

Based on physical – chemical properties the dimer component is not likely to penetrate skin to a large extent as the high log Pow value of 4.2 does not favour dermal penetration. The two other components with log Pow values of 1.31 and 1.3 favour dermal penetration. Furthermore the substance is a skin corrosive and applied to the skin of guinea pigs, sensitizing effects were observed. This indicates the substance is dermal available.

Details on distribution in tissues:
When reaching the body the test item will be widely distributed due to low molecular weight and high water solubility. Based on its low BCF and log Pow values the test item is not considered to bioaccumulative in the human body. The 90-day repeated dose toxicity study revealed in necropsy findings (dark colored or dark reddish mottled lungs, dark red liver) and in histological examinations in both cases acute catarrhal-purulent tracheitis accompanied with abundant fibrinous exudation into the lumen and diffuse congestion and edema in the lungs as cause of the death. These lesions were probably due to intra-tracheal applications of the test item in both animals. A slight and reversible elevation of the percentage of reticulocytes was observed in a dose related manner in male and female animals at 150 and 50 mg/kg bw/day at the termination of the treatment period. Although all values were lying well within the historical background range, the slight elevation correlated with the slight changes in the splenic weight, therefore a test item influence cannot be excluded. These findings indicate that the molecules of the test item are well distributed in the body through the bloodstream.
Details on excretion:
Based on the water solubility and the molecular weight value, excretion via the urine is likely. As discussed above the test item will hydrolyse rapidly, and will thus not be excreted in its unhydrolysed form.

Metabolite characterisation studies

Metabolites identified:
Details on metabolites:
Neither in the in-vitro nor in the in-vivo studies, the test substance induced genetic toxicity effects in the presence of metabolic activation. The chromosome aberration test showed clastogenic effects in the absence of metabolic activation. The other studies showed no effects in the absence of metabolic activation. Cytotoxic effects were observed in all studies in the absence and in the presence of metabolic activation. No difference was found between cytotoxic effects with and without metabolic activation. Based on these results it can be assumed that the test substance is not enzymatically activated (toxified) during the metabolism as the metabolized substances showed no higher toxicity compared to the parent compound. Based on the structure of the molecule and its nature, metabolism in the human body will mainly consist of phase-II metabolising steps, leading to an even better water solubility for excretion.

Applicant's summary and conclusion

Based on physical-chemical characteristics, particularly water solubility, octanol-water partition coefficient and vapour pressure absorption may occur by the dermal and inhalation routes. This assumption is further supported by inhalative and dermal toxicity studies. Also the oral route uptake of the test item or its hydrolysis products is relevant. Bioaccumulation of the test item and the hydrolysis products is not likely to occur based on the physical-chemical properties. Excretion is expected to occur mainly via urine.