Reaction mass of 2-methylpent-2-ene and diisopropyl ether

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

Based on the low molecular weight (around 100 g/mol), the structure, and physico-chemical data (medium water solubility, moderate log Pow value) of the main components (DIPE, 2-Methyl-2-pentene) contained in production stream 7, absorption through aqueous pores or bulk passage with water through the epithelial barrier and absorption by passive diffusion is possible, and the substances may dissolve into gastrointestinal fluids. The structure of the constituents indicates that ionization is not an issue; hence, pH will have no effect on absorption. Oral toxicity data are not available for the mixture, however, results for DIPE show that it is absorbed [3, 6].

 

Due to the medium volatility (13 kPa at 20°C) and boiling point (56 -83°C), the moderate log Pow value (overall range for the mixture 0 - 4.3; main range 2.4 - 4.3) and medium water solubility (2.8 g/l for the mixture), the substance can be taken up via the respiratory tract and absorption will occur directly across the respiratory tract epithelium by passive diffusion. Signs of systemic toxicity were not observed in an inhalation toxicity test. Hence, this result is unsuggestive of respiratory absorption of the substance. Nevertheless, DIPE, a major component, is known to be absorbed over the respiratory pathway [1].

 

Since DIPE is not metabolised in vivo [2] and alkenes, the main constituents, are generally resistant to hydrolysis, it is likely that the parent compounds will be present as such in the gastrointestinal and respiratory tracts.

 

Physical data, i.e. physical state (liquid) and low molecular weight (around 100 g/mol) indicate that the substance can also be absorbed via the skin. The water solubility of the substance (2.8 g/L) falls between 100-10’000 mg/l, a range where dermal absorption is anticipated to be moderate to high. In addition, log Pow values for the substance falls into the range 2.4-4.3 and values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high. Above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. However, the high vapour pressure (15519 Pa at 25°C) suggests that the substance could be too volatile to penetrate further into the skin. Dermal uptake and penetration is not enhanced since the substance is not a surfactant and not a skin irritant (if it was a skin irritant, damage to the skin surface may enhance penetration). Furthermore, animals in the skin sensitization test showed no clinical signs during the course of the study. In addition, in dermal toxicity studies with DIPE, no compound-related clinical or biochemical effects were observed (at 2000 mg/kg) [4, 7]. Although the lack of observed effects suggests that the substance was not absorbed, it does not preclude the absorption of some of the applied dose in the test.

 

From the small size and medium water solubility of the molecules in the mixture, wide diffusive distribution in the body is expected. From the log Pow values of the substance and the main constituents (>0), the molecules are likely to distribute into cells. For the main constituent DIPE, studies indicate that it distributes to the liver, crosses the blood-brain barrier and is widely distributed upon systemic absorption [1, 4, 5]. The results of a prenatal developmental toxicity study suggest that DIPE likely crosses the placental barrier in rats [5]. Neither the data for DIPE nor for production stream 7 give indication for distribution to the CNS.

 

The main range of log Pow values for the substance is 2.4 – 4.3. The log Pow of 2 -methylpent-2 -ene was estimated to be 3.1, but measurements using the HPLC method indicated a peak with a log Pow 4.3 which may correspond to 2 -methylpent-2-ene and other methylpentene or methylpentane isomers. Hence, some of the substances in production stream 7 (mainly DIPE with a log Pow of 1.5 -2.5) are unlikely to accumulate with the repeated intermittent exposure patterns normally encountered in the workplace but may accumulate if exposure is continuous. Once exposure to the substance stops, it will be gradually eliminated at a rate dependent on the half-life of the substance. One study suggests that DIPE may be rapidly eliminated, and may therefore be unlikely to bioaccumulate [4]. However, daily exposure to a substance with a log Pow value of around 4 or higher could result in a build up of that substance within the body. Following oral or inhalation exposure, members of the higher olefin category – and, in analogy, to some extent 2-methyl-2-pentene and its isomers - are expected to be absorbed by the blood and to accumulate in the brain, liver, kidneys and perirenal fat [8]. However, due to the low carbon number of 6, accumulation will be limited. Since unchanged alkenes are not considered to be toxic, and because tissue levels rapidly cleared after exposure ceased, this concentration, especially in fat tissues, is unlikely to have any biological effect [8]. In summary, DIPE will likely not bioaccumulate, whereas 2 -methyl-2 -pentene and some minor components may be subject to limited accumulation in the body due to their higher log Pow values.

 

No experimental data are available on metabolism for the mixture. For DIPE it has been reported that it is not metabolised in vivo [2]. No data are available on metabolism of 2-methyl-2-pentene or its isomers. However, an in vitro study on 3-ethyl-2-pentene in the presence of rat liver microsomes and NADPH, the substance was converted to the glycol with no trace of epoxide [8]. However, the rate of the reaction for the branched olefine was slowest compared to linear olefins. Nevetheless, further experiments with specific enzyme inhibitors showed that it is likely that the biological conversion of the alkenes proceeds through epoxides.

 

From physico-chemical data, excretion via urine and exhaled air are likely the most prevalent pathways of excretion. One study suggests that DIPE is rapidly eliminated; however, the pathway of excretion was not assessed [4]. 2 -methyl-2-pentene and its isomers, in analogy to other higher olefins, may be metabolized to the corresponding glycol or conjugated with glutathione, which are expected to be excreted in urine as mercapturic acids [8]. Furthermore, in addition to excretion in urine, the lower volatile alkenes are likely to be exhaled unchanged [8].

 

 

REFERENCES

 

[1]    Linde HW, Berman ML (1971) Nonspecific stimulation of drug-metabolizing enzymes by inhalation anesthetic agents. Anesth Anal Curr Res, 50(4):656-667

 

[2]    Hake CL, Row VK (1963) Patty’s Industrial Hygiene and Toxicology, Vol. II, Second Revised Edition. Interscience Publishers,New York

 

[3]    Kimura ET, Ebert DM, Dodge PW (1971) Acute toxicity and limits of solvents residue for sixteen organic solvents. Toxicol Appl Pharm, 19:699-704

 

[4]    Machle W, Scott EW, Treon J (1938) The physiological response to isopropyl ether and to a mixture of isopropyl ether and gasoline. J Hyg Toxicol, 21:72-96

 

[5]    Dalbey W, Feuston M (1996) Subchronic and developmental toxicity studies of vaporised diisopropyl ether in rats. J Toxicol Env Health, 49:29-43

 

[6]    Belpoggi F, Soffritti M, Minardi F, Bua L, Cattin E, Maltoni C (2002) Results of long-term carcinogenicity bioassays on tert-amyl-methyl-ether (TAME) and di-isopropyl-ether (DIPE) in rats. Ann NY Acad Sci., 982:70-86

 

[7]    Rodriguez SC, Dalbey WE (1997) Subchronic Neurotoxicity of Vaporized Diisopropyl Ether in Rats. Int J Toxicol, 16:599-610

 

[8]   OECD SIDS: Higher Olefins-Category, SIDS Initial Assessment Report For SIAM19; Berlin, Germany, 19-21 October 2004, prepared by the American Chemistry Council, Higher Olefins Panel