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Administrative data

Link to relevant study record(s)

Description of key information

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 P value) of the main components (DSBE, DIPE, SBA, TBA) contained in production stream 4, 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 the main constituents DIPE, DSBE, SBA and TBA show that the substances are absorbed [3, 6, 8, 9, 10].

 

Due to the medium volatility (7 kPa at 20°C) and boiling point (70-122°C), the moderate log P value (main constituents between 0 and 4; production stream 4: 0.59 -3.79) and medium water solubility, the substance can be taken up via the respiratory tract and absorption will occur directly across the respiratory tract epithelium by passive diffusion. DIPE, a major component, is known to be absorbed over the respiratory pathway [1]. Lethality of SBA and TBA in acute inhalation toxicity studies show that these substances have been absorbed [9, 10]. An acute inhalation toxicity study does not exist for DSBE, but conclusions for DSBE are drawn from its analogue/degradation product SBA [8]. Signs of systemic toxicity in an inhalation toxicity test (decreased activity, general incoordination) with production stream 4 show that the substance or at least some components of the mixture are absorbed via inhalation.

 

Since DIPE is not metabolised in vivo [2] and ethers and simple alcohols, the main constituents, are generally resistant to hydrolysis [9, 11], it is likely that most of the parent compounds will be present as such in the gastrointestinal and respiratory tracts. The only exception is DSBE, which has the potential to hydrolyze, resulting in two molecules of SBA [8].

 

Physical data, i.e. physical state (liquid) and low molecular weight indicate that the substance can also be absorbed via the skin. The water solubility of the substance (2.431 – 4.776 g/L) falls between 100-10’000 mg/l, a range where dermal absorption is anticipated to be moderate to high. In addition, log P values for the main constituents fall into the range 0.35-3.8 (production stream 4: 0.59 - 2.79) and values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal). However, the high vapour pressure (9 kPa 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, SBA and TBA, no compound-related clinical or biochemical effects were observed (at 2000 mg/kg each) [4, 7, 8, 9, 10]. Although the lack of observed effects could indicate that the substances were not absorbed, it does not preclude the absorption of some of the applied dose in the tests.

 

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 P values of the main constituents (>0), the molecules are likely to distribute into cells. Studies for DIPE indicate that it distributes to the liver, crosses the blood-brain barrier and is widely distributed upon systemic absorption [1, 4, 5]. Repeated-dose toxicity studies for SBA and TBA show that these substances likely distribute to the liver and kidneys. The results of prenatal developmental toxicity studies for DIPE, SBA and TBA show that these substances likely cross the placental barrier in rats [5, 8, 9, 10].

General incoordination in an acute inhalation toxicity test with production stream 4 could be a CNS effect; hence, the substances may distribute to the CNS. Distribution to the CNS is at least known for SBA, which, like many other organic solvents, produces reversible depression of central nervous system (CNS) activity in laboratory animals at high exposure doses [8].

 

None of the substances for which the log Pow is known has a log Pow >4; with the exception of DSBE, log Pow values for the main constituents are <3, and for production stream 4 a log Pow range of 0.59 - 2.79 was measured. Substances with log P values of 3 or less would be unlikely to accumulate with the repeated intermittent exposure patterns normally encountered in the workplace but may accumulate if exposures are continuous. Once exposure to the substance stops, it will be gradually eliminated at a rate dependent on the half-life of the substance. Findings for some of the constituents of production stream 4 generally agree with this conclusion: One study suggests that DIPE may be rapidly eliminated, and may therefore be unlikely to bioaccumulate [4]. TBA does not significantly bioaccumulate [12].

 

No experimental data are available on metabolism for the mixture. However, several studies on the main components of production stream 4 exist. For DIPE it has been reported that it is not metabolised in vivo [2]. DSBE has the potential to hydrolyze, resulting in two molecules of SBA. In mammalian systems SBA is either partly conjugated and excreted, or mostly fairly rapidly metabolized by alcohol dehydrogenase to MEK. MEK is further metabolized to 3-hydroxy-2-butanone and 2,3-butanediol, which can also be conjugated and excreted [8]. The biotransformation of TBA (by unidentified microsomal enzymes) yields 2-metyl-1,2-propanediol andα-hydroxyisobutyric acid. In addition, low concentrations of TBA-glucuronide, free TBA and another conjugate, which was probably TBA-sulfate, were identified in urine. T½ for TBA in blood is about 3 h in the rat and 10 h in humans [12]. In summary, diverse metabolic pathways (no metabolism at all, hydrolysis, conjugation, metabolization) exist for the components of production stream 4.

 

From physico-chemical data, elimination 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]. DSBE is hydrolyzed to SBA, which is partly excreted as conjugates, but mostly metabolized to MEK [8]. The MEK is subsequently converted to metabolites that are exhaled, excreted in the urine, or incorporated into endogenous metabolism. SBA was excreted via exhalation (3.3% of the original dose) and urine (2.6%), but more of the original SBA was excreted as its metabolite MEK. MEK excretion via exhalation and urine were 22.3% and 4.1% of the original dose, respectively [8]. TBA is exhaled via the lung to a small extent and detected in urine. The main excretion pathway, however, is over the degradation to metabolites with subsequent excretion [12].

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]      HIGH PRODUCTION VOLUME (HPV) CHEMICAL CHALLENGE PROGRAM TEST PLAN For sec-Butyl Ether CAS NO. 6863-58-7, Prepared by: ExxonMobil Chemical Company November 28,2006

[9] OECD HPV Chemical Programme, SIDS Dossier, approved at SIAM14, 26-28 March 2002, for 78-92-2, butan-2-ol

[10] U.S.Environmental Protection Agency December, 2009, Hazard Characterization Document, Sponsored Chemical: t-Butyl Alcohol (CASRN 75-65-0)

 

[11] I U C L I D Data Set: I D: 108-20-3: diisopropyl ether

 

[12] European Commission. 2002. European Union Risk Assessment Report. 3rd Priority List, Volume: 19, tert.-butyl methyl ether.