2-Butanone, peroxide

Endpoint summary

Description of key information

Based on physical-chemical characteristics, 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. Regarding oral route, uptake of MEKP and/or its hydrolysis products have to be taken into consideration. Bioaccumulation of MEKP and the hydrolysis products is not likely to occur based on the physical-chemical properties. Excretion is expected to occur mainly via urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

 General

 

MEKP is used as initiator to start chain reactions in the synthesis of polymers. The substance is stable only in solvents. Studies with MEKP in different solvents are available, as pure MEKP is not stable and and studies with pure MEKP are technically not feasible. Different solvents were used: TXIB = 2,2,4-trimethylpentane-1,3-diyl bis(2-methylpropanoate), diacetone alcohol and DMP = dimethyl phthalate. From a toxicological point of view the solvent DMP is most critical, although all three substances are not classified, according to the data available and according to dossiers submitted under REACH.

 

Toxicological profile of Methyl-ethylketone peroxide (MEKP)

 

An acute oral toxicity study with rats revealed a LD50-value of 1017 mg/kg bw (solvent: DMP). In a further study, the LD50 for a single oral gavage dose in rats was 484 mg/kg of methyl-ethylketone peroxide in DMP (Zeiger, 1993). An acute inhalation toxicity study with rats revealed a LC50-value of 17 mg/L (aerosol, solvent: DMP). In two further studies, inhalation of methyl-ethylketone peroxide in DMP for 4 hours produced an LC50 of 200 ppm for rats and 170 ppm for mice (Zeiger, 1993). In an acute dermal toxicity study with rats a LD50 of 4000 mg/kg bw was determined (solvent: DMP).

A single intraperitoneal injection of methyl-ethylketone peroxide in rats led to prostration, followed by death; the LD50 was estimated to be 65 mg/kg for methyl-ethylketone peroxide in DMP (Zeiger, 1993). In a skin irritation study corrosive effects were observed in rabbits (solvent: DMP). An eye irritation test showed that MEKP causes severe damage to the rabbit’s eye (solvent: DMP). A guinea pig maximation test revealed that MEKP induces no skin sensitisation (solvent: DMP/diacetone alcohol). Notably, local effects are directly linked to corrosive properties of the organic peroxide MEKP.

MEKP was not mutagenic in a bacterial mutagenicity test (a reverse mutation test - Ames test), in an in vitro chromosome aberration test and in an in vitro HPRT assay all in thepresence and absence of metabolic activation (solvent used in all assays: TXIB/diacetone alcohol).

 

Mutagenicity data with the solvent DMP also show negative results in Ames test. However positive results were obtained in a mouse lymphoma test (without metabolic activation), an chromosome aberrations test and a sister chromatid exchange test (both with and without metabolic activation). An in vivo mouse chromosome aberrations test showed negative results. DMP itself is not classified mutagenicaccording to in vivo data available and of dossiers submitted under REACH. Taking all data together, MEKP is not classified with respect to mutagenicity.

 

A 28-day oral (gavage) toxicity study was performed with MEKP (solvent: TXIB/diacetone alcohol) in male and female Fischer, F344/DuCrl rats. The test substance caused a series of unspecific and minor alterations in general appearance (reduced-well being), in body weights, feed consumption, haematology, clinical biochemistry and organ weights. None of the alterations gives a clear evidence for a target organ; none bears severe or life-threatening effects. Alterations partly returned to normal during the follow-up period. No test substance related findings were made in the low and mid dosed groups (20 and/or 65 mg/kg bw/day). There was no clear sex difference in the response to the test substance. At necropsy no test substance related or uncommon spontaneous findings were observed. There was no test substance related alteration noted histopathologically. Under the design and the conditions of this study the No-Observed-Adverse-Effect-Level (NOAEL) of MEKP was at 65 mg per kg body weight for male and female animals.

 

A 90-day repeated dose toxicity study with MEKP (solvent: TXIB/diacetone alcohol) is also available. The test item was administered orally (by gavage) to Hsd.Han: Wistar rats (n=15 animals/sex in the control and high dose groups, n= 10 animals/sex in the low and middle dose groups) once a day at 0 (vehicle control), 150, 50 and 20 mg/kg bw/day doses corresponding to concentrations of 0, 75, 25 and 10 mg/mL, applied in a dose volume of 2 mL/kg bw for 90 or 91 days. 5 animals/ sex in the control and high dose groups assigned to the recovery groups were treated identically up to Day 89, then they were observed without administration for four weeks (recovery observations). Toxic signs related to the test item were not detected at any dose level (150, 50 or 20 mg/kg bw/day) at the daily and detailed weekly clinical observations and in the course of the functional observation battery. No test item related body weight, or body weight gain changes were observed with respect to controls at any dose level during the course of the study (150, 50 or 20 mg/kg bw/day). The daily mean food consumption was similar in animals of the control and test item treated groups (150, 50 and 20 mg/kg bw/day). There were no abnormalities in the eyes of animals in the high dose group at termination of the treatment (150 mg/kg bw/day). 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. A test item influence on the estrous cycle was not detected (150, 50 and 20 mg/kg bw/day). Sperm analysis did not reveal test item influence on the sperm cells (count, motility and morphology) at 150 mg/kg bw/day dose. Specific macroscopic alterations related to treatment with the test item were not observed at the terminal necropsy or at the end of the recovery period. A test item influence cannot be excluded in changes of the weights of spleen (absolute and relative to body and brain weight) in male and female animals at 150 mg/kg bw/day and in female animals at 50 mg/kg bw/day. There were no histological lesions related to the test item. The NOAEL was determined to be 150 mg/kg bw/day.

 

A reproduction/developmental toxicity screening test with the test item methyl-ethylketone peroxide (solvent: TXIB/DMP) was performed according to OECD 421. This study was conducted to provide preliminary information on the potential adverse effects of methyl-ethylketone peroxide on male and female reproduction. This investigation encompassed gonadal function, mating behaviour, conception, parturition and lactation of the F0 generation and the development of offspring from conception through day 4 of postnatal life. Three groups of male and female Crl:CD (SD) rats (12/sex/group) were administered the test article, methyl-ethylketone peroxide (MEKP), in the vehicle (0.1% polysorbate 80), daily by oral gavage for at least 14 consecutive days prior to mating. Dosage levels for the F0 generation were 25, 50 and 100 mg/kg/day; however, due to the mortality/moribundity of 1 male and 2 females in the 100 mg/kg/day group following 2 days of dose administration, the dosage level was lowered to 75 mg/kg/day. The no-observed-adverse-effect level (NOAEL) for parental systemic toxicity was 50 mg/kg/day. No effects on F0 reproduction were noted in animals administered methyl-ethylketone peroxide at dosage levels of 25, 50 or 100/75 mg/kg/day, therefore the NOAEL for F0 reproductive toxicity was 75 mg/kg/day. The NOAEL for F1 neonatal toxicity was 50 mg/kg bw/day.

 

Besides that, a prenatal developmental toxicity study according to OECD Guideline 414 was performed with MEKP. Groups of 24 sperm-positive female Hsd. Brl. Han: Wistar rats were treated with the test substance by oral administration daily at three dose levels of 20, 65 and 200 mg/kg bw/day from day 5 up to and including day 19 post coitum. A control group of 24 sperm positive females was included and the animals were given the vehicle sunflower oil. The treatment volume was 2 mL/kg bw. The day when sperm was detected in the vaginal smear was regarded as day 0 of gestation. Caesarean section and gross pathology were performed on gestational day 20. The number of implantations, early and late resorptions, live and dead fetuses in each uterine horn and the number of corpora lutea were recorded. Each fetus was weighed and examined for sex and gross external abnormalities. The placentas were weighed and examined externally. About half of each litter was preserved for visceral examination and the other half of the litters were preserved for skeletal evaluation. No test item related effects regarding developmental toxicity were found. The NOAEL for developmental toxicity was therefore determined to be 200 mg/kg bw/day. The maternal NOAEL was considered to be 65 mg/kg bw/day based on reduced body weight gains in the dams.

 

Toxicokinetic analysis of Methyl-ethylketone peroxide (MEKP)

 

Methyl-ethylketone peroxide (MEKP) is a colourless liquid at room temperature with a molecular weight of 122.12 g/mol (monomer) and 210.23 g/mol (dimer). The substance is highly soluble in water (6.53 g/L). The log Pow of MEKP monomer was estimated to be < 0.3 (monomer) and <2.04 (dimer). Based on the log Pow a log BCF of 0.5 (monomer) and 0.66 (dimer) was calculated. MEKP has a vapour pressure of 73.6 Pa (monomer) and 0.184 Pa (dimer) at 25°C (estimated by QSAR).

MEKP may be degraded hydrolytically to acetic acid (CAS 64-19-7), ethyl acetate (CAS 141-78-6), methyl ethyl ketone (butanone, CAS 78-93-3) and hydrogen peroxide (CAS 7722-84-1). All four substances have very low log Pow values, too (range: -1.5 to 0.6). Based on these very low log Pow values no bioaccumulation potential is expected. The only available BCF of 30 for ethyl acetate confirms this assumption. The degradation products are highly soluble in water (range: 2.5 g/L to completely miscible).

 

Oral absorption is favoured for molecular weights below 500 g/mol. Based on the high water solubility and the low log Pow value MEKP is expected to be readily absorbed via the GI tract. As the substance is water soluble and the molecular weight is low (less than 200) MEKP may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. MEKP revealed NOAELs of 150 mg/kg bw/day and 200 mg/kg bw/day in repeated dose and reproduction toxicity studies, respectively. Administered in an acute study MEKP leads to a LD50 of 1017 mg/kg bw/day (potentially due to local tissue damage). 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 MEKP may be expected to partially hydrolyze to acetic acid, ethyl acetate, methyl ethyl ketone and hydrogen peroxide. Based on their physical/chemical properties described above, all substances are expected to pass the epithelium.

Based on the vapour pressure (0.184 to 73.6 Pa) inhalation exposure is limited. Nevertheless, if the substance reaches the lung, MEKP may be absorbed. MEKP showed only toxic effects after inhalation administration, in an acute inhalation toxicity study when applied at high doses (LC50 = 17 mg/L). Together, this indicates low systemic availability after inhalation and if bioavailable, low toxicity via this route of administration.

Similarly, based on physical – chemical properties of MEKP 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 of MEKP to skin of rabbits did not cause systemic effects (mortality) in a skin irritation/corrosion study and an acute dermal toxicity study. Applied to the skin of guinea pigs, sensitising effects were not observed.

When reaching the body MEKP will be widely distributed due to low molecular weight and high water solubility. Based on its low BCF value MEKP is not considered to bioaccumulative in the human body. Target organs in the 90-dy oral repeated dose toxicity study in rats were the spleens, accompanied by slightly elevated percentages of reticulocytes in the 150 and 50 mg/kg bw/dose groups. Spleen weight values remained within the historical control ranges, however along with changes in the percentages of reticulocytes a test item influence cannot be excluded.

MEKP itself as well as its hydrolysis products may reach the blood. All degradation products have very low log Pow values and are in consequence expected to have low BCF values (Ethyl acetate BCF = 30) and are thus not bioaccumulative.

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. 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.

Based on the water solubility and the log Pow value, excretion via the urine is likely. As discussed above MEKP may hydrolyse partially. It may thus be excreted in its hydrolysed form as well. All degradation products represent small good soluble and hydrophilic substances, which are in conclusion most likely excreted via the urine.

 

Summary:

Based on physical-chemical characteristics, 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 of MEKP or its hydrolysis products is more relevant. Bioaccumulation of MEKP and the hydrolysis products is not likely to occur based on the physical-chemical properties. Excretion is expected to occur mainly via urine.

 

References

ECHA (2014), Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance

Marquardt H., et al., (1999). Toxicology.Academic Press, 1999

Mutschler E., et al., (2001).Arzneimittelwirkungen. Lehrbuch der Pharmakologie und Toxikologie.Wissenschaftliche Verlagsgesellschaft,, 2001

Zeiger, Errol (1993) United States Department of Health and Human Services; NIH publication 93-3341, 1993