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Administrative data

Link to relevant study record(s)

Description of key information

Short description of key information on bioaccumulation potential result:

In accordance with Regulation (EC) No 1907/2006 Annex VIII section 8.8.1, a toxicokinetics study is not required as assessment of the toxicokinetic behaviour of the substance has been derived from the relevant available information. This assessment is located within the endpoint summary for toxicokinetics, metabolism and distribution.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
100
Absorption rate - inhalation (%):
100

Additional information

The low molecular weight (102.17 g/mol), log Pow, physical state, moderate vapour pressure (19.9 kPa at 25°C), and high water solubility of di-isopropyl ether (DIPE) favour its absorption via various routes of exposure (i.e., oral, dermal, and respiratory). Data regarding the hydrolysis and metabolism of DIPE are limited, although it has been reported that the compound is not metabolised in vivo [5]. The absorption of DIPE and its distribution to the liver following respiratory exposure in rats was demonstrated by the results of a toxicokinetic study by Linde and Berman (1971) [4]. In this study, it was demonstrated that exposure to DIPE increased the rate of hepatic metabolism of hexobarbitol. These results imply that upon systemic absorption, DIPE is distributed to the liver, where it likely causes increased production, stabilization, and/or activity of the enzymes responsible for the metabolism of hexobarbitol. However, the results of this study did not provide any information regarding the metabolism or excretion of DIPE. The absorption of DIPE following oral exposure was supported by the results of 2 studies, in which mortality or increased incidence of malignant tumours, but no tissue-specific systemic effects, were reported [8, 11]. Since no compound-related clinical effects were reported, no information regarding distribution, metabolism, or excretion could be deduced from the results of these studies. No compound-related clinical or biochemical effects were observed in the available inhalation neurotoxicity and dermal toxicity studies [9, 12]. Although the lack of observed effects suggests that DIPE was not absorbed, it does not preclude the absorption of some of the applied dose.

 

The rapid intoxication (i.e., salivation, lack of coordination, excitation, shivering, slowed respiration, and depressed behaviour) and eventual respiratory depression observed following oral and respiratory exposure in monkeys, rabbits, and guinea pigs demonstrates that DIPE is absorbed, and that it crosses the blood-brain barrier [9, 10]. Pathological changes to brain, heart, liver, and kidney tissue were observed following oral and respiratory exposure to DIPE in rats, monkeys, rabbits, and guinea pigs, suggesting that DIPE is widely distributed upon systemic absorption [9, 10]. Whether DIPE is metabolized and/or excreted via the liver and kidneys could not be deduced based on the results of these studies. In the study by Machle et al. (1938) [9], animals administered the lowest dose level associated with reported effects in all species tested (i.e., 30000 ppm DIPE) recovered from the observed anaesthesia, cyanosis, and respiratory depression within 20 minutes of cessation of exposure. As excretion and metabolism were not assessed in this study, the observation of rapid recovery suggests (but does not demonstrate) that DIPE may be rapidly eliminated, and may therefore be unlikely to bioaccumulate.

 

Dose-related fetal effects (i.e., increased incidence of rudimentary and short 14th ribs) were observed following respiratory exposure of pregnant rats to DIPE during fetal organogenesis, but the authors argued that this was not indicative of adverse effects on development [10]. Since evidence of systemic maternal toxicity was not observed, the results of this study suggest that DIPE likely crosses the placental barrier in rats.

 

REFERENCES

 

[1]    Lide DR(2008) CRC Handbook of Chemistry and Physics (89th Ed). CRC Press Taylor & Francis Group, Boca Raton, FL, USA

 

[2]    O'Neil MJ (2006) The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals (14th Edition). Merck & Co., Inc.

 

[3]    Lide DR(2000) CRC Handbook of Chemistry and Physics (81st Ed). CRC Press Taylor & Francis Group, Boca Raton, FL, USA

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

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

[6]    ExxonMobil Biomedical Sciences Inc. (2008) High Production Volume (HPV): IUCLID Dataset, Diisopropyl Ether, CAS 108-20-3, 02.02.2008 

 

[7]    Szymanska JA, Bruchajzer E (2007) Podstawy i Metody Oceny Srodowiska Pracy [Diisopropyl ether. Documentation of permissible occupational exposure values]. Uniw Med Łódź 23(1):39-55. Publisher: Centralny Instytut Ochrony Pracy, CODEN: PMOSC3 ISSN: 1231-868X. [Journal written in Polish.] CAN 147:306689 AN 2007:659757 CAPLUS

 

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

 

[9]    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

 

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

 

[11]    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

 

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