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

DIETHYLENE GLYCOL DIMETHYL ETHER

Please note that the lay out and pagination of this pdf file are not necessarily identical to those of the printed CICAD

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 Organiza- tions), 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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Printed by Wissenschaftliche Verlagsgesellschaft mbH, D-70009 Stuttgart 10 TABLE OF CONTENTS

FOREWORD ...... 1

1. EXECUTIVE SUMMARY ...... 4

2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES ...... 5

3. ANALYTICAL METHODS ...... 5

4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE ...... 6

4.1 Natural sources ...... 6 4.2 Anthropogenic sources ...... 6 4.3 Uses ...... 6 4.4 Estimated global release ...... 7

5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, TRANSFORMATION, AND ACCUMULATION ...... 7

5.1 Transport and distribution between media ...... 7 5.2 Transformation ...... 7 5.3 Accumulation ...... 7

6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE ...... 8

6.1 Environmental levels ...... 8 6.2 Human exposure ...... 8 6.2.1 Workplaces ...... 8 6.2.2 Consumer exposure ...... 9 6.2.3 Biological monitoring ...... 9

7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS ...... 9

7.1 Absorption ...... 9 7.2 Distribution and accumulation ...... 9 7.3 Metabolism...... 10 7.4 Elimination ...... 11

8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS ...... 11

8.1 Single exposure ...... 11 8.1.1 Inhalation ...... 11 8.1.2 Oral administration ...... 11 8.1.3 Dermal administration ...... 12 8.2 Irritation and sensitization ...... 12 8.2.1 Irritation ...... 12 8.2.2 Sensitization ...... 12 8.3 Short-term exposure ...... 12 8.3.1 Inhalation ...... 12 8.3.2 Oral ...... 12 8.4 Medium-term exposure ...... 12

iii Concise International Chemical Assessment Document 41

8.5 Long-term exposure and carcinogenicity ...... 12 8.6 Genotoxicity and related end-points ...... 12 8.6.1 In vitro studies ...... 12 8.6.2 In vivo studies ...... 12 8.7 Reproductive toxicity ...... 13 8.7.1 Effects on fertility ...... 13 8.7.1.1 Inhalation ...... 13 8.7.1.2 Oral ...... 15 8.7.2 Developmental toxicity ...... 15 8.7.2.1 Inhalation ...... 15 8.7.2.2 Oral ...... 15 8.8 Other toxicity/mode of action ...... 17

9. EFFECTS ON HUMANS ...... 17

9.1 Reproductive effects ...... 18 9.2 Haematological effects ...... 19

10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD ...... 19

10.1 Aquatic environment ...... 19 10.2 Terrestrial environment ...... 19

11. EFFECTS EVALUATION ...... 20

11.1 Evaluation of health effects ...... 20 11.1.1 Hazard identification and exposure–response assessment ...... 20 11.1.2 Criteria for setting tolerable intakes/concentrations or guidance values for diglyme ...... 20 11.1.3 Sample risk characterization ...... 21 11.1.4 Uncertainties in the evaluation of human health effects ...... 21 11.2 Evaluation of environmental effects ...... 21

12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES ...... 21

REFERENCES ...... 22

APPENDIX 1 — SOURCE DOCUMENTS ...... 26

APPENDIX 2 — CICAD PEER REVIEW ...... 26

APPENDIX 3 — CICAD FINAL REVIEW BOARD ...... 27

INTERNATIONAL CHEMICAL SAFETY CARD ...... 28

RÉSUMÉ D’ORIENTATION ...... 30

RESUMEN DE ORIENTACIÓN ...... 32

iv Diethylene glycol dimethyl ether

FOREWORD provided as guidance only. The reader is referred to EHC 1701 for advice on the derivation of health-based Concise International Chemical Assessment guidance values. Documents (CICADs) are the latest in a family of publications from the International Programme on While every effort is made to ensure that CICADs Chemical Safety (IPCS) — a cooperative programme of represent the current status of knowledge, new informa- the World Health Organization (WHO), the International tion is being developed constantly. Unless otherwise Labour Organization (ILO), and the United Nations stated, CICADs are based on a search of the scientific Environment Programme (UNEP). CICADs join the literature to the date shown in the executive summary. In Environmental Health Criteria documents (EHCs) as the event that a reader becomes aware of new informa- authoritative documents on the risk assessment of tion that would change the conclusions drawn in a chemicals. CICAD, the reader is requested to contact IPCS to inform it of the new information. International Chemical Safety Cards on the relevant chemical(s) are attached at the end of the Procedures CICAD, to provide the reader with concise information on the protection of human health and on emergency The flow chart on page 2 shows the procedures action. They are produced in a separate peer-reviewed followed to produce a CICAD. These procedures are procedure at IPCS. They may be complemented by designed to take advantage of the expertise that exists information from IPCS Poison Information Monographs around the world — expertise that is required to produce (PIM), similarly produced separately from the CICAD the high-quality evaluations of toxicological, exposure, process. and other data that are necessary for assessing risks to human health and/or the environment. The IPCS Risk CICADs are concise documents that provide sum- Assessment Steering Group advises the Co-ordinator, maries of the relevant scientific information concerning IPCS, on the selection of chemicals for an IPCS risk the potential effects of chemicals upon human health assessment, the appropriate form of the document (i.e., and/or the environment. They are based on selected EHC or CICAD), and which institution bears the national or regional evaluation documents or on existing responsibility of the document production, as well as on EHCs. Before acceptance for publication as CICADs by the type and extent of the international peer review. IPCS, these documents undergo extensive peer review by internationally selected experts to ensure their The first draft is based on an existing national, completeness, accuracy in the way in which the original regional, or international review. Authors of the first data are represented, and the validity of the conclusions draft are usually, but not necessarily, from the institution drawn. that developed the original review. A standard outline has been developed to encourage consistency in form. The primary objective of CICADs is characteri- The first draft undergoes primary review by IPCS and zation of hazard and dose–response from exposure to a one or more experienced authors of criteria documents to chemical. CICADs are not a summary of all available data ensure that it meets the specified criteria for CICADs. on a particular chemical; rather, they include only that information considered critical for characterization of the The draft is then sent to an international peer risk posed by the chemical. The critical studies are, review by scientists known for their particular expertise however, presented in sufficient detail to support the and by scientists selected from an international roster conclusions drawn. For additional information, the compiled by IPCS through recommendations from IPCS reader should consult the identified source documents national Contact Points and from IPCS Participating upon which the CICAD has been based. Institutions. Adequate time is allowed for the selected experts to undertake a thorough review. Authors are Risks to human health and the environment will required to take reviewers’ comments into account and vary considerably depending upon the type and extent revise their draft, if necessary. The resulting second draft of exposure. Responsible authorities are strongly encouraged to characterize risk on the basis of locally measured or predicted exposure scenarios. To assist the 1 International Programme on Chemical Safety (1994) reader, examples of exposure estimation and risk Assessing human health risks of chemicals: derivation characterization are provided in CICADs, whenever of guidance values for health-based exposure limits. possible. These examples cannot be considered as Geneva, World Health Organization (Environmental representing all possible exposure situations, but are Health Criteria 170).

1 Concise International Chemical Assessment Document 41

CICAD PREPARATION FLOW CHART

SELECTION OF PRIORITY CHEMICAL

SELECTION OF HIGH QUALITY NATIONAL/REGIONAL ASSESSMENT DOCUMENT(S)

FIRST DRAFT PREPARED

PRIMARY REVIEW BY IPCS ( REVISIONS AS NECESSARY)

REVIEW BY IPCS CONTACT POINTS/ SPECIALIZED EXPERTS

REVIEW OF COMMENTS (PRODUCER/RESPONSIBLE OFFICER), PREPARATION OF SECOND DRAFT 1

FINAL REVIEW BOARD 2

FINAL DRAFT 3

EDITING

APPROVAL BY DIRECTOR, IPCS

PUBLICATION

1 Taking into account the comments from reviewers. 2 The second draft of documents is submitted to the Final Review Board together with the reviewers’ comments. 3 Includes any revisions requested by the Final Review Board.

2 Diethylene glycol dimethyl ether

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:

– to ensure that each CICAD has been subjected to an appropriate and thorough peer review; – to verify that the peer reviewers’ comments have been addressed appropriately; – to provide guidance to those responsible for the preparation of CICADs on how to resolve any remaining issues if, in the opinion of the Board, the author has not adequately addressed all comments of the reviewers; and – to approve CICADs as international assessments.

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.

3 Concise International Chemical Assessment Document 41

1. EXECUTIVE SUMMARY 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 This CICAD on diethylene glycol dimethyl ether lowest-observed-adverse-effect level (LOAEL) was 100 (in the following called diglyme) was prepared by the ppm (558 mg/m3). Experiments with mice showed Fraunhofer Institute of Toxicology and Aerosol morphologically altered sperm, mainly with amorphous Research, Hanover, Germany. Diglyme was selected for heads, after exposure to 1000 ppm (5580 mg/m3). After review in the CICAD series owing to concerns for human exposure by inhalation to high concentrations, male and health, notably potential reproductive effects. The female animals also showed effects on the CICAD is based on reports compiled by the GDCh haematopoietic system, such as changes in leukocyte Advisory Committee on Existing Chemicals of Environ- counts and atrophy in spleen and thymus. mental Relevance (BUA, 1993a) and the German MAK- Kommission (Greim, 1994). A comprehensive literature No long-term studies are available for diglyme; search of relevant databases was conducted in March therefore, all end-points cannot be reliably assessed. 2000 to identify any relevant references published Several Ames tests as well as an unscheduled DNA subsequent to those incorporated in these reports. synthesis test did not reveal a genotoxic potential of Information on the preparation and peer review of the diglyme in vitro. Nor was the number of chromosomal source documents is presented in Appendix 1. Informa- aberrations increased in bone marrow cells in vivo. tion on the peer review of this CICAD is presented in Appendix 2. This CICAD was approved as an interna- In a dominant lethal test with rats, the number of tional assessment at a meeting of the Final Review pregnancies was significantly reduced after exposure to Board, held in Geneva, Switzerland, on 8–12 January 1000 ppm (5580 mg/m3) but not to 250 ppm (1395 mg/m3). 2001. Participants at the Final Review Board meeting are The positive results may be due to the effects of diglyme listed in Appendix 3. The International Chemical Safety on fertility. Card on diglyme (ICSC 1357), produced by the Inter- national Programme on Chemical Safety (IPCS, 2000), has In teratogenicity studies with rats, rabbits, and also been reproduced in this document. mice, diglyme showed dose-dependent effects on fetal weights, number of resorptions, and incidence of varia- Diglyme (CAS No. 111-96-6) is a colourless liquid tions and malformations in a wide variety of tissues and with a slight, pleasant odour. It is miscible with water organ systems, at concentrations that were not and a number of common organic solvents. In the maternally toxic. The LOAEL for developmental effects presence of oxidation agents, peroxide may form. Due to in an inhalation study with rats was 25 ppm (140 mg/m3); its dipolar aprotic properties, diglyme is used mainly as a the NOAEL for the oral route was 25 mg/kg body weight solvent (semiconductor industry, chemical synthesis, in rabbits and 62.5 mg/kg body weight in mice. The lacquers), as an inert reaction medium in chemical reproductive toxicity of diglyme is attributed to the minor synthesis, and as a separating agent in distillations. metabolite 2-methoxyacetic acid.

Diglyme liquid or vapour is readily absorbed by Epidemiological studies of female semiconductor any route of exposure, metabolized, and excreted mainly workers occupationally exposed to ethylene glycol in the urine. The main metabolite is 2-methoxyethoxy- ethers (EGEs), including diglyme, have found an acetic acid. 2-Methoxyacetic acid is a minor metabolite; increased risk of spontaneous abortions and lower in rats, it amounts to about 5–15% in the urine. fecundity. Workers in the semiconductor industry are exposed to a number of potential reproductive toxicants, The acute toxicity of diglyme is low after oral however, including EGEs and other chemicals. From exposure or inhalation. these data, it is not possible to determine the contribution of diglyme to the increased risk of adverse Diglyme is slightly irritating to the skin or eye. No reproductive effects. Painters exposed to a variety of investigations are available on the sensitizing effects of metals, organic solvents, and other chemicals, including diglyme. 2-methoxyethanol, a metabolite of diglyme, but not to diglyme itself, were found to have an increased risk of The main targets in male animals after repeated oligospermia. intake of diglyme are the reproductive organs. In 2-week inhalation studies in male rats, dose-dependent The main environmental target compartment of decreases in weights of testes, epididymides, prostate, diglyme is the hydrosphere. The chemical is hydrolyti- and seminal vesicles were observed. The testes were cally stable. The half-life in air for the reaction of diglyme

4 Diethylene glycol dimethyl ether

with hydroxyl radicals is calculated to be about 19 h. compounds, such as vegetable oils, waxes and resins, Diglyme is inherently biodegradable, with a rather long boron hydrides, organic boron compounds, sulfur, sulfur log phase and significant adsorption to activated sludge. dioxide, hydrogen peroxide, and carbon dioxide. With From the n-octanol/water partition coefficient and the water, azeotrope formation is observed at a water miscibility of the chemical, a negligible potential concentration ratio of 23 wt. % diglyme and 77 wt. % for bioaccumulation and geoaccumulation is derived. water (BUA, 1993a). Diglyme has an n-octanol/water

partition coefficient (log Kow) of !0.36, determined by a From valid test results available on the toxicity of shake flask experiment (Funasaki et al., 1984). Its vapour diglyme to various aquatic organisms, this compound pressure at 20 °C ranges from 0.23 to 1.1 kPa. The can be classified as a chemical exhibiting low acute tox- chemical is volatile with water vapour (BUA, 1993a). The icity in the aquatic compartment. The 48-h EC0 value for calculated Henry’s law constant is given as 3 daphnia (Daphnia magna) and the 72-h EC10 value for 0.041 PaAm /mol (J. Gmehling, personal communication, algae (Scenedesmus subspicatus) were $1000 mg/litre 1991). (highest measured concentration). For the golden orfe

(Leuciscus idus), a 96-h LC0 of $2000 mg/litre was The conversion factors for diglyme for the gas determined. Only very few studies concerning the tox- phase (101.3 kPa, 20 °C) are as follows: icity of diglyme towards terrestrial species are available. The fungus Cladosporium resinae exhibited a toxic 1 mg/m3 = 0.18 ppm threshold concentration of about 9.4 g/litre. 1 ppm = 5.58 mg/m3

From the sample risk characterization for the Diglyme is chemically stable. In the presence of workplace, there is high concern for possible human strong oxidation agents, peroxide may form. Commercial health effects. Exposure of the general population to products typically contain peroxides at a concentration diglyme should be avoided. of 5 mg/kg. To avoid the further formation of peroxides, commercial products may contain antioxidants, such as The available data do not indicate a significant risk 2,6-di-tert-butyl-4-methylphenol (BUA, 1993a). associated with exposure of aquatic organisms to diglyme. Due to the lack of measured exposure levels, a Additional physical and chemical properties of sample risk characterization with respect to terrestrial diglyme are presented in the International Chemical organisms cannot be performed. However, from the use Safety Card (ICSC 1357) reproduced in this document. pattern of diglyme, significant exposure of terrestrial organisms is not to be expected.

3. ANALYTICAL METHODS

2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES Two general methods for the determination of glycol derivatives in ambient and workplace air are described: Diglyme (CAS No. 111-96-6; relative molecular mass 134.17) is also known as bis(2-methoxyethyl)ether # adsorption onto modified silica containing cyano- (IUPAC name), diethylene glycol dimethyl ether, propyl groups, synthetic polymers such as XAD 2 DEGDM(E), dimethyl carbitol, and 2,5,8-trioxynonane. It or XAD 7, or modified activated charcoal, with belongs to the group of ethylene glycol ethers (EGEs). subsequent solvent elution (e.g., acetone,

The molecular structure of diglyme (C6H14O3) is shown dichloromethane, dichloromethane/methanol); and below: # adsorption onto TENAX TA with subsequent thermal desorption.

CH3 – O – CH2 – CH2 – O – CH2 – CH2 – O – CH3 In either case, detection is carried out via gas Diglyme is a colourless liquid of low viscosity with chromatography/flame ionization detection (GC/FID) or a slight, pleasant odour. The chemical freezes at about gas chromatography/mass spectrometric detection !64 °C. Depending on the presence of impurities, its (GC/MSD) (NIOSH, 1990, 1991, 1996; Stolz et al., 1999). boiling point is between 155 and 165 °C (Hoechst, 1990). For the determination of diglyme in indoor air, the Diglyme is miscible with water and with a number of chemical was adsorbed onto activated charcoal, eluted common organic solvents. It dissolves numerous with dichloromethane/methanol, and determined by

5 Concise International Chemical Assessment Document 41 capillary GC/MSD (internal standard toluene-d8 4. SOURCES OF HUMAN AND and 1,2,3-trichloropropane). The detection limit was ENVIRONMENTAL EXPOSURE 3 µg/m3; data on recovery rate and standard deviation are not available (Plieninger & Marchl, 1999). 4.1 Naturalsources The enrichment of diglyme from water samples is also in general carried out by adsorption onto XAD 4 or There are no known natural sources of diglyme. XAD 8 material with subsequent solvent elution (e.g., diethylether, dichloromethane) and determination by 4.2 Anthropogenic sources capillary GC/MSD (Morra et al., 1979; Lauret et al., 1989). Recovery rates and standard deviations are not Diglyme is manufactured in a closed system by the available. A detection limit of 0.01 µg/litre is reported catalytic conversion of dimethyl ether and ethylene (Morra et al., 1979). oxide under elevated pressure (1000–1500 kPa) and temperatures (50–60 °C) with a maximum yield of 60%. Analytical methods for the determination of The by-products tri- and tetraethylene glycol dimethyl diglyme in soil or sediment are not available. ether and small amounts of a high-molecular-mass ethylene glycol dimethyl ether are separated by Diglyme was determined together with other glycol fractional distillation (Hoechst, 1991). This process is ethers in human urine by enrichment on diatomaceous based on the classic Williamson ether synthesis earth, extraction with dichloromethane/acetone (90:10), (Rebsdat & Mayer, 1999). and detection by capillary GC/FID. The validation results of the method are given only as ranges for total glycol In 1982, about 47 200 tonnes of diglyme were ethers: detection limits 0.25–1 mg/litre, standard produced in the USA (HSDB, 1983). In 1990, about deviation 1.5–17.1% (at 5 mg/litre), and recovery rates 400 tonnes of the chemical were manufactured in 92.0–125.2% (at 2, 5, and 10 mg/litre) (Hubner et al., Germany, of which 200 tonnes were exported (BUA, 1992). [14C]Diglyme was determined in rat urine for 1993a). More recent data or data from other countries are metabolism studies by high-performance liquid chroma- not available. Diglyme is registered as a high- tography/scintillation detection on a reversed-phase C18 production-volume chemical by the Organisation for column (gradient elution with methanol/acetic acid) after Economic Co-operation and Development (OECD) (i.e., acidification of the sample (Cheever et al., 1988). Infor- its production volume in at least one OECD member state mation on detection methods for other biological mater- is $1000 tonnes/year) (OECD, 1997). ials is not available. 4.3 Uses The metabolite 2-methoxyacetic acid is assumed to play a major role in the toxic effects of diglyme (see Because of its dipolar aprotic properties and its sections 8 and 9). Therefore, common detection methods chemical stability (see sections 2 and 5.2), diglyme is for this compound in urine after inhalation exposure to used mainly as a solvent, as an inert reaction medium in related EGEs are described briefly here. The basis of chemical synthesis, and as a separating agent in distilla- these methods is an esterification of 2-methoxyacetic tions. These uses include industrial applications, such acid with diazomethane after lyophilization of the alkaline as polymerization reactions (e.g., of isoprene, styrene), urine solution and uptake in hydrochloric acid/dichloro- the manufacture of perfluorinated organic compounds methane (Groeseneken et al., 1986) or with (BUA, 1993a), reactions in boron chemistry (Brotherton trimethylsilyldiazomethane after extraction of the acid et al., 1999; Rittmeyer & Wietelmann, 1999), and its urine solution with dichloromethane/isopropyl alcohol application as a solvent for, for example, textile dyes, (Sakai et al., 1993). The determination was carried out in lacquers, and cosmetics (BUA, 1993a; Baumann & Muth, both cases with a GC/FID using a capillary column. The 1997). recovery rates were reported to be 31% (Groeseneken et al., 1986) and 98% (Sakai et al., 1993). The detection limits Diglyme is also used in the manufacture of inte- were 0.15 mg/litre (Groeseneken et al., 1986) and 0.05 grated circuit boards, primarily as a solvent for the mg/litre (Sakai et al., 1993). 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).

6 Diethylene glycol dimethyl ether

this and its use pattern, it is expected that the main target Diglyme is included in the European Inventory of compartment of the chemical will be the hydrosphere. Cosmetics Ingredients in the solvent category (EC, 1996). Its use in cosmetics in Germany and Canada was not 5.2 Transformation reported (BUA, 1993a; Clariant GmbH, personal communication, 2000; IKW [German Trade Association From GC measurements with an aqueous solution on Cosmetic and Detergent Preparations], personal of 47.2 g diglyme/litre (5% v/v) kept in the dark for communication, 2000; R. Gomes, Health Canada, 21 days (NTP, 1987), it has been concluded that the personal communication, 2001). Data for other countries chemical is hydrolytically stable. This is also to be are also not available. expected from diglyme’s chemical structure (Harris, 1990). EGEs in general are also used as auxiliary solvents in water-based paints that are industrially applied (e.g., Direct photolysis of diglyme is assumed to be of in the spraying of automobiles, metal furniture, house- minor importance due to diglyme’s weak absorption at hold appliances, and machines) (Karsten & Lueckert, wavelengths above 230 nm (Ogata et al., 1978a,b). NTP 1992; Baumann & Muth, 1997). It is not possible with the (1987) determined no decrease in the concentration of an available data to estimate the annual amount of diglyme aqueous solution of diglyme (47.2 g/litre) exposed to in this field of use or its application in water-based room light for 72 h. paints for consumer use. The reaction of gaseous diglyme with hydroxyl 4.4 Estimated global release radicals in the atmosphere has an experimentally deter- –11 3 mined rate constant KOH of 1.7 × 10 cm /molecule The global releases of diglyme cannot be estimated per second (Dagaut et al., 1988). Assuming an average with the available data. tropospheric hydroxyl radical concentration of about 6 × 105 molecules/cm3 (BUA, 1993b), the half-life of The releases from the production of diglyme at the diglyme can be calculated to about 19 h. Due to the German manufacturer for the year 1990 are estimated as miscibility of diglyme with water and its low Henry’s law follows: <2.5 g/tonne released into air, about 133–188 g/ constant (see section 2), diglyme is furthermore expected tonne released into water, and <7.5 kg/tonne released to be deposited easily with rain or other wet deposition. with solid wastes. The liquid wastes are disposed of in From this and its short half-life in atmospheric reactions, approved chemical waste incinerators (BUA, 1993a). long-distance transport of diglyme in ambient air is assumed to be negligible. Data on the degree of recycling of diglyme from its application as a solvent or as an inert reaction medium in From a Zahn-Wellens test following OECD Guide- industrial processes are not available. line 302B, adsorption of diglyme onto activated sludge was 17% after 3 h, and total removal was 42% after Information on the content of diglyme in consumer 28 days. The degree of elimination and the degradation products such as cosmetics or paints and lacquers is not curve are indicative of inherent primary degradation, available. It is assumed that any diglyme used in this according to OECD criteria (Hoechst, 1989a). way will end up in ambient air or domestic wastewater. 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 5. ENVIRONMENTAL TRANSPORT, further experiment in which diglyme was tested together DISTRIBUTION, TRANSFORMATION, AND with dioxane and other unspecified organic chemicals, ACCUMULATION 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 5.1 Transport and distribution between efficient in the presence of other carbon sources. High media salt concentrations in the wastewater, however, result in a decrease in biodegradation, indicated by a significant Diglyme is miscible with water and has a low increase in the lag phase. Henry’s law constant (see section 2), leading to a low Data on the anaerobic degradation of diglyme are volatility from aqueous solutions (Thomas, 1990). From not available.

7 Concise International Chemical Assessment Document 41

Data on the concentration of diglyme in soil or 5.3 Accumulation sediment are not available.

The log Kow of diglyme (!0.36; see section 2) indi- Data on the concentration of diglyme in biological cates a negligible potential for bioaccumulation. material are not available.

Measurements concerning the geoaccumulation of diglyme are not available. Data on the adsorption of the 6.2 Human exposure chemical onto activated sludge in the Zahn-Wellens test (see section 5.2) cannot be used for the estimation of 6.2.1 Workplaces adsorption onto soil. It is to be expected that the oxygen atoms in the diglyme molecule will lead to a high affinity There is a potential for inhalation or dermal contact for the microorganisms of the activated sludge but not in the chemical and allied product industries where for the humic acids or inorganic components of soils. diglyme is used as a solvent. From the physicochemical properties of the substance

(miscibility with water, low log Kow; see section 2), a low During the diglyme production process and its use tendency to sorption onto inorganic and organic soil as a solvent in chemical synthesis, inhalation and dermal substances is to be expected. contact are assumed to occur mainly during cleaning and maintenance operations, as solvents are handled mainly As a result of its highly hydrophilic character and in closed systems. its low tendency to volatilize from aqueous solutions or to adsorb to soil constituents, diglyme may reach No data are available on diglyme exposure con- groundwater. EGEs were detected particularly in anoxic centrations at the workplace. Data on other EGEs that are groundwater in the vicinity of US landfill sites (Ross et produced in the same way and that have a comparable al., 1992). The possibility that the chemical will subse- use pattern and similar volatilization behaviour may quently enter wells and drinking-water cannot be serve as a rough approximation. excluded. 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 6. ENVIRONMENTAL LEVELS AND correspond to airborne diglyme concentrations between HUMAN EXPOSURE 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 calcu- 6.1 Environmental levels lation model Estimation and Assessment of Substance Exposure (EASE) to be a maximum of 0.1 mg/cm2 per day, Data on the concentrations of diglyme in ambient based on the assumption that trained workers inci- or workplace air are not available. dentally have direct skin contact with diglyme during cleaning and maintenance operations. Assuming further 2 Diglyme was detected in surface water in the that exclusively the palms (an area about 420 cm ) are Dutch parts of the river Rhine at concentrations ranging exposed, this would lead to a maximum dermal body dose between 0.1 and 0.3 µg/litre (1978; five samples), 0.03 and of 0.6 mg/kg body weight per day (assuming a body 0.3 µg/litre (1979; five samples), and 0.5 and 5 µg/litre weight of 70 kg). (1985; six samples) (Morra et al., 1979; Linders et al., 1981; KIWA, 1986). More recent data or data from For the use of EGEs in the semiconductor industry, surface waters in other countries are not available. TWA exposure values between 0.01 and 0.55 ppm are reported (workplace operation not specified; ECETOC, In 1987, the chemical was determined in the bio- 1995). This would correspond to airborne diglyme 3 logically treated leakage from two French landfills at concentrations between about 0.06 and 3.1 mg/m . As concentrations in the order of 2–20 µg/litre (Lauret et al., diglyme is obviously used in mixtures with other EGEs 1989). Diglyme was furthermore determined but not (see, for example, Messner, 1988), the diglyme exposure quantified in 1992 in wastewater samples, from a German levels cannot be estimated from these data.The maximum oil reclaiming company, that had been pretreated by dermal dose could be assumed to be equal to the dose equalization, neutralization, adsorption to activated estimated for the production process (0.6 mg/kg body sludge, flocculation, and flotation (Gulyas et al., 1994). weight per day). Some authors report significant

8 Diethylene glycol dimethyl ether

permeation of protective gloves of different materials by tions (see section 5.1), inhalation exposure is assumed to EGEs. Gloves made of nitrile and butyl rubber or neo- be of minor importance. Dermal exposure cannot be prene provide the best protection (breakthrough rates quantified with the available data. $45 min) and are now the ones being used most fre- quently in the semiconductor industry (for review, see 6.2.3 Biological monitoring Paustenbach, 1988). As dermal exposure is significant, measurement of For the use of glycol ethers in professional diglyme in air is not sufficient for exposure monitoring. painting operations, the geometric means of the TWA Therefore, biological monitoring of the metabolite 2- exposure values were between 1.7 and 5.6 ppm, with methoxyacetic acid, which belongs to the metabolic maximum concentrations up to about 37.6 ppm pathway that is responsible for the developmental (workplace operation not specified; ECETOC, 1995). For effects and effects on the reproductive system, is diglyme, this would correspond to airborne preferable. Methods for detecting this metabolite in urine concentrations between 9.5 and 31 mg/m3, with a are described in section 3. 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 7. COMPARATIVE KINETICS AND synthesis (incidental contact during transferring/ METABOLISM IN LABORATORY ANIMALS weighing/mixing or cleaning and maintenance AND HUMANS procedures, exposure of palms [420 cm2] only: 0.1 mg 2 lacquer/cm per day). Assuming a maximum diglyme 7.1 Absorption content of the lacquer of 25% (Baumann & Muth, 1997), this results in a maximum dermal body dose of about 0.15 Studies on the metabolism of diglyme in rats show mg diglyme/kg body weight per day. that diglyme is absorbed from the gastrointestinal tract (Cheever et al., 1986, 1988). Absorption following 6.2.2 Consumer exposure inhalation can be concluded from the observation of poisoning symptoms in studies on single- and repeated- The main target compartment of diglyme is the dose exposure to diglyme and in analogy with other hydrosphere (see section 5.1). The chemical is inherently glycol ethers. biodegradable with a rather long log phase and a signifi- cant tendency to adsorb onto activated sludge (see In an in vitro study with human skin, the high section 5.2). From this and from its suspected use as a percutaneous absorption of glycol ethers (ECETOC, solvent in consumer products such as lacquers and 1995; Johanson, 1996) was confirmed. The permeability cosmetics, the main route of exposure of the general constant was 1 × 10–3 cm/h, and the lag time was approxi- population to diglyme is likely via the ingestion of mately half an hour. With these findings, diglyme was drinking-water and via dermal contact with the respec- among the glycol ethers with the highest absorption rate tive consumer products. (Filon et al., 1999).

The database is not sufficient to estimate the daily Dermal absorption of glycol ether liquids or intake of diglyme by the general population. vapours is very high (Johanson & Boman, 1991; ECETOC, 1995; Kezic et al., 1997; Brooke et al., 1998; Data on the concentration of diglyme in drinking- Johanson, 2000). With 2-methoxyethanol, for example, water are not available. dermal absorption of the vapour is approximately as high as absorption via inhalation. Dermal uptake of the liquid Quantitative information on dermal exposure to is very high: exposure of an area of 2000 cm2 for 1 h diglyme via cosmetic products is not available. Although resulted in a body dose of 5920 mg in a study with diglyme is included in the European Union’s Inventory human volunteers (Kezic et al., 1997). on Cosmetics Ingredients, its use was not reported for Germany or Canada (see section 4.3). For other countries, 7.2 Distribution and accumulation data are also not available. No studies are available that investigate the dis- Measured data on exposure to diglyme-containing tribution of radioactively labelled diglyme within the water-based paints and lacquers for consumer use are body. Glycol ethers in general are readily distributed not available. Furthermore, the relevance of diglyme as throughout the body (ECETOC, 1995). an auxiliary solvent in paints for consumer use cannot be estimated with the available data. Due to the low ten- The metabolite 2-methoxyacetic acid has shown dency of volatilization of diglyme from aqueous solu- evidence of accumulation in animals and humans. In

9 Concise International Chemical Assessment Document 41

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

Male Sprague-Dawley rats Pregnant CD-1 mice Cheever et al. Cheever et al. Richards et Daniel et al. Daniel et (1988) (1989a) al. (1993) (1986) 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 22 days – – – diglyme 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. humans, its half-life was calculated as 77.1 h (ECETOC, microsomes were found to be 7 times more effective than 1995). rat microsomes in converting diglyme to 2-methoxy- ethanol (Tirmenstein, 1993; Toraason et al., 1996). 7.3 Metabolism There is no apparent quantitative difference in the The metabolites identified in the urine following spectrum of metabolites, including 2-methoxyethoxy- oral application in different studies are given in Table 1. acetic acid and 2-methoxyacetic acid, over a 100-fold The metabolic pathway of diglyme is shown in Figure 1. dose range (6.84–684 mg/kg body weight; see Table 1).

The principal pathway of biotransformation of Repeated doses of diglyme or induction with diglyme involves O-demethylation with subsequent phenobarbital or ethanol increases the cleavage of the oxidation to form the main metabolite 2-methoxyethoxy- central ether linkage of diglyme as a result of cytochrome acetic acid, which accounts for about 60–70% of the P-450 enzyme induction in the liver (Cheever et al., 1988, dose in the urine of rats and pregnant mice after 48–96 h 1989a; Tirmenstein, 1993; ECETOC, 1995; Toraason et al., (Daniel et al., 1986; Cheever et al., 1988; Toraason et al., 1996). 1996) (see Table 1).

In addition, cleavage (O-dealkylation) of the cen- tral ether bond results in the formation of 2-methoxy- ethanol, which is subsequently oxidized to 2-methoxy- acetic 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

10 Diethylene glycol dimethyl ether

CH3 -O-CH2 -CH2 -O-CH 2-CH 2-O-CH3 Diethylene glycol dimethyl ether

CH3 -O-CH2 -CH2 -O-CH 2-CH 2-OH CH3 -O-CH2 -CH2 -OH 2-(2-Methoxyethoxy)ethanol 2-Methoxyethanol

CH3 -O-CH2 -CH2 -O-CH 2-COOH CH3 -O-CH2 -COOH 2-(2-Methoxyethoxy)acetic acid Methoxyacetic acid

HOOC-CH 2-O-CH2 -COOH CH3 -O-CH2 -CO-NH-CH2 -COOH Diglycolic acid N-Methoxyacetyl glycine

U R I N E

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

Although the main metabolite in rat urine is 2- 8. EFFECTS ON LABORATORY methoxyethoxyacetic acid, numerous studies indicate MAMMALS AND IN VITRO TEST SYSTEMS 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; 8.1 Single exposure BUA, 1993a). Further, 2-methoxyacetic acid was trans- ferred to the fetus and found as the sole metabolite in 8.1.1 Inhalation the fetus (no parent compound was detected in the fetus either) after dosing diglyme to mice at day 11 or 12 of A 7-h nose-only exposure (inhalation hazard test) pregnancy (Daniel et al., 1986, 1991). The highest levels to an atmosphere saturated with diglyme at room tem- for the average embryo (whole embryos analysed) were perature (about 10 g/m3) caused restlessness, narrowing detected at 6 h after dosing. Significantly lower amounts of palpebral fissures, and irregular breathing in rats. All were detected in blood taken from the dam at that time animals survived. Necropsy 14 days after exposure point (Daniel et al., 1991). revealed no macroscopic findings (Hoechst, 1979a).

7.4 Elimination 8.1.2 Oral administration

The major route of elimination is through the urine. The acute oral toxicity of diglyme is low. The oral Ninety-six hours after oral application of 6.84 mg LD50 for the female rat is 4760 mg/kg body weight diglyme/kg body weight to male Sprague-Dawley rats, (Hoechst, 1979b) and for the female mouse is 2978 mg/kg 90% of the dose was excreted via urine, 3.6% as carbon body weight (Plasterer et al., 1985). Poisoning symptoms dioxide, and 2.9% in the faeces. Only 1.7% of the dose were restlessness and breathing difficulties. Necropsy of remained in the carcass (Cheever et al., 1988). animals found dead revealed changes in lung and liver (no further information available).

11 Concise International Chemical Assessment Document 41

irritation after 24 h (Hoechst, 1979c; no further imately 7000 mg/kg body weight, assuming an intake of 7 information available). ml/day and a body weight of 20 g), the number of total white blood cells was more than doubled compared with 8.2.2 Sensitization controls. This increase was not, however, statistically significant (Nagano et al., 1984). For repeated-dose There are no data available. studies on effects of diglyme on male reproductive organs, see section 8.7. 8.3 Short-term exposure 8.4 Medium-term exposure 8.3.1 Inhalation There are no medium-term exposure studies Groups of 20 male and 10 female Crl:CD rats were available. 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 8.5 Long-term exposure and rats were killed after 10 days of exposure and 14, 42, or 84 carcinogenicity days post-exposure, respectively. Female rats were killed after the 10th exposure and 14 days post-exposure. Urine No studies are available on long-term exposure or analysis, haematological analyses, and histopathology carcinogenicity. were performed. Changes in the haematopoietic system occurred in both sexes and involved the bone marrow, 8.6 Genotoxicity and related end-points spleen, thymus, leukocytes, and erythrocytes. According to the authors, the no-observed-adverse- 8.6.1 In vitro studies effect level (NOAEL) for female rats was 370 ppm (2065 mg/m3). Males were more sensitive than females: Results of investigations of genotoxicity in vitro compared with controls, body weight gain as well as are given in Table 2. Diglyme was not mutagenic in mean leukocyte counts were dose dependently several Ames tests with or without S9 mix (Hoechst, decreased in all dose groups. Further, stage-specific 1979d,e; McGregor et al., 1983; Mortelmans et al., 1986). germ cell damage occurred at all concentrations and was concentration and time dependent (see section 8.7.1.1). Diglyme also had no effect in a test for unsched- Thus, for male rats, a NOAEL could not be established in uled DNA synthesis in human embryo fibroblasts this study (DuPont, 1988b; Lee et al., 1989; Valentine et (McGregor et al., 1983). al., 1999). 8.6.2 In vivo studies In another study with four male and four female Alderley Park rats per group exposed for 3 weeks, Diglyme did not induce chromosomal aberrations 6 h/day, to 200 and 600 ppm (1116 and 3348 mg/m3) in bone marrow cells in groups of 10 male and 10 female diglyme, urine analysis, haematological analyses, and CD rats exposed to 250 or 1000 ppm (1395 or 5580 mg/m3) histopathology (of a limited number of organs without diglyme 7 h/day for 1 or 5 days (McGregor et al., 1983). testes) were also performed. In contrast to the DuPont study cited above, no changes in haematological A dominant lethal test is described in section parameters were noted after exposure to 600 ppm 8.7.1.1 (McGregor et al., 1983). The reduced number of (3348 mg/m3). However, similar to the observations in pregnancies and an increase in preimplantation losses that study, body weight gain was affected and thymus may be due either to a dominant lethal effect or to was atrophied. Further, adrenals were congested. No reduced fertility of the males. Considering the known effects were found in the 200 ppm (1116 mg/m3) dose effects of diglyme on fertility, the authors of the study group (Gage, 1970). assume that reduced fertility is a cause of the effects. Also, the post-implantation losses may be due to 8.3.2 Oral reduced fertility instead of a dominant lethal effect, as it is known that early deaths may be a consequence of a In four male JCL-ICR mice that received diglyme in low number of implantations. the drinking-water for 25 days at a level of 2% (approx-

12 Diethylene glycol dimethyl ether

Table 2: Genotoxicity of diglyme in vitro.

Result Test system Strain/cell type Concentrations tested !S9 +S9 Remarks Reference Salmonella strain TA1535, TA1537, 0.3–100 µl per plate – – cytotoxicity at McGregor et al., mutagenicity test TA1538, TA98, TA100 100 µl per plate 1983

Salmonella strain TA1538, TA98, 20–70 µl per plate not tested – no cytotoxicity McGregor et al., mutagenicity test TA100 1983

Salmonella strain TA1535, TA1538, 0.01–10 mg per plate – – tested with rat Mortelmans et mutagenicity test TA98, TA100 and hamster S9, al., 1986 no cytotoxicity Salmonella strain TA1535, TA1537, 0.005–50 µl per plate – – cytotoxicity at 25 Hoechst, mutagenicity test TA1538, TA98, TA100 and 50 µl per 1979d,e plate

Unscheduled DNA human embryo fibroblasts 0.148–19 mg/ml – – no information on McGregor et al., synthesis cytotoxicity 1983 available

also affected. At 1100 ppm (6138 mg/m3) diglyme, marked A recessive lethal test on Drosophila testicular atrophy was found affecting all spermatogenic melanogaster exposed to 250 ppm (1395 mg/m3) for 2.75 stages. The effects were reversible within 84 days with h could not be evaluated because of an unusually high 110 and 370 ppm (614 and 2065 mg/m3), but not with 1100 death rate in a control group (McGregor et al., 1983). ppm (6138 mg/m3) (DuPont, 1988b; Lee et al., 1989; Valentine et al., 1999). 8.7 Reproductive toxicity In order to identify a NOAEL for effects on the 8.7.1 Effects on fertility testes, a second study was performed with the same study design but using lower concentrations of diglyme 8.7.1.1 Inhalation — 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 There are several well conducted studies available 98 ppm, corresponding to 0, 17.3, 55.2, 167, and 547 in which toxicity to the male reproductive organs has mg/m3). The post-exposure period was 14 days. Mean been investigated. body weights of rats exposed to 100 ppm (558 mg/m3) were significantly lower than those of controls at the end Groups of 20 male Crl:CD rats were exposed to 0, of the exposure period. The weights of testes, seminal 110, 370, or 1100 ppm (0, 614, 2065, or 6138 mg/m3) vesicles, prostate, and epididymides were similar to diglyme, 6 h/day, 5 days/week, for 2 weeks. Exposed rats those of controls. Microscopic examination of the testes were killed after 10 days of exposure and 14, 42, or revealed minimal or mild testicular atrophy in the 100 84 days post-exposure. Body weight gain was dose ppm (558 mg/m3) group. As is demonstrated in Table 3, dependently decreased. At 370 and 1100 ppm (2065 and some effects, such as degenerative germ cells in epidid- 6138 mg/m3), absolute weights of testes, epididymides, ymal tubules, spermatic granuloma in the epididymis, seminal vesicles, and prostrate were reduced; relative and prostatitis, also occurred at lower concentrations weights of testes were reduced at 1100 ppm (10 ppm [55.8 mg/m3] and higher) at the end of the (6138 mg/m3). Stage-specific germ cell damage was dose exposure as well as after the 14-day recovery period. and time dependent: at 110 ppm (614 mg/m3) diglyme, Most lesions were minimal to mild and occurred in 1/10 spermatocytes in pachytene and meiotic division at animals. However, it is not clear whether the different spermatogenic stages XII–XIV were mainly affected. At lesions observed occurred in the same or different ani- 370 ppm (2065 mg/m3) diglyme, affected germ cells were mals. Taking into consideration results from historical similar to those seen at 110 ppm (614 mg/m3) diglyme, but controls (no data given) as well, the authors of round spermatids at spermatogenic stages I–VIII were

13 Concise International Chemical Assessment Document 41

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 12 1, minimal 1, minimal cells 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.

this study considered 30 ppm (167 mg/m3) to be the but particularly in weeks 5 through 7 after exposure, NOAEL (DuPont, 1989). when frequencies were only about 10%. Further, preimplantation losses in these weeks were large, and In a dominant lethal test, groups of 10 male adult there was evidence of post-implantation losses. CD rats were exposed to 0, 250, or 1000 ppm (0, 1395, or Recovery from the influence of diglyme in exposed males 5580 mg/m3) diglyme for 7 h/day on 5 consecutive days, was complete in week 10 (McGregor et al., 1981, 1983; then serially mated at weekly intervals for 10 weeks to Hardin, 1983). untreated virgin females in the ratio 1 male:2 females. Male rats exposed to 1000 ppm (5580 mg/m3) showed a Changes in sperm shape were investigated in mice: reduction in body weight. The female rats were killed and groups of 10 B6C3F1 mice were exposed to 0, 250, or 1000 examined 17 days after they were first caged with the ppm (0, 1395, or 5580 mg/m3) 7 h/day for 4 days, and males. No effect on frequency of pregnancy was seen in sperm were isolated 35 days after the exposure. Four the 250 ppm (1395 mg/m3) group. However, large mice of the 1000 ppm (5580 mg/m3) group were found reductions in pregnancy frequency occurred in the 1000 dead on the morning of the 4th exposure day. Mice of ppm (5580 mg/m3) exposure group in weeks 4 through 9, both exposure groups showed a reduction in body

14 Diethylene glycol dimethyl ether

weight gain. While no changes compared with the (Nagano et al., 1984; Price et al., 1987; Schwetz et al., controls were observed in the 250 ppm (1395 mg/m3) 1992). group, a significant increase in morphologically altered sperm (32%; control 5%) was found in the 1000 ppm (5580 8.7.2.1 Inhalation mg/m3) group. All categories of abnormalities were involved to some extent: hook upturned or hook In a teratogenicity study, rats exposed by inhala- elongated, banana-shaped head, amorphous head, folded tion to 25, 100, or 400 ppm (140, 558, or 2232 mg/m3) tail, and others. Most frequent were amorphous heads, diglyme during days 7–16 of gestation, the highest which were increased to 20.87% in the 1000 ppm (5580 concentration of 400 ppm (2232 mg/m3) caused 100% mg/m3) group compared with 2.18% in the air control. resorptions (DuPont, 1988a; Driscoll et al., 1998). From the timing of exposure and investigations, the Malformations found in low incidences at all dosages authors concluded that the spermatocytes had been included abnormally formed tails, distended lateral damaged (McGregor et al., 1981, 1983). ventricles of the brain, axial skeletal malformations (vertebral fusions, hemivertebrae), and appendicular In conclusion, from these studies, the NOAEL malformations (aberrant clavicular and scapular for effects on the testes/spermatocytes is 30 ppm formation, bent fibula, radius, tibia, and ulna). Further, (167 mg/m3). structural variations, primarily delayed ossification, were found. The lowest dose of 25 ppm (140 mg/m3) caused a 8.7.1.2 Oral slightly increased incidence of variations. Although these defects were not significantly different from Groups of five Sprague-Dawley rats received up control values (with the exception of the incidence of to 20 daily oral doses of distilled water or diglyme at skeletal developmental variations), the pattern, type, and 684 mg/kg body weight. Testicular changes were incidence of variations were similar to those seen at analysed, including a subsequent recovery over an 100 ppm (558 mg/m3), suggesting, according to the 8-week period. Primary and secondary spermatocyte authors, that 25 ppm (140 mg/m3) was an effect level that degeneration and spermatidic giant cells were observed approaches the lower end of the developmental toxicity after 6–8 treatments. From day 12 of treatment until response curve. Therefore, the authors of the study 8 weeks after cessation of exposure, the testes to body concluded that a NOAEL could not clearly be demon- weight ratio was significantly reduced (Cheever et al., strated for the fetus. As increased relative liver weights 1985, 1986, 1988). Testicular LDH-X activity, a pachytene were found in the dams at 100 ppm (558 mg/m3), the spermatocyte marker enzyme, was significantly decreased NOAEL for diglyme exposure in the dams is 25 ppm (140 in animals by day 18 of treatment (Cheever et al., 1985, mg/m3). 1989b). 8.7.2.2 Oral No changes compared with controls were found in testicular weight and the combined weight of seminal In an oral application study with rabbits, similar vesicles and coagulating gland in four male JCL-ICR mice effects were noted as after inhalation (NTP, 1987; that received diglyme in the drinking-water for 25 days at Schwetz et al., 1992). The number of resorptions as well a level of 2% (approximately 7000 mg/kg body weight, as the number of malformations were increased at doses assuming an uptake of 7 ml/day and a body weight of 20 of $100 mg/kg body weight. Abnormal development of g) (Nagano et al., 1984). the kidneys and axial skeleton and clubbing of the limbs without underlying skeletal involvement were the most 8.7.2 Developmental toxicity frequently presented individual defects. At 50 mg/kg body weight, percentages of prenatal mortality and Studies on the developmental toxicity of diglyme, malformed fetuses per litter were both (statistically non- including experimental details, are summarized in Table 4. significantly) increased but accounted for a significant Diglyme was a developmental toxicant both via inhalation overall increase in the percentage of adversely affected and by the oral route in rats, rabbits, and mice. It is implants per litter. In the NTP (1987) study as well as in capable of disrupting normal morphogenesis in a wide the analysis by Kimmel (1996), 50 mg/kg body weight is variety of tissues and organ systems, and the diversity of considered as the lowest-observed-adverse-effect level fetal malformations observed was hypothesized to be due (LOAEL), and 25 mg/kg body weight as the NOAEL. In to a general toxic effect upon proliferating cells, which contrast, in the subsequent publication by Schwetz et al. was also evident from the studies on male fertility (1992), the authors discussed that 50 mg/kg body weight

15 Table 4: Developmental toxicity of diglyme.

Species/ Maternal Fetal strain/ Concentration/ NOAEL/ NOAEL/ number per group Exposurea dose Effects b LOAEL LOAEL Reference rats inhalation, 6 0, 25, 100, 400 $25 ppm (140 mg/m3): fetal weights 9, variations (delayed ossification, NOAEL LOAEL DuPont (1988a), CD h/day, days 7–16 ppm (0, 140, rudimentary ribs) (mean percentage of fetuses per litter with variations): 25 ppm 25 ppm Driscoll et al. (1998) 25–26 558, 2232 44.5% versus controls 32.1% (140 mg/m3) (140 mg/m3) mg/m3) 100 ppm (558 mg/m3): dams: relative liver weight 8, 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 9; variations (mean percentage of fetuses per litter with variations): 74.5% versus controls 32.1% 400 ppm (2232 mg/m3): dams: food consumption 9, body weight gain 9; resorptions 100% rabbits gavage in distilled 0, 25, 50, 100, $50 mg/kg body weight: dams: weight gain 9 (due to decrease in gravid NOAEL NOAEL NTP (1987) New Zealand water, days 6–19 175 mg/kg body uterine weight), 100 mg/kg body weight 25 mg/kg body weight 15–25 weight adversely affected implants per litter 8 (21.4%, controls 7.9%) $100 mg/kg body weight: gravid uterine weight 9, prenatal mortality (mainly from resorptions) 8, malformations 8 (mainly abnormal development of the kidneys and axial skeleton and clubbing of the NOAEL NOAEL Schwetz et al. limbs) 25 mg/kg body weight 50 mg/kg body weight (1992) 175 mg/kg body weight: dams: faecal output 9, mortality 8 (15%, controls 4%) mice gavage in distilled 0, 62.5, 125, $125 mg/kg body weight: fetal weights 9 NOAEL NOAEL NTP (1985), Price et CD-1 water, days 6–15 250, 500 mg/kg $250 mg/kg body weight: dams: weight gain 9 (due to decrease in 500 mg/kg body weight 62.5 mg/kg body al. (1987) 20–24 body weight gravid uterine weight); late fetal deaths 8, malformations 8 (mainly weight 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) 9; resorptions 8 mice gavage in distilled 0, 537 mg/kg only examination for gross external malformations and fetal body weight Hardin & CD-1 water, on day 11 body weight 537 mg/kg body weight: malformations 8 (paws, digits) Eisenmann (1986, not given 1987) mice gavage in distilled 0, 3000 mg/kg reproductive screening according to Chernoff and Kavlock, no systematic Schuler et al. CD-1 water, days 6–13 body weight examination for malformations (1984), Plasterer et 49 3000 mg/kg body weight: dams: mortality 8 (20/49); no viable litters al. (1985), Hardin et (0/27) al. (1987) a Days refers to days of pregnancy. b 8 = increased compared with controls; 9 = decreased compared with controls. Diethylene glycol dimethyl ether

appears to be the bottom end of the dose–response curve concentration of 1000 ppm (5580 mg/m3) caused a higher and therefore considered 50 mg/kg body weight as the number of abnormal sperm than 500 ppm (1550 mg/m3) 2- NOAEL. methoxyethanol; thus, considering equimolar concentrations, diglyme seems to be somewhat more In mice, the NOAELs were 500 mg/kg body weight toxic. Mice produce higher concentrations of 2- for maternal effects and 62.5 mg/kg body weight for methoxyacetic acid than rats; therefore, mice may be developmental effects. At 125 mg/kg body weight, the more susceptible than rats to the toxic effects of diglyme. only fetal effects were reduced body weights. Malfor- Considering that 2-methoxyethanol is only a minor mations were seen at 250 mg/kg body weight and above. metabolite of diglyme, other metabolites or other Characteristic malformations associated with diglyme pharmacokinetic behaviours of diglyme compared with 2- were neural tube closure defects and dysmorphogenesis methoxyethanol may contribute to the toxicity of of the axial and appendicular skeleton (NTP, 1985; Price et diglyme. al., 1987). Further defects of digits and paws were found, which also occurred in another study with mice (Hardin & In both fertility and developmental studies, the Eisenmann, 1986, 1987) dosed with 537 mg/kg body metabolite 2-methoxyethanol (DuPont, 1988a; Driscoll et weight only on day 11 of pregnancy. al., 1998) and other ethylene glycol dimethyl ethers (Plasterer et al., 1985; Hardin & Eisenmann, 1986, 1987; The NTP study in mice (NTP, 1985; Price et al., Hardin et al., 1987) gave similar results. In the DuPont 1987) has served to illustrate a model that was developed study (DuPont, 1988a; Driscoll et al., 1998), both 25 ppm for assessing the probability of being abnormal by (78 mg/m3) 2-methoxyethanol and 25 ppm (140 mg/m3) applying the combination of the parameters fetal death, diglyme resulted in significantly more total variations weight, and malformation (Catalano et al., 1993). The and variations due to retarded development in rats.

LED05 (the lower 95% confidence limit of the dose Mean percentages of fetuses per litter with variations corresponding to 5% excess risk), which was derived were 46% for 2-methoxyethanol and 45% for diglyme according to the benchmark dose approach, was 99 mg/kg compared with 32% in the control. Similarly, in the body weight. This was lower than the LED05 for the studies of Hardin et al. (Hardin & Eisenmann, 1986, 1987; individual parameters, but higher than the NOAEL of 62.5 Hardin et al., 1987), the teratogenic potency for paw mg/kg body weight. defects in mice was higher with 2-methoxyethanol than with diglyme when used in equimolar concentrations. 8.8 Other toxicity/mode of action After treatment with 304 mg 2-methoxyethanol/kg body weight, 60.1% of the fetuses had alterations in the hind The main metabolite of diglyme, 2-methoxyethoxy- paws, compared with 38% after treatment with 537 mg acetic acid, did not show any effect on the testes at diglyme/kg body weight and 0.6 or 0% in concurrent equimolar concentrations (Cheever et al., 1986, 1988). controls. Further, monoethylene glycol dimethyl ether Instead, the pattern of diglyme-induced testicular injury is showed a similar toxicity in this study, with 30.4% of the qualitatively similar to that produced by the metabolite 2- fetuses with alterations of the hind paws, while trieth- methoxyethanol (McGregor et al., 1981, 1983; Cheever et ylene glycol dimethyl ether did not show any effect. al., 1985, 1986, 1988; Lee et al., 1989). In the study of Finally, the study of Plasterer et al. (1985) with mice Cheever et al. (1985) with rats, both compounds exhibited showed that very high doses of monoethylene glycol testicular toxicity primarily affecting pachytene and dimethyl ether, diglyme, and triethylene glycol dimethyl dividing stages of spermatocytes at lower exposure ether all caused complete resorptions. levels. In comparing the testicular toxicity of equimolar dosages of 2-methoxyethanol (388 mg/kg body weight) Thymus atrophy has been reported in rats in two and diglyme (684 mg/kg body weight), 2-methoxyethanol inhalation studies (Gage, 1970; DuPont, 1988b; Lee et al., was more potent than diglyme. Spermatocytes were 1989; Valentine et al., 1999) following exposure to high affected after only one treatment with 2-methoxyethanol, concentrations of diglyme. Further, the number of whereas repeated diglyme treatments were required to leukocytes was decreased. This is consistent with produce the same effects. Similarly, in the inhalation studies on other EGEs, where mechanistic studies study of Lee et al. (1989) with rats, the toxic effects of 300 indicate that the immune system is a sensitive target for ppm (930 mg/m3) 2-methoxyethanol in the testes were toxicity in the rat and that the proximate immunotoxicant very similar to but more severe than those of 370 ppm is methoxyacetic acid (ECETOC, 1995). (2065 mg/m3) diglyme. In mice, both compounds produced sperm anomalies (McGregor et al., 1981, 1983). A diglyme

17 Concise International Chemical Assessment Document 41

The metabolite 2-methoxyacetic acid, which is the retrospective study, information on pregnancy generated from 2-methoxyethanol by the action of alcohol outcomes and potential confounders (age, smoking, dehydrogenase, may be important for the toxic effects. It ethnicity, education, income, year of pregnancy, and can undergo activation to methoxyacetyl coenzyme A stress) was obtained through a comprehensive inter- and enter the Krebs cycle or fatty acid biosynthesis. viewer-administered interview of female employees Several metabolites of 2-methoxyethanol — for example, (Beaumont et al., 1995). The prospective study of early 2-methoxy-N-acetyl glycine — have been identified that fetal loss and fecundity (probability of conception per support this pathway (Sumner et al., 1992; Jenkins- menstrual cycle) was conducted in a subset of female Sumner et al., 1996). Thus, 2-methoxyacetic acid may employees from five plants. Daily diaries and measure- interfere with essential metabolic pathways of the cell, ments of daily urinary human chorionic gonadotrophin and it was hypothetized that this causes the testicular (hCG) levels for 6 months were collected in addition to lesions and malformations. This is supported by the the comprehensive interview (Eskanazi et al., 1995a,b). Of finding that simple physiological compounds (e.g., serine, the 891 medically verified pregnancies identified for the formate, acetate, glycine, and glucose) are able to protect retrospective study, 774 (86.9%) were live births, 113 against these effects (Johanson, 2000). (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 9. EFFECTS ON HUMANS 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 As a consequence of the results of the animal significantly increased for female workers in the studies revealing effects on fertility as well as develop- photolithography group (RR = 1.67; 95% CI = 1.04–2.55) mental toxicity of EGEs, several epidemiological studies and in the etching group (RR = 2.08; 95% CI = 1.27–3.19). have been carried out to investigate reproductive end- For women working with higher levels of EGE only in points in workers with exposure to EGEs. Diglyme is only masking, the risk for spontaneous abortion was one compound of this substance class, however increased 3-fold (RR = 3.38; 95% CI = 1.61–5.73) (Swan & (see section 2). A metabolite of EGEs and diglyme, 2- Forest, 1996). In the prospective study, no statistically methoxyethanol, is also used as a solvent, and one significant differences were detected in the overall rate of epidemiological study of painters exposed to 2-methoxy- spontaneous abortions between fabrication and non- ethanol is also discussed. fabrication workers or when pregnancy outcomes were examined by work group (Eskenazi et al., 1995a). 9.1 Reproductive effects However, the ability to conceive was lower among female workers exposed to EGEs (fertility rate [FR] = 0.37; EGEs including diglyme are used in the manufacture 95% CI = 0.11–1.19) (Eskenazi et al., 1995b). of semiconductors. Epidemiological studies of three semiconductor populations evaluated potential adverse Correa et al. (1996) conducted a retrospective reproductive outcomes. It is unclear from the descriptions evaluation of reproductive outcomes among both provided by the authors whether these populations women employed and wives of men employed at two overlapped. In each of these studies, workers were semiconductor plants in the eastern USA (also reported exposed to mixtures including diglyme but not to diglyme by Gray et al., 1996). Gray et al. (1996) also reported on alone. In a single study of painters, exposure included a the results of a prospective study of reproductive metabolite of diglyme and EGEs. outcomes at the same plants. Exposure to EGEs in the retrospective study was assessed by questionnaire One of the semiconductor populations included administered to the employees in combination with workers from 14 different companies. The study included company records. There were 115 pregnancies to both retrospective and prospective study designs. semiconductor manufacturing workers — 561 to female Exposure to EGEs was determined using questionnaires employees and 589 to wives of male employees. There from subjects about the work performed and an was a significantly elevated risk of spontaneous assessment of the work environment by industrial abortion (odds ratio [OR] = 2.8; 95% CI = 1.4–5.6) and hygienists, but no measurements of personal or area subfertility (taking more than 1 year of sexual intercourse exposures were made (Hammond et al., 1995). Workers in to conceive) (OR = 4.6; 95% CI = 1.6–13.3) among female the fabrication area were considered exposed to EGEs. For employees in the highest exposure group. The risks of

18 Diethylene glycol dimethyl ether

spontaneous abortion and subfertility were not diglyme measured or used alone. In a cross-sectional significantly elevated in the low and medium exposure study of 94 shipyard painters exposed to measurable groups. A significant (P = 0.02) dose–response levels of 2-ethoxyethanol and 2-methoxyethanol and relationship across low, medium, and high exposure 55 unexposed controls, Welch & Cullen (1988) found categories was found for both end-points for EGE 10% of painters with haemoglobin levels consistent with exposure. Among wives of male employees exposed to anaemia (P = 0.02) and 3.4% of painters and no controls EGEs, there was no evidence of an increased risk of with abnormally low levels of polymorphonuclear spontaneous abortion but a suggestion of an increased leukocytes (P = 0.07). In a second cross-sectional study risk of subfertility. In the prospective study (Gray et al. of 40 workers employed in the production of ethylene 1996), early-morning urine samples were assayed for hCG glycol monoether, the overall proportion of exposed and ovarian steroid hormones to detect early pregnancy workers with abnormal haemoglobin levels or white and early pregnancy loss. The study found no evidence blood cell counts did not differ from unexposed controls of a decreased conception rate, but there was a non- (n = 25) (Cook et al., 1982). Controlling for potential age, significantly elevated risk of pregnancy loss. duration, and intensity of exposure using logistic regression suggested a statistically significant decrease Pastides et al. (1988) found an increased risk of (27%) in white blood cell counts. A small study of nine spontaneous abortion among females employed in the individuals who laid parquet floors and matched pairs of diffusion area of a semiconductor manufacturing plant healthy donors showed no changes in haemoglobin or (RR = 2.2; n = 18 pregnancies; 95% CI = 1.1–3.6) and in erythrocyte levels but higher frequencies of NK-cells the photolithographic area (RR = 1.8; n = 16 pregnancies; (anti-Leu7) and B lymphocytes (Denkhaus et al., 1986). 95% CI = 0.8–3.3) compared with unexposed controls (n Exposures included measurable concentrations of 2- = 398 pregnancies). No measurements of workplace butoxyethanol, 2-ethoxyethanol, 2-methoxyethanol, exposure were available in this study. Exposures toluene, xylene, 2-butanone, and other solvents. No included several glycol ethers and other chemicals, such association was found between use of products contain- as arsine, phosphine, diborane, xylene, toluene, and ing glycol ethers and myeloid acute leukaemia in a study hexamethyldisilane. of 198 matched pairs (Hours et al., 1996).

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 10. EFFECTS ON OTHER ORGANISMS IN 2-methoxyethanol/m3 (mean 2.6 mg/m3) and to 0–80.5 mg THE LABORATORY AND FIELD 2-ethoxyethanol (= ethylene glycol monoethyl ether)/m3 (mean 9.9 mg/m3). Skin contact with 2-methoxyethanol and 2-ethoxyethanol was also considered possible. 10.1 Aquatic environment Exposure to numerous other substances, including organic solvents and metals, was also known to occur. For the toxicity data mentioned in this section, it is While no effects were seen in hormone levels or in sperm not always stated whether the cited effect values are viability, motility, and morphology, the prevalence of based on nominal or measured concentrations of those with oligospermia differed between the groups. diglyme. In some cases (Hoechst, 1994, 1995), the The proportion of men with a sperm density #100 concentration of the test substance is detected by the 3 million/cm was higher in the exposed group than in the determination of dissolved organic carbon or carbon in unexposed group (33% vs. 20%; P = 0.20). The the solution. However, due to the water solubility, low proportion of those with oligospermia among painters volatility, and low adsorption potential of diglyme (see who did not smoke compared with controls was 36% vs. sections 2 and 5), all nominal concentrations of the test 16% (P = 0.05). The proportion of those with substance are expected to correspond to effective oligospermia was similar between painters and controls concentrations, even in tests with open systems and who smoked (30% vs. 38%; P = 0.49). The proportion of longer exposure periods. painters with azoospermia was 5% compared with 0% in the controls. The acute toxicity of diglyme to golden orfes (Leuciscus idus) was determined in a static test, which 9.2 Haematological effects 1 gave a 96-h LC0 of $2000 mg/litre. An acute toxicity test

The relationship between exposure to EGEs and haematological effects has been evaluated in three 1 Hoechst (1979) Abwasserbiologische Untersuchung von occupational populations. In none of these studies was Dialkylglykoläthern auf die Goldorfe (Leuciscus idus).

19 Concise International Chemical Assessment Document 41 with Daphnia magna conducted according to OECD 11. EFFECTS EVALUATION 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 concern- 11.1 Evaluation of health effects ing the toxicity of diglyme to algae (Scenedesmus sub- spicatus), conducted according to OECD Guideline 201, 11.1.1 Hazard identification and the 72-h EC10 was $1000 mg/litre (highest concentration exposure–response assessment tested) (Hoechst, 1995). Diglyme is rapidly absorbed from the gastrointes-

The LC50 values for the acute effect of diglyme on tinal tract, metabolized, and excreted mainly in the urine. tadpoles of the frog species Rana brevipoda were In analogy to other EGEs, it is assumed that diglyme is between 22 000 and 8300 mg/litre (test periods between 3 readily absorbed through the skin. The main metabolite and 48 h) (Nishiuchi, 1984). is 2-methoxyethoxyacetic acid. The reproductive toxicity of diglyme, however, is attributed to the minor metabolite In an activated sludge respiration inhibition test 2-methoxyacetic acid, which is generated from 2- conducted according to EC Guideline 88/302 Part C methoxyethanol. There are species differences in the

(OECD Guideline 209), an EC10 of >1000 mg/litre was amount metabolized to this metabolite: mice and humans determined (Hoechst, 1989b). may produce higher amounts and thus be more suscep- tible than rats. Only acute toxic effects have been examined in the tests above. One should be aware of possible effects of The acute toxicity of diglyme is low after oral diglyme on reproduction, as observed in tests with exposure or inhalation. Diglyme is slightly irritating to mammals (see sections 8.7 and 9.1). the skin or eye. No investigations are available on the sensitizing effects of diglyme. 10.2 Terrestrial environment Several Ames tests as well as an unscheduled A study of the effect of diglyme on the spore DNA synthesis test did not reveal a genotoxic potential germination rate and the mycelial growth rate of the of diglyme in vitro. Further, the number of chromosomal terrestrial fungus Cladosporium resinae (strain 35A) aberrations was not increased in bone marrow cells in isolated from Australian soil samples gave a toxic vivo. The positive results of a dominant lethal test may threshold concentration of 9430 mg/litre (1% v/v) and be due to the effects of diglyme on fertility. a concentration for complete inhibition of the mycelial growth of 188 600 mg/litre (Lee & Wong, 1979). The main targets of the toxicity of diglyme are the reproductive organs in male animals. Dose-dependent In a screening test on fumigating agents against changes have been shown for weights of testes, oriental and Mediterranean fruit flies (Dacus dorsalis epididymides, prostate, and seminal vesicles. 3 and Ceratitis capitata), a 48-h LD50 of >98 mg/m was Microscopic evaluation revealed atrophy of the testes, determined for 24-h-old shell-less eggs and mature larvae with developing spermatocytes being the cells mainly of each species after a 2-h fumigation (Burditt et al., affected. Effects were found in rats and mice in several 1963). 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 Frankfurt am Main, Hoechst AG, 2 pp. (unpublished test of resorptions, and an increased incidence of variations/ results). malformations in a wide variety of tissues and organ

20 Diethylene glycol dimethyl ether

systems have been found. A LOAEL of 25 ppm body weight. Applying safety factors of 10 for inter- (140 mg/m3) has been identified in rats for the inhalation individual variability and 10 for interspecies variation, a route, and a NOAEL of 25 mg/kg body weight has been guidance value of 0.25 mg/kg body weight would be identified in rabbits for the oral route. Maternal toxicity obtained. indicated by reduced weight gain was rather low. The relevance of these findings for humans is shown by the 11.1.3 Sample risk characterization fact that they are found in three different species — rats, rabbits, and mice — and also by different routes of Assuming that exposure concentrations for exposure (inhalation and oral). diglyme are the same as for other EGEs, the TWA for exposure in the production process may be up to 36 The risk for spontaneous abortion was evaluated mg/m3, in the semiconductor industry up to 3 mg/m3, and in two large epidemiological studies of female workers in in painting operations up to 31 mg/m3. These the semiconductor industry with exposure to EGEs concentrations are considerably higher than the including diglyme. One of these studies also examined guidance value for the general population of 0.6 mg/m3, the risk to wives of male employees with EGE exposure. derived above. In addition, high dermal uptake of The studies found an association of the risk of sponta- diglyme has to be taken into consideration. It has to be neous abortion with occupational exposure to EGEs. One recognized, furthermore, that protective gloves may of these studies found evidence of a dose–response allow significant permeation of diglyme. Gloves made of relationship. The risk of spontaneous abortion from nitrile and butyl rubber or neoprene provide the best exposure to diglyme alone could not be evaluated. protection.

The effect of EGEs on conception rates in exposed In conclusion, from the sample risk characterization female workers is not clear. The conception rate was for the workplace, there is high concern for possible assessed in two prospective studies. One study found human health effects. No information is available on the slightly decreased rates; no effects were observed in the presence or concentrations of diglyme in cosmetics; other. because of its reprotoxic potency, all exposure of the general public to diglyme should be avoided. Painters exposed to the solvent 2-methoxyethanol, which is also a metabolite of diglyme, were found to 11.1.4 Uncertainties in the evaluation of human have an increased prevalence of oligospermia and health effects azoospermia. The painters were also exposed to numer- ous other substances, including organic solvents and There is a high degree of confidence that the metals, however. reproductive system is the target of the toxicity of diglyme. This is concluded from consistent results from 11.1.2 Criteria for setting tolerable intakes/ experiments in several animal species with different concentrations or guidance values for routes of application. Epidemiological studies indicate a diglyme risk for humans as well.

A guidance value for uptake of diglyme via No long-term animal studies have been conducted inhalation according to EHC 170 (IPCS, 1994) can be with diglyme. Therefore, not all end-points could be based on the developmental toxicity study in rats reliably assessed, and there is some uncertainty con- (DuPont, 1988a; Driscoll et al., 1998), which gave a cerning the NOAELs derived from short-term studies. LOAEL of 25 ppm (140 mg/m3). As the LOAEL of 25 ppm (140 mg/m3) is, according to the authors, at the bottom No data are available for the possible use of end of the dose–response curve, a safety factor of 2 diglyme in cosmetics, which may be an important source seems to be sufficient to extrapolate to a NOAEL. of consumer exposure. Applying further a safety factor of 10 for interindividual variability and 10 for interspecies variation, a guidance 11.2 Evaluation of environmental effects value of about 0.1 ppm (0.6 mg/m3) would be obtained. Diglyme releases into the environment are to be For the oral route, no NOAEL from a reliable expected from its use as a solvent, reaction medium, and repeated-dose toxicity study is available. If one assumes, separating agent in industrial processes. A minor con- however, that, as in inhalation studies, developmental tribution from diglyme-containing consumer products toxicity is the most relevant end-point, one could use the (cosmetics, water-based paints) is possible but cannot study with rabbits, which gave a NOAEL of 25 mg/kg be quantified with the available data.

21 Concise International Chemical Assessment Document 41

The main target compartment of diglyme is the REFERENCES hydrosphere. The chemical is inherently biodegradable with a rather long log phase and significant adsorption to activated sludge. Bioaccumulation and Atkinson R (1989) Kinetics and mechanisms of the gas-phase geoaccumulation are of minor importance. reactions of the hydroxyl radical with organic compounds. Journal of physical and chemical reference data, 1:143.

In the available experimental studies, diglyme Baumann W, Muth A (1997) Farben und Lacke: Daten und exhibited a low toxicity to aquatic organisms. The 48-h Fakten zum Umweltschutz. Berlin, Springer.

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 Beaumont JJ, Swan SH, Hammond SK, Samuels SJ, Green RS, Hallock MF, Dominguez C, Boyd P, Schenker MB (1995) expected that the given EC0/EC10 concentrations will be Historical cohort investigation of spontaneous abortion in the exceeded in surface waters, where monitoring measure- semiconductor health study: Epidemiologic methods and ments in the early 1980s gave diglyme concentrations of analyses of risk in fabrication overall and in fabrication work American journal of industrial medicine #0.005 mg/litre. Therefore, the available data do not groups. , 28:735–750. indicate a significant risk of diglyme to aquatic organ- Brooke I, Cocker J, Delic JI, Payne M, Jones K, Gregg NC, Dyne isms. D (1998) Dermal uptake of solvents from the vapour phase: an experimental study in humans. Annals of occupational hygiene, Due to the lack of measured exposure levels, a 42:531–540. sample risk characterization with respect to terrestrial Brotherton RJ, Weber CJ, Guibert CR, Little JL (1999) Boron organisms cannot be performed. However, from the use compounds. In: Ullmann’s encyclopedia of industrial chemistry, pattern of diglyme, significant exposure of terrestrial 6th ed. Weinheim, Wiley VCH (electronic release). organisms is not to be expected. 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). 12. PREVIOUS EVALUATIONS BY BUA (1993b) OH-Radikale in der Troposphäre; Konzentration INTERNATIONAL BODIES und Auswirkung. GDCh Advisory Committee on Existing Chemicals of Environmental Relevance (BUA). Stuttgart, Hirzel, pp. 1–163 (BUA-Report 100).

Previous evaluations by international bodies were Burditt AK Jr, Hinman FG, Balock JW (1963) Screening of fumi- not identified. gants for toxicity to eggs and larvae of the oriental fruit fly and Mediterranean fruit fly. Journal of economic entomology, 56:261–265.

Catalano PJ, Scharfstein DO, Ryan LM, Kimmel CA, Kimmel GL (1993) Statistical model for fetal death, fetal weight, and malfor- mation in developmental toxicity studies. Teratology, 47(4):281– 290.

Cheever KL, Weigel WW, Richards DE, Lal JB, Plotnick HB (1985) Testicular effects of bis(2-methoxyethyl) ether in the adult male rat: equimolar dose comparison with 2-methoxyethanol and 2-ethoxyethanol. Toxicologist, 5:140.

Cheever KL, Richards DE, Weigel WW, Lal JB, Dinsmore AM, Daniel FB (1986) Metabolism of a testicular toxin, bis(2- methoxyethyl) ether, in the rat. Toxicologist, 6:32.

Cheever KL, Richards DE, Weigel WW, Lal JB, Dinsmore AM, Daniel FB (1988) Metabolism of bis(2-methoxyethyl) ether in the adult male rat: evaluation of the principal metabolite as a testicular toxicant. Toxicology and applied pharmacology, 94:150–159.

Cheever KL, Richards DE, Weigel WW, Begley KB (1989a) The role of enzyme induction on metabolite formation of bis(2- methoxyethyl) ether in the rat. Toxicology and industrial health, 5:601–607.

22 Diethylene glycol dimethyl ether

Cheever KL, Weigel WW, Richards DE, Lal JB, Plotnick HB Prospective assessment of fecundability of female (1989b) Testicular effects of bis(2-methoxyethyl)ether in the semiconductor workers. American journal of industrial medicine, adult male rat. Toxicology and industrial health, 5:1099–1109. 28(6):817–831.

Cook RR, Bodner KM, Kolesar RC, Uhlmann CS, VanPeenen Filon FL, Fiorito A, Adami G, Barbiere P, Coceani N, Bussar R, PFD, Dickson GS, Flanagan K (1982) A cross-sectional study of Reisenhofer E (1999) Skin absorption in vitro of glycol ethers. ethylene glycol monomethyl ether process employees. Archives International archives of occupational and environmental health, of environmental health, 37(6):346–351. 72:480–484.

Corn M, Cohen R (1993) Real-time measurement of sub-ppm Funasaki N, Hada S, Neya S, Machida K (1984) Intramolecular concentrations of airborne chemicals in semiconductor hydrophobic association of two alkyl chains of oligoethylene manufacturing. Journal of exposure analysis and environmental glycol diethers and diesters in water. Journal of physical epidemiology, 3(S1):37–49. chemistry, 88:5786–5790.

Correa A, Gray RH, Cohen R, Rothman N, Shah F, Seacat H, Gage JC (1970) The subacute inhalation toxicity of 109 Corn M (1996) Ethylene glycol ethers and risks of spontaneous industrial chemicals. British journal of industrial medicine, abortion and subfertility. American journal of epidemiology, 27:1–18. 143(7):707–717. Gray RH, Correa A, Hakim R, Cohen R, Corn M, Shah F, Dagaut P, Wallington IJ, Liu R, Kurylo MJ (1988) 22nd Rothman N, Hou W, Secat H (1996) Ethylene glycol ethers and International Symposium on Combustion, Seattle, WA [cited in reproductive health in semiconductor workers. Occupational Atkinson, 1989]. hygiene, 2(1–6):331–338.

Daniel FB, Eisenmann C, Cheever KL, Richards DE, Weigel WW Greim H, ed. (1994) Diethylene glycol dimethyl ether. In: (1986) Metabolism of a reproductive toxin bis-2-methoxyethyl Occupational toxicants. Critical data evaluation for MAK values ether in the pregnant mouse. Teratology, 33:75C. and classification of carcinogens. Weinheim, Wiley-VCH, pp. 41–50. Daniel FB, Cheever KL, Begley KB, Richards DE, Weigel WW, Eisenmann CJ (1991) Bis(2-methoxyethyl)ether: metabolism and Groeseneken D, van Vlem E, Veulemans H, Masschelein R embryonic disposition of a developmental toxicant in the (1986) Gas chromatographic determination of methoxyacetic pregnant CD-1 mouse. Fundamental and applied toxicology, and ethoxyacetic acid in urine. British journal of industrial 16(3):567–575. medicine, 43:62–65.

Denkhaus W, Steldern DV, Botzenhardt U, Konietzko H (1986) Gulyas H, Reich M, Sekoulov I (1994) Characterisation of a Lymphocyte subpopulations in solvent-exposed workers. Inter- biologically treated wastewater from oil reclaiming: recording of national archives of occupational and environmental health, low molecular weight organics and estimation of humic 57:109–115. substances. Water science and technology, 29(9):195–198.

Driscoll CD, Valentine R, Staples RE, Chromey NC, Kennedy GL Hammond SK, Hines CJ, Hallock MF, Woskie SR, Jr (1998) Developmental toxicity of diglyme by inhalation in the Abdollahzadeh S, Iden CR, Anson E, Ramsey F, Schenker MB rat. Drug and chemical toxicology, 21(2):119–136. (1995) Tiered exposure-assessment strategy in the semiconductor health study. American journal of industrial medicine, DuPont (1988a) Teratogenicity study of diglyme in the rat. 28(6):661–680. Newark, NJ, E.I. Du Pont de Nemours & Co., 289 pp. Hardin BD (1983) Reproductive toxicity of the glycol ethers. DuPont (1988b) Subchronic inhalation toxicity study with Toxicology, 27:91–102. diglyme. Newark, NJ, E.I. Du Pont de Nemours & Co., 445 pp. Hardin BD, Eisenmann CJ (1986) Relative potency of four DuPont (1989) Subchronic inhalation toxicity study with ethylene glycol ethers for induction of paw malformations in the diglyme. Newark, NJ, E.I. Du Pont de Nemours & Co., 187 pp. mouse. Teratology, 33:85C.

EC (1996) The international nomenclature of cosmetic Hardin BD, Eisenmann CJ (1987) Relative potency of four ingredients. European Commission (http://www.cosmetic- ethylene glycol ethers for induction of paw malformations in the world.com/inci/default.htm). CD-1 mouse. Teratology, 35:321–328.

ECETOC (1995) The toxicology of glycol ethers and its Hardin BD, Schuler RL, Burg JR, Booth GM, Hazelden KP, relevance to man. Brussels, European Centre for Ecotoxicology MacKenzie KM, Piccirillo VJ, Smith KN (1987) Evaluation of 60 and Toxicology of Chemicals, pp. 1–350 (Technical Report No. chemicals in a preliminary developmental toxicity test. Terato- 64). genesis, carcinogenesis, mutagenesis, 7:29–48.

Eskenazi B, Gold EB, Lasley BL, Samuels SJ, Hammond SK, Harris JC (1990) Rate of hydrolysis. In: Lyman WJ, Reehl WF, Wight S, O’Neill Rasor M, Hines CJ, Schenker MB (1995a) Rosenblatt DH, eds. Handbook of chemical property estimation Prospective monitoring of early fetal loss and clinical methods: Environmental behavior of organic compounds. New spontaneous abortion among female semiconductor workers. York, NY, McGraw-Hill Book Company, pp. 7-1–7-48. American journal of industrial medicine, 28(6):833–846. Hoechst (1979a) Inhalationstoxizität im Zeitsättigungstest von Eskenazi B, Gold EB, Samuels SJ, Wight S, Lasley BL, Diethylenglykol-dimethylether an männlichen und weiblichen Hammond SK, O’Neill Rasor M, Schenker MB (1995b)

23 Concise International Chemical Assessment Document 41

SPF-Wistar-Ratten. Frankfurt am Main, Hoechst AG, 10 pp. Johanson G (1996) An overview of glycol ethers metabolism and (Report 488/79; unpublished). toxicokinetics. Occupational hygiene, 2:5–24.

Hoechst (1979b) Akute orale Toxizität von Diethylenglykol- Johanson G (2000) Toxicity review of ethylene glycol dimethylether an weiblichen Ratten. Frankfurt am Main, Hoechst monomethyl ether and its acetate ester. Critical reviews in AG, 4 pp. (Report 376/79; unpublished). toxicology, 30:307–345.

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Hoechst (1979d) Test for mutagenicity in bacteria strains in the Karsten E, Lueckert O (1992) Lackrohstofftabellen, 9th ed. absence and presence of a liver preparation. Frankfurt am Main, Hanover, Curt R. Vincentz Verlag. Hoechst AG, 7 pp. (Report 53/79; unpublished). Kezic S, Mahieu K, Monster AC, de Wolff FA (1997) Dermal Hoechst (1979e) Mutagenicity evaluation of diethyleneglycol- absorption of vaporous and liquid 2-methoxyethanol and 2- dimethylether in the Ames Salmonella/microsome plate test. ethoxyethanol in volunteers. Occupational and environmental Frankfurt am Main, Hoechst AG, 15 pp. (Report 743/79, medicine, 54:38–43. unpublished). Kimmel CA (1996) Reproductive and developmental effects of Hoechst (1989a) Prüfberichte: ökologische Untersuchungen. diethylene and triethylene glycol (methyl-, ethyl-) ethers. Frankfurt am Main, Hoechst AG, 4 pp. (unpublished report). Occupational hygiene, 2:131–151.

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Hoechst (1990) DIN-Sicherheitsdatenblatt vom 06.07.1990. Lauret J-M, Prud’homme E, Salmon P (1989) Recherche sur le Frankfurt am Main, Hoechst AG, 2 pp. (unpublished report). traitement biologique des lixiviats des centres d’enfouissement technique. Techniques sciences methodes, 3:149–158. Hoechst (1991) Schriftliche Mitteilung vom 12.09.1991. Frankfurt am Main, Hoechst AG, 8 pp. (unpublished report). Lee KH, Wong HA (1979) Toxic effects of some alcohol and ethylene glycol derivatives on Cladosporium resinae. Applied Hoechst (1994) Prüfung der toxischen Wirkung von Diethylen- and environmental microbiology, 38:24–28. glykoldimethylether auf Kleinkrebse (Daphnia magna). Hoechst AG, Frankfurt am Main (unpublished report). Lee KP, Kinney LA, Valentine R (1989) Comparative testicular toxicity of bis(2-methoxyethyl)ether and 2-methoxyethanol in Hoechst (1995) Prüfung der Schadwirkung gegenüber Algen rats. Toxicology, 59:239–258. (Algentoxizität) von Diethylenglykoldimethylether. Hoechst AG, Frankfurt am Main (unpublished report). Linders JBHJ, Morra CFH, den Boer AC, Ruijgrok CTM (1981) Inventory of organic substances in the river Rhine in 1979. Hours M, Dananche B, Caillat-Vallet E, Fevotte J, Philippe J, Leidschendam, National Institute for Water Supply, pp. 1–42. Boiron O, Fabry J (1996) Glycol ethers and myeloid acute leukemia: a multicenter case control study. Occupational McGregor DB, Willins MJ, McDonald P, Holmstrom M, McDonald hygiene, 2:405–410. D, Neimeier R (1981) Bis-2-methoxyethyl ether and 2-methoxy ethanol results from multiple assay for genotoxic potential. HSDB (1983) Hazardous Substances Data Bank. Bethesda, MD, Environmental mutagenesis, 3:381–382. National Library of Medicine. McGregor DB, Willins MJ, McDonald D, Holmstrom M, McDonald Hubner B, Geibel K, Angerer J (1992) Gas-chromatographic D, Niemeier RW (1983) Genetic effects of 2-methoxyethanol and determination of propylene- and diethylene glycol ethers in bis(2-methoxyethyl)ether. Toxicology and applied pharmacology, urine. Fresenius journal of analytical chemistry, 342:746–748. 70:303–316.

IPCS (1994) Assessing human health risks of chemicals: Messner G (1988) Experiences and considerations to derivation of guidance values for health-based exposure limits. environmental and working place protection. Processing of Geneva, World Health Organization, International Programme Probimer 52. Galvanotechnik, 79:3072–3079. on Chemical Safety (Environmental Health Criteria 170). Morra CF, Linders JB, den Boer A, Ruijgrok TM, Zoeteman BC IPCS (2000) International Chemical Safety Card — Diethylene (1979) Organic chemicals measured during 1978 in the river glycol dimethyl ether. Geneva, World Health Organization, Rhine in the Netherlands. Leidenschendam, National Institute International Programme on Chemical Safety (ICSC 1357). for Water Supply, pp. 1–21.

Jenkins-Sumner S, Stedman D, Cheng S, Welsch F, Fennell T Mortelmans K, Haworth S, Lawlor T, Speck W, Tainer B, Zeiger (1996) Characterization of urinary metabolites produced E (1986) Salmonella mutagenicity tests: II. Results from the following administration of [1,2, methoxy-13C]-2-methoxyethanol testing of 270 chemicals. Environmental mutagenesis, to male F-344 rats and pregnant CD-1 mice. Occupational 8(S7):1–119. hygiene, 2:25–31.

24 Diethylene glycol dimethyl ether

Nagano K, Nakayama E, Oobayashi H, Nishizawa T, Okuda H, p-nitrophenol, sodium selenite, dimethyl phthalate, Yamazaki K (1984) Experimental studies on toxicity of ethylene ethylenethiourea, and four glycol ether derivatives. Journal of glycol alkyl ethers in Japan. Environmental health perspectives, toxicology and environmental health, 15:25–38. 57:75–84. Plieninger P, Marchl D (1999) Occurrence of ester and ether NIOSH (1990) Criteria for a recommended standard: derivatives of polyvalent alcohols in indoor air of 200 Berlin occupational exposure to ethylene glycol monobutyl ether and households. In: Indoor Air ’99, Proceedings of the 8th ethylene glycol monobutyl acetate. Appendix A. Methods for International Conference on Indoor Air Quality and Climate, sampling and analysis of EGBE and EGBEA in air. Cincinnati, Edinburgh, Scotland, 8–13 August 1999. Vol. 4. London, OH, National Institute for Occupational Safety and Health Construction Research Communications Ltd., pp. 171–176. (DHHS (NIOSH) Publication No. 90-118; http://www.cdc.gov/niosh/90-118.html). Price CJ, Kimmel CA, George JD, Marr MC (1987) The develop- mental toxicity of diethylene glycol dimethyl ether in mice. NIOSH (1991) Criteria for a recommended standard: Fundamental and applied toxicology, 8:115–126. occupational exposure to ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, and their acetates. Appendix Rebsdat S, Mayer D (1999) Ethylene glycol. In: Ullmann’s ency- A. Methods for sampling and analysis of EGME, EGEE, EGMEA, clopedia of industrial chemistry, 6th ed. Weinheim, Wiley VCH and EGEEA in air. Cincinnati, OH, National Institute for (electronic release). Occupational Safety and Health (DHHS (NIOSH) Publication No. 91-119). Richards DE, Begley KB, DeBord DG, Cheever KL, Weigel WW, Tirmenstein MA, Savage RE Jr (1993) Comparative metabolism NIOSH (1996) Volatile organic compounds (screening) Method of bis(2-methoxyethyl)ether in isolated rat hepatocytes and in 2549. In: NIOSH manual of analytical methods, 4th ed. the intact rat: effects of ethanol on in vitro metabolism. Archives Cincinnati, OH, National Institute for Occupational Safety and of toxicology, 67(8):531–537. Health, 8 pp. (http://ehs.clemson.edu/niosh/pdfs/2549.pdf). Rittmeyer P, Wietelmann U (1999) Hydrides. In: Ullmann’s Nishiuchi Y (1984) Toxicity of agrochemicals to freshwater encyclopedia of industrial chemistry, 6th ed. Weinheim, Wiley organisms. III. Solvents. Suisan Zoshoku, 32:115–119. VCH (electronic release).

NTP (1985) Teratologic evaluation of diethylene glycol dimethyl Ross B, Johanson G, Foster GD, Eckel WP (1992) Glycol ethers ether (CAS No. 111-96-6) administered to CD-1 mice on as groundwater contaminants. Applied hydrogeology, 1:66–76. gestational day 6 through 15. Research Triangle Park, NC, National Institute of Environmental Health Sciences, National Roy D, Anagnostu G, Chaphalkar P (1994) Biodegradation of Toxicology Program (NTP-85-255; PB86-135233). dioxane and diglyme in industrial waters. Journal of environmental science and health, Part A, Environmental NTP (1987) Teratologic evaluation of diethylene glycol dimethyl science and engineering, 29(1):129–147. ether (CAS No. 111-96-6) administered to New Zealand White rabbits on gestation days 6 through 19. Research Triangle Park, Sakai T, Araki T, Masuyama Y (1993) Determination of urinary NC, National Institute of Environmental Health Sciences, alkoxyacetic acids by a rapid and simple method for biological National Toxicology Program (NTP-87-108; PB 87-209532). monitoring of workers exposed to glycol ethers and their acetates. International archives of occupational and OECD (1997) The 1997 OECD list of high production volume environmental health, 64:495–498. chemicals. Paris, Organisation for Economic Co-operation and Development. Schuler RL, Hardin BD, Niemeier RW, Booth G, Hazelden K, Piccirillo V, Smith K (1984) Results of testing fifteen glycol Ogata Y, Tomizawa K, Fujii K (1978a) Photo-induced oxidation ethers in a short-term in vivo reproductive toxicity assay. of diethylene glycol dimethyl ether and analogues with aqueous Environmental health perspectives, 57:141–146. hydrogen peroxide. Bulletin of the Chemical Society of Japan, 51:2628–2633. Schwetz BA, Price CJ, George JD, Kimmel CA, Morrissey RE, Marr MC (1992) The developmental toxicity of diethylene and Ogata Y, Takagi K, Suzuki T (1978b) Photolytic oxidation of triethylene glycol dimethyl ethers in rabbits. Fundamental and ethylene glycol dimethyl ether and related compounds by applied toxicology, 19(2):238–245. aqueous hypochlorite. Journal of the Chemical Society — Perkin Transactions II, 2:562–567. Stolz P, Weis N, Krooss J (1999) Nomenclature and occurrence of glycols and their derivatives in indoor air. In: Salthammer T, Pastides H, Calabrese EJ, Hosmer DW, Harris DR Jr (1988) ed. Organic indoor air pollutants, occurrence-measurement- Spontaneous abortion and general illness symptoms among evaluation. Weinheim, Wiley VCH, pp. 117–125. semiconductor manufacturers. Journal of occupational medicine, 30:543–551. Sumner SCJ, Stedman DB, Clarke DO, Welsch F, Fennell TRJ (1992) Characterization of urinary metabolites from [1,2, Paustenbach DJ (1988) Assessment of the developmental risks methoxy-13C]-2-methoxyethanol in mice using 13C nuclear resulting from occupational exposure to selected glycol ethers magnetic resonance spectroscopy. Chemical research in within the semiconductor industry. Journal of toxicology and toxicology, 5:553–560. environmental health, 23:29–75. Swan SH, Forest W (1996) Reproductive risks of glycol ethers and Plasterer MR, Bradshaw WS, Booth GM, Carter MW, Schuler RL, other agents used in semiconductor manufacturing. Hardin BD (1985) Developmental toxicity of nine selected com- Occupational hygiene, 2(1–6):373–385. pounds following prenatal exposure in the mouse: naphthalene,

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Thomas RG (1990) Volatilization from water. In: Lyman WJ, Reehl WF, Rosenblatt DH, eds. Handbook of chemical property estimation methods: Environmental behavior of organic compounds. New York, NY, McGraw-Hill Book Company, pp. 15.1–15.34.

Tirmenstein MA (1993) Comparative metabolism of bis(2- methoxyethyl) ether by rat and human hepatic microsomes: Formation of 2-methoxyethanol. Toxicology in vitro, 7(5):645–652.

Toraason M, Richards DE, Tirmenstein MA (1996) Metabolism of diglyme by rat hepatocytes and human microsomes. Occupational hygiene, 2(1–6):33–43.

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Welch LS, Schrader SM, Turner TW, Cullen MR (1988) Effects of exposure to ethylene glycol ethers on shipyard painters: II. Male reproduction. American journal of industrial medicine, 14:509–526.

26 Diethylene glycol dimethyl ether

APPENDIX 1 — SOURCE DOCUMENTS APPENDIX 2 — CICAD PEER REVIEW

BUA (1993a) Diethylene glycol dimethyl ether The draft CICAD on diglyme was sent for review to institu- (bis(2-methoxyethyl)-ether). GDCh Advisory tions and organizations identified by IPCS after contact with IPCS national contact points and Participating Institutions, as Committee on Existing Chemicals of Environ- well as to identified experts. Comments were received from: mental Relevance (BUA). Stuttgart, Hirzel, pp. 1–64 (BUA Report 67) M. Baril, International Programme on Chemical Safety/ Institut de Recherche en Santé et en Sécurité du Travail For the BUA review process, the company that is in charge du Québec, Canada of writing the report (usually the largest producer in Germany) prepares a draft report using literature from an extensive R. Benson, Drinking Water Program, US Environmental literature search as well as internal company studies. This draft is Protection Agency, USA subject to a peer review in several readings of a working group consisting of representatives from government agencies, the R. Cary, Health and Safety Executive, United Kingdom scientific community, and industry. R. Chhabra, National Institute of Environmental Health The original German version of this report was published Sciences, National Institutes of Health, USA in 1991. J. Gift, National Center for Environmental Assessment, US Environmental Protection Agency, USA

Greim H, ed. (1994) Diethylene glycol dimethyl R. Hertel, Federal Institute for Health Protection of ether. In: Occupational toxicants. Critical data Consumers and Veterinary Medicine, Germany evaluation for MAK values and classification of carcinogens. Weinheim, Wiley-VCH, pp. 41–50 C. Hiremath, National Center for Environmental Assessment, US Environmental Protection Agency, USA The scientific documentations of the German Commission P. Howden, Health and Safety Executive, United for the Investigation of Health Hazards of Chemical Compounds Kingdom in the Work Area (MAK) are based on critical evaluations of the available toxicological and occupational medical data from G. Johanson, National Institute for Working Life, Sweden extensive literature searches and of well documented industrial data. The evaluation documents involve a critical examination S. Kristensen, National Industrial Chemicals Notification of the quality of the database indicating inadequacy or doubtful and Assessment Scheme, Australia validity of data and identification of data gaps. This critical evaluation and the classification of substances are the result of J. Montelius, National Institute for Working Life, Sweden an extensive discussion process by the members of the Commission proceeding from a draft documentation prepared by H. Savolainen, Ministry of Social Affairs and Health, members of the Commission, by ad hoc experts, or by the Finland Scientific Secretariat of the Commission. Scientific expertise is guaranteed by the members of the Commission, consisting of K. Ziegler-Skylakakis, Commission of the European experts from the scientific community, industry, and employers Communities/European Union, Luxembourg associations.

27 Concise International Chemical Assessment Document 41

APPENDIX 3 — CICAD FINAL REVIEW Professor M. van den Berg, Environmental Sciences and Toxicology, Institute for Risk Assessment Sciences, University of BOARD Utrecht, Utrecht, The Netherlands

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

28 Diethylene glycol dimethyl ether

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

29 DIETHYLENE GLYCOL DIMETHYL ETHER 1357 October 2000 CAS No: 111-96-6 Bis(2-methoxyethyl) ether RTECS No: KN3339000 Diglyme UN No: 1993 1,1'-Oxybis(2-methoxyethane) Dimethyl carbitol

C6H14O3 / (CH3OCH2CH2)2O Molecular mass: 134.2

TYPES OF HAZARD/ ACUTE HAZARDS/SYMPTOMS PREVENTION FIRST AID/FIRE FIGHTING EXPOSURE

FIRE Flammable. NO open flames, NO sparks, and Powder, water spray, foam, carbon NO smoking. dioxide.

EXPLOSION Above 51°C explosive vapour/air Above 51°C use a closed system, In case of fire: keep drums, etc., mixtures may be formed. ventilation. cool by spraying with water.

EXPOSURE AVOID EXPOSURE OF (PREGNANT) WOMEN!

Inhalation Cough. Shortness of breath. Ventilation, local exhaust, or Fresh air, rest. breathing protection.

Skin MAY BE ABSORBED! Redness. Protective gloves. Protective Remove contaminated clothes. clothing. Rinse skin with plenty of water or shower.

Eyes Redness. Pain. Safety spectacles. First rinse with plenty of water for several minutes (remove contact lenses if easily possible), then take to a doctor.

Ingestion Burning sensation. Do not eat, drink, or smoke during Rinse mouth. work.

SPILLAGE DISPOSAL PACKAGING & LABELLING

Ventilation. Collect leaking liquid in sealable UN Hazard Class: 3 containers. Absorb remaining liquid in sand or inert UN Pack Group: III absorbent and remove to safe place. (Extra personal protection: filter respirator for organic gases and vapours).

EMERGENCY RESPONSE STORAGE

NFPA Code: H1; F2; R1 Fireproof. Separated from strong oxidants, strong bases, and strong acids.

Prepared in the context of cooperation between the International IPCS Programme on Chemical Safety and the European Commission International © IPCS 2000 Programme on Chemical Safety SEE IMPORTANT INFORMATION ON THE BACK. 1357 DIETHYLENE GLYCOL DIMETHYL ETHER

IMPORTANT DATA Physical State; Appearance Routes of exposure COLOURLESS LIQUID, WITH CHARACTERISTIC ODOUR. The substance can be absorbed into the body by inhalation of its vapour and through the skin. Chemical dangers The substance can form explosive peroxides. Reacts with Inhalation risk strong acids, strong bases, and strong oxidants. A harmful contamination of the air can be reached rather quickly on evaporation of this substance at 20°C. Occupational exposure limits TLV not established. Effects of short-term exposure MAK: 5 ppm; 27 mg/m3; H (1999) The substance irritates the eyes, the skin and the respiratory MAK: class II,1 (1999) tract.

Effects of long-term or repeated exposure May cause reproductive toxicity in humans.

PHYSICAL PROPERTIES

Boiling point: 162°C Relative density of the vapour/air-mixture at 20°C (air = 1): 1.01 Melting point: -68°C Flash point: 51°C c.c. Relative density (water = 1): 0.95 Auto-ignition temperature: 190°C Solubility in water: miscible Explosive limits, vol% in air: 1.5-17.4 Vapour pressure, kPa at 20°C: 0.33 Octanol/water partition coefficient as log Pow: -0.36 Relative vapour density (air = 1): 4.6

ENVIRONMENTAL DATA

NOTES Check for peroxides prior to distillation; eliminate if found.

ADDITIONAL INFORMATION

LEGAL NOTICE Neither the EC nor the IPCS nor any person acting on behalf of the EC or the IPCS is responsible for the use which might be made of this information

©IPCS 2000 Concise International Chemical Assessment Document 41

RÉSUMÉ D’ORIENTATION Il est légèrement irritant pour la peau et la muqueuse oculaire. On ne dispose d’aucune étude sur l’effet sensibilisant de ce composé. Le présent CICAD consacré à l’éther diméthylique de diéthylène-glycol (désigné sous le nom de diglyme L’expérimentation animale montre que chez le mâle, dans ce qui suit) a été préparé par l’Institut Fraunhofer c’est principalement l’appareil reproducteur qui est de recherche sur la toxicologie et les aérosols, de touché après exposition répétée. Lors d’une étude au Hanovre (Allemagne). La décision d’inclure le diglyme cours de laquelle on a fait inhaler du diglyme pendant dans la série des CICAD a été prise en raison de la 2 semaines à des rats mâles, on a observé une diminution crainte que l’on peut avoir au sujet d’éventuels effets de du poids du testicule, de l’épididyme, de la prostate et ce composé sur la santé humaine, notamment en ce qui des vésicules séminales. Les testicules étaient atrophiés concerne la fonction de reproduction. Ce CICAD repose et on a constaté une atteinte des spermatocytes. Ces sur un certain nombre de rapports établis par le Comité études ont permis de fixer à 30 ppm (167 mg/m3) la consultatif GDCh sur les substances chimiques d’impor- concentration sans effet nocif observable (NOAEL) et à tance écologique (BUA, 1993a) ainsi que par la MAK- 100 ppm (558 mg/m3) la concentration la plus faible Komission allemande (Greim, 1994). Il a été procédé en produisant un effet observable (LOAEL). Des études sur mars 2000 à un dépouillement bibliographique exhaustif la souris ont révélé des anomalies morphologiques des bases de données existantes, afin de rechercher des affectant les spermatozoïdes et consistant principalement références à des publications postérieures aux rapports dans la présence d’une tête amorphe, après exposition à en question. Des informations sur la préparation et 1000 ppm (5580 mg/m3). Après avoir été exposés par la l’examen par des pairs des sources documentaires voie respiratoire à de fortes concentrations de diglyme, utilisées sont données à l’appendice 1. L’appendice 2 mâles et femelles ont également présenté des anomalies fournit des renseignements sur l’examen par des pairs du affectant le système hématopoïétique et consistant présent CICAD. Ce CICAD a été approuvé en tant notamment en une modification du nombre de qu’évaluation internationale lors d’une réunion du leucocytes et une atrophie splénique et thymique. Comité d’évaluation finale qui s’est tenue à Genève du 8 au 12 janvier 2001. La liste des participants à cette On ne dispose d’aucune étude à long terme sur le réunion figure à l’appendice 3. La Fiche internationale diglyme; il n’est donc pas possible d’évaluer tous les sur la sécurité chimique du diglyme (ICSC 1357), établie points d’aboutissement éventuels de son action toxique. par le Programme international sur la sécurité chimique Aucune génotoxicité n’a été mise en évidence in vitro, (IPCS, 2000), est également reproduite dans le présent que ce soit par divers tests d’Ames ou par recherche document. d’une synthèse non programmée de l’ADN. In vivo, on ne constate pas non plus d’augmentation du nombre des Le diglyme (No CAS 111-96-6) se présente sous la aberrations chromosomiques dans les cellules de la forme d’un liquide incolore dégageant une odeur légère moelle osseuse. et agréable. Il est miscible à l’eau et à un certain nombre de solvants organiques courants. Il peut donner Des tests de létalité dominante effectués sur des naissance à des peroxydes en présence d’oxydants. rats ont montré que le nombre de gravidités était Comme il est dipolaire et aprotique, on l’utilise sensiblement réduit chez le rat après exposition à principalement comme solvant (dans l’industrie des 1000 ppm (5580 mg/m3), mais pas à la concentration de semi-conducteurs, en synthèse chimique et dans les 250 ppm (1395 mg/m3). Les résultats positifs de ces tests laques), comme milieu réactionnel inerte en synthèse et pourraient s’expliquer par une action du diglyme sur la pour certaines séparations par distillation. fertilité.

A l’état liquide ou sous forme de vapeurs, le Les études de tératogénicité effectuées sur des diglyme est facilement absorbé quelle que soit la voie rats, des lapins et des souris ont révélé des effets d’exposition, puis métabolisé et excrété dans les urines. dépendant de la dose sur le poids foetal, le nombre de Son principal métabolite est l’acide 2-méthoxyéthoxy- résorptions et l’incidence des anomalies et des acétique, l’acide 2-méthoxyacétique étant un métabolite malformations affectant un grand nombre de tissus et secondaire. Chez le rat, il est présent dans la proportion d’organes à des concentrations par ailleurs non toxiques de 5 à 15 % dans les urines. pour les mères. Lors d’une étude consacrée aux effets sur le développement avec exposition par la voie Après exposition par voie orale ou respiratoire, le respiratoire, on a trouvé une LOAEL égale à 25 ppm (140 diglyme ne présente qu’une faible toxicité aiguë. mg/m3); dans le cas d’une exposition par voie orale, la NOAEL était de 25 mg/kg de poids corporel pour le lapin

32 Diethylene glycol dimethyl ether

et de 62,5 mg/kg de poids corporel pour la souris. Les Selon les données disponibles, l’exposition au effets toxique du diglyme sur la fonction de reproduction diglyme n’implique pas de risque important pour les sont attribués à son métabolite secondaire, l’acide 2- organismes aquatiques. Comme on ne connaît pas les méthoxyacétique. niveaux d’exposition, il n’est pas possible de donner une caractérisation représentative du risque couru par les Des études épidémiologiques sur des femmes organismes terrestres. Toutefois, compte tenu du mode travaillant dans l’industrie des semi-conducteurs et d’utilisation du diglyme, il n’y a pas lieu de craindre une exposées de par leur profession à des éthers éthyliques exposition importante. 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 travail- leurs de l’industrie des semi-conducteurs sont exposés à un certain nombre de substances potentiellement tox- iques 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 logarith- mique 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 bio- accumulation 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.

33 Concise International Chemical Assessment Document 41

RESUMEN DE ORIENTACIÓN El destino principal en los animales machos tras ingestas repetidas de diglime son los órganos reproduc- tores. En estudios de inhalación de dos semanas en ratas Este CICAD relativo al éter de dietilenglicoldimetilo macho, se observó una reducción dependiente de la (denominado en lo sucesivo diglime) fue preparado por dosis del peso de los testículos, el epidídimo, la próstata el Instituto Fraunhofer de Toxicología y de Investigación y las vesículas seminales. Se atrofiaron los testículos y sobre los Aerosoles de Hannover, Alemania. Se se detectaron daños en los espermatocitos. La seleccionó el diglime para someterlo a examen en la serie concentración sin efectos adversos observados de los CICAD debido a las preocupaciones que (NOAEL) en estos estudios fue de 30 ppm (167 mg/m3); suscitaba en relación con la salud humana, en particular la concentración más baja con efectos adversos sus posibles efectos reproductivos. El CICAD se basa observados (LOAEL) fue de 100 ppm (558 mg/m3). En los en los informes compilados por el Comité Consultivo experimentos con ratones se puso de manifiesto una Alemán sobre las Sustancias Químicas Importantes para alteración morfológica del esperma, principalmente con el Medio Ambiente (BUA, 1993a) y la MAK-Kommission cabezas amorfas, tras la exposición a 1000 ppm alemana (Greim, 1994). En marzo de 2000 se realizó una (5580 mg/m3). Tras la exposición por inhalación a investigación bibliográfica amplia de bases de datos concentraciones elevadas, también se observaron pertinentes para buscar cualquier referencia publicada efectos en el sistema hematopoyético de los animales con posterioridad a las incorporadas a estos informes. La machos y hembras, por ejemplo cambios en el recuento información sobre la preparación de los documentos de leucocitos y atrofia del bazo y el timo. originales y su examen colegiado figura en el Apéndice 1. La información acerca del examen colegiado de este No hay estudios prolongados disponibles del CICAD se presenta en el Apéndice 2. Este CICAD se diglime; por consiguiente, no se pueden evaluar de aprobó como evaluación internacional en una reunión de manera fidedigna todos los efectos finales. En varias la Junta de Evaluación Final celebrada en Ginebra (Suiza) pruebas de Ames y en una prueba de síntesis de ADN del 8 al 12 de enero de 2001. La lista de participantes en no programado no apareció ningún posible efecto geno- esta reunión figura en el Apéndice 3. La Ficha tóxico del diglime in vitro. Tampoco se observó un internacional de seguridad química (ICSC 1357) para el aumento del número de aberraciones cromosómicas en diglime, preparada por el Programa Internacional de las células de la médula ósea in vivo. Seguridad de las Sustancias Químicas (IPCS, 2000), también se reproduce en el presente documento. En una prueba de dominancia letal con ratas, el número de gestaciones se redujo significativamente tras El diglime (CAS Nº 111-96-6) es un líquido incoloro la exposición a 1000 ppm (5580 mg/m3), pero no con ligeramente aromático. Es miscible en agua y en algunos 250 ppm (1395 mg/m3). Los resultados positivos pueden disolventes orgánicos comunes. En presencia de deberse a los efectos del diglime en la fecundidad. agentes oxidantes, puede formar peróxido. Debido a sus propiedades apróticas dipolares, el diglime se utiliza En estudios de teratogenicidad con ratas, conejos principalmente como disolvente (industria de los semi- y ratones se detectaron efectos del diglime dependientes conductores, síntesis química, barnices), como medio de de la dosis en el peso fetal, el número de resorciones y la reacción inerte en la síntesis química y como agente incidencia de variaciones y malformaciones en una separador en las destilaciones. amplia variedad de tejidos y sistemas de órganos a concentraciones que no eran tóxicas para la madre. En El diglime, en forma líquida o de vapor, se absorbe un estudio de inhalación en ratas, la LOAEL para los fácilmente por todas las vías de exposición, se metabo- efectos en el desarrollo fue de 25 ppm (140 mg/m3); la liza y se excreta principalmente en la orina. El metabolito NOAEL para la vía oral fue de 25 mg/kg de peso corporal más importante es el ácido 2-metoxietoxiacético. El ácido en conejos y de 62,5 mg/kg de peso corporal en ratones. 2-metoxiacético es un metabolito secundario; en ratas, La toxicidad reproductiva del diglime se atribuye al ácido alcanza un valor aproximado del 5-15% en la orina. 2-metoxiacético, que es un metabolito secundario.

La toxicidad aguda del diglime es baja tras la En estudios epidemiológicos de trabajadoras de la exposición oral o por inhalación. industria de los semiconductores expuestas en el lugar de trabajo a los éteres de etilenglicol, incluido el diglime, El diglime es ligeramente irritante de la piel o los se ha registrado un aumento del número de abortos ojos. No se dispone de investigaciones sobre sus espontáneos y una reducción de la fecundidad. Sin efectos de sensibilización. embargo, los trabajadores de esta industria están expuestos a varias sustancias con posible toxicidad

34 Diethylene glycol dimethyl ether

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.

35 THE CONCISE INTERNATIONAL CHEMICAL ASSESSMENT DOCUMENT SERIES

Acrylonitrile (No. 39, 2002) Azodicarbonamide (No. 16, 1999) Barium and barium compounds (No. 33, 2001) Benzoic acid and sodium benzoate (No. 26, 2000) Benzyl butyl phthalate (No. 17, 1999) Beryllium and beryllium compounds (No. 32, 2001) Biphenyl (No. 6, 1999) 1,3-Butadiene: Human health aspects (No. 30, 2001) 2-Butoxyethanol (No. 10, 1998) Chloral hydrate (No. 25, 2000) Chlorinated naphthalenes (No. 34, 2001) Chlorine dioxide (No. 37, 2001) Crystalline silica, Quartz (No. 24, 2000) Cumene (No. 18, 1999) 1,2-Diaminoethane (No. 15, 1999) 3,3'-Dichlorobenzidine (No. 2, 1998) 1,2-Dichloroethane (No. 1, 1998) 2,2-Dichloro-1,1,1-trifluoroethane (HCFC-123) (No. 23, 2000) N,N-Dimethylformamide (No. 31, 2001) Diphenylmethane diisocyanate (MDI) (No. 27, 2000) Ethylenediamine (No. 15, 1999) Ethylene glycol: environmental aspects (No. 22, 2000) Formaldehyde (No. 40, 2002) 2-Furaldehyde (No. 21, 2000) HCFC-123 (No. 23, 2000) Limonene (No. 5, 1998) Manganese and its compounds (No. 12, 1999) Methyl and ethyl cyanoacrylates (No. 36, 2001) Methyl chloride (No. 28, 2000) Methyl methacrylate (No. 4, 1998) N-Methyl-2-pyrrolidone (No. 35, 2001) Mononitrophenols (No. 20, 2000) N-Nitrosodimethylamine (No. 38, 2001) Phenylhydrazine (No. 19, 2000) N-Phenyl-1-naphthylamine (No. 9, 1998) 1,1,2,2-Tetrachloroethane (No. 3, 1998) 1,1,1,2-Tetrafluoroethane (No. 11, 1998) o-Toluidine (No. 7, 1998) Tributyltin oxide (No. 14, 1999) Triglycidyl isocyanurate (No. 8, 1998) Triphenyltin compounds (No. 13, 1999) Vanadium pentoxide and other inorganic vanadium compounds (No. 29, 2001)

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