dimethyl 1,2-benzenedicarboxylate;reaction mass of: 1,2-dimethylpropylidene dihydroperoxide

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics

Adequacy of study:

supporting study

Reliability:

other:

Rationale for reliability incl. deficiencies:

other: No studies are available on the toxicokinetics, metabolism and distribution of Methyl isopropyl ketone peroxide. Predictions were made based on physical-chemical properties and stability data.

Principles of method if other than guideline:

Predictions based on physical-chemical properties and stability.

Conclusions:

The toxicokinetic profile of the substance shows that based on physical-chemical characteristics and stability data, particularly water solubility, octanol-water partition coefficient and vapour pressure, no or only limited absorption by the dermal and inhalation routes is expected, which is further supported by the dermal and inhalation acute toxicity studies results. For the oral route uptake is more relevant. Bioaccumulation products is not likely to occur. Excretion is expected to occur mainly via urine.

Executive summary:

 

 

There is no direct in vitro or in vivo experimental data on toxicokinetics for MIPKP. The discussion on toxicokinetics is therefore based on the available physico-chemical and stability data.The available physico-chemical and toxicological information of the substance has been evaluated and used to assess the toxicokinetic behaviour. The results of this analysis will address the question on how the chemical will react in the body. The ECHA “Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance June 2017” document provides guidance, which physico-chemical properties commonly determine oral, inhalatory and dermal absorption, distribution, metabolism and elimination of substances.

 

The substance MIPKP is a liquid at room temperature with a molecular weight of 136.1 / 238.3 (Monomer/Dimer) g/mol, respectively. The water solubility is high for the monomer and lower for the dimer. The log Pow of was calculated to be calculated 0.80 / 3.18(Monomer/Dimer) for MIPKP and also reflects this.

 

Absorption

Oral absorption is favoured for molecular weights below 500 g/mol. Based on the high water solubility and the low log Pow value MIPKP is expected to be readily absorbed via the GI tract. As the substances are water soluble and the molecular weight is low (less than 200/close to) MIPKP may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water.

Administered in an acute study for MIPKP the oral LD50 is 200-2000 mg/kg bw. Mortality occurred at 2000 mg/kg bw. For MIPKP no advserse effects were observed up to 75 mg/kg bw/d in a 28-day and repro/developmental toxicity screening study. However, effects on the liver and bodyweight were observed. Therefore, it can be assumed that the substance becomes systemically available and direct absorption across the gastrointestinal tract epithelium will occur when applied orally.

 

Based on the low vapour pressure the inhalation exposure is limited. Nevertheless, if the substance reaches the lung, it may be absorbed. There is no inhalation data available for MIPKP.

 

Similarly, based on physical – chemical properties of MIPKP the substance is not likely to penetrate skin to a large extent as the low logPow value does not favour dermal penetration, as the substance is too hydrophilic to pass the skin. Furthermore, application to skin of rabbits did not cause systemic effects or mortality in acute dermal toxicity study at very high doses, 2000 mg/kg bw for MIPKP. In a skin irritation studies corrosion was observed but no mortalities. Applied to the skin of guinea pigs skin MIPKP is classified a weak sensitizer, reaction observed in 3/10 animals. Part of the reaction on the skin in these studies may be attributed to the corrosive/irritating nature of the substances. 

 

Distribution

When reaching the body MIPKP will be widely distributed due to low molecular weight and high water solubility.

 

Metabolism

MIPKP is readily biodegradable and hydrolytically stable. The substance is probably sufficiently long-lived to become systemically available. Based on the structure of the molecules, metabolism in the human body will mainly consist of phase-II metabolising steps, leading to an even better water solubility for excretion. This is in compliance with the results obtained in the genotoxic tests showing no effects with and without metabolising system. Metabolic activation leading to more toxic metabolites is thus not very likely.

 

Excretion

The bioaccumulation factors (BCF) were calculated using the EPIWIN software. These values are calculated to be 58.25 L/kg or 1.765 log BCF for dimer and 3.262 L/kg or 0.5 log BCF for the monomer of MIPKP. Based on these properties the substances are not considered to bioaccumulate in the human body. For both substance based on the water solubility and the log Pow value, excretion via the urine is likely.

 

Summary

The toxicokinetic profile of the substance shows that based on physical-chemical characteristics and stability data, particularly water solubility, octanol-water partition coefficient and vapour pressure, no or only limited absorption by the dermal and inhalation routes is expected, which is further supported by the dermal and inhalation acute toxicity studies results. For the oral route uptake is more relevant. Bioaccumulation products is not likely to occur. Excretion is expected to occur mainly via urine.

Description of key information

The toxicokinetic profile of the substance shows that based on physical-chemical characteristics and stability data, particularly water solubility, octanol-water partition coefficient and vapour pressure, no or only limited absorption by the dermal and inhalation routes is expected, which is further supported by the dermal and inhalation acute toxicity studies results. For the oral route uptake is more relevant. Bioaccumulation products is not likely to occur. Excretion is expected to occur mainly via urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100