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Administrative data

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Description of key information

Short description of key information on bioaccumulation potential result:  

In accordance with Regulation (EC) 1907/2006, the toxicokinetic behaviour of the substance has been assessed to the extent that can be derived from the relevant available information.

Short description of key information on absorption rate:  

Dermal absorption of the substance has been assessed to the extent that can be derived from the relevant available information.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - dermal (%):
100

Additional information

Basic toxicokinetics

 

The substance Reaction Products of C3 alcohols and C3 alkenes obtained as by-products from the manufacture of propan-2-ol by hydration of propylene is a UVCB substance. The main constituent (approximately 50%) is isopropyl ether. Minor constituents are propylene dimers (~20%, C6 hydrocarbons, mainly C6 alkenes), propylene trimers (~10%, C9 hydrocarbons), hexanols (~10%) and C3 alcohols (~10% consisting of both isopropanol and n-propanol).

The toxicokinetic behaviour of the UVCB substance can be predicted based on the toxicokinetic behaviour of its main constituents.

 

Isopropyl ether (IPE, also known as diisopropylether, DIPE) is expected to be efficiently absorbed orally and via inhalation, based on its water solubility and molecular weight. Some dermal absorption is expected, although to a limited extent. The metabolism of IPE was investigated by Stagliola and Schatz (2007) to determine if the two major metabolites were as predicted, isopropyl alcohol (IPA) and acetone (dimethyl ketone or DMK). Using rat nasal mucosa microsomes in vitro, they found that the metabolites, IPA and DMK, were produced in a concentration-dependent manner. P450 isoforms, CYP2A3 and 2E1, were identified as the key enzymes involved in IPE metabolism. In vivo studies showed a rapid systemic clearance of DIPE, SBA and DMK from the blood of rats within 24 hours following a 6-hour inhalation exposure to 5000 ppm IPE. Therefore, IPE nor its biotransformation products are expected to bioaccumulate.

 

Data on propylene dimers can be derived by reading across from data on C6 hydrocarbons (represented by 2-methyl pentane) and C6 alkenes. 2-Methyl pentane is poorly absorbed dermally with a measured percutaneous absorption rate in rat skin and in vitro of approximately 0.1 µg/cm2/hr or <1% of the total fluid applied (Tsuruta, 1982). When dermally absorbed, 2-methyl pentane is rapidly eliminated. Data from human biomonitoring in urine show that the main metabolite identified in urine upon exposure to 2-methyl pentane is 2-methyl-2-pentanol. 2-Methyl derivatives of 1-, 3-, and 4-propanol, and 2-methylpentane-2,4-diol were minor metabolites (Kawai et al., 1995). 2-Methyl pentane nor its biotransformation products are expected to bioaccumulate.

The uptake, distribution, and elimination of C2-C10 1-alkenes after inhalation exposure has been investigated in the rat (Zahlsen, 1993 and Eide et al., 1995). Male Sprague-Dawley rats were exposed via whole body inhalation to 100 or 300 ppm vapour of the individual test substances for 12 hours/day for 3 consecutive days. Concentrations of the hydrocarbons were measured in blood, brain, liver, kidney and perirenal fat immediately following each 12 hour exposure and 12 hours following the last exposure. The results show that concentrations of 1-alkenes in blood and organs reached a steady-state level after the first 12 h exposure, and the concentrations 12 h after the last exposure were generally low, except in fat tissue. Higher concentrations of linear alpha olefins were measured in each of the respective organs compared with measured concentrations of the corresponding isoalkanes. Concentrations of 1-alkenes in blood and the different tissues increased with increasing number of carbon atoms.

 

Data on propylene trimers can be derived by reading across from data on C9 alkanes and C9 alkenes.

Based on available data on C9 alkanes and structurally related compounds, these hydrocarbons are expected to be readily absorbed and distributed through the body (Zahlsen et al., 1992). n-Alkanes are readily metabolized and excreted in urine and expired as CO2. Iso-alkanes are less readily metabolized to a range of metabolites that are excreted in the urine. The C9 alkenes are expected to be eliminated at a lower rate than C9 alkanes, with the C9 alkenes being distributed mainly to the fat tissue.

 

Hexanol is expected to be absorbed by the most common routes of exposure, with dermal absorption expected to be significant (Scheuplein and Blank, 1973). After absorption hexanol is widely distributed within the body and efficiently eliminated. The initial step in the mammalian metabolism of primary alcohols is the oxidation to the corresponding carboxylic acid, with the corresponding aldehyde being a transient intermediate. These carboxylic acids are susceptible to further degradation via acyl-CoA intermediates by the mitochondrial ß-oxidation process, in which C2 units are stepwise eliminated. Hexanol nor its biotransformation products are expected to bioaccumulate (WHO, 1998).

 

Based on their physico-chemical properties, both isopropanol and n-propanol are expected to be readily absorbed and distributed throughout the body following ingestion (European Chemicals Bureau, 2008; OECD 1997). Dermal absorption is expected to be slow. n-Propanol is metabolized by alcohol dehydrogenase to propionic acid via its corresponding aldehyde and may enter the tricarboxylic acid cycle. Isopropanol is quickly metabolized to acetone and subsequently excreted as CO2. Both n-propanol and isopropanol are rapidly and efficiently excreted.

 

Overall, the data on the main constituents of Reaction Products of C3 alcohols and C3 alkenes obtained as by-products from the manufacture of propan-2-ol by hydration of propylene show that this UVCB substance is expected to be readily absorbed via the oral and inhalation routes of exposure and to a limited extent via the dermal route. The substance is expected to be efficiently metabolized resulting in a rapid systemic clearance, with the C6 and C9 alkenes being eliminated at a lower rate than the other constituents. The substance is not expected to bioaccumulate.

 

References

Eide I., Hagemann R., Zahlsen K., Tareke E., Tornqvist M., Kumar R., Vodicka P., and Hemminki K. (1995) Uptake, distribution, and formation of hemoglobin and DNA adducts after inhalation of C2-C8 1-alkenes (olefins) in the rat. Carcinogenesis 16(7):1603-1609.

 

European Chemicals Bureau (2008) European Union Risk Assessment Report of propan-1-ol. Volume 82. Ispra, Italy.

 

Kawai T., Mizunuma K., Yasugi T., Horiguchi S., Iguchi H., Mutti A., Ghittori S., and Ikeda M. (1995) Monitoring of exposure to methylpentanes by diffusive sampling and urine analysis for alcoholic metabolites. Occup. Environ. Med. 52(11):757-63.

 

OECD (1997) SIDS dossier on the HPV chemical Isopropanol. UNEP.

 

Scheuplein R.J. and Blank I.H. (1973) Mechanism of Percutaneous Absorption. IV. Penetration of Nonelectrolytes (Alcohols) from Aqueous Solutions and from Pure Liquids. J. Investigat. Dermatol. 60(5):286-296.

 

Stagliola E. and Schatz R. (2007) In vivo and in vitro metabolism of diisopropyl ether (DIPE). The Toxicologist, Abstract 971.

 

Tsuruta, H. (1982) Percutaneous absorption of organic solvents III. On the penetration rates of hydrophobic solvents through the excised rat skin.  Industrial Health 20(4):335-345.

 

World Health Organization – WHO (1998) Technical Report Series 884 Evaluation of certain food additives and contaminants. 49thReport of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), Geneva.

Zahlsen K., Eide I., Nilsen A.M., and Nilsen O.G. (1993).Inhalation kinetics of C8 to C10 1-alkenes and iso-alkanes in the rat after repeated doses. Pharmacology and Toxicology 73:163-168. Testing laboratory: Department of Pharmacology and Toxicology Faculty of Medicine, University Medical Center, N-7005 Trondheim, & Statoil Research Center, N-7004 Trondheim, Norway.

 

 

 

Discussion on absorption rate:

Dermal absorption

 

The substance Reaction Products of C3 alcohols and C3 alkenes obtained as by-products from the manufacture of propan-2-ol by hydration of propylene is a UVCB substance. The main constituent (approximately 50%) is isopropyl ether. Minor constituents are propylene dimers (~20%, C6 hydrocarbons, mainly C6 alkenes), propylene trimers (~10%, C9 hydrocarbons), hexanols (~10%) and C3 alcohols (~10% consisting of both isopropanol and n-propanol).

 

The dermal absorption of the UVCB substance can be predicted based on the dermal absorption of its main constituents.

Quantitative dermal absorption information is available for the constituents 2-methyl pentane, isopropanol and hexanol.

 

The dermal absorption of 2-methyl pentane was determined in rat skin and in vitro (Tsuruta, 1982). The percutaneous absorption was determined to be 0.1 µg/cm2/hr or <1% of the total fluid applied.

The dermal absorption of hexanol was determined in vitro using human epidermis (Scheuplein and Blank, 1973). Sheets of dermis and epidermis were obtained at autopsy, and were supported as diaphragms on standard diffusion cells. Primary alcohols with 1 to 10 carbon atoms, in pure form or in saturated aqueous solution, were placed in the donor side of the diffusion cell. The receptor side was filled with distilled water. Contents of both sides were analyzed at regular intervals, and permeation rates were calculated. For saturated aqueous solutions, permeation rates through dermis declined with increasing carbon number and ranged from 5.3 micromoles per 0.01 cm per 0.1 hours for aqueous methanol to 0.09 for aqueous octanol. Permeation rates through epidermis rose from 0.05 for aqueous methanol to 0.71 for aqueous hexanol, then declined to 0.02 for aqueous decanol. Permeation rates of propanol through octanol ranged from 2.12 to 0.063 through epidermis and 24 through 0.13 through dermis.

For IPE no experimental data on dermal absorption are present. Considering the physicochemical properties of IPE, some dermal absorption is expected.

Boatman et al. (1995) investigated the dermal absorption of isopropanol in male and female Fischer 344 rats exposed to a single dose of isopropanol for 4 hours. Dermal absorption rates were calculated to be 0.78 and 0.85 mg/cm2/hour for males and 0.77 and 0.78 mg/cm2/hour for females, using two independent methods. Calculated permeability coefficients of 1.37 to 1.50 x 10-3cm/hour for males and 1.35 to 1.38 x 10-3cm/hour for females indicate that isopropanol is rapidly absorbed dermally. Of the applied radioactivity dose, 84 to 86% was recovered from the skin at the end of the 4-hour exposure and 8 to 9% was lost (presumably to volatilization). Thus, approximately 5 to 8% of the applied dose was absorbed systemically over the course of the 4-hour exposure.

 

Based on the dermal absorption information from 2-methyl pentane, hexanol and IPE it can be concluded that some dermal absorption of Reaction Products of C3 alcohols and C3 alkenes obtained as by-products from the manufacture of propan-2-ol by hydration of propylene may be expected.

 

References

Boatman R.J., Perry L.G., and Fiorica L.A. (1995) Dermal absorption and pharmacokinetics of isopropanol in the male and female F-344 rat.

Report no.: 066094. American Chemistry Council, Inc. Study number: 94-0301.

 

Scheuplein R.J. and Blank I.H. (1973) Mechanism of Percutaneous Absorption. IV. Penetration of Nonelectrolytes (Alcohols) from Aqueous Solutions and from Pure Liquids. J. Investigat. Dermatol. 60(5):286-296.

 

Tsuruta H. (1982) Percutaneous absorption of organic solvents III. On the penetration rates of hydrophobic solvents through the excised rat skin.  Industrial Health 20(4):335-345.