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DIETHYLENE GLYCOL DIMETHYL ETHER

This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the United Nations Environment Programme, the International Labour Organization, or the World Health Organization.

Concise International Chemical Assessment Document 41

First draft prepared by Drs I. Mangelsdorf, A. Boehncke, and G. Könnecker, Fraunhofer Institute of Toxicology and Aerosol Research, Hanover, Germany

Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organization, and the World Health Organization, and produced within the framework of the Inter-Organization Programme for the Sound Management of Chemicals.

World Health Organization

Geneva, 2002

The International Programme on Chemical Safety (IPCS), established in 1980, is a joint venture of the United Nations Environment Programme (UNEP), the International Labour Organization (ILO), and the World Health Organization (WHO). The overall objectives of the IPCS are to establish the scientific basis for assessment of the risk to human health and the environment from exposure to chemicals, through international peer review processes, as a prerequisite for the promotion of chemical safety, and to provide technical assistance in strengthening national capacities for the sound management of chemicals.

The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and Agriculture Organization of the United Nations, WHO, the United Nations Industrial Development Organization, the United Nations Institute for Training and Research, and the Organisation for Economic Co-operation and Development (Participating Organizations), following recommendations made by the 1992 UN Conference on Environment and Development to strengthen cooperation and increase coordination in the field of chemical safety. The purpose of the IOMC is to promote coordination of the policies and activities pursued by the Participating Organizations, jointly or separately, to achieve the sound management of chemicals in relation to human health and the environment.

WHO Library Cataloguing-in-Publication Data

Diethylene glycol dimethyl ether.

(Concise international chemical assessment document ; 41)

1.Ethylene glycols - adverse effects 2.Ethylene glycols - toxicity

3.Methyl ethers - adverse effects 4.Methyl ethers - toxicity

5.Risk assessment 6.Environmental exposure

I.International Programme on Chemical Safety II.Series

ISBN 92 4 153041 3        (NLM Classification: QV 81)

ISSN 1020-6167

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TABLE OF CONTENTS

FOREWORD

1. EXECUTIVE SUMMARY

2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES

3. ANALYTICAL METHODS

4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

4.1 Natural sources

4.2 Anthropogenic sources

4.3 Uses

4.4 Estimated global release

5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, TRANSFORMATION, AND ACCUMULATION

5.1 Transport and distribution between media

5.2 Transformation

5.3 Accumulation

6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

6.1 Environmental levels

6.2 Human exposure

6.2.1 Workplaces

6.2.2 Consumer exposure

6.2.3 Biological monitoring

7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS

7.1 Absorption

7.2 Distribution and accumulation

7.3 Metabolism

7.4 Elimination

8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

8.1 Single exposure

8.1.1 Inhalation

8.1.2 Oral administration

8.1.3 Dermal administration

8.2 Irritation and sensitization

8.2.1 Irritation

8.2.2 Sensitization

8.3 Short-term exposure

8.3.1 Inhalation

8.3.2 Oral

8.4 Medium-term exposure

8.5 Long-term exposure and carcinogenicity

8.6 Genotoxicity and related end-points

8.6.1 In vitro studies

8.6.2 In vivo studies

8.7 Reproductive toxicity

8.7.1 Effects on fertility

8.7.1.1 Inhalation

8.7.1.2 Oral

8.7.2 Developmental toxicity

8.7.2.1 Inhalation

8.7.2.2 Oral

8.8 Other toxicity/mode of action

9. EFFECTS ON HUMANS

9.1 Reproductive effects

9.2 Haematological effects

10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

10.1 Aquatic environment

10.2 Terrestrial environment

11. EFFECTS EVALUATION

11.1 Evaluation of health effects

11.1.1 Hazard identification and exposure–response assessment

11.1.2 Criteria for setting tolerable intakes/concentrations or guidance values for diglyme

11.1.3 Sample risk characterization

11.1.4 Uncertainties in the evaluation of human health effects

11.2 Evaluation of environmental effects

12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

REFERENCES

APPENDIX 1 — SOURCE DOCUMENTS

APPENDIX 2 — CICAD PEER REVIEW

APPENDIX 3 — CICAD FINAL REVIEW BOARD

INTERNATIONAL CHEMICAL SAFETY CARD

RÉSUMÉ D’ORIENTATION

RESUMEN DE ORIENTACIÓN

FOREWORD

Concise International Chemical Assessment Documents (CICADs) are the latest in a family of publications from the International Programme on Chemical Safety (IPCS) — a cooperative programme of the World Health Organization (WHO), the International Labour Organization (ILO), and the United Nations Environment Programme (UNEP). CICADs join the Environmental Health Criteria documents (EHCs) as authoritative documents on the risk assessment of chemicals.

International Chemical Safety Cards on the relevant chemical(s) are attached at the end of the CICAD, to provide the reader with concise information on the protection of human health and on emergency action. They are produced in a separate peer-reviewed procedure at IPCS. They may be complemented by information from IPCS Poison Information Monographs (PIM), similarly produced separately from the CICAD process.

CICADs are concise documents that provide summaries of the relevant scientific information concerning the potential effects of chemicals upon human health and/or the environment. They are based on selected national or regional evaluation documents or on existing EHCs. Before acceptance for publication as CICADs by IPCS, these documents undergo extensive peer review by internationally selected experts to ensure their completeness, accuracy in the way in which the original data are represented, and the validity of the conclusions drawn.

The primary objective of CICADs is characterization of hazard and dose–response from exposure to a chemical. CICADs are not a summary of all available data on a particular chemical; rather, they include only that information considered critical for characterization of the risk posed by the chemical. The critical studies are, however, presented in sufficient detail to support the conclusions drawn. For additional information, the reader should consult the identified source documents upon which the CICAD has been based.

Risks to human health and the environment will vary considerably depending upon the type and extent of exposure. Responsible authorities are strongly encouraged to characterize risk on the basis of locally measured or predicted exposure scenarios. To assist the reader, examples of exposure estimation and risk characterization are provided in CICADs, whenever possible. These examples cannot be considered as representing all possible exposure situations, but are provided as guidance only. The reader is referred to EHC 1701 for advice on the derivation of health-based guidance values.

While every effort is made to ensure that CICADs represent the current status of knowledge, new information is being developed constantly. Unless otherwise stated, CICADs are based on a search of the scientific literature to the date shown in the executive summary. In the event that a reader becomes aware of new information that would change the conclusions drawn in a CICAD, the reader is requested to contact IPCS to inform it of the new information.

Procedures

The flow chart shows the procedures followed to produce a CICAD. These procedures are designed to take advantage of the expertise that exists around the world — expertise that is required to produce the high-quality evaluations of toxicological, exposure, and other data that are necessary for assessing risks to human health and/or the environment. The IPCS Risk Assessment Steering Group advises the Co-ordinator, IPCS, on the selection of chemicals for an IPCS risk assessment, the appropriate form of the document (i.e., EHC or CICAD), and which institution bears the responsibility of the document production, as well as on the type and extent of the international peer review.

FLOWCHART

The first draft is based on an existing national, regional, or international review. Authors of the first draft are usually, but not necessarily, from the institution that developed the original review. A standard outline has been developed to encourage consistency in form. The first draft undergoes primary review by IPCS and one or more experienced authors of criteria documents to ensure that it meets the specified criteria for CICADs.

The draft is then sent to an international peer review by scientists known for their particular expertise and by scientists selected from an international roster compiled by IPCS through recommendations from IPCS national Contact Points and from IPCS Participating Institutions. Adequate time is allowed for the selected experts to undertake a thorough review. Authors are required to take reviewers’ comments into account and revise their draft, if necessary. The resulting second draft is submitted to a Final Review Board together with the reviewers’ comments.

A consultative group may be necessary to advise on specific issues in the risk assessment document.

The CICAD Final Review Board has several important functions:

Board members serve in their personal capacity, not as representatives of any organization, government, or industry. They are selected because of their expertise in human and environmental toxicology or because of their experience in the regulation of chemicals. Boards are chosen according to the range of expertise required for a meeting and the need for balanced geographic representation.

Board members, authors, reviewers, consultants, and advisers who participate in the preparation of a CICAD are required to declare any real or potential conflict of interest in relation to the subjects under discussion at any stage of the process. Representatives of nongovernmental organizations may be invited to observe the proceedings of the Final Review Board. Observers may participate in Board discussions only at the invitation of the Chairperson, and they may not participate in the final decision-making process.

1. EXECUTIVE SUMMARY

This CICAD on diethylene glycol dimethyl ether (in the following called diglyme) was prepared by the Fraunhofer Institute of Toxicology and Aerosol Research, Hanover, Germany. Diglyme was selected for review in the CICAD series owing to concerns for human health, notably potential reproductive effects. The CICAD is based on reports compiled by the GDCh Advisory Committee on Existing Chemicals of Environmental Relevance (BUA, 1993a) and the German MAK-Kommission (Greim, 1994). A comprehensive literature search of relevant databases was conducted in March 2000 to identify any relevant references published subsequent to those incorporated in these reports. Information on the preparation and peer review of the source documents is presented in Appendix 1. Information on the peer review of this CICAD is presented in Appendix 2. This CICAD was approved as an international assessment at a meeting of the Final Review Board, held in Geneva, Switzerland, on 8–12 January 2001. Participants at the Final Review Board meeting are listed in Appendix 3. The International Chemical Safety Card on diglyme (ICSC 1357), produced by the International Programme on Chemical Safety (IPCS, 2000), has also been reproduced in this document.

Diglyme (CAS No. 111-96-6) is a colourless liquid with a slight, pleasant odour. It is miscible with water and a number of common organic solvents. In the presence of oxidation agents, peroxide may form. Due to its dipolar aprotic properties, diglyme is used mainly as a solvent (semiconductor industry, chemical synthesis, lacquers), as an inert reaction medium in chemical synthesis, and as a separating agent in distillations.

Diglyme liquid or vapour is readily absorbed by any route of exposure, metabolized, and excreted mainly in the urine. The main metabolite is 2-methoxyethoxyacetic acid. 2-Methoxyacetic acid is a minor metabolite; in rats, it amounts to about 5–15% in the urine.

The acute toxicity of diglyme is low after oral exposure or inhalation.

Diglyme is slightly irritating to the skin or eye. No investigations are available on the sensitizing effects of diglyme.

The main targets in male animals after repeated intake of diglyme are the reproductive organs. In 2-week inhalation studies in male rats, dose-dependent decreases in weights of testes, epididymides, prostate, and seminal vesicles were observed. The testes were atrophic, and damage of the spermatocytes was observed. The no-observed-adverse-effect level (NOAEL) in these studies was 30 ppm (167 mg/m3); the lowest-observed-adverse-effect level (LOAEL) was 100 ppm (558 mg/m3). Experiments with mice showed morphologically altered sperm, mainly with amorphous heads, after exposure to 1000 ppm (5580 mg/m3). After exposure by inhalation to high concentrations, male and female animals also showed effects on the haematopoietic system, such as changes in leukocyte counts and atrophy in spleen and thymus.

No long-term studies are available for diglyme; therefore, all end-points cannot be reliably assessed. Several Ames tests as well as an unscheduled DNA synthesis test did not reveal a genotoxic potential of diglyme in vitro. Nor was the number of chromosomal aberrations increased in bone marrow cells in vivo.

In a dominant lethal test with rats, the number of pregnancies was significantly reduced after exposure to 1000 ppm (5580 mg/m3) but not to 250 ppm (1395 mg/m3). The positive results may be due to the effects of diglyme on fertility.

In teratogenicity studies with rats, rabbits, and mice, diglyme showed dose-dependent effects on fetal weights, number of resorptions, and incidence of variations and malformations in a wide variety of tissues and organ systems, at concentrations that were not maternally toxic. The LOAEL for developmental effects in an inhalation study with rats was 25 ppm (140 mg/m3); the NOAEL for the oral route was 25 mg/kg body weight in rabbits and 62.5 mg/kg body weight in mice. The reproductive toxicity of diglyme is attributed to the minor metabolite 2-methoxyacetic acid.

Epidemiological studies of female semiconductor workers occupationally exposed to ethylene glycol ethers (EGEs), including diglyme, have found an increased risk of spontaneous abortions and lower fecundity. Workers in the semiconductor industry are exposed to a number of potential reproductive toxicants, however, including EGEs and other chemicals. From these data, it is not possible to determine the contribution of diglyme to the increased risk of adverse reproductive effects. Painters exposed to a variety of metals, organic solvents, and other chemicals, including 2-methoxyethanol, a metabolite of diglyme, but not to diglyme itself, were found to have an increased risk of oligospermia.

The main environmental target compartment of diglyme is the hydrosphere. The chemical is hydrolytically stable. The half-life in air for the reaction of diglyme with hydroxyl radicals is calculated to be about 19 h. Diglyme is inherently biodegradable, with a rather long log phase and significant adsorption to activated sludge. From the n-octanol/water partition coefficient and the water miscibility of the chemical, a negligible potential for bioaccumulation and geoaccumulation is derived.

From valid test results available on the toxicity of diglyme to various aquatic organisms, this compound can be classified as a chemical exhibiting low acute toxicity in the aquatic compartment. The 48-h EC0 value for daphnia (Daphnia magna) and the 72-h EC10 value for algae (Scenedesmus subspicatus) were >1000 mg/litre (highest measured concentration). For the golden orfe (Leuciscus idus), a 96-h LC0 of >2000 mg/litre was determined. Only very few studies concerning the toxicity of diglyme towards terrestrial species are available. The fungus Cladosporium resinae exhibited a toxic threshold concentration of about 9.4 g/litre.

From the sample risk characterization for the workplace, there is high concern for possible human health effects. Exposure of the general population to diglyme should be avoided.

The available data do not indicate a significant risk associated with exposure of aquatic organisms to diglyme. Due to the lack of measured exposure levels, a sample risk characterization with respect to terrestrial organisms cannot be performed. However, from the use pattern of diglyme, significant exposure of terrestrial organisms is not to be expected.

2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES

Diglyme (CAS No. 111-96-6; relative molecular mass 134.17) is also known as bis(2-methoxyethyl)ether (IUPAC name), diethylene glycol dimethyl ether, DEGDM(E), dimethyl carbitol, and 2,5,8-trioxynonane. It belongs to the group of ethylene glycol ethers (EGEs). The molecular structure of diglyme (C6H14O3) is shown below:

CH3 – O – CH2 – CH2 – O – CH2 – CH2 – O – CH3

Diglyme is a colourless liquid of low viscosity with a slight, pleasant odour. The chemical freezes at about -64 °C. Depending on the presence of impurities, its boiling point is between 155 and 165 °C (Hoechst, 1990). Diglyme is miscible with water and with a number of common organic solvents. It dissolves numerous compounds, such as vegetable oils, waxes and resins, boron hydrides, organic boron compounds, sulfur, sulfur dioxide, hydrogen peroxide, and carbon dioxide. With water, azeotrope formation is observed at a concentration ratio of 23 wt. % diglyme and 77 wt. % water (BUA, 1993a). Diglyme has an n-octanol/water partition coefficient (log Kow) of -0.36, determined by a shake flask experiment (Funasaki et al., 1984). Its vapour pressure at 20 °C ranges from 0.23 to 1.1 kPa. The chemical is volatile with water vapour (BUA, 1993a). The calculated Henry’s law constant is given as 0.041 Pa·m3/mol (J. Gmehling, personal communication, 1991).

The conversion factors for diglyme for the gas phase (101.3 kPa, 20 °C) are as follows:

1 mg/m3 = 0.18 ppm

1 ppm = 5.58 mg/m3

Diglyme is chemically stable. In the presence of strong oxidation agents, peroxide may form. Commercial products typically contain peroxides at a concentration of 5 mg/kg. To avoid the further formation of peroxides, commercial products may contain antioxidants, such as 2,6-di-tert-butyl-4-methylphenol (BUA, 1993a).

Additional physical and chemical properties of diglyme are presented in the International Chemical Safety Card (ICSC 1357) reproduced in this document.

3. ANALYTICAL METHODS

Two general methods for the determination of glycol derivatives in ambient and workplace air are described:

In either case, detection is carried out via gas chromatography/flame ionization detection (GC/FID) or gas chromatography/mass spectrometric detection (GC/MSD) (NIOSH, 1990, 1991, 1996; Stolz et al., 1999). For the determination of diglyme in indoor air, the chemical was adsorbed onto activated charcoal, eluted with dichloromethane/methanol, and determined by capillary GC/MSD (internal standard toluene-d8 and 1,2,3-trichloropropane). The detection limit was 3 µg/m3; data on recovery rate and standard deviation are not available (Plieninger & Marchl, 1999).

The enrichment of diglyme from water samples is also in general carried out by adsorption onto XAD 4 or XAD 8 material with subsequent solvent elution (e.g., diethylether, dichloromethane) and determination by capillary GC/MSD (Morra et al., 1979; Lauret et al., 1989). Recovery rates and standard deviations are not available. A detection limit of 0.01 µg/litre is reported (Morra et al., 1979).

Analytical methods for the determination of diglyme in soil or sediment are not available.

Diglyme was determined together with other glycol ethers in human urine by enrichment on diatomaceous earth, extraction with dichloromethane/acetone (90:10), and detection by capillary GC/FID. The validation results of the method are given only as ranges for total glycol ethers: detection limits 0.25–1 mg/litre, standard deviation 1.5–17.1% (at 5 mg/litre), and recovery rates 92.0–125.2% (at 2, 5, and 10 mg/litre) (Hubner et al., 1992). [14C]Diglyme was determined in rat urine for metabolism studies by high-performance liquid chromatography/scintillation detection on a reversed-phase C18 column (gradient elution with methanol/acetic acid) after acidification of the sample (Cheever et al., 1988). Information on detection methods for other biological materials is not available.

The metabolite 2-methoxyacetic acid is assumed to play a major role in the toxic effects of diglyme (see sections 8 and 9). Therefore, common detection methods for this compound in urine after inhalation exposure to related EGEs are described briefly here. The basis of these methods is an esterification of 2-methoxyacetic acid with diazomethane after lyophilization of the alkaline urine solution and uptake in hydrochloric acid/dichloromethane (Groeseneken et al., 1986) or with trimethylsilyldiazomethane after extraction of the acid urine solution with dichloromethane/isopropyl alcohol (Sakai et al., 1993). The determination was carried out in both cases with a GC/FID using a capillary column. The recovery rates were reported to be 31% (Groeseneken et al., 1986) and 98% (Sakai et al., 1993). The detection limits were 0.15 mg/litre (Groeseneken et al., 1986) and 0.05 mg/litre (Sakai et al., 1993).

4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

4.1 Natural sources

There are no known natural sources of diglyme.

4.2 Anthropogenic sources

Diglyme is manufactured in a closed system by the catalytic conversion of dimethyl ether and ethylene oxide under elevated pressure (1000–1500 kPa) and temperatures (50–60 °C) with a maximum yield of 60%. The by-products tri- and tetraethylene glycol dimethyl ether and small amounts of a high-molecular-mass ethylene glycol dimethyl ether are separated by fractional distillation (Hoechst, 1991). This process is based on the classic Williamson ether synthesis (Rebsdat & Mayer, 1999).

In 1982, about 47 200 tonnes of diglyme were produced in the USA (HSDB, 1983). In 1990, about 400 tonnes of the chemical were manufactured in Germany, of which 200 tonnes were exported (BUA, 1993a). More recent data or data from other countries are not available. Diglyme is registered as a high-production-volume chemical by the Organisation for Economic Co-operation and Development (OECD) (i.e., its production volume in at least one OECD member state is >1000 tonnes/year) (OECD, 1997).

4.3 Uses

Because of its dipolar aprotic properties and its chemical stability (see sections 2 and 5.2), diglyme is used mainly as a solvent, as an inert reaction medium in chemical synthesis, and as a separating agent in distillations. These uses include industrial applications, such as polymerization reactions (e.g., of isoprene, styrene), the manufacture of perfluorinated organic compounds (BUA, 1993a), reactions in boron chemistry (Brotherton et al., 1999; Rittmeyer & Wietelmann, 1999), and its application as a solvent for, for example, textile dyes, lacquers, and cosmetics (BUA, 1993a; Baumann & Muth, 1997).

Diglyme is also used in the manufacture of integrated circuit boards, primarily as a solvent for the photoresists. These are used as photosensitive materials for the coating of the wafer during microlithographic patterning in the photo/apply process (Messner, 1988; Correa et al., 1996; Gray et al., 1996) and in the production of semiconductors (Corn & Cohen, 1993).

Diglyme is included in the European Inventory of Cosmetics Ingredients in the solvent category (EC, 1996). Its use in cosmetics in Germany and Canada was not reported (BUA, 1993a; Clariant GmbH, personal communication, 2000; IKW [German Trade Association on Cosmetic and Detergent Preparations], personal communication, 2000; R. Gomes, Health Canada, personal communication, 2001). Data for other countries are also not available.

EGEs in general are also used as auxiliary solvents in water-based paints that are industrially applied (e.g., in the spraying of automobiles, metal furniture, household appliances, and machines) (Karsten & Lueckert, 1992; Baumann & Muth, 1997). It is not possible with the available data to estimate the annual amount of diglyme in this field of use or its application in water-based paints for consumer use.

4.4 Estimated global release

The global releases of diglyme cannot be estimated with the available data.

The releases from the production of diglyme at the German manufacturer for the year 1990 are estimated as follows: <2.5 g/tonne released into air, about 133–188 g/tonne released into water, and <7.5 kg/tonne released with solid wastes. The liquid wastes are disposed of in approved chemical waste incinerators (BUA, 1993a).

Data on the degree of recycling of diglyme from its application as a solvent or as an inert reaction medium in industrial processes are not available.

Information on the content of diglyme in consumer products such as cosmetics or paints and lacquers is not available. It is assumed that any diglyme used in this way will end up in ambient air or domestic wastewater.

5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, TRANSFORMATION, AND ACCUMULATION

5.1 Transport and distribution between media

Diglyme is miscible with water and has a low Henry’s law constant (see section 2), leading to a low volatility from aqueous solutions (Thomas, 1990). From this and its use pattern, it is expected that the main target compartment of the chemical will be the hydrosphere.

5.2 Transformation

From GC measurements with an aqueous solution of 47.2 g diglyme/litre (5% v/v) kept in the dark for 21 days (NTP, 1987), it has been concluded that the chemical is hydrolytically stable. This is also to be expected from diglyme’s chemical structure (Harris, 1990).

Direct photolysis of diglyme is assumed to be of minor importance due to diglyme’s weak absorption at wavelengths above 230 nm (Ogata et al., 1978a,b). NTP (1987) determined no decrease in the concentration of an aqueous solution of diglyme (47.2 g/litre) exposed to room light for 72 h.

The reaction of gaseous diglyme with hydroxyl radicals in the atmosphere has an experimentally determined rate constant KOH of 1.7 × 10–11 cm3/molecule per second (Dagaut et al., 1988). Assuming an average tropospheric hydroxyl radical concentration of about 6 × 105 molecules/cm3 (BUA, 1993b), the half-life of diglyme can be calculated to about 19 h. Due to the miscibility of diglyme with water and its low Henry’s law constant (see section 2), diglyme is furthermore expected to be deposited easily with rain or other wet deposition. From this and its short half-life in atmospheric reactions, long-distance transport of diglyme in ambient air is assumed to be negligible.

From a Zahn-Wellens test following OECD Guideline 302B, adsorption of diglyme onto activated sludge was 17% after 3 h, and total removal was 42% after 28 days. The degree of elimination and the degradation curve are indicative of inherent primary degradation, according to OECD criteria (Hoechst, 1989a).

Roy et al. (1994) achieved a similar result in an electrolytic respirometer test with industrial wastewater from a manufacturer of synthetic organic chemicals. In a further experiment in which diglyme was tested together with dioxane and other unspecified organic chemicals, the degree of biodegradation was significantly higher than in the test with diglyme alone (80% after 32 days), suggesting that the biodegradation of diglyme is more efficient in the presence of other carbon sources. High salt concentrations in the wastewater, however, result in a decrease in biodegradation, indicated by a significant increase in the lag phase.

Data on the anaerobic degradation of diglyme are not available.

5.3 Accumulation

The log Kow of diglyme (-0.36; see section 2) indicates a negligible potential for bioaccumulation.

Measurements concerning the geoaccumulation of diglyme are not available. Data on the adsorption of the chemical onto activated sludge in the Zahn-Wellens test (see section 5.2) cannot be used for the estimation of adsorption onto soil. It is to be expected that the oxygen atoms in the diglyme molecule will lead to a high affinity for the microorganisms of the activated sludge but not for the humic acids or inorganic components of soils. From the physicochemical properties of the substance (miscibility with water, low log Kow; see section 2), a low tendency to sorption onto inorganic and organic soil substances is to be expected.

As a result of its highly hydrophilic character and its low tendency to volatilize from aqueous solutions or to adsorb to soil constituents, diglyme may reach groundwater. EGEs were detected particularly in anoxic groundwater in the vicinity of US landfill sites (Ross et al., 1992). The possibility that the chemical will subsequently enter wells and drinking-water cannot be excluded.

6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

6.1 Environmental levels

Data on the concentrations of diglyme in ambient or workplace air are not available.

Diglyme was detected in surface water in the Dutch parts of the river Rhine at concentrations ranging between 0.1 and 0.3 µg/litre (1978; five samples), 0.03 and 0.3 µg/litre (1979; five samples), and 0.5 and 5 µg/litre (1985; six samples) (Morra et al., 1979; Linders et al., 1981; KIWA, 1986). More recent data or data from surface waters in other countries are not available.

In 1987, the chemical was determined in the biologically treated leakage from two French landfills at concentrations in the order of 2–20 µg/litre (Lauret et al., 1989). Diglyme was furthermore determined but not quantified in 1992 in wastewater samples, from a German oil reclaiming company, that had been pretreated by equalization, neutralization, adsorption to activated sludge, flocculation, and flotation (Gulyas et al., 1994).

Data on the concentration of diglyme in soil or sediment are not available.

Data on the concentration of diglyme in biological material are not available.

6.2 Human exposure

6.2.1 Workplaces

There is a potential for inhalation or dermal contact in the chemical and allied product industries where diglyme is used as a solvent.

During the diglyme production process and its use as a solvent in chemical synthesis, inhalation and dermal contact are assumed to occur mainly during cleaning and maintenance operations, as solvents are handled mainly in closed systems.

No data are available on diglyme exposure concentrations at the workplace. Data on other EGEs that are produced in the same way and that have a comparable use pattern and similar volatilization behaviour may serve as a rough approximation.

ECETOC (1995) reported time-weighted average (TWA) exposures for several other EGEs between 0.01 and 6.5 ppm for the production process. This would correspond to airborne diglyme concentrations between about 0.06 and 36 mg/m3, taking its conversion factor for the gas phase into account (see section 2). The dermal exposure to diglyme can be estimated with the calculation model Estimation and Assessment of Substance Exposure (EASE) to be a maximum of 0.1 mg/cm2 per day, based on the assumption that trained workers incidentally have direct skin contact with diglyme during cleaning and maintenance operations. Assuming further that exclusively the palms (an area about 420 cm2) are exposed, this would lead to a maximum dermal body dose of 0.6 mg/kg body weight per day (assuming a body weight of 70 kg).

For the use of EGEs in the semiconductor industry, TWA exposure values between 0.01 and 0.55 ppm are reported (workplace operation not specified; ECETOC, 1995). This would correspond to airborne diglyme concentrations between about 0.06 and 3.1 mg/m3. As diglyme is obviously used in mixtures with other EGEs (see, for example, Messner, 1988), the diglyme exposure levels cannot be estimated from these data.The maximum dermal dose could be assumed to be equal to the dose estimated for the production process (0.6 mg/kg body weight per day). Some authors report significant permeation of protective gloves of different materials by EGEs. Gloves made of nitrile and butyl rubber or neoprene provide the best protection (breakthrough rates >45 min) and are now the ones being used most frequently in the semiconductor industry (for review, see Paustenbach, 1988).

For the use of glycol ethers in professional painting operations, the geometric means of the TWA exposure values were between 1.7 and 5.6 ppm, with maximum concentrations up to about 37.6 ppm (workplace operation not specified; ECETOC, 1995). For diglyme, this would correspond to airborne concentrations between 9.5 and 31 mg/m3, with a maximum of 210 mg/m3. The maximum dermal exposure could be assumed to be equal to the dose estimated for the production and solvent use of diglyme in chemical synthesis (incidental contact during transferring/weighing/mixing or cleaning and maintenance procedures, exposure of palms [420 cm2] only: 0.1 mg lacquer/cm2 per day). Assuming a maximum diglyme content of the lacquer of 25% (Baumann & Muth, 1997), this results in a maximum dermal body dose of about 0.15 mg diglyme/kg body weight per day.

6.2.2 Consumer exposure

The main target compartment of diglyme is the hydrosphere (see section 5.1). The chemical is inherently biodegradable with a rather long log phase and a significant tendency to adsorb onto activated sludge (see section 5.2). From this and from its suspected use as a solvent in consumer products such as lacquers and cosmetics, the main route of exposure of the general population to diglyme is likely via the ingestion of drinking-water and via dermal contact with the respective consumer products.

The database is not sufficient to estimate the daily intake of diglyme by the general population.

Data on the concentration of diglyme in drinking-water are not available.

Quantitative information on dermal exposure to diglyme via cosmetic products is not available. Although diglyme is included in the European Union’s Inventory on Cosmetics Ingredients, its use was not reported for Germany or Canada (see section 4.3). For other countries, data are also not available.

Measured data on exposure to diglyme-containing water-based paints and lacquers for consumer use are not available. Furthermore, the relevance of diglyme as an auxiliary solvent in paints for consumer use cannot be estimated with the available data. Due to the low tendency of volatilization of diglyme from aqueous solutions (see section 5.1), inhalation exposure is assumed to be of minor importance. Dermal exposure cannot be quantified with the available data.

6.2.3 Biological monitoring

As dermal exposure is significant, measurement of diglyme in air is not sufficient for exposure monitoring. Therefore, biological monitoring of the metabolite 2-methoxyacetic acid, which belongs to the metabolic pathway that is responsible for the developmental effects and effects on the reproductive system, is preferable. Methods for detecting this metabolite in urine are described in section 3.

7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS

7.1 Absorption

Studies on the metabolism of diglyme in rats show that diglyme is absorbed from the gastrointestinal tract (Cheever et al., 1986, 1988). Absorption following inhalation can be concluded from the observation of poisoning symptoms in studies on single- and repeated-dose exposure to diglyme and in analogy with other glycol ethers.

In an in vitro study with human skin, the high percutaneous absorption of glycol ethers (ECETOC, 1995; Johanson, 1996) was confirmed. The permeability constant was 1 × 10–3 cm/h, and the lag time was approximately half an hour. With these findings, diglyme was among the glycol ethers with the highest absorption rate (Filon et al., 1999).

Dermal absorption of glycol ether liquids or vapours is very high (Johanson & Boman, 1991; ECETOC, 1995; Kezic et al., 1997; Brooke et al., 1998; Johanson, 2000). With 2-methoxyethanol, for example, dermal absorption of the vapour is approximately as high as absorption via inhalation. Dermal uptake of the liquid is very high: exposure of an area of 2000 cm2 for 1 h resulted in a body dose of 5920 mg in a study with human volunteers (Kezic et al., 1997).

7.2 Distribution and accumulation

No studies are available that investigate the distribution of radioactively labelled diglyme within the body. Glycol ethers in general are readily distributed throughout the body (ECETOC, 1995).

The metabolite 2-methoxyacetic acid has shown evidence of accumulation in animals and humans. In humans, its half-life was calculated as 77.1 h (ECETOC, 1995).

7.3 Metabolism

The metabolites identified in the urine following oral application in different studies are given in Table 1. The metabolic pathway of diglyme is shown in Figure 1.

Table 1: Metabolites in the urine after single oral application of diglyme.

 

Male Sprague-Dawley rats

Pregnant CD-1 mice

Cheever et al.
(1988)

Cheever et al.
(1989a)

Richards et al. (1993)

Daniel et al. (1986)

Daniel et al. (1991)

Dose (mg/kg body weight)

6.84

684

684

684

684

300

500

Application at day of gestation

12

11

Duration of urine collection (h)

96

96

96

96

48

48

48

Pretreatment

22 days
diglyme

22 days
phenobarbital

 

% of dose

Metabolite I (not identified)

<0.1

0.3

0.4

0.7

n.g.a

n.g.

n.g.

N-(Methoxyacetyl)glycine

0.1

0.3

0.7

0.9

n.g.

n.g.

n.g.

Diglycolic acid

6.7

3.9

2.2

4.6

n.g.

n.g.

n.g.

Metabolite IV (not identified)

2.5

1.0

1.1

1.6

n.g.

n.g.

n.g.

2-Methoxyacetic acidb

5.8

6.2

10.0

13.4

n.g.

26.1–27.0

28.0

2-Methoxyethanol

2.2

0.8

2.1

1.5

n.g.

n.g.

n.g.

2-Methoxyethoxyacetic acidb

70.3

67.9

68.5

64.2

67.0

64.5–67.1

63.0

Metabolite VIII (not identified)

0.4

1.2

2.3

1.0

n.g.

n.g.

n.g.

2-(2-Methoxyethoxy)ethanol

0.3

<0.1

1.2

0.7

n.g.

n.g.

n.g.

Diglyme

0.4

1.8

1.3

0.3

n.g.

n.g.

n.g.

Total

88.7

83.4

88.8

88.9

81.0

n.g.

n.g.

a n.g. = not given.

b Bold indicates main metabolites.

FIGURE 1

Figure 1: Metabolism and disposition of diethylene glycol dimethyl ether (bis(2-methoxyethyl)ether).

The principal pathway of biotransformation of diglyme involves O-demethylation with subsequent oxidation to form the main metabolite 2-methoxyethoxyacetic acid, which accounts for about 60–70% of the dose in the urine of rats and pregnant mice after 48–96 h (Daniel et al., 1986; Cheever et al., 1988; Toraason et al., 1996) (see Table 1).

In addition, cleavage (O-dealkylation) of the central ether bond results in the formation of 2-methoxyethanol, which is subsequently oxidized to 2-methoxyacetic acid. This metabolite accounts for about 5–15% of the dose in the urine of rats after 48–96 h (Cheever et al., 1988, 1989a). In the urine of pregnant mice, it was found in higher concentrations (26–28% of the dose; Daniel et al., 1986, 1991) (see Table 1). Also, humans may form this metabolite in higher concentrations. Based on nmol 2-methoxyethanol generated per nmol P-450, human microsomes were found to be 7 times more effective than rat microsomes in converting diglyme to 2-methoxyethanol (Tirmenstein, 1993; Toraason et al., 1996).

There is no apparent quantitative difference in the spectrum of metabolites, including 2-methoxyethoxyacetic acid and 2-methoxyacetic acid, over a 100-fold dose range (6.84–684 mg/kg body weight; see Table 1).

Repeated doses of diglyme or induction with phenobarbital or ethanol increases the cleavage of the central ether linkage of diglyme as a result of cytochrome P-450 enzyme induction in the liver (Cheever et al., 1988, 1989a; Tirmenstein, 1993; ECETOC, 1995; Toraason et al., 1996).

Although the main metabolite in rat urine is 2-methoxyethoxyacetic acid, numerous studies indicate that 2-methoxyacetic acid is the metabolite responsible for the toxicity of diglyme for the male reproductive organs (see also section 8.7) (Cheever et al., 1985, 1988; BUA, 1993a). Further, 2-methoxyacetic acid was transferred to the fetus and found as the sole metabolite in the fetus (no parent compound was detected in the fetus either) after dosing diglyme to mice at day 11 or 12 of pregnancy (Daniel et al., 1986, 1991). The highest levels for the average embryo (whole embryos analysed) were detected at 6 h after dosing. Significantly lower amounts were detected in blood taken from the dam at that time point (Daniel et al., 1991).

7.4 Elimination

The major route of elimination is through the urine. Ninety-six hours after oral application of 6.84 mg diglyme/kg body weight to male Sprague-Dawley rats, 90% of the dose was excreted via urine, 3.6% as carbon dioxide, and 2.9% in the faeces. Only 1.7% of the dose remained in the carcass (Cheever et al., 1988).

8. EFFECTS ON LABORATORY MAMMALS AND
IN VITRO TEST SYSTEMS

8.1 Single exposure

8.1.1 Inhalation

A 7-h nose-only exposure (inhalation hazard test) to an atmosphere saturated with diglyme at room temperature (about 10 g/m3) caused restlessness, narrowing of palpebral fissures, and irregular breathing in rats. All animals survived. Necropsy 14 days after exposure revealed no macroscopic findings (Hoechst, 1979a).

8.1.2 Oral administration

The acute oral toxicity of diglyme is low. The oral LD50 for the female rat is 4760 mg/kg body weight (Hoechst, 1979b) and for the female mouse is 2978 mg/kg body weight (Plasterer et al., 1985). Poisoning symptoms were restlessness and breathing difficulties. Necropsy of animals found dead revealed changes in lung and liver (no further information available).

8.1.3 Dermal administration

No data are available. From the oral and inhalation studies, it can be assumed that acute dermal toxicity of diglyme is also low.

8.2 Irritation and sensitization

8.2.1 Irritation

In an occlusive patch test performed according to US Food and Drug Administration (FDA) guidelines on albino Himalayan rabbits, the application of 0.5 ml of the undiluted chemical to intact and scarified skin caused slight irritation after 24 h. Isolated cases of dry chapped skin were seen, especially after 72 h (Hoechst, 1979c; no further information available).

In a test on mucous membrane tolerance conducted according to FDA guidelines, an application of 0.1 ml undiluted diglyme to the eye caused slight irritation after 24 h (Hoechst, 1979c; no further information available).

8.2.2 Sensitization

There are no data available.

8.3 Short-term exposure

8.3.1 Inhalation

Groups of 20 male and 10 female Crl:CD rats were exposed to 0, 110, 370, or 1100 ppm (0, 614, 2065, or 6138 mg/m3) diglyme, 6 h/day, 5 days/week, for 2 weeks. Male rats were killed after 10 days of exposure and 14, 42, or 84 days post-exposure, respectively. Female rats were killed after the 10th exposure and 14 days post-exposure. Urine analysis, haematological analyses, and histopathology were performed. Changes in the haematopoietic system occurred in both sexes and involved the bone marrow, spleen, thymus, leukocytes, and erythrocytes. According to the authors, the no-observed-adverse-effect level (NOAEL) for female rats was 370 ppm (2065 mg/m3). Males were more sensitive than females: compared with controls, body weight gain as well as mean leukocyte counts were dose dependently decreased in all dose groups. Further, stage-specific germ cell damage occurred at all concentrations and was concentration and time dependent (see section 8.7.1.1). Thus, for male rats, a NOAEL could not be established in this study (DuPont, 1988b; Lee et al., 1989; Valentine et al., 1999).

In another study with four male and four female Alderley Park rats per group exposed for 3 weeks, 6 h/day, to 200 and 600 ppm (1116 and 3348 mg/m3) diglyme, urine analysis, haematological analyses, and histopathology (of a limited number of organs without testes) were also performed. In contrast to the DuPont study cited above, no changes in haematological parameters were noted after exposure to 600 ppm (3348 mg/m3). However, similar to the observations in that study, body weight gain was affected and thymus was atrophied. Further, adrenals were congested. No effects were found in the 200 ppm (1116 mg/m3) dose group (Gage, 1970).

8.3.2 Oral

In four male JCL-ICR mice that received diglyme in the drinking-water for 25 days at a level of 2% (approximately 7000 mg/kg body weight, assuming an intake of 7 ml/day and a body weight of 20 g), the number of total white blood cells was more than doubled compared with controls. This increase was not, however, statistically significant (Nagano et al., 1984). For repeated-dose studies on effects of diglyme on male reproductive organs, see section 8.7.

8.4 Medium-term exposure

There are no medium-term exposure studies available.

8.5 Long-term exposure and carcinogenicity

No studies are available on long-term exposure or carcinogenicity.

8.6 Genotoxicity and related end-points

8.6.1 In vitro studies

Results of investigations of genotoxicity in vitro are given in Table 2. Diglyme was not mutagenic in several Ames tests with or without S9 mix (Hoechst, 1979d,e; McGregor et al., 1983; Mortelmans et al., 1986).

Table 2: Genotoxicity of diglyme in vitro.

 

 

 

Result

 

 

Test system

Strain/cell type

Concentrations tested

-S9

+S9

Remarks

Reference

Salmonella mutagenicity test

strain TA1535, TA1537, TA1538, TA98, TA100

0.3–100 µl per plate

cytotoxicity at 100 µl per plate

McGregor et al., 1983

Salmonella mutagenicity test

strain TA1538, TA98, TA100

20–70 µl per plate

not tested

no cytotoxicity

McGregor et al., 1983

Salmonella mutagenicity test

strain TA1535, TA1538, TA98, TA100

0.01–10 mg per plate

tested with rat and hamster S9, no cytotoxicity

Mortelmans et al., 1986

Salmonella mutagenicity test

strain TA1535, TA1537, TA1538, TA98, TA100

0.005–50 µl per plate

cytotoxicity at 25 and 50 µl per plate

Hoechst, 1979d,e

Unscheduled DNA synthesis

human embryo fibroblasts

0.148–19 mg/ml

no information on cytotoxicity available

McGregor et al., 1983

Diglyme also had no effect in a test for unscheduled DNA synthesis in human embryo fibroblasts (McGregor et al., 1983).

8.6.2 In vivo studies

Diglyme did not induce chromosomal aberrations in bone marrow cells in groups of 10 male and 10 female CD rats exposed to 250 or 1000 ppm (1395 or 5580 mg/m3) diglyme 7 h/day for 1 or 5 days (McGregor et al., 1983).

A dominant lethal test is described in section 8.7.1.1 (McGregor et al., 1983). The reduced number of pregnancies and an increase in preimplantation losses may be due either to a dominant lethal effect or to reduced fertility of the males. Considering the known effects of diglyme on fertility, the authors of the study assume that reduced fertility is a cause of the effects. Also, the post-implantation losses may be due to reduced fertility instead of a dominant lethal effect, as it is known that early deaths may be a consequence of a low number of implantations.

A recessive lethal test on Drosophila melanogaster exposed to 250 ppm (1395 mg/m3) for 2.75 h could not be evaluated because of an unusually high death rate in a control group (McGregor et al., 1983).

8.7 Reproductive toxicity

8.7.1 Effects on fertility

8.7.1.1 Inhalation

There are several well conducted studies available in which toxicity to the male reproductive organs has been investigated.

Groups of 20 male Crl:CD rats were exposed to 0, 110, 370, or 1100 ppm (0, 614, 2065, or 6138 mg/m3) diglyme, 6 h/day, 5 days/week, for 2 weeks. Exposed rats were killed after 10 days of exposure and 14, 42, or 84 days post-exposure. Body weight gain was dose dependently decreased. At 370 and 1100 ppm (2065 and 6138 mg/m3), absolute weights of testes, epididymides, seminal vesicles, and prostrate were reduced; relative weights of testes were reduced at 1100 ppm (6138 mg/m3). Stage-specific germ cell damage was dose and time dependent: at 110 ppm (614 mg/m3) diglyme, spermatocytes in pachytene and meiotic division at spermatogenic stages XII–XIV were mainly affected. At 370 ppm (2065 mg/m3) diglyme, affected germ cells were similar to those seen at 110 ppm (614 mg/m3) diglyme, but round spermatids at spermatogenic stages I–VIII were also affected. At 1100 ppm (6138 mg/m3) diglyme, marked testicular atrophy was found affecting all spermatogenic stages. The effects were reversible within 84 days with 110 and 370 ppm (614 and 2065 mg/m3), but not with 1100 ppm (6138 mg/m3) (DuPont, 1988b; Lee et al., 1989; Valentine et al., 1999).

In order to identify a NOAEL for effects on the testes, a second study was performed with the same study design but using lower concentrations of diglyme — 0, 3, 10, 30, and 100 ppm (0, 16.7, 55.8, 167, and 558 mg/m3) (measured concentrations: 0, 3.1, 9.9, 30, and 98 ppm, corresponding to 0, 17.3, 55.2, 167, and 547 mg/m3). The post-exposure period was 14 days. Mean body weights of rats exposed to 100 ppm (558 mg/m3) were significantly lower than those of controls at the end of the exposure period. The weights of testes, seminal vesicles, prostate, and epididymides were similar to those of controls. Microscopic examination of the testes revealed minimal or mild testicular atrophy in the 100 ppm (558 mg/m3) group. As is demonstrated in Table 3, some effects, such as degenerative germ cells in epididymal tubules, spermatic granuloma in the epididymis, and prostatitis, also occurred at lower concentrations (10 ppm [55.8 mg/m3] and higher) at the end of the exposure as well as after the 14-day recovery period. Most lesions were minimal to mild and occurred in 1/10 animals. However, it is not clear whether the different lesions observed occurred in the same or different animals. Taking into consideration results from historical controls (no data given) as well, the authors of this study considered 30 ppm (167 mg/m3) to be the NOAEL (DuPont, 1989).

Table 3: Effects of diglyme on the male reproductive tract in rats.a

Effect

dayb

0 ppm

3 ppm

10 ppm

30 ppm

100 ppm

Body weight gain (g)

day 1–12

 

63.4

58.1

57.4

57.1

51.2c

day 15–26

 

68.8

70.0

68.2

64.5

62.8

Number of animals affected, severity of lesion

Testicular atrophy

 

 

 

 

 

 

Sertoli cell only

12

 

 

 

 

 

 

26

 

 

 

 

1, minimal

Bilateral

12

 

 

 

 

 

 

26

 

 

 

 

1, minimal

Unilateral

12

1, minimal

 

1, minimal

 

1, minimal

 

26

 

 

 

 

1, mild

Epididymides

 

 

 

 

 

 

Degenerative germ cells

12

 

 

1, minimal

 

1, minimal

 

26

 

 

1, minimal

 

 

Spermatic granuloma

12

 

 

 

1, minimal

 

 

26

 

 

1, moderate

 

 

Prostate

 

 

 

 

 

 

Prostatitis

12

 

 

1, moderate

 

1, minimal

 

26

 

1, mild

1, mild

2, minimal
1, mild

 

Seminal vesicles

 

 

 

 

 

 

Atrophy acini

12

 

 

 

 

 

 

26

 

1, minimal

 

 

 

a From DuPont (1989).

b Day 12: end of exposure; day 26: after 14 days of recovery.

c Statistically significant.

In a dominant lethal test, groups of 10 male adult CD rats were exposed to 0, 250, or 1000 ppm (0, 1395, or 5580 mg/m3) diglyme for 7 h/day on 5 consecutive days, then serially mated at weekly intervals for 10 weeks to untreated virgin females in the ratio 1 male:2 females. Male rats exposed to 1000 ppm (5580 mg/m3) showed a reduction in body weight. The female rats were killed and examined 17 days after they were first caged with the males. No effect on frequency of pregnancy was seen in the 250 ppm (1395 mg/m3) group. However, large reductions in pregnancy frequency occurred in the 1000 ppm (5580 mg/m3) exposure group in weeks 4 through 9, but particularly in weeks 5 through 7 after exposure, when frequencies were only about 10%. Further, preimplantation losses in these weeks were large, and there was evidence of post-implantation losses. Recovery from the influence of diglyme in exposed males was complete in week 10 (McGregor et al., 1981, 1983; Hardin, 1983).

Changes in sperm shape were investigated in mice: groups of 10 B6C3F1 mice were exposed to 0, 250, or 1000 ppm (0, 1395, or 5580 mg/m3) 7 h/day for 4 days, and sperm were isolated 35 days after the exposure. Four mice of the 1000 ppm (5580 mg/m3) group were found dead on the morning of the 4th exposure day. Mice of both exposure groups showed a reduction in body weight gain. While no changes compared with the controls were observed in the 250 ppm (1395 mg/m3) group, a significant increase in morphologically altered sperm (32%; control 5%) was found in the 1000 ppm (5580 mg/m3) group. All categories of abnormalities were involved to some extent: hook upturned or hook elongated, banana-shaped head, amorphous head, folded tail, and others. Most frequent were amorphous heads, which were increased to 20.87% in the 1000 ppm (5580 mg/m3) group compared with 2.18% in the air control. From the timing of exposure and investigations, the authors concluded that the spermatocytes had been damaged (McGregor et al., 1981, 1983).

In conclusion, from these studies, the NOAEL for effects on the testes/spermatocytes is 30 ppm (167 mg/m3).

8.7.1.2 Oral

Groups of five Sprague-Dawley rats received up to 20 daily oral doses of distilled water or diglyme at 684 mg/kg body weight. Testicular changes were analysed, including a subsequent recovery over an 8-week period. Primary and secondary spermatocyte degeneration and spermatidic giant cells were observed after 6–8 treatments. From day 12 of treatment until 8 weeks after cessation of exposure, the testes to body weight ratio was significantly reduced (Cheever et al., 1985, 1986, 1988). Testicular LDH-X activity, a pachytene spermatocyte marker enzyme, was significantly decreased in animals by day 18 of treatment (Cheever et al., 1985, 1989b).

No changes compared with controls were found in testicular weight and the combined weight of seminal vesicles and coagulating gland in four male JCL-ICR mice that received diglyme in the drinking-water for 25 days at a level of 2% (approximately 7000 mg/kg body weight, assuming an uptake of 7 ml/day and a body weight of 20 g) (Nagano et al., 1984).

8.7.2 Developmental toxicity

Studies on the developmental toxicity of diglyme, including experimental details, are summarized in Table 4. Diglyme was a developmental toxicant both via inhalation and by the oral route in rats, rabbits, and mice. It is capable of disrupting normal morphogenesis in a wide variety of tissues and organ systems, and the diversity of fetal malformations observed was hypothesized to be due to a general toxic effect upon proliferating cells, which was also evident from the studies on male fertility (Nagano et al., 1984; Price et al., 1987; Schwetz et al., 1992).

Table 4: Developmental toxicity of diglyme.

Species/
strain/
number per group

Exposurea

Concentration/
dose

Effectsb

Maternal
NOAEL/
LOAEL

Fetal
NOAEL/
LOAEL

Reference

rats
CD
25–26

inhalation, 6 h/day, days 7–16

0, 25, 100, 400
ppm (0, 140, 558, 2232 mg/m3)

> 25 ppm (140 mg/m3): fetal weights *, variations (delayed ossification, rudimentary ribs) (mean percentage of fetuses per litter with variations): 44.5% versus controls 32.1%
100 ppm (558 mg/m3): dams: relative liver weight +, fetus: structural malformations, mainly skeletal (abnormally formed tails, distended lateral brain ventricles, axial skeletal malformations, appendicular malformations [bent limbs], 6.2% compared with 1.7% in controls); fetal weight *; variations (mean percentage of fetuses per litter with variations): 74.5% versus controls 32.1%
400 ppm (2232 mg/m3): dams: food consumption *, body weight gain *; resorptions 100%

NOAEL
25 ppm
(140 mg/m3)

LOAEL
25 ppm
(140 mg/m3)

DuPont (1988a), Driscoll et al. (1998)

rabbits
New Zealand
15–25

gavage in distilled water, days 6–19

0, 25, 50, 100, 175 mg/kg body weight

> 50 mg/kg body weight: dams: weight gain * (due to decrease in gravid uterine weight),
adversely affected implants per litter + (21.4%, controls 7.9%)
>100 mg/kg body weight: gravid uterine weight *, prenatal mortality (mainly from resorptions) +, malformations + (mainly abnormal development of the kidneys and axial skeleton and clubbing of the limbs)
175 mg/kg body weight: dams: faecal output *, mortality + (15%, controls 4%)

NOAEL
100 mg/kg body weight




NOAEL
25 mg/kg body weight

NOAEL
25 mg/kg body weight




NOAEL
50 mg/kg body weight

NTP (1987)






Schwetz et al. (1992)

mice
CD-1
20–24

gavage in distilled water, days 6–15

0, 62.5, 125, 250, 500 mg/kg body weight

>125 mg/kg body weight: fetal weights *
> 250 mg/kg body weight: dams: weight gain * (due to decrease in gravid uterine weight); late fetal deaths +, malformations + (mainly neural tube, limbs and digits, craniofacial structures, abdominal wall, cardiovascular system, urogenital organs, axial and appendicular skeleton)
500 mg/kg body weight: dams: weight gain (due to decrease in gravid uterine weight) *; resorptions +

NOAEL
500 mg/kg body weight

NOAEL
62.5 mg/kg body weight

NTP (1985), Price et al. (1987)

mice
CD-1
not given

gavage in distilled water, on day 11

0, 537 mg/kg body weight

only examination for gross external malformations and fetal body weight
537 mg/kg body weight: malformations + (paws, digits)

 

 

Hardin & Eisenmann (1986, 1987)

mice
CD-1
49

gavage in distilled water, days 6–13

0, 3000 mg/kg body weight

reproductive screening according to Chernoff and Kavlock, no systematic examination for malformations
3000 mg/kg body weight: dams: mortality + (20/49); no viable litters (0/27)

 

 

Schuler et al. (1984), Plasterer et al. (1985), Hardin et al. (1987)

a Days refers to days of pregnancy.

b + = increased compared with controls; * = decreased compared with controls.

8.7.2.1 Inhalation

In a teratogenicity study, rats exposed by inhalation to 25, 100, or 400 ppm (140, 558, or 2232 mg/m3) diglyme during days 7–16 of gestation, the highest concentration of 400 ppm (2232 mg/m3) caused 100% resorptions (DuPont, 1988a; Driscoll et al., 1998). Malformations found in low incidences at all dosages included abnormally formed tails, distended lateral ventricles of the brain, axial skeletal malformations (vertebral fusions, hemivertebrae), and appendicular malformations (aberrant clavicular and scapular formation, bent fibula, radius, tibia, and ulna). Further, structural variations, primarily delayed ossification, were found. The lowest dose of 25 ppm (140 mg/m3) caused a slightly increased incidence of variations. Although these defects were not significantly different from control values (with the exception of the incidence of skeletal developmental variations), the pattern, type, and incidence of variations were similar to those seen at 100 ppm (558 mg/m3), suggesting, according to the authors, that 25 ppm (140 mg/m3) was an effect level that approaches the lower end of the developmental toxicity response curve. Therefore, the authors of the study concluded that a NOAEL could not clearly be demonstrated for the fetus. As increased relative liver weights were found in the dams at 100 ppm (558 mg/m3), the NOAEL for diglyme exposure in the dams is 25 ppm (140 mg/m3).

8.7.2.2 Oral

In an oral application study with rabbits, similar effects were noted as after inhalation (NTP, 1987; Schwetz et al., 1992). The number of resorptions as well as the number of malformations were increased at doses of 100 mg/kg body weight. Abnormal development of the kidneys and axial skeleton and clubbing of the limbs without underlying skeletal involvement were the most frequently presented individual defects. At 50 mg/kg body weight, percentages of prenatal mortality and malformed fetuses per litter were both (statistically non-significantly) increased but accounted for a significant overall increase in the percentage of adversely affected implants per litter. In the NTP (1987) study as well as in the analysis by Kimmel (1996), 50 mg/kg body weight is considered as the lowest-observed-adverse-effect level (LOAEL), and 25 mg/kg body weight as the NOAEL. In contrast, in the subsequent publication by Schwetz et al. (1992), the authors discussed that 50 mg/kg body weight appears to be the bottom end of the dose–response curve and therefore considered 50 mg/kg body weight as the NOAEL.

In mice, the NOAELs were 500 mg/kg body weight for maternal effects and 62.5 mg/kg body weight for developmental effects. At 125 mg/kg body weight, the only fetal effects were reduced body weights. Malformations were seen at 250 mg/kg body weight and above. Characteristic malformations associated with diglyme were neural tube closure defects and dysmorphogenesis of the axial and appendicular skeleton (NTP, 1985; Price et al., 1987). Further defects of digits and paws were found, which also occurred in another study with mice (Hardin & Eisenmann, 1986, 1987) dosed with 537 mg/kg body weight only on day 11 of pregnancy.

The NTP study in mice (NTP, 1985; Price et al., 1987) has served to illustrate a model that was developed for assessing the probability of being abnormal by applying the combination of the parameters fetal death, weight, and malformation (Catalano et al., 1993). The LED05 (the lower 95% confidence limit of the dose corresponding to 5% excess risk), which was derived according to the benchmark dose approach, was 99 mg/kg body weight. This was lower than the LED05 for the individual parameters, but higher than the NOAEL of 62.5 mg/kg body weight.

8.8 Other toxicity/mode of action

The main metabolite of diglyme, 2-methoxyethoxyacetic acid, did not show any effect on the testes at equimolar concentrations (Cheever et al., 1986, 1988). Instead, the pattern of diglyme-induced testicular injury is qualitatively similar to that produced by the metabolite 2-methoxyethanol (McGregor et al., 1981, 1983; Cheever et al., 1985, 1986, 1988; Lee et al., 1989). In the study of Cheever et al. (1985) with rats, both compounds exhibited testicular toxicity primarily affecting pachytene and dividing stages of spermatocytes at lower exposure levels. In comparing the testicular toxicity of equimolar dosages of 2-methoxyethanol (388 mg/kg body weight) and diglyme (684 mg/kg body weight), 2-methoxyethanol was more potent than diglyme. Spermatocytes were affected after only one treatment with 2-methoxyethanol, whereas repeated diglyme treatments were required to produce the same effects. Similarly, in the inhalation study of Lee et al. (1989) with rats, the toxic effects of 300 ppm (930 mg/m3) 2-methoxyethanol in the testes were very similar to but more severe than those of 370 ppm (2065 mg/m3) diglyme. In mice, both compounds produced sperm anomalies (McGregor et al., 1981, 1983). A diglyme concentration of 1000 ppm (5580 mg/m3) caused a higher number of abnormal sperm than 500 ppm (1550 mg/m3) 2-methoxyethanol; thus, considering equimolar concentrations, diglyme seems to be somewhat more toxic. Mice produce higher concentrations of 2-methoxyacetic acid than rats; therefore, mice may be more susceptible than rats to the toxic effects of diglyme. Considering that 2-methoxyethanol is only a minor metabolite of diglyme, other metabolites or other pharmacokinetic behaviours of diglyme compared with 2-methoxyethanol may contribute to the toxicity of diglyme.

In both fertility and developmental studies, the metabolite 2-methoxyethanol (DuPont, 1988a; Driscoll et al., 1998) and other ethylene glycol dimethyl ethers (Plasterer et al., 1985; Hardin & Eisenmann, 1986, 1987; Hardin et al., 1987) gave similar results. In the DuPont study (DuPont, 1988a; Driscoll et al., 1998), both 25 ppm (78 mg/m3) 2-methoxyethanol and 25 ppm (140 mg/m3) diglyme resulted in significantly more total variations and variations due to retarded development in rats. Mean percentages of fetuses per litter with variations were 46% for 2-methoxyethanol and 45% for diglyme compared with 32% in the control. Similarly, in the studies of Hardin et al. (Hardin & Eisenmann, 1986, 1987; Hardin et al., 1987), the teratogenic potency for paw defects in mice was higher with 2-methoxyethanol than with diglyme when used in equimolar concentrations. After treatment with 304 mg 2-methoxyethanol/kg body weight, 60.1% of the fetuses had alterations in the hind paws, compared with 38% after treatment with 537 mg diglyme/kg body weight and 0.6 or 0% in concurrent controls. Further, monoethylene glycol dimethyl ether showed a similar toxicity in this study, with 30.4% of the fetuses with alterations of the hind paws, while triethylene glycol dimethyl ether did not show any effect. Finally, the study of Plasterer et al. (1985) with mice showed that very high doses of monoethylene glycol dimethyl ether, diglyme, and triethylene glycol dimethyl ether all caused complete resorptions.

Thymus atrophy has been reported in rats in two inhalation studies (Gage, 1970; DuPont, 1988b; Lee et al., 1989; Valentine et al., 1999) following exposure to high concentrations of diglyme. Further, the number of leukocytes was decreased. This is consistent with studies on other EGEs, where mechanistic studies indicate that the immune system is a sensitive target for toxicity in the rat and that the proximate immunotoxicant is methoxyacetic acid (ECETOC, 1995).

The metabolite 2-methoxyacetic acid, which is generated from 2-methoxyethanol by the action of alcohol dehydrogenase, may be important for the toxic effects. It can undergo activation to methoxyacetyl coenzyme A and enter the Krebs cycle or fatty acid biosynthesis. Several metabolites of 2-methoxyethanol — for example, 2-methoxy-N-acetyl glycine — have been identified that support this pathway (Sumner et al., 1992; Jenkins-Sumner et al., 1996). Thus, 2-methoxyacetic acid may interfere with essential metabolic pathways of the cell, and it was hypothetized that this causes the testicular lesions and malformations. This is supported by the finding that simple physiological compounds (e.g., serine, formate, acetate, glycine, and glucose) are able to protect against these effects (Johanson, 2000).

9. EFFECTS ON HUMANS

As a consequence of the results of the animal studies revealing effects on fertility as well as developmental toxicity of EGEs, several epidemiological studies have been carried out to investigate reproductive end-points in workers with exposure to EGEs. Diglyme is only one compound of this substance class, however (see section 2). A metabolite of EGEs and diglyme, 2-methoxyethanol, is also used as a solvent, and one epidemiological study of painters exposed to 2-methoxyethanol is also discussed.

9.1 Reproductive effects

EGEs including diglyme are used in the manufacture of semiconductors. Epidemiological studies of three semiconductor populations evaluated potential adverse reproductive outcomes. It is unclear from the descriptions provided by the authors whether these populations overlapped. In each of these studies, workers were exposed to mixtures including diglyme but not to diglyme alone. In a single study of painters, exposure included a metabolite of diglyme and EGEs.

One of the semiconductor populations included workers from 14 different companies. The study included both retrospective and prospective study designs. Exposure to EGEs was determined using questionnaires from subjects about the work performed and an assessment of the work environment by industrial hygienists, but no measurements of personal or area exposures were made (Hammond et al., 1995). Workers in the fabrication area were considered exposed to EGEs. For the retrospective study, information on pregnancy outcomes and potential confounders (age, smoking, ethnicity, education, income, year of pregnancy, and stress) was obtained through a comprehensive interviewer-administered interview of female employees (Beaumont et al., 1995). The prospective study of early fetal loss and fecundity (probability of conception per menstrual cycle) was conducted in a subset of female employees from five plants. Daily diaries and measurements of daily urinary human chorionic gonadotrophin (hCG) levels for 6 months were collected in addition to the comprehensive interview (Eskanazi et al., 1995a,b). Of the 891 medically verified pregnancies identified for the retrospective study, 774 (86.9%) were live births, 113 (12.7%) were spontaneous abortions, and 4 (0.4%) were stillbirths (Beaumont et al., 1995). The overall unadjusted relative risk (RR) for spontaneous abortions was 1.45 (95% confidence interval [CI] = 1.02–2.05) and changed little after adjusting for confounders (adjusted RR =1.43; 95% CI = 0.95–2.09). When stratified by work group, the risk of spontaneous abortion was statistically significantly increased for female workers in the photolithography group (RR = 1.67; 95% CI = 1.04–2.55) and in the etching group (RR = 2.08; 95% CI = 1.27–3.19). For women working with higher levels of EGE only in masking, the risk for spontaneous abortion was increased 3-fold (RR = 3.38; 95% CI = 1.61–5.73) (Swan & Forest, 1996). In the prospective study, no statistically significant differences were detected in the overall rate of spontaneous abortions between fabrication and non-fabrication workers or when pregnancy outcomes were examined by work group (Eskenazi et al., 1995a). However, the ability to conceive was lower among female workers exposed to EGEs (fertility rate [FR] = 0.37; 95% CI = 0.11–1.19) (Eskenazi et al., 1995b).

Correa et al. (1996) conducted a retrospective evaluation of reproductive outcomes among both women employed and wives of men employed at two semiconductor plants in the eastern USA (also reported by Gray et al., 1996). Gray et al. (1996) also reported on the results of a prospective study of reproductive outcomes at the same plants. Exposure to EGEs in the retrospective study was assessed by questionnaire administered to the employees in combination with company records. There were 115 pregnancies to semiconductor manufacturing workers — 561 to female employees and 589 to wives of male employees. There was a significantly elevated risk of spontaneous abortion (odds ratio [OR] = 2.8; 95% CI = 1.4–5.6) and subfertility (taking more than 1 year of sexual intercourse to conceive) (OR = 4.6; 95% CI = 1.6–13.3) among female employees in the highest exposure group. The risks of spontaneous abortion and subfertility were not significantly elevated in the low and medium exposure groups. A significant (P = 0.02) dose–response relationship across low, medium, and high exposure categories was found for both end-points for EGE exposure. Among wives of male employees exposed to EGEs, there was no evidence of an increased risk of spontaneous abortion but a suggestion of an increased risk of subfertility. In the prospective study (Gray et al. 1996), early-morning urine samples were assayed for hCG and ovarian steroid hormones to detect early pregnancy and early pregnancy loss. The study found no evidence of a decreased conception rate, but there was a non-significantly elevated risk of pregnancy loss.

Pastides et al. (1988) found an increased risk of spontaneous abortion among females employed in the diffusion area of a semiconductor manufacturing plant (RR = 2.2; n = 18 pregnancies; 95% CI = 1.1–3.6) and in the photolithographic area (RR = 1.8; n = 16 pregnancies; 95% CI = 0.8–3.3) compared with unexposed controls (n = 398 pregnancies). No measurements of workplace exposure were available in this study. Exposures included several glycol ethers and other chemicals, such as arsine, phosphine, diborane, xylene, toluene, and hexamethyldisilane.

Semen samples from 73 painters and 40 controls from a shipyard were analysed (Welch et al., 1988). The painters were exposed by inhalation to 0–17.7 mg 2-methoxyethanol/m3 (mean 2.6 mg/m3) and to 0–80.5 mg 2-ethoxyethanol (= ethylene glycol monoethyl ether)/m3 (mean 9.9 mg/m3). Skin contact with 2-methoxyethanol and 2-ethoxyethanol was also considered possible. Exposure to numerous other substances, including organic solvents and metals, was also known to occur. While no effects were seen in hormone levels or in sperm viability, motility, and morphology, the prevalence of those with oligospermia differed between the groups. The proportion of men with a sperm density 100 million/cm3 was higher in the exposed group than in the unexposed group (33% vs. 20%; P = 0.20). The proportion of those with oligospermia among painters who did not smoke compared with controls was 36% vs. 16% (P = 0.05). The proportion of those with oligospermia was similar between painters and controls who smoked (30% vs. 38%; P = 0.49). The proportion of painters with azoospermia was 5% compared with 0% in the controls.

9.2 Haematological effects

The relationship between exposure to EGEs and haematological effects has been evaluated in three occupational populations. In none of these studies was diglyme measured or used alone. In a cross-sectional study of 94 shipyard painters exposed to measurable levels of 2-ethoxyethanol and 2-methoxyethanol and 55 unexposed controls, Welch & Cullen (1988) found 10% of painters with haemoglobin levels consistent with anaemia (P = 0.02) and 3.4% of painters and no controls with abnormally low levels of polymorphonuclear leukocytes (P = 0.07). In a second cross-sectional study of 40 workers employed in the production of ethylene glycol monoether, the overall proportion of exposed workers with abnormal haemoglobin levels or white blood cell counts did not differ from unexposed controls (n = 25) (Cook et al., 1982). Controlling for potential age, duration, and intensity of exposure using logistic regression suggested a statistically significant decrease (27%) in white blood cell counts. A small study of nine individuals who laid parquet floors and matched pairs of healthy donors showed no changes in haemoglobin or erythrocyte levels but higher frequencies of NK-cells (anti-Leu7) and B lymphocytes (Denkhaus et al., 1986). Exposures included measurable concentrations of 2-butoxyethanol, 2-ethoxyethanol, 2-methoxyethanol, toluene, xylene, 2-butanone, and other solvents. No association was found between use of products containing glycol ethers and myeloid acute leukaemia in a study of 198 matched pairs (Hours et al., 1996).

10. EFFECTS ON OTHER ORGANISMS IN
THE LABORATORY AND FIELD

10.1 Aquatic environment

For the toxicity data mentioned in this section, it is not always stated whether the cited effect values are based on nominal or measured concentrations of diglyme. In some cases (Hoechst, 1994, 1995), the concentration of the test substance is detected by the determination of dissolved organic carbon or carbon in the solution. However, due to the water solubility, low volatility, and low adsorption potential of diglyme (see sections 2 and 5), all nominal concentrations of the test substance are expected to correspond to effective concentrations, even in tests with open systems and longer exposure periods.

The acute toxicity of diglyme to golden orfes (Leuciscus idus) was determined in a static test, which gave a 96-h LC0 of >2000 mg/litre.2 An acute toxicity test with Daphnia magna conducted according to OECD Guideline 202 resulted in no adverse effects at the two tested concentrations of 100 and 1000 mg/litre (48-h EC0 >1000 mg/litre) (Hoechst, 1994). Also, in a test concerning the toxicity of diglyme to algae (Scenedesmus subspicatus), conducted according to OECD Guideline 201, the 72-h EC10 was 1000 mg/litre (highest concentration tested) (Hoechst, 1995).

The LC50 values for the acute effect of diglyme on tadpoles of the frog species Rana brevipoda were between 22 000 and 8300 mg/litre (test periods between 3 and 48 h) (Nishiuchi, 1984).

In an activated sludge respiration inhibition test conducted according to EC Guideline 88/302 Part C (OECD Guideline 209), an EC10 of >1000 mg/litre was determined (Hoechst, 1989b).

Only acute toxic effects have been examined in the tests above. One should be aware of possible effects of diglyme on reproduction, as observed in tests with mammals (see sections 8.7 and 9.1).

10.2 Terrestrial environment

A study of the effect of diglyme on the spore germination rate and the mycelial growth rate of the terrestrial fungus Cladosporium resinae (strain 35A) isolated from Australian soil samples gave a toxic threshold concentration of 9430 mg/litre (1% v/v) and a concentration for complete inhibition of the mycelial growth of 188 600 mg/litre (Lee & Wong, 1979).

In a screening test on fumigating agents against oriental and Mediterranean fruit flies (Dacus dorsalis and Ceratitis capitata), a 48-h LD50 of >98 mg/m3 was determined for 24-h-old shell-less eggs and mature larvae of each species after a 2-h fumigation (Burditt et al., 1963).

11. EFFECTS EVALUATION

11.1 Evaluation of health effects

11.1.1 Hazard identification and exposure–response assessment

Diglyme is rapidly absorbed from the gastrointestinal tract, metabolized, and excreted mainly in the urine. In analogy to other EGEs, it is assumed that diglyme is readily absorbed through the skin. The main metabolite is 2-methoxyethoxyacetic acid. The reproductive toxicity of diglyme, however, is attributed to the minor metabolite 2-methoxyacetic acid, which is generated from 2-methoxyethanol. There are species differences in the amount metabolized to this metabolite: mice and humans may produce higher amounts and thus be more susceptible than rats.

The acute toxicity of diglyme is low after oral exposure or inhalation. Diglyme is slightly irritating to the skin or eye. No investigations are available on the sensitizing effects of diglyme.

Several Ames tests as well as an unscheduled DNA synthesis test did not reveal a genotoxic potential of diglyme in vitro. Further, the number of chromosomal aberrations was not increased in bone marrow cells in vivo. The positive results of a dominant lethal test may be due to the effects of diglyme on fertility.

The main targets of the toxicity of diglyme are the reproductive organs in male animals. Dose-dependent changes have been shown for weights of testes, epididymides, prostate, and seminal vesicles. Microscopic evaluation revealed atrophy of the testes, with developing spermatocytes being the cells mainly affected. Effects were found in rats and mice in several experiments after inhalation and oral exposure. The effects were reversible at lower concentrations; at concentrations of about 1100 ppm (6138 mg/m3), the effects persisted in the investigated time period of 84 days. The NOAEL for reproductive effects in rats was 30 ppm (167 mg/m3). In a dominant lethal test, it was shown that the morphological alterations in the testes were also associated with decreased fertility in the 1000 ppm (5580 mg/m3) group but not in the 250 ppm (1395 mg/m3) group. No long-term studies are available for diglyme.

Diglyme is a strong teratogen. Developmental effects occur at low concentrations without maternal toxicity. Effects on fetal weights, an increased number of resorptions, and an increased incidence of variations/malformations in a wide variety of tissues and organ systems have been found. A LOAEL of 25 ppm (140 mg/m3) has been identified in rats for the inhalation route, and a NOAEL of 25 mg/kg body weight has been identified in rabbits for the oral route. Maternal toxicity indicated by reduced weight gain was rather low. The relevance of these findings for humans is shown by the fact that they are found in three different species — rats, rabbits, and mice — and also by different routes of exposure (inhalation and oral).

The risk for spontaneous abortion was evaluated in two large epidemiological studies of female workers in the semiconductor industry with exposure to EGEs including diglyme. One of these studies also examined the risk to wives of male employees with EGE exposure. The studies found an association of the risk of spontaneous abortion with occupational exposure to EGEs. One of these studies found evidence of a dose–response relationship. The risk of spontaneous abortion from exposure to diglyme alone could not be evaluated.

The effect of EGEs on conception rates in exposed female workers is not clear. The conception rate was assessed in two prospective studies. One study found slightly decreased rates; no effects were observed in the other.

Painters exposed to the solvent 2-methoxyethanol, which is also a metabolite of diglyme, were found to have an increased prevalence of oligospermia and azoospermia. The painters were also exposed to numerous other substances, including organic solvents and metals, however.

11.1.2 Criteria for setting tolerable intakes/concentrations or guidance values for diglyme

A guidance value for uptake of diglyme via inhalation according to EHC 170 (IPCS, 1994) can be based on the developmental toxicity study in rats (DuPont, 1988a; Driscoll et al., 1998), which gave a LOAEL of 25 ppm (140 mg/m3). As the LOAEL of 25 ppm (140 mg/m3) is, according to the authors, at the bottom end of the dose–response curve, a safety factor of 2 seems to be sufficient to extrapolate to a NOAEL. Applying further a safety factor of 10 for interindividual variability and 10 for interspecies variation, a guidance value of about 0.1 ppm (0.6 mg/m3) would be obtained.

For the oral route, no NOAEL from a reliable repeated-dose toxicity study is available. If one assumes, however, that, as in inhalation studies, developmental toxicity is the most relevant end-point, one could use the study with rabbits, which gave a NOAEL of 25 mg/kg body weight. Applying safety factors of 10 for interindividual variability and 10 for interspecies variation, a guidance value of 0.25 mg/kg body weight would be obtained.

11.1.3 Sample risk characterization

Assuming that exposure concentrations for diglyme are the same as for other EGEs, the TWA for exposure in the production process may be up to 36 mg/m3, in the semiconductor industry up to 3 mg/m3, and in painting operations up to 31 mg/m3. These concentrations are considerably higher than the guidance value for the general population of 0.6 mg/m3, derived above. In addition, high dermal uptake of diglyme has to be taken into consideration. It has to be recognized, furthermore, that protective gloves may allow significant permeation of diglyme. Gloves made of nitrile and butyl rubber or neoprene provide the best protection.

In conclusion, from the sample risk characterization for the workplace, there is high concern for possible human health effects. No information is available on the presence or concentrations of diglyme in cosmetics; because of its reprotoxic potency, all exposure of the general public to diglyme should be avoided.

11.1.4 Uncertainties in the evaluation of human health effects

There is a high degree of confidence that the reproductive system is the target of the toxicity of diglyme. This is concluded from consistent results from experiments in several animal species with different routes of application. Epidemiological studies indicate a risk for humans as well.

No long-term animal studies have been conducted with diglyme. Therefore, not all end-points could be reliably assessed, and there is some uncertainty concerning the NOAELs derived from short-term studies.

No data are available for the possible use of diglyme in cosmetics, which may be an important source of consumer exposure.

11.2 Evaluation of environmental effects

Diglyme releases into the environment are to be expected from its use as a solvent, reaction medium, and separating agent in industrial processes. A minor contribution from diglyme-containing consumer products (cosmetics, water-based paints) is possible but cannot be quantified with the available data.

The main target compartment of diglyme is the hydrosphere. The chemical is inherently biodegradable with a rather long log phase and significant adsorption to activated sludge. Bioaccumulation and geoaccumulation are of minor importance.

In the available experimental studies, diglyme exhibited a low toxicity to aquatic organisms. The 48-h EC0 value for daphnia and the 72-h EC10 value for algae were both reported to be >1000 mg/litre. It is not to be expected that the given EC0/EC10 concentrations will be exceeded in surface waters, where monitoring measurements in the early 1980s gave diglyme concentrations of <0.005 mg/litre. Therefore, the available data do not indicate a significant risk of diglyme to aquatic organisms.

Due to the lack of measured exposure levels, a sample risk characterization with respect to terrestrial organisms cannot be performed. However, from the use pattern of diglyme, significant exposure of terrestrial organisms is not to be expected.

12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

Previous evaluations by international bodies were not identified.

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APPENDIX 1 — SOURCE DOCUMENTS

BUA (1993a) Diethylene glycol dimethyl ether (bis(2-methoxyethyl)-ether). GDCh Advisory Committee on Existing Chemicals of Environmental Relevance (BUA). Stuttgart, Hirzel, pp. 1–64 (BUA Report 67)

For the BUA review process, the company that is in charge of writing the report (usually the largest producer in Germany) prepares a draft report using literature from an extensive literature search as well as internal company studies. This draft is subject to a peer review in several readings of a working group consisting of representatives from government agencies, the scientific community, and industry.

The original German version of this report was published in 1991.

Greim H, ed. (1994) Diethylene glycol dimethyl ether. In: Occupational toxicants. Critical data evaluation for MAK values and classification of carcinogens. Weinheim, Wiley-VCH, pp. 41–50

The scientific documentations of the German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (MAK) are based on critical evaluations of the available toxicological and occupational medical data from extensive literature searches and of well documented industrial data. The evaluation documents involve a critical examination of the quality of the database indicating inadequacy or doubtful validity of data and identification of data gaps. This critical evaluation and the classification of substances are the result of an extensive discussion process by the members of the Commission proceeding from a draft documentation prepared by members of the Commission, by ad hoc experts, or by the Scientific Secretariat of the Commission. Scientific expertise is guaranteed by the members of the Commission, consisting of experts from the scientific community, industry, and employers associations.

APPENDIX 2 — CICAD PEER REVIEW

The draft CICAD on diglyme was sent for review to institutions and organizations identified by IPCS after contact with IPCS national contact points and Participating Institutions, as well as to identified experts. Comments were received from:

M. Baril, International Programme on Chemical Safety/Institut de Recherche en Santé et en Sécurité du Travail du Québec, Canada

R. Benson, Drinking Water Program, US Environmental Protection Agency, USA

R. Cary, Health and Safety Executive, United Kingdom

R. Chhabra, National Institute of Environmental Health Sciences, National Institutes of Health, USA

J. Gift, National Center for Environmental Assessment, US Environmental Protection Agency, USA

R. Hertel, Federal Institute for Health Protection of Consumers and Veterinary Medicine, Germany

C. Hiremath, National Center for Environmental Assessment, US Environmental Protection Agency, USA

P. Howden, Health and Safety Executive, United Kingdom

G. Johanson, National Institute for Working Life, Sweden

S. Kristensen, National Industrial Chemicals Notification and Assessment Scheme, Australia

J. Montelius, National Institute for Working Life, Sweden

H. Savolainen, Ministry of Social Affairs and Health, Finland

K. Ziegler-Skylakakis, Commission of the European Communities/European Union, Luxembourg

APPENDIX 3 — CICAD FINAL REVIEW BOARD

Geneva, Switzerland, 8–12 January 2001

Members

Dr A.E. Ahmed, Molecular Toxicology Laboratory, Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA

Mr R. Cary, Health and Safety Executive, Merseyside, United Kingdom (Chairperson)

Dr R.S. Chhabra, General Toxicology Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA

Dr S. Czerczak, Department of Scientific Information, Nofer Institute of Occupational Medicine, Lodz, Poland

Dr S. Dobson, Centre for Ecology and Hydrology, Cambridgeshire, United Kingdom

Dr O.M. Faroon, Division of Toxicology, Agency for Toxic Substances and Disease Registry, Atlanta, GA, USA

Dr H. Gibb, National Center for Environmental Assessment, US Environmental Protection Agency, Washington, DC, USA

Dr R.F. Hertel, Federal Institute for Health Protection of Consumers and Veterinary Medicine, Berlin, Germany

Dr A. Hirose, Division of Risk Assessment, National Institute of Health Sciences, Tokyo, Japan

Dr P.D. Howe, Centre for Ecology and Hydrology, Cambridgeshire, United Kingdom (Rapporteur)

Dr D. Lison, Industrial Toxicology and Occupational Medicine Unit, Université Catholique de Louvain, Brussels, Belgium

Dr R. Liteplo, Existing Substances Division, Bureau of Chemical Hazards, Health Canada, Ottawa, Ontario, Canada

Dr I. Mangelsdorf, Chemical Risk Assessment, Fraunhofer Institute of Toxicology and Aerosol Research, Hanover, Germany

Ms M.E. Meek, Existing Substances Division, Safe Environments Program, Health Canada, Ottawa, Ontario, Canada (Vice-Chairperson)

Dr S. Osterman-Golkar, Department of Molecular Genome Research, Stockholm University, Stockholm, Sweden

Dr J. Sekizawa, Division of Chem-Bio Informatics, National Institute of Health Sciences, Tokyo, Japan

Dr S. Soliman, Department of Pesticide Chemistry, Faculty of Agriculture, Alexandria University, El-Shatby, Alexandria, Egypt

Dr M. Sweeney, Education and Information Division, National Institute for Occupational Safety and Health, Cincinnati, OH, USA

Professor M. van den Berg, Environmental Sciences and Toxicology, Institute for Risk Assessment Sciences, University of Utrecht, Utrecht, The Netherlands

Observers

Dr W.F. ten Berge, DSM Corporate Safety and Environment, Heerlen, The Netherlands

Dr K. Ziegler-Skylakakis, Commission of the European Communities, Luxembourg

Secretariat

Dr A. Aitio, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland

Dr Y. Hayashi, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland

Dr P.G. Jenkins, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland

Dr M. Younes, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland

INTERNATIONAL CHEMICAL SAFETY CARD

DIETHYLENE GLYCOL DIMETHYL ETHER ICSC:1357

RÉSUMÉ D’ORIENTATION

Le présent CICAD consacré à l’éther diméthylique de diéthylène-glycol (désigné sous le nom de diglyme dans ce qui suit) a été préparé par l’Institut Fraunhofer de recherche sur la toxicologie et les aérosols, de Hanovre (Allemagne). La décision d’inclure le diglyme dans la série des CICAD a été prise en raison de la crainte que l’on peut avoir au sujet d’éventuels effets de ce composé sur la santé humaine, notamment en ce qui concerne la fonction de reproduction. Ce CICAD repose sur un certain nombre de rapports établis par le Comité consultatif GDCh sur les substances chimiques d’importance écologique (BUA, 1993a) ainsi que par la MAK-Komission allemande (Greim, 1994). Il a été procédé en mars 2000 à un dépouillement bibliographique exhaustif des bases de données existantes, afin de rechercher des références à des publications postérieures aux rapports en question. Des informations sur la préparation et l’examen par des pairs des sources documentaires utilisées sont données à l’appendice 1. L’appendice 2 fournit des renseignements sur l’examen par des pairs du présent CICAD. Ce CICAD a été approuvé en tant qu’évaluation internationale lors d’une réunion du Comité d’évaluation finale qui s’est tenue à Genève du 8 au 12 janvier 2001. La liste des participants à cette réunion figure à l’appendice 3. La Fiche internationale sur la sécurité chimique du diglyme (ICSC 1357), établie par le Programme international sur la sécurité chimique (IPCS, 2000), est également reproduite dans le présent document.

Le diglyme (No CAS 111-96-6) se présente sous la forme d’un liquide incolore dégageant une odeur légère et agréable. Il est miscible à l’eau et à un certain nombre de solvants organiques courants. Il peut donner naissance à des peroxydes en présence d’oxydants. Comme il est dipolaire et aprotique, on l’utilise principalement comme solvant (dans l’industrie des semi-conducteurs, en synthèse chimique et dans les laques), comme milieu réactionnel inerte en synthèse et pour certaines séparations par distillation.

A l’état liquide ou sous forme de vapeurs, le diglyme est facilement absorbé quelle que soit la voie d’exposition, puis métabolisé et excrété dans les urines. Son principal métabolite est l’acide 2-méthoxyéthoxyacétique, l’acide 2-méthoxyacétique étant un métabolite secondaire. Chez le rat, il est présent dans la proportion de 5 à 15 % dans les urines.

Après exposition par voie orale ou respiratoire, le diglyme ne présente qu’une faible toxicité aiguë.

Il est légèrement irritant pour la peau et la muqueuse oculaire. On ne dispose d’aucune étude sur l’effet sensibilisant de ce composé.

L’expérimentation animale montre que chez le mâle, c’est principalement l’appareil reproducteur qui est touché après exposition répétée. Lors d’une étude au cours de laquelle on a fait inhaler du diglyme pendant 2 semaines à des rats mâles, on a observé une diminution du poids du testicule, de l’épididyme, de la prostate et des vésicules séminales. Les testicules étaient atrophiés et on a constaté une atteinte des spermatocytes. Ces études ont permis de fixer à 30 ppm (167 mg/m3) la concentration sans effet nocif observable (NOAEL) et à 100 ppm (558 mg/m3) la concentration la plus faible produisant un effet observable (LOAEL). Des études sur la souris ont révélé des anomalies morphologiques affectant les spermatozoïdes et consistant principalement dans la présence d’une tête amorphe, après exposition à 1000 ppm (5580 mg/m3). Après avoir été exposés par la voie respiratoire à de fortes concentrations de diglyme, mâles et femelles ont également présenté des anomalies affectant le système hématopoïétique et consistant notamment en une modification du nombre de leucocytes et une atrophie splénique et thymique.

On ne dispose d’aucune étude à long terme sur le diglyme; il n’est donc pas possible d’évaluer tous les points d’aboutissement éventuels de son action toxique. Aucune génotoxicité n’a été mise en évidence in vitro, que ce soit par divers tests d’Ames ou par recherche d’une synthèse non programmée de l’ADN. In vivo, on ne constate pas non plus d’augmentation du nombre des aberrations chromosomiques dans les cellules de la moelle osseuse.

Des tests de létalité dominante effectués sur des rats ont montré que le nombre de gravidités était sensiblement réduit chez le rat après exposition à 1000 ppm (5580 mg/m3), mais pas à la concentration de 250 ppm (1395 mg/m3). Les résultats positifs de ces tests pourraient s’expliquer par une action du diglyme sur la fertilité.

Les études de tératogénicité effectuées sur des rats, des lapins et des souris ont révélé des effets dépendant de la dose sur le poids foetal, le nombre de résorptions et l’incidence des anomalies et des malformations affectant un grand nombre de tissus et d’organes à des concentrations par ailleurs non toxiques pour les mères. Lors d’une étude consacrée aux effets sur le développement avec exposition par la voie respiratoire, on a trouvé une LOAEL égale à 25 ppm (140 mg/m3); dans le cas d’une exposition par voie orale, la NOAEL était de 25 mg/kg de poids corporel pour le lapin et de 62,5 mg/kg de poids corporel pour la souris. Les effets toxique du diglyme sur la fonction de reproduction sont attribués à son métabolite secondaire, l’acide 2-méthoxyacétique.

Des études épidémiologiques sur des femmes travaillant dans l’industrie des semi-conducteurs et exposées de par leur profession à des éthers éthyliques de glycol, dont le diglyme, ont mis en évidence un accroissement du risque d’avortement spontané et une baisse de la fécondité. D’une façon générale, les travailleurs de l’industrie des semi-conducteurs sont exposés à un certain nombre de substances potentiellement toxiques pour la fonction de reproduction, notamment des éthers éthyliques de glycol. Ces données ne permettent pas de déterminer quelle est la part du diglyme dans cet accroissement du risque d’effets génésiques nocifs. Chez des peintres exposés à divers métaux, solvants organiques et autres substances chimiques, parmi lesquels le 2-méthoxyéthanol (qui est également un métabolite du diglyme), mais pas au diglyme lui-même, on a constaté un accroissement du risque d’oligospermie.

Dans l’environnement, c’est principalement dans l’hydrosphère que le diglyme se rassemble. Le composé resiste à l’hydrolyse. Le calcul montre que le t1/2 de la réaction du diglyme avec les radicaux hydroxyles atmosphériques est de 19 h environ. Le diglyme est intrinsèquement biodégradable avec une phase logarithmique relativement longue est une adsorption notable aux boues activées. Compte tenu de la valeur de son coefficient de partage entre le n-octanol et l’eau et de sa miscibilité à l’eau, il semble que le potentiel de bioaccumulation et de géoaccumulation du diglyme soit négligeable.

Les résultats expérimentaux valables dont on peut disposer au sujet de la toxicité du diglyme vis-à-vis de divers organismes aquatiques, permettent de considérer ce composé comme présentant une faible toxicité aiguë pour les biotes de l’hydrosphère. La CE0 à 48 h pour la daphnie (Daphnia magna) et la CE10 à 72 h pour les algues (Scenedesmus subspicatus) sont >1000 mg/litre (concentration maximale mesurée). Dans le cas de l’ide rouge (Leuciscus idus), on a trouvé une CL0 à 96 h de >2000 mg/litre. On ne dispose que de quelques études concernant la toxicité du diglyme pour les espèces terrestres. Le seuil de toxicité pour un champignon, Cladosporium resinae, est d’environ 9,4 g/litre.

D’après les exemples représentatifs de caractérisa tion du risque sur le lieu de travail, il y a amplement lieu de craindre des effets sur la santé humaine. Il faut donc éviter que la population soit exposée au diglyme.

Selon les données disponibles, l’exposition au diglyme n’implique pas de risque important pour les organismes aquatiques. Comme on ne connaît pas les niveaux d’exposition, il n’est pas possible de donner une caractérisation représentative du risque couru par les organismes terrestres. Toutefois, compte tenu du mode d’utilisation du diglyme, il n’y a pas lieu de craindre une exposition importante.

RESUMEN DE ORIENTACIÓN

Este CICAD relativo al éter de dietilenglicoldimetilo (denominado en lo sucesivo diglime) fue preparado por el Instituto Fraunhofer de Toxicología y de Investigación sobre los Aerosoles de Hannover, Alemania. Se seleccionó el diglime para someterlo a examen en la serie de los CICAD debido a las preocupaciones que suscitaba en relación con la salud humana, en particular sus posibles efectos reproductivos. El CICAD se basa en los informes compilados por el Comité Consultivo Alemán sobre las Sustancias Químicas Importantes para el Medio Ambiente (BUA, 1993a) y la MAK-Kommission alemana (Greim, 1994). En marzo de 2000 se realizó una investigación bibliográfica amplia de bases de datos pertinentes para buscar cualquier referencia publicada con posterioridad a las incorporadas a estos informes. La información sobre la preparación de los documentos originales y su examen colegiado figura en el Apéndice 1. La información acerca del examen colegiado de este CICAD se presenta en el Apéndice 2. Este CICAD se aprobó como evaluación internacional en una reunión de la Junta de Evaluación Final celebrada en Ginebra (Suiza) del 8 al 12 de enero de 2001. La lista de participantes en esta reunión figura en el Apéndice 3. La Ficha internacional de seguridad química (ICSC 1357) para el diglime, preparada por el Programa Internacional de Seguridad de las Sustancias Químicas (IPCS, 2000), también se reproduce en el presente documento.

El diglime (CAS Nş 111-96-6) es un líquido incoloro ligeramente aromático. Es miscible en agua y en algunos disolventes orgánicos comunes. En presencia de agentes oxidantes, puede formar peróxido. Debido a sus propiedades apróticas dipolares, el diglime se utiliza principalmente como disolvente (industria de los semiconductores, síntesis química, barnices), como medio de reacción inerte en la síntesis química y como agente separador en las destilaciones.

El diglime, en forma líquida o de vapor, se absorbe fácilmente por todas las vías de exposición, se metaboliza y se excreta principalmente en la orina. El metabolito más importante es el ácido 2-metoxietoxiacético. El ácido 2-metoxiacético es un metabolito secundario; en ratas, alcanza un valor aproximado del 5-15% en la orina.

La toxicidad aguda del diglime es baja tras la exposición oral o por inhalación.

El diglime es ligeramente irritante de la piel o los ojos. No se dispone de investigaciones sobre sus efectos de sensibilización.

El destino principal en los animales machos tras ingestas repetidas de diglime son los órganos reproductores. En estudios de inhalación de dos semanas en ratas macho, se observó una reducción dependiente de la dosis del peso de los testículos, el epidídimo, la próstata y las vesículas seminales. Se atrofiaron los testículos y se detectaron daños en los espermatocitos. La concentración sin efectos adversos observados (NOAEL) en estos estudios fue de 30 ppm (167 mg/m3); la concentración más baja con efectos adversos observados (LOAEL) fue de 100 ppm (558 mg/m3). En los experimentos con ratones se puso de manifiesto una alteración morfológica del esperma, principalmente con cabezas amorfas, tras la exposición a 1000 ppm (5580 mg/m3). Tras la exposición por inhalación a concentraciones elevadas, también se observaron efectos en el sistema hematopoyético de los animales machos y hembras, por ejemplo cambios en el recuento de leucocitos y atrofia del bazo y el timo.

No hay estudios prolongados disponibles del diglime; por consiguiente, no se pueden evaluar de manera fidedigna todos los efectos finales. En varias pruebas de Ames y en una prueba de síntesis de ADN no programado no apareció ningún posible efecto genotóxico del diglime in vitro. Tampoco se observó un aumento del número de aberraciones cromosómicas en las células de la médula ósea in vivo.

En una prueba de dominancia letal con ratas, el número de gestaciones se redujo significativamente tras la exposición a 1000 ppm (5580 mg/m3), pero no con 250 ppm (1395 mg/m3). Los resultados positivos pueden deberse a los efectos del diglime en la fecundidad.

En estudios de teratogenicidad con ratas, conejos y ratones se detectaron efectos del diglime dependientes de la dosis en el peso fetal, el número de resorciones y la incidencia de variaciones y malformaciones en una amplia variedad de tejidos y sistemas de órganos a concentraciones que no eran tóxicas para la madre. En un estudio de inhalación en ratas, la LOAEL para los efectos en el desarrollo fue de 25 ppm (140 mg/m3); la NOAEL para la vía oral fue de 25 mg/kg de peso corporal en conejos y de 62,5 mg/kg de peso corporal en ratones. La toxicidad reproductiva del diglime se atribuye al ácido 2-metoxiacético, que es un metabolito secundario.

En estudios epidemiológicos de trabajadoras de la industria de los semiconductores expuestas en el lugar de trabajo a los éteres de etilenglicol, incluido el diglime, se ha registrado un aumento del número de abortos espontáneos y una reducción de la fecundidad. Sin embargo, los trabajadores de esta industria están expuestos a varias sustancias con posible toxicidad reproductiva, entre ellas los éteres de etilenglicol y otras. A partir de estos datos, no es posible determinar la contribución del diglime al aumento del riesgo de efectos reproductivos adversos. Se observó que los pintores expuestos a diversos metales, disolventes orgánicos y otros productos químicos, entre ellos el 2-metoxietanol, metabolito del diglime, pero no al propio diglime, presentaban un mayor riesgo de oligospermia.

El principal compartimento destinatario del diglime en el medio ambiente es la hidrosfera. Esta sustancia química presenta estabilidad hidrolítica. La semivida en el aire para la reacción del diglime con los radicales hidroxilo se calcula en unas 19 horas. El diglime es básicamente biodegradable, con una fase logarítmica larga y una adsorción importante a los lodos activados. Del coeficiente de reparto n-octanol/agua y la miscibilidad en agua de esta sustancia se deriva un potencial insignificante para la bioacumulación y la geoacumulación.

Teniendo en cuenta los resultados de pruebas válidas disponibles sobre la toxicidad del diglime para diversos organismos acuáticos, este compuesto se puede clasificar como sustancia con una toxicidad aguda baja en el compartimento acuático. El valor de la CE0 a las 48 horas para Daphnia magna y el valor de la CE10 a las 72 horas para las algas (Scenedesmus subspicatus) fue de >1000 mg/litro (la concentración medida más alta). Para el cacho (Leuciscus idus), se determinó una CL0 a las 96 horas de >2000 mg/litro. Son muy pocos los estudios disponibles relativos a la toxicidad del diglime para las especies terrestres. El hongo Cladosporium resinae mostró una concentración umbral tóxica de unos 9,4 g/litro.

Los resultados de la caracterización del riesgo de muestra para el lugar de trabajo suscitan una gran preocupación por sus posibles efectos en la salud humana. Se debe evitar la exposición de la población general al diglime.

Los datos disponibles no indican un riesgo importante asociado con la exposición de los organismos acuáticos a esta sustancia. Debido a la falta de mediciones de los niveles de exposición, no se puede realizar una caracterización del riesgo de muestra para los organismos terrestres. Sin embargo, teniendo en cuenta las pautas de uso del diglime, no cabe esperar una exposición importante de los organismos terrestres.

ENDNOTES

1International Programme on Chemical Safety (1994) Assessing human health risks of chemicals: derivation of guidance values for health-based exposure limits. Geneva, World Health Organization (Environmental Health Criteria 170).

2Hoechst (1979) Abwasserbiologische Untersuchung von Dialkylglykoläthern auf die Goldorfe (Leuciscus idus). Frankfurt am Main, Hoechst AG, 2 pp. (unpublished test results).



    See Also:
       Toxicological Abbreviations
       Diethylene glycol dimethyl ether (ICSC)