Diethylene Glycol Dimethyl Ether: Concise International Chemical Assessment Document 41

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
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First draft prepared by Drs I. Mangelsdorf, A. Boehncke, and G. Knnecker, Fraunhofer Institute
of Toxicology and Aerosol Research, Hanover, Germany
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Geneva, 2002
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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
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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
4.2
4.3
4.4
5.
Environmental levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Human exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2.1 Workplaces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2.2 Consumer exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2.3 Biological monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
8
8
9
9
COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND

HUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
7.1
7.2
7.3
7.4
8.
Transport and distribution between media . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Transformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Accumulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

6.1
6.2
7.
6
6
6
7
ENVIRONMENTAL TRANSPORT, DISTRIBUTION, TRANSFORMATION, AND

ACCUMULATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
5.1
5.2
5.3
6.
Natural sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Anthropogenic sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Estimated global release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Distribution and accumulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
9
10
11
EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS . . . . . . . . . . . . . . . . . . . . . . . . 11

8.1
8.2
8.3
8.4
Single exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.1.1 Inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.1.2 Oral administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.1.3 Dermal administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Irritation and sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.1 Irritation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.2 Sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Short-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3.1 Inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3.2 Oral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Medium-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
iii
11
11
11
12
12
12
12
12
12
12
12
8.5
8.6
8.7
8.8
9.
Long-term exposure and carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Genotoxicity and related end-points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.6.1 In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.6.2 In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Reproductive toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.7.1 Effects on fertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.7.1.1 Inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.7.1.2 Oral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.7.2 Developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.7.2.1 Inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.7.2.2 Oral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Other toxicity/mode of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
12
12
12
13
13
13
15
15
15
15
17
EFFECTS ON HUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
9.1
9.2
Reproductive effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Haematological effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

10.1
10.2
Aquatic environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Terrestrial environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
11. EFFECTS EVALUATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

11.1
11.2
Evaluation of health effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11.1.1 Hazard identification and exposureresponse assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.1.2 Criteria for setting tolerable intakes/concentrations or guidance values for diglyme . . . . . . . .
11.1.3 Sample risk characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.1.4 Uncertainties in the evaluation of human health effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Evaluation of environmental effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20
20
20
21
21
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
RSUM DORIENTATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
RESUMEN DE ORIENTACIN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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
guidance values.
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International Programme on Chemical Safety (1994)

Assessing human health risks of chemicals: derivation
of guidance values for health-based exposure limits.
Geneva, World Health Organization (Environmental
Health Criteria 170).
1
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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
lowest-observed-adverse-effect level (LOAEL) was 100
ppm (558 mg/m3). Experiments with mice showed
morphologically altered sperm, mainly with amorphous
heads, after exposure to 1000 ppm (5580 mg/m3). After
exposure by inhalation to high concentrations, male and
female animals also showed effects on the
haematopoietic system, such as changes in leukocyte
counts and atrophy in spleen and thymus.
This CICAD on diethylene glycol dimethyl ether

(in the following called diglyme) was prepared by the
Fraunhofer Institute of Toxicology and Aerosol
Research, Hanover, Germany. Diglyme was selected for
review in the CICAD series owing to concerns for human
health, notably potential reproductive effects. The
CICAD is based on reports compiled by the GDCh
Advisory Committee on Existing Chemicals of Environmental Relevance (BUA, 1993a) and the German MAKKommission (Greim, 1994). A comprehensive literature
search of relevant databases was conducted in March
2000 to identify any relevant references published
subsequent to those incorporated in these reports.
Information on the preparation and peer review of the
source documents is presented in Appendix 1. Information on the peer review of this CICAD is presented in
Appendix 2. This CICAD was approved as an international assessment at a meeting of the Final Review
Board, held in Geneva, Switzerland, on 812 January
2001. Participants at the Final Review Board meeting are
listed in Appendix 3. The International Chemical Safety
Card on diglyme (ICSC 1357), produced by the International Programme on Chemical Safety (IPCS, 2000), has
also been reproduced in this document.
No long-term studies are available for diglyme;

therefore, all end-points cannot be reliably assessed.
Several Ames tests as well as an unscheduled DNA
synthesis test did not reveal a genotoxic potential of
diglyme in vitro. Nor was the number of chromosomal
aberrations increased in bone marrow cells in vivo.
In a dominant lethal test with rats, the number of
pregnancies was significantly reduced after exposure to
1000 ppm (5580 mg/m3) but not to 250 ppm (1395 mg/m3).
The positive results may be due to the effects of diglyme
on fertility.
In teratogenicity studies with rats, rabbits, and
mice, diglyme showed dose-dependent effects on fetal
weights, number of resorptions, and incidence of variations and malformations in a wide variety of tissues and
organ systems, at concentrations that were not
maternally toxic. The LOAEL for developmental effects
in an inhalation study with rats was 25 ppm (140 mg/m3);
the NOAEL for the oral route was 25 mg/kg body weight
in rabbits and 62.5 mg/kg body weight in mice. The
reproductive toxicity of diglyme is attributed to the minor
metabolite 2-methoxyacetic acid.
Diglyme (CAS No. 111-96-6) is a colourless liquid

with a slight, pleasant odour. It is miscible with water
and a number of common organic solvents. In the
presence of oxidation agents, peroxide may form. Due to
its dipolar aprotic properties, diglyme is used mainly as a
solvent (semiconductor industry, chemical synthesis,
lacquers), as an inert reaction medium in chemical
synthesis, and as a separating agent in distillations.
Epidemiological studies of female semiconductor

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

any route of exposure, metabolized, and excreted mainly
in the urine. The main metabolite is 2-methoxyethoxyacetic acid. 2-Methoxyacetic acid is a minor metabolite;
in rats, it amounts to about 515% in the urine.
The acute toxicity of diglyme is low after oral
exposure or inhalation.
Diglyme is slightly irritating to the skin or eye. No
investigations are available on the sensitizing effects of
diglyme.
The main targets in male animals after repeated
intake of diglyme are the reproductive organs. In 2-week
inhalation studies in male rats, dose-dependent
decreases in weights of testes, epididymides, prostate,
and seminal vesicles were observed. The testes were
The main environmental target compartment of

diglyme is the hydrosphere. The chemical is hydrolytically stable. The half-life in air for the reaction of diglyme
4
with hydroxyl radicals is calculated to be about 19 h.

Diglyme is inherently biodegradable, with a rather long
log phase and significant adsorption to activated sludge.
From the n-octanol/water partition coefficient and the
water miscibility of the chemical, a negligible potential
for bioaccumulation and geoaccumulation is derived.
compounds, such as vegetable oils, waxes and resins,

boron hydrides, organic boron compounds, sulfur, sulfur
dioxide, hydrogen peroxide, and carbon dioxide. With
water, azeotrope formation is observed at a
concentration ratio of 23 wt. % diglyme and 77 wt. %
water (BUA, 1993a). Diglyme has an n-octanol/water
partition coefficient (log Kow) of !0.36, determined by a
shake flask experiment (Funasaki et al., 1984). Its vapour
pressure at 20 C ranges from 0.23 to 1.1 kPa. The
chemical is volatile with water vapour (BUA, 1993a). The
calculated Henrys law constant is given as
0.041 PaA m3/mol (J. Gmehling, personal communication,
1991).
From valid test results available on the toxicity of

diglyme to various aquatic organisms, this compound
can be classified as a chemical exhibiting low acute toxicity in the aquatic compartment. The 48-h EC0 value for
daphnia (Daphnia magna) and the 72-h EC 10 value for
algae (Scenedesmus subspicatus) were $1000 mg/litre
(highest measured concentration). For the golden orfe
(Leuciscus idus), a 96-h LC0 of $2000 mg/litre was
determined. Only very few studies concerning the toxicity of diglyme towards terrestrial species are available.
The fungus Cladosporium resinae exhibited a toxic
threshold concentration of about 9.4 g/litre.
The conversion factors for diglyme for the gas

phase (101.3 kPa, 20 C) are as follows:
1 mg/m3
1 ppm
From the sample risk characterization for the

workplace, there is high concern for possible human
health effects. Exposure of the general population to
diglyme should be avoided.
=
=
0.18 ppm
5.58 mg/m3
Diglyme is chemically stable. In the presence of

strong oxidation agents, peroxide may form. Commercial
products typically contain peroxides at a concentration
of 5 mg/kg. To avoid the further formation of peroxides,
commercial products may contain antioxidants, such as
2,6-di-tert-butyl-4-methylphenol (BUA, 1993a).
The available data do not indicate a significant risk

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

diglyme are presented in the International Chemical
Safety Card (ICSC 1357) reproduced in this document.
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
(IUPAC name), diethylene glycol dimethyl ether,
DEGDM(E), dimethyl carbitol, and 2,5,8-trioxynonane. It
belongs to the group of ethylene glycol ethers (EGEs).
The molecular structure of diglyme (C 6H14O3) is shown
below:
adsorption onto modified silica containing cyanopropyl groups, synthetic polymers such as XAD 2
or XAD 7, or modified activated charcoal, with
subsequent solvent elution (e.g., acetone,
dichloromethane, dichloromethane/methanol); and
adsorption onto TENAX TA with subsequent
thermal desorption.
CH3 O CH 2 CH 2 O CH 2 CH 2 O CH 3
In either case, detection is carried out via gas
chromatography/flame ionization detection (GC/FID) or
gas chromatography/mass spectrometric detection
(GC/MSD) (NIOSH, 1990, 1991, 1996; Stolz et al., 1999).
For the determination of diglyme in indoor air, the
chemical was adsorbed onto activated charcoal, eluted
with dichloromethane/methanol, and determined by
Diglyme is a colourless liquid of low viscosity with

a slight, pleasant odour. The chemical freezes at about
!64 C. Depending on the presence of impurities, its
boiling point is between 155 and 165 C (Hoechst, 1990).
Diglyme is miscible with water and with a number of
common organic solvents. It dissolves numerous
5
4. SOURCES OF HUMAN AND

ENVIRONMENTAL EXPOSURE
capillary GC/MSD (internal standard toluene-d8

and 1,2,3-trichloropropane). The detection limit was
3 g/m3; data on recovery rate and standard deviation
are not available (Plieninger & Marchl, 1999).
4.1
The enrichment of diglyme from water samples is

also in general carried out by adsorption onto XAD 4 or
XAD 8 material with subsequent solvent elution (e.g.,
diethylether, dichloromethane) and determination by
capillary GC/MSD (Morra et al., 1979; Lauret et al., 1989).
Recovery rates and standard deviations are not
available. A detection limit of 0.01 g/litre is reported
(Morra et al., 1979).
Naturalsources
There are no known natural sources of diglyme.
4.2
Anthropogenic sources
Diglyme is manufactured in a closed system by the

catalytic conversion of dimethyl ether and ethylene
oxide under elevated pressure (10001500 kPa) and
temperatures (5060 C) with a maximum yield of 60%.
The by-products tri- and tetraethylene glycol dimethyl
ether and small amounts of a high-molecular-mass
ethylene glycol dimethyl ether are separated by
fractional distillation (Hoechst, 1991). This process is
based on the classic Williamson ether synthesis
(Rebsdat & Mayer, 1999).
Analytical methods for the determination of

diglyme in soil or sediment are not available.
Diglyme was determined together with other glycol
ethers in human urine by enrichment on diatomaceous
earth, extraction with dichloromethane/acetone (90:10),
and detection by capillary GC/FID. The validation results
of the method are given only as ranges for total glycol
ethers: detection limits 0.251 mg/litre, standard
deviation 1.517.1% (at 5 mg/litre), and recovery rates
92.0125.2% (at 2, 5, and 10 mg/litre) (Hubner et al.,
1992). [14C]Diglyme was determined in rat urine for
metabolism studies by high-performance liquid chromatography/scintillation detection on a reversed-phase C18
column (gradient elution with methanol/acetic acid) after
acidification of the sample (Cheever et al., 1988). Information on detection methods for other biological materials is not available.
In 1982, about 47 200 tonnes of diglyme were

produced in the USA (HSDB, 1983). In 1990, about
400 tonnes of the chemical were manufactured in
Germany, of which 200 tonnes were exported (BUA,
1993a). More recent data or data from other countries are
not available. Diglyme is registered as a highproduction-volume chemical by the Organisation for
Economic Co-operation and Development (OECD) (i.e.,
its production volume in at least one OECD member state
is $1000 tonnes/year) (OECD, 1997).
4.3
The metabolite 2-methoxyacetic acid is assumed to

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

chemical stability (see sections 2 and 5.2), diglyme is
used mainly as a solvent, as an inert reaction medium in
chemical synthesis, and as a separating agent in distillations. These uses include industrial applications, such
as polymerization reactions (e.g., of isoprene, styrene),
the manufacture of perfluorinated organic compounds
(BUA, 1993a), reactions in boron chemistry (Brotherton
et al., 1999; Rittmeyer & Wietelmann, 1999), and its
application as a solvent for, for example, textile dyes,
lacquers, and cosmetics (BUA, 1993a; Baumann & Muth,
1997).
Diglyme is also used in the manufacture of integrated circuit boards, primarily as a solvent for the
photoresists. These are used as photosensitive materials
for the coating of the wafer during microlithographic
patterning in the photo/apply process (Messner, 1988;
Correa et al., 1996; Gray et al., 1996) and in the
production of semiconductors (Corn & Cohen, 1993).
this and its use pattern, it is expected that the main target
compartment of the chemical will be the hydrosphere.
Diglyme is included in the European Inventory of

Cosmetics Ingredients in the solvent category (EC, 1996).
Its use in cosmetics in Germany and Canada was not
reported (BUA, 1993a; Clariant GmbH, personal
communication, 2000; IKW [German Trade Association
on Cosmetic and Detergent Preparations], personal
communication, 2000; R. Gomes, Health Canada,
personal communication, 2001). Data for other countries
are also not available.
5.2
From GC measurements with an aqueous solution

of 47.2 g diglyme/litre (5% v/v) kept in the dark for
21 days (NTP, 1987), it has been concluded that the
chemical is hydrolytically stable. This is also to be
expected from diglymes chemical structure (Harris,
1990).
EGEs in general are also used as auxiliary solvents

in water-based paints that are industrially applied (e.g.,
in the spraying of automobiles, metal furniture, household appliances, and machines) (Karsten & Lueckert,
1992; Baumann & Muth, 1997). It is not possible with the
available data to estimate the annual amount of diglyme
in this field of use or its application in water-based
paints for consumer use.
4.4
Direct photolysis of diglyme is assumed to be of

minor importance due to diglymes weak absorption at
wavelengths above 230 nm (Ogata et al., 1978a,b). NTP
(1987) determined no decrease in the concentration of an
aqueous solution of diglyme (47.2 g/litre) exposed to
room light for 72 h.
The reaction of gaseous diglyme with hydroxyl
radicals in the atmosphere has an experimentally determined rate constant KOH of 1.7 1011 cm3/molecule
per second (Dagaut et al., 1988). Assuming an average
tropospheric hydroxyl radical concentration of about
6 105 molecules/cm3 (BUA, 1993b), the half-life of
diglyme can be calculated to about 19 h. Due to the
miscibility of diglyme with water and its low Henrys law
constant (see section 2), diglyme is furthermore expected
to be deposited easily with rain or other wet deposition.
From this and its short half-life in atmospheric reactions,
long-distance transport of diglyme in ambient air is
assumed to be negligible.
Estimated global release
The global releases of diglyme cannot be estimated

with the available data.
The releases from the production of diglyme at the
German manufacturer for the year 1990 are estimated as
follows: <2.5 g/tonne released into air, about 133188 g/
tonne released into water, and <7.5 kg/tonne released
with solid wastes. The liquid wastes are disposed of in
approved chemical waste incinerators (BUA, 1993a).
Data on the degree of recycling of diglyme from its
application as a solvent or as an inert reaction medium in
industrial processes are not available.
From a Zahn-Wellens test following OECD Guideline 302B, adsorption of diglyme onto activated sludge
was 17% after 3 h, and total removal was 42% after
28 days. The degree of elimination and the degradation
curve are indicative of inherent primary degradation,
according to OECD criteria (Hoechst, 1989a).
Information on the content of diglyme in consumer

products such as cosmetics or paints and lacquers is not
available. It is assumed that any diglyme used in this
way will end up in ambient air or domestic wastewater.
Roy et al. (1994) achieved a similar result in an

electrolytic respirometer test with industrial wastewater
from a manufacturer of synthetic organic chemicals. In a
further experiment in which diglyme was tested together
with dioxane and other unspecified organic chemicals,
the degree of biodegradation was significantly higher
than in the test with diglyme alone (80% after 32 days),
suggesting that the biodegradation of diglyme is more
efficient in the presence of other carbon sources. High
salt concentrations in the wastewater, however, result in
a decrease in biodegradation, indicated by a significant
increase in the lag phase.
5. ENVIRONMENTAL TRANSPORT,
DISTRIBUTION, TRANSFORMATION, AND
ACCUMULATION
5.1
Transformation
Transport and distribution between

media
Diglyme is miscible with water and has a low

Henrys law constant (see section 2), leading to a low
volatility from aqueous solutions (Thomas, 1990). From
Data on the anaerobic degradation of diglyme are

not available.
7
5.3
Data on the concentration of diglyme in soil or

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

material are not available.
Measurements concerning the geoaccumulation of

diglyme are not available. Data on the adsorption of the
chemical onto activated sludge in the Zahn-Wellens test
(see section 5.2) cannot be used for the estimation of
adsorption onto soil. It is to be expected that the oxygen
atoms in the diglyme molecule will lead to a high affinity
for the microorganisms of the activated sludge but not
for the humic acids or inorganic components of soils.
From the physicochemical properties of the substance
(miscibility with water, low log Kow; see section 2), a low
tendency to sorption onto inorganic and organic soil
substances is to be expected.
Human exposure
6.2.1
Workplaces
There is a potential for inhalation or dermal contact

in the chemical and allied product industries where
diglyme is used as a solvent.
During the diglyme production process and its use
as a solvent in chemical synthesis, inhalation and dermal
contact are assumed to occur mainly during cleaning and
maintenance operations, as solvents are handled mainly
in closed systems.
As a result of its highly hydrophilic character and

its low tendency to volatilize from aqueous solutions or
to adsorb to soil constituents, diglyme may reach
groundwater. EGEs were detected particularly in anoxic
groundwater in the vicinity of US landfill sites (Ross et
al., 1992). The possibility that the chemical will subsequently enter wells and drinking-water cannot be
excluded.
No data are available on diglyme exposure concentrations at the workplace. Data on other EGEs that are
produced in the same way and that have a comparable
use pattern and similar volatilization behaviour may
serve as a rough approximation.
ECETOC (1995) reported time-weighted average
(TWA) exposures for several other EGEs between 0.01
and 6.5 ppm for the production process. This would
correspond to airborne diglyme concentrations between
about 0.06 and 36 mg/m3, taking its conversion factor for
the gas phase into account (see section 2). The dermal
exposure to diglyme can be estimated with the calculation model Estimation and Assessment of Substance
Exposure (EASE) to be a maximum of 0.1 mg/cm2 per day,
based on the assumption that trained workers incidentally have direct skin contact with diglyme during
cleaning and maintenance operations. Assuming further
that exclusively the palms (an area about 420 cm2) are
exposed, this would lead to a maximum dermal body dose
of 0.6 mg/kg body weight per day (assuming a body
weight of 70 kg).
6. ENVIRONMENTAL LEVELS AND

HUMAN EXPOSURE
6.1
6.2
Environmental levels
Data on the concentrations of diglyme in ambient

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

TWA exposure values between 0.01 and 0.55 ppm are
reported (workplace operation not specified; ECETOC,
1995). This would correspond to airborne diglyme
concentrations between about 0.06 and 3.1 mg/m3. As
diglyme is obviously used in mixtures with other EGEs
(see, for example, Messner, 1988), the diglyme exposure
levels cannot be estimated from these data.The maximum
dermal dose could be assumed to be equal to the dose
estimated for the production process (0.6 mg/kg body
weight per day). Some authors report significant
In 1987, the chemical was determined in the biologically treated leakage from two French landfills at
concentrations in the order of 220 g/litre (Lauret et al.,
1989). Diglyme was furthermore determined but not
quantified in 1992 in wastewater samples, from a German
oil reclaiming company, that had been pretreated by
equalization, neutralization, adsorption to activated
sludge, flocculation, and flotation (Gulyas et al., 1994).
8
permeation of protective gloves of different materials by

EGEs. Gloves made of nitrile and butyl rubber or neoprene provide the best protection (breakthrough rates
$45 min) and are now the ones being used most frequently in the semiconductor industry (for review, see
Paustenbach, 1988).
tions (see section 5.1), inhalation exposure is assumed to

be of minor importance. Dermal exposure cannot be
quantified with the available data.
6.2.3
As dermal exposure is significant, measurement of

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

painting operations, the geometric means of the TWA
exposure values were between 1.7 and 5.6 ppm, with
maximum concentrations up to about 37.6 ppm
(workplace operation not specified; ECETOC, 1995). For
diglyme, this would correspond to airborne
concentrations between 9.5 and 31 mg/m3, with a
maximum of 210 mg/m3. The maximum dermal exposure
could be assumed to be equal to the dose estimated for
the production and solvent use of diglyme in chemical
synthesis (incidental contact during transferring/
weighing/mixing or cleaning and maintenance
procedures, exposure of palms [420 cm2] only: 0.1 mg
lacquer/cm2 per day). Assuming a maximum diglyme
content of the lacquer of 25% (Baumann & Muth, 1997),
this results in a maximum dermal body dose of about 0.15
mg diglyme/kg body weight per day.
6.2.2
Biological monitoring
7. COMPARATIVE KINETICS AND

METABOLISM IN LABORATORY ANIMALS
AND HUMANS
7.1
Absorption
Studies on the metabolism of diglyme in rats show

that diglyme is absorbed from the gastrointestinal tract
(Cheever et al., 1986, 1988). Absorption following
inhalation can be concluded from the observation of
poisoning symptoms in studies on single- and repeateddose exposure to diglyme and in analogy with other
glycol ethers.
Consumer exposure
The main target compartment of diglyme is the

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

percutaneous absorption of glycol ethers (ECETOC,
1995; Johanson, 1996) was confirmed. The permeability
constant was 1 10 3 cm/h, and the lag time was approximately half an hour. With these findings, diglyme was
among the glycol ethers with the highest absorption rate
(Filon et al., 1999).
The database is not sufficient to estimate the daily

intake of diglyme by the general population.
Dermal absorption of glycol ether liquids or

vapours is very high (Johanson & Boman, 1991;
ECETOC, 1995; Kezic et al., 1997; Brooke et al., 1998;
Johanson, 2000). With 2-methoxyethanol, for example,
dermal absorption of the vapour is approximately as high
as absorption via inhalation. Dermal uptake of the liquid
is very high: exposure of an area of 2000 cm2 for 1 h
resulted in a body dose of 5920 mg in a study with
human volunteers (Kezic et al., 1997).
Data on the concentration of diglyme in drinkingwater are not available.

Quantitative information on dermal exposure to
diglyme via cosmetic products is not available. Although
diglyme is included in the European Unions Inventory
on Cosmetics Ingredients, its use was not reported for
Germany or Canada (see section 4.3). For other countries,
data are also not available.
7.2
Distribution and accumulation
No studies are available that investigate the distribution of radioactively labelled diglyme within the
body. Glycol ethers in general are readily distributed
throughout the body (ECETOC, 1995).
Measured data on exposure to diglyme-containing

water-based paints and lacquers for consumer use are
not available. Furthermore, the relevance of diglyme as
an auxiliary solvent in paints for consumer use cannot be
estimated with the available data. Due to the low tendency of volatilization of diglyme from aqueous solu-
The metabolite 2-methoxyacetic acid has shown

evidence of accumulation in animals and humans. In
9
Table 1: Metabolites in the urine after single oral application of diglyme.

Male Sprague-Dawley rats
Cheever et al.
(1988)
Dose (mg/kg body weight)
6.84
Cheever et al.
(1989a)
684
684
684
Pregnant CD-1 mice

Richards et
al. (1993)
Daniel et al.
(1986)
Daniel et
al. (1991)
684
300
500
Application at day of gestation
12
11
Duration of urine collection (h)
96
96
96
96
48
48
48
Pretreatment
22 days
diglyme
22 days
phenobarbital
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.
2.5
1.0
1.1
1.6
n.g.
n.g.
n.g.
5.8
6.2
10.0
13.4
n.g.
26.127.0
28.0
2.2
0.8
2.1
1.5
n.g.
n.g.
n.g.
% of dose
Metabolite IV (not identified)

2-Methoxyacetic acid
2-Methoxyethanol
2-Methoxyethoxyacetic acid
a
b
70.3
67.9
68.5
64.2
67.0
64.567.1
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.
n.g. = not given.

Bold indicates main metabolites.
humans, its half-life was calculated as 77.1 h (ECETOC,

1995).
7.3
microsomes were found to be 7 times more effective than

rat microsomes in converting diglyme to 2-methoxyethanol (Tirmenstein, 1993; Toraason et al., 1996).
Metabolism
There is no apparent quantitative difference in the
spectrum of metabolites, including 2-methoxyethoxyacetic acid and 2-methoxyacetic acid, over a 100-fold
dose range (6.84684 mg/kg body weight; see Table 1).
The metabolites identified in the urine following

oral application in different studies are given in Table 1.
The metabolic pathway of diglyme is shown in Figure 1.
The principal pathway of biotransformation of
diglyme involves O-demethylation with subsequent
oxidation to form the main metabolite 2-methoxyethoxyacetic acid, which accounts for about 6070% of the
dose in the urine of rats and pregnant mice after 4896 h
(Daniel et al., 1986; Cheever et al., 1988; Toraason et al.,
1996) (see Table 1).
Repeated doses of diglyme or induction with

phenobarbital or ethanol increases the cleavage of the
central ether linkage of diglyme as a result of cytochrome
P-450 enzyme induction in the liver (Cheever et al., 1988,
1989a; Tirmenstein, 1993; ECETOC, 1995; Toraason et al.,
1996).
In addition, cleavage (O-dealkylation) of the central ether bond results in the formation of 2-methoxyethanol, which is subsequently oxidized to 2-methoxyacetic acid. This metabolite accounts for about 515% of
the dose in the urine of rats after 4896 h (Cheever et al.,
1988, 1989a). In the urine of pregnant mice, it was found
in higher concentrations (2628% of the dose; Daniel et
al., 1986, 1991) (see Table 1). Also, humans may form this
metabolite in higher concentrations. Based on nmol 2methoxyethanol generated per nmol P-450, human
10
CH3 -O-CH2 -CH2 -O-CH 2-CH 2-O-CH 3

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-CH 2 -COOH
CH3 -O-CH2 -CO-NH-CH2 -COOH
Diglycolic acid
N-Methoxyacetyl glycine
URINE
Figure 1: Metabolism and disposition of diethylene glycol dimethyl ether (bis(2-methoxyethyl)ether).
8. EFFECTS ON LABORATORY
MAMMALS AND IN VITRO TEST SYSTEMS
Although the main metabolite in rat urine is 2methoxyethoxyacetic acid, numerous studies indicate
that 2-methoxyacetic acid is the metabolite responsible
for the toxicity of diglyme for the male reproductive
organs (see also section 8.7) (Cheever et al., 1985, 1988;
BUA, 1993a). Further, 2-methoxyacetic acid was transferred to the fetus and found as the sole metabolite in
the fetus (no parent compound was detected in the fetus
either) after dosing diglyme to mice at day 11 or 12 of
pregnancy (Daniel et al., 1986, 1991). The highest levels
for the average embryo (whole embryos analysed) were
detected at 6 h after dosing. Significantly lower amounts
were detected in blood taken from the dam at that time
point (Daniel et al., 1991).
7.4
8.1
Single exposure
8.1.1
Inhalation
A 7-h nose-only exposure (inhalation hazard test)

to an atmosphere saturated with diglyme at room temperature (about 10 g/m3) caused restlessness, narrowing
of palpebral fissures, and irregular breathing in rats. All
animals survived. Necropsy 14 days after exposure
revealed no macroscopic findings (Hoechst, 1979a).
Elimination
8.1.2
The major route of elimination is through the urine.

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

LD 50 for the female rat is 4760 mg/kg body weight
(Hoechst, 1979b) and for the female mouse is 2978 mg/kg
body weight (Plasterer et al., 1985). Poisoning symptoms
were restlessness and breathing difficulties. Necropsy of
animals found dead revealed changes in lung and liver
(no further information available).
11
irritation after 24 h (Hoechst, 1979c; no further

information available).
8.2.2
imately 7000 mg/kg body weight, assuming an intake of 7

ml/day and a body weight of 20 g), the number of total
white blood cells was more than doubled compared with
controls. This increase was not, however, statistically
significant (Nagano et al., 1984). For repeated-dose
studies on effects of diglyme on male reproductive
organs, see section 8.7.
Sensitization
There are no data available.
8.3
Short-term exposure
8.3.1
Inhalation
8.4
There are no medium-term exposure studies

available.
Groups of 20 male and 10 female Crl:CD rats were

exposed to 0, 110, 370, or 1100 ppm (0, 614, 2065, or 6138
mg/m3) diglyme, 6 h/day, 5 days/week, for 2 weeks. Male
rats were killed after 10 days of exposure and 14, 42, or 84
days post-exposure, respectively. Female rats were killed
after the 10th exposure and 14 days post-exposure. Urine
analysis, haematological analyses, and histopathology
were performed. Changes in the haematopoietic system
occurred in both sexes and involved the bone marrow,
spleen, thymus, leukocytes, and erythrocytes.
According to the authors, the no-observed-adverseeffect level (NOAEL) for female rats was 370 ppm (2065
mg/m3). Males were more sensitive than females:
compared with controls, body weight gain as well as
mean leukocyte counts were dose dependently
decreased in all dose groups. Further, stage-specific
germ cell damage occurred at all concentrations and was
concentration and time dependent (see section 8.7.1.1).
Thus, for male rats, a NOAEL could not be established in
this study (DuPont, 1988b; Lee et al., 1989; Valentine et
al., 1999).
8.5
Long-term exposure and

carcinogenicity
No studies are available on long-term exposure or

carcinogenicity.
8.6
Genotoxicity and related end-points
8.6.1
In vitro studies
Results of investigations of genotoxicity in vitro

are given in Table 2. Diglyme was not mutagenic in
several Ames tests with or without S9 mix (Hoechst,
1979d,e; McGregor et al., 1983; Mortelmans et al., 1986).
Diglyme also had no effect in a test for unscheduled DNA synthesis in human embryo fibroblasts
(McGregor et al., 1983).
8.6.2
In another study with four male and four female

Alderley Park rats per group exposed for 3 weeks,
6 h/day, to 200 and 600 ppm (1116 and 3348 mg/m3)
diglyme, urine analysis, haematological analyses, and
histopathology (of a limited number of organs without
testes) were also performed. In contrast to the DuPont
study cited above, no changes in haematological
parameters were noted after exposure to 600 ppm
(3348 mg/m3). However, similar to the observations in
that study, body weight gain was affected and thymus
was atrophied. Further, adrenals were congested. No
effects were found in the 200 ppm (1116 mg/m3) dose
group (Gage, 1970).
8.3.2
Medium-term exposure
In vivo studies
Diglyme did not induce chromosomal aberrations

in bone marrow cells in groups of 10 male and 10 female
CD rats exposed to 250 or 1000 ppm (1395 or 5580 mg/m3)
diglyme 7 h/day for 1 or 5 days (McGregor et al., 1983).
A dominant lethal test is described in section
8.7.1.1 (McGregor et al., 1983). The reduced number of
pregnancies and an increase in preimplantation losses
may be due either to a dominant lethal effect or to
reduced fertility of the males. Considering the known
effects of diglyme on fertility, the authors of the study
assume that reduced fertility is a cause of the effects.
Also, the post-implantation losses may be due to
reduced fertility instead of a dominant lethal effect, as it
is known that early deaths may be a consequence of a
low number of implantations.
Oral
In four male JCL-ICR mice that received diglyme in

the drinking-water for 25 days at a level of 2% (approx-
12
Table 2: Genotoxicity of diglyme in vitro.

Result
! S9
+S9
Remarks
Reference
cytotoxicity at
100 l per plate
McGregor et al.,
1983
not tested
no cytotoxicity
McGregor et al.,
1983
0.0110 mg per plate
tested with rat

and hamster S9,
no cytotoxicity
Mortelmans et
al., 1986
0.00550 l per plate
cytotoxicity at 25
and 50 l per
plate
Hoechst,
1979d,e
no information on McGregor et al.,

cytotoxicity
1983
available
Test system
Strain/cell type
Concentrations tested
Salmonella
mutagenicity test
strain TA1535, TA1537,

TA1538, TA98, TA100
0.3100 l per plate
Salmonella
mutagenicity test

TA100
2070 l per plate
Salmonella
mutagenicity test

TA98, TA100
Salmonella
mutagenicity test

TA1538, TA98, TA100
Unscheduled DNA
synthesis
human embryo fibroblasts 0.14819 mg/ml
also affected. At 1100 ppm (6138 mg/m3) diglyme, marked

testicular atrophy was found affecting all spermatogenic
stages. The effects were reversible within 84 days with
110 and 370 ppm (614 and 2065 mg/m3), but not with 1100
ppm (6138 mg/m3) (DuPont, 1988b; Lee et al., 1989;
Valentine et al., 1999).
A recessive lethal test on Drosophila

melanogaster exposed to 250 ppm (1395 mg/m3) for 2.75
h could not be evaluated because of an unusually high
death rate in a control group (McGregor et al., 1983).
8.7
Reproductive toxicity
8.7.1
Effects on fertility
8.7.1.1
Inhalation
In order to identify a NOAEL for effects on the

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

in which toxicity to the male reproductive organs has
been investigated.
Groups of 20 male Crl:CD rats were exposed to 0,
110, 370, or 1100 ppm (0, 614, 2065, or 6138 mg/m3)
diglyme, 6 h/day, 5 days/week, for 2 weeks. Exposed rats
were killed after 10 days of exposure and 14, 42, or
84 days post-exposure. Body weight gain was dose
dependently decreased. At 370 and 1100 ppm (2065 and
6138 mg/m3), absolute weights of testes, epididymides,
seminal vesicles, and prostrate were reduced; relative
weights of testes were reduced at 1100 ppm
(6138 mg/m3). Stage-specific germ cell damage was dose
and time dependent: at 110 ppm (614 mg/m3) diglyme,
spermatocytes in pachytene and meiotic division at
spermatogenic stages XIIXIV were mainly affected. At
370 ppm (2065 mg/m3) diglyme, affected germ cells were
similar to those seen at 110 ppm (614 mg/m3) diglyme, but
round spermatids at spermatogenic stages IVIII were
13
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 112
63.4
58.1
57.4
57.1
51.2 c
day 1526
68.8
70.0
68.2
64.5
62.8
Number of animals affected, severity of lesion

Testicular atrophy
Sertoli cell only
12
26
Bilateral
1, minimal
12
26
Unilateral
12
1, minimal
1, minimal
1, minimal
1, minimal
26
1, mild
Epididymides
Degenerative germ
cells
Spermatic granuloma
12
1, minimal
26
1, minimal
12
1, minimal
1, minimal
26
1, moderate
12
1, moderate
Prostate
Prostatitis
26
1, mild
1, mild
1, minimal
2, minimal
1, mild
Seminal vesicles
Atrophy acini
12
26
a
b
c
1, minimal
From DuPont (1989).

Day 12: end of exposure; day 26: after 14 days of recovery.
Statistically significant.
this study considered 30 ppm (167 mg/m3) to be the

NOAEL (DuPont, 1989).
but particularly in weeks 5 through 7 after exposure,

when frequencies were only about 10%. Further,
preimplantation losses in these weeks were large, and
there was evidence of post-implantation losses.
Recovery from the influence of diglyme in exposed males
was complete in week 10 (McGregor et al., 1981, 1983;
Hardin, 1983).
In a dominant lethal test, groups of 10 male adult

CD rats were exposed to 0, 250, or 1000 ppm (0, 1395, or
5580 mg/m3) diglyme for 7 h/day on 5 consecutive days,
then serially mated at weekly intervals for 10 weeks to
untreated virgin females in the ratio 1 male:2 females.
Male rats exposed to 1000 ppm (5580 mg/m3) showed a
reduction in body weight. The female rats were killed and
examined 17 days after they were first caged with the
males. No effect on frequency of pregnancy was seen in
the 250 ppm (1395 mg/m3) group. However, large
reductions in pregnancy frequency occurred in the 1000
ppm (5580 mg/m3) exposure group in weeks 4 through 9,
Changes in sperm shape were investigated in mice:

groups of 10 B6C3F1 mice were exposed to 0, 250, or 1000
ppm (0, 1395, or 5580 mg/m3) 7 h/day for 4 days, and
sperm were isolated 35 days after the exposure. Four
mice of the 1000 ppm (5580 mg/m3) group were found
dead on the morning of the 4th exposure day. Mice of
both exposure groups showed a reduction in body
14
weight gain. While no changes compared with the

controls were observed in the 250 ppm (1395 mg/m3)
group, a significant increase in morphologically altered
sperm (32%; control 5%) was found in the 1000 ppm (5580
mg/m3) group. All categories of abnormalities were
involved to some extent: hook upturned or hook
elongated, banana-shaped head, amorphous head, folded
tail, and others. Most frequent were amorphous heads,
which were increased to 20.87% in the 1000 ppm (5580
mg/m3) group compared with 2.18% in the air control.
From the timing of exposure and investigations, the
authors concluded that the spermatocytes had been
damaged (McGregor et al., 1981, 1983).
(Nagano et al., 1984; Price et al., 1987; Schwetz et al.,

1992).
8.7.2.1
In a teratogenicity study, rats exposed by inhalation to 25, 100, or 400 ppm (140, 558, or 2232 mg/m3)
diglyme during days 716 of gestation, the highest
concentration of 400 ppm (2232 mg/m3) caused 100%
resorptions (DuPont, 1988a; Driscoll et al., 1998).
Malformations found in low incidences at all dosages
included abnormally formed tails, distended lateral
ventricles of the brain, axial skeletal malformations
(vertebral fusions, hemivertebrae), and appendicular
malformations (aberrant clavicular and scapular
formation, bent fibula, radius, tibia, and ulna). Further,
structural variations, primarily delayed ossification, were
found. The lowest dose of 25 ppm (140 mg/m3) caused a
slightly increased incidence of variations. Although
these defects were not significantly different from
control values (with the exception of the incidence of
skeletal developmental variations), the pattern, type, and
incidence of variations were similar to those seen at
100 ppm (558 mg/m3), suggesting, according to the
authors, that 25 ppm (140 mg/m3) was an effect level that
approaches the lower end of the developmental toxicity
response curve. Therefore, the authors of the study
concluded that a NOAEL could not clearly be demonstrated for the fetus. As increased relative liver weights
were found in the dams at 100 ppm (558 mg/m3), the
NOAEL for diglyme exposure in the dams is 25 ppm (140
mg/m3).
In conclusion, from these studies, the NOAEL

for effects on the testes/spermatocytes is 30 ppm
(167 mg/m3).
8.7.1.2
Oral
Groups of five Sprague-Dawley rats received up

to 20 daily oral doses of distilled water or diglyme at
684 mg/kg body weight. Testicular changes were
analysed, including a subsequent recovery over an
8-week period. Primary and secondary spermatocyte
degeneration and spermatidic giant cells were observed
after 68 treatments. From day 12 of treatment until
8 weeks after cessation of exposure, the testes to body
weight ratio was significantly reduced (Cheever et al.,
1985, 1986, 1988). Testicular LDH-X activity, a pachytene
spermatocyte marker enzyme, was significantly decreased
in animals by day 18 of treatment (Cheever et al., 1985,
1989b).
8.7.2.2
No changes compared with controls were found in
testicular weight and the combined weight of seminal
vesicles and coagulating gland in four male JCL-ICR mice
that received diglyme in the drinking-water for 25 days at
a level of 2% (approximately 7000 mg/kg body weight,
assuming an uptake of 7 ml/day and a body weight of 20
g) (Nagano et al., 1984).
8.7.2
Inhalation
Oral
In an oral application study with rabbits, similar

effects were noted as after inhalation (NTP, 1987;
Schwetz et al., 1992). The number of resorptions as well
as the number of malformations were increased at doses
of $100 mg/kg body weight. Abnormal development of
the kidneys and axial skeleton and clubbing of the limbs
without underlying skeletal involvement were the most
frequently presented individual defects. At 50 mg/kg
body weight, percentages of prenatal mortality and
malformed fetuses per litter were both (statistically nonsignificantly) increased but accounted for a significant
overall increase in the percentage of adversely affected
implants per litter. In the NTP (1987) study as well as in
the analysis by Kimmel (1996), 50 mg/kg body weight is
considered as the lowest-observed-adverse-effect level
(LOAEL), and 25 mg/kg body weight as the NOAEL. In
contrast, in the subsequent publication by Schwetz et al.
(1992), the authors discussed that 50 mg/kg body weight
Developmental toxicity
Studies on the developmental toxicity of diglyme,

including experimental details, are summarized in Table 4.
Diglyme was a developmental toxicant both via inhalation
and by the oral route in rats, rabbits, and mice. It is
capable of disrupting normal morphogenesis in a wide
variety of tissues and organ systems, and the diversity of
fetal malformations observed was hypothesized to be due
to a general toxic effect upon proliferating cells, which
was also evident from the studies on male fertility
15
Table 4: Developmental toxicity of diglyme.

Species/
strain/
number per group
a
b
Exposurea
Concentration/
dose
0, 25, 100, 400
ppm (0, 140,
558, 2232
mg/m 3)
Effects b
$25
$ ppm (140 mg/m3): fetal weights 9, variations (delayed ossification,
rudimentary ribs) (mean percentage of fetuses per litter with variations):
44.5% versus controls 32.1%
100 ppm (558 mg/m3): dams: relative liver weight 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%
rats
CD
2526
inhalation, 6
h/day, days 716
rabbits
New Zealand
1525
gavage in distilled 0, 25, 50, 100,

$50
$ mg/kg body weight: dams: weight gain 9 (due to decrease in gravid
water, days 619
175 mg/kg body uterine weight),
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
limbs)
175 mg/kg body weight: dams: faecal output 9, mortality 8 (15%,
controls 4%)
Maternal
NOAEL/
LOAEL
Fetal
NOAEL/
LOAEL
NOAEL
25 ppm
(140 mg/m 3)
LOAEL
25 ppm
(140 mg/m 3)
DuPont (1988a),
Driscoll et al. (1998)
NOAEL
100 mg/kg body weight
NOAEL
NTP (1987)
NOAEL
NOAEL
Schwetz et al.
(1992)
NOAEL
NOAEL
62.5 mg/kg body
weight
NTP (1985), Price et

al. (1987)
Reference
mice
CD-1
2024
gavage in distilled 0, 62.5, 125,

water, days 615
250, 500 mg/kg
body weight
$125
$
mg/kg body weight: fetal weights 9
$250
$
mg/kg body weight: dams: weight gain 9 (due to decrease in
gravid uterine weight); late fetal deaths 8, malformations 8 (mainly
neural tube, limbs and digits, craniofacial structures, abdominal wall,
cardiovascular system, urogenital organs, axial and appendicular
skeleton)
500 mg/kg body weight: dams: weight gain (due to decrease in gravid
uterine weight) 9; resorptions 8
mice
CD-1
not given
gavage in distilled 0, 537 mg/kg

water, on day 11
body weight
only examination for gross external malformations and fetal body weight
537 mg/kg body weight: malformations 8 (paws, digits)
Hardin &
Eisenmann (1986,
1987)
mice
CD-1
49
gavage in distilled 0, 3000 mg/kg

water, days 613
body weight
reproductive screening according to Chernoff and Kavlock, no systematic

examination for malformations
3000 mg/kg body weight: dams: mortality 8 (20/49); no viable litters
(0/27)
Schuler et al.
(1984), Plasterer et
al. (1985), Hardin et
al. (1987)
Days refers to days of pregnancy.

8 = increased compared with controls; 9 = decreased compared with controls.
concentration of 1000 ppm (5580 mg/m3) caused a higher

number of abnormal sperm than 500 ppm (1550 mg/m3) 2methoxyethanol; thus, considering equimolar
concentrations, diglyme seems to be somewhat more
toxic. Mice produce higher concentrations of 2methoxyacetic acid than rats; therefore, mice may be
more susceptible than rats to the toxic effects of diglyme.
Considering that 2-methoxyethanol is only a minor
metabolite of diglyme, other metabolites or other
pharmacokinetic behaviours of diglyme compared with 2methoxyethanol may contribute to the toxicity of
diglyme.
appears to be the bottom end of the doseresponse curve

and therefore considered 50 mg/kg body weight as the
NOAEL.
In mice, the NOAELs were 500 mg/kg body weight
for maternal effects and 62.5 mg/kg body weight for
developmental effects. At 125 mg/kg body weight, the
only fetal effects were reduced body weights. Malformations were seen at 250 mg/kg body weight and above.
Characteristic malformations associated with diglyme
were neural tube closure defects and dysmorphogenesis
of the axial and appendicular skeleton (NTP, 1985; Price et
al., 1987). Further defects of digits and paws were found,
which also occurred in another study with mice (Hardin &
Eisenmann, 1986, 1987) dosed with 537 mg/kg body
weight only on day 11 of pregnancy.
In both fertility and developmental studies, the

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

1987) has served to illustrate a model that was developed
for assessing the probability of being abnormal by
applying the combination of the parameters fetal death,
weight, and malformation (Catalano et al., 1993). The
LED 05 (the lower 95% confidence limit of the dose
corresponding to 5% excess risk), which was derived
according to the benchmark dose approach, was 99 mg/kg
body weight. This was lower than the LED 05 for the
individual parameters, but higher than the NOAEL of 62.5
mg/kg body weight.
8.8
Other toxicity/mode of action
The main metabolite of diglyme, 2-methoxyethoxyacetic acid, did not show any effect on the testes at
equimolar concentrations (Cheever et al., 1986, 1988).
Instead, the pattern of diglyme-induced testicular injury is
qualitatively similar to that produced by the metabolite 2methoxyethanol (McGregor et al., 1981, 1983; Cheever et
al., 1985, 1986, 1988; Lee et al., 1989). In the study of
Cheever et al. (1985) with rats, both compounds exhibited
testicular toxicity primarily affecting pachytene and
dividing stages of spermatocytes at lower exposure
levels. In comparing the testicular toxicity of equimolar
dosages of 2-methoxyethanol (388 mg/kg body weight)
and diglyme (684 mg/kg body weight), 2-methoxyethanol
was more potent than diglyme. Spermatocytes were
affected after only one treatment with 2-methoxyethanol,
whereas repeated diglyme treatments were required to
produce the same effects. Similarly, in the inhalation
study of Lee et al. (1989) with rats, the toxic effects of 300
ppm (930 mg/m3) 2-methoxyethanol in the testes were
very similar to but more severe than those of 370 ppm
(2065 mg/m3) diglyme. In mice, both compounds produced
sperm anomalies (McGregor et al., 1981, 1983). A diglyme
Thymus atrophy has been reported in rats in two

inhalation studies (Gage, 1970; DuPont, 1988b; Lee et al.,
1989; Valentine et al., 1999) following exposure to high
concentrations of diglyme. Further, the number of
leukocytes was decreased. This is consistent with
studies on other EGEs, where mechanistic studies
indicate that the immune system is a sensitive target for
toxicity in the rat and that the proximate immunotoxicant
is methoxyacetic acid (ECETOC, 1995).
17
The metabolite 2-methoxyacetic acid, which is

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

outcomes and potential confounders (age, smoking,
ethnicity, education, income, year of pregnancy, and
stress) was obtained through a comprehensive interviewer-administered interview of female employees
(Beaumont et al., 1995). The prospective study of early
fetal loss and fecundity (probability of conception per
menstrual cycle) was conducted in a subset of female
employees from five plants. Daily diaries and measurements of daily urinary human chorionic gonadotrophin
(hCG) levels for 6 months were collected in addition to
the comprehensive interview (Eskanazi et al., 1995a,b). Of
the 891 medically verified pregnancies identified for the
retrospective study, 774 (86.9%) were live births, 113
(12.7%) were spontaneous abortions, and 4 (0.4%) were
stillbirths (Beaumont et al., 1995). The overall unadjusted
relative risk (RR) for spontaneous abortions was 1.45
(95% confidence interval [CI] = 1.022.05) and changed
little after adjusting for confounders (adjusted RR =1.43;
95% CI = 0.952.09). When stratified by work group, the
risk of spontaneous abortion was statistically
significantly increased for female workers in the
photolithography group (RR = 1.67; 95% CI = 1.042.55)
and in the etching group (RR = 2.08; 95% CI = 1.273.19).
For women working with higher levels of EGE only in
masking, the risk for spontaneous abortion was
increased 3-fold (RR = 3.38; 95% CI = 1.615.73) (Swan &
Forest, 1996). In the prospective study, no statistically
significant differences were detected in the overall rate of
spontaneous abortions between fabrication and nonfabrication workers or when pregnancy outcomes were
examined by work group (Eskenazi et al., 1995a).
However, the ability to conceive was lower among
female workers exposed to EGEs (fertility rate [FR] = 0.37;
95% CI = 0.111.19) (Eskenazi et al., 1995b).
9. EFFECTS ON HUMANS
As a consequence of the results of the animal

studies revealing effects on fertility as well as developmental toxicity of EGEs, several epidemiological studies
have been carried out to investigate reproductive endpoints in workers with exposure to EGEs. Diglyme is only
one compound of this substance class, however
(see section 2). A metabolite of EGEs and diglyme, 2methoxyethanol, is also used as a solvent, and one
epidemiological study of painters exposed to 2-methoxyethanol is also discussed.
9.1
Reproductive effects
EGEs including diglyme are used in the manufacture

of semiconductors. Epidemiological studies of three
semiconductor populations evaluated potential adverse
reproductive outcomes. It is unclear from the descriptions
provided by the authors whether these populations
overlapped. In each of these studies, workers were
exposed to mixtures including diglyme but not to diglyme
alone. In a single study of painters, exposure included a
metabolite of diglyme and EGEs.
Correa et al. (1996) conducted a retrospective

evaluation of reproductive outcomes among both
women employed and wives of men employed at two
semiconductor plants in the eastern USA (also reported
by Gray et al., 1996). Gray et al. (1996) also reported on
the results of a prospective study of reproductive
outcomes at the same plants. Exposure to EGEs in the
retrospective study was assessed by questionnaire
administered to the employees in combination with
company records. There were 115 pregnancies to
semiconductor manufacturing workers 561 to female
employees and 589 to wives of male employees. There
was a significantly elevated risk of spontaneous
abortion (odds ratio [OR] = 2.8; 95% CI = 1.45.6) and
subfertility (taking more than 1 year of sexual intercourse
to conceive) (OR = 4.6; 95% CI = 1.613.3) among female
employees in the highest exposure group. The risks of
One of the semiconductor populations included

workers from 14 different companies. The study included
both retrospective and prospective study designs.
Exposure to EGEs was determined using questionnaires
from subjects about the work performed and an
assessment of the work environment by industrial
hygienists, but no measurements of personal or area
exposures were made (Hammond et al., 1995). Workers in
the fabrication area were considered exposed to EGEs. For
18
spontaneous abortion and subfertility were not

significantly elevated in the low and medium exposure
groups. A significant (P = 0.02) doseresponse
relationship across low, medium, and high exposure
categories was found for both end-points for EGE
exposure. Among wives of male employees exposed to
EGEs, there was no evidence of an increased risk of
spontaneous abortion but a suggestion of an increased
risk of subfertility. In the prospective study (Gray et al.
1996), early-morning urine samples were assayed for hCG
and ovarian steroid hormones to detect early pregnancy
and early pregnancy loss. The study found no evidence
of a decreased conception rate, but there was a nonsignificantly elevated risk of pregnancy loss.
diglyme measured or used alone. In a cross-sectional

study of 94 shipyard painters exposed to measurable
levels of 2-ethoxyethanol and 2-methoxyethanol and
55 unexposed controls, Welch & Cullen (1988) found
10% of painters with haemoglobin levels consistent with
anaemia (P = 0.02) and 3.4% of painters and no controls
with abnormally low levels of polymorphonuclear
leukocytes (P = 0.07). In a second cross-sectional study
of 40 workers employed in the production of ethylene
glycol monoether, the overall proportion of exposed
workers with abnormal haemoglobin levels or white
blood cell counts did not differ from unexposed controls
(n = 25) (Cook et al., 1982). Controlling for potential age,
duration, and intensity of exposure using logistic
regression suggested a statistically significant decrease
(27%) in white blood cell counts. A small study of nine
individuals who laid parquet floors and matched pairs of
healthy donors showed no changes in haemoglobin or
erythrocyte levels but higher frequencies of NK-cells
(anti-Leu7) and B lymphocytes (Denkhaus et al., 1986).
Exposures included measurable concentrations of 2butoxyethanol, 2-ethoxyethanol, 2-methoxyethanol,
toluene, xylene, 2-butanone, and other solvents. No
association was found between use of products containing glycol ethers and myeloid acute leukaemia in a study
of 198 matched pairs (Hours et al., 1996).
Pastides et al. (1988) found an increased risk of

spontaneous abortion among females employed in the
diffusion area of a semiconductor manufacturing plant
(RR = 2.2; n = 18 pregnancies; 95% CI = 1.13.6) and in
the photolithographic area (RR = 1.8; n = 16 pregnancies;
95% CI = 0.83.3) compared with unexposed controls (n
= 398 pregnancies). No measurements of workplace
exposure were available in this study. Exposures
included several glycol ethers and other chemicals, such
as arsine, phosphine, diborane, xylene, toluene, and
hexamethyldisilane.
Semen samples from 73 painters and 40 controls
from a shipyard were analysed (Welch et al., 1988).
The painters were exposed by inhalation to 017.7 mg
2-methoxyethanol/m3 (mean 2.6 mg/m3) and to 080.5 mg
2-ethoxyethanol (= ethylene glycol monoethyl ether)/m3
(mean 9.9 mg/m3). Skin contact with 2-methoxyethanol
and 2-ethoxyethanol was also considered possible.
Exposure to numerous other substances, including
organic solvents and metals, was also known to occur.
While no effects were seen in hormone levels or in sperm
viability, motility, and morphology, the prevalence of
those with oligospermia differed between the groups.
The proportion of men with a sperm density #100
million/cm3 was higher in the exposed group than in the
unexposed group (33% vs. 20%; P = 0.20). The
proportion of those with oligospermia among painters
who did not smoke compared with controls was 36% vs.
16% (P = 0.05). The proportion of those with
oligospermia was similar between painters and controls
who smoked (30% vs. 38%; P = 0.49). The proportion of
painters with azoospermia was 5% compared with 0% in
the controls.
9.2
10. EFFECTS ON OTHER ORGANISMS IN

THE LABORATORY AND FIELD
10.1
Aquatic environment
For the toxicity data mentioned in this section, it is

not always stated whether the cited effect values are
based on nominal or measured concentrations of
diglyme. In some cases (Hoechst, 1994, 1995), the
concentration of the test substance is detected by the
determination of dissolved organic carbon or carbon in
the solution. However, due to the water solubility, low
volatility, and low adsorption potential of diglyme (see
sections 2 and 5), all nominal concentrations of the test
substance are expected to correspond to effective
concentrations, even in tests with open systems and
longer exposure periods.
The acute toxicity of diglyme to golden orfes
(Leuciscus idus) was determined in a static test, which
gave a 96-h LC0 of $2000 mg/litre.1 An acute toxicity test
Haematological effects
The relationship between exposure to EGEs and

haematological effects has been evaluated in three
occupational populations. In none of these studies was
Hoechst (1979) Abwasserbiologische Untersuchung von

Dialkylglykolthern auf die Goldorfe (Leuciscus idus).
1
19
11. EFFECTS EVALUATION
with Daphnia magna conducted according to OECD

Guideline 202 resulted in no adverse effects at the two
tested concentrations of 100 and 1000 mg/litre (48-h EC0
$1000 mg/litre) (Hoechst, 1994). Also, in a test concerning the toxicity of diglyme to algae (Scenedesmus subspicatus), conducted according to OECD Guideline 201,
the 72-h EC10 was $1000 mg/litre (highest concentration
tested) (Hoechst, 1995).
Evaluation of health effects
11.1.1
Hazard identification and

exposureresponse assessment
Diglyme is rapidly absorbed from the gastrointestinal tract, metabolized, and excreted mainly in the urine.
In analogy to other EGEs, it is assumed that diglyme is
readily absorbed through the skin. The main metabolite
is 2-methoxyethoxyacetic acid. The reproductive toxicity
of diglyme, however, is attributed to the minor metabolite
2-methoxyacetic acid, which is generated from 2methoxyethanol. There are species differences in the
amount metabolized to this metabolite: mice and humans
may produce higher amounts and thus be more susceptible than rats.
The LC50 values for the acute effect of diglyme on

tadpoles of the frog species Rana brevipoda were
between 22 000 and 8300 mg/litre (test periods between 3
and 48 h) (Nishiuchi, 1984).
In an activated sludge respiration inhibition test
conducted according to EC Guideline 88/302 Part C
(OECD Guideline 209), an EC10 of >1000 mg/litre was
determined (Hoechst, 1989b).
Only acute toxic effects have been examined in the
tests above. One should be aware of possible effects of
diglyme on reproduction, as observed in tests with
mammals (see sections 8.7 and 9.1).
10.2
11.1
The acute toxicity of diglyme is low after oral

exposure or inhalation. Diglyme is slightly irritating to
the skin or eye. No investigations are available on the
sensitizing effects of diglyme.
Terrestrial environment
Several Ames tests as well as an unscheduled
DNA synthesis test did not reveal a genotoxic potential
of diglyme in vitro. Further, the number of chromosomal
aberrations was not increased in bone marrow cells in
vivo. The positive results of a dominant lethal test may
be due to the effects of diglyme on fertility.
A study of the effect of diglyme on the spore

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

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

oriental and Mediterranean fruit flies (Dacus dorsalis
and Ceratitis capitata), a 48-h LD 50 of >98 mg/m3 was
determined for 24-h-old shell-less eggs and mature larvae
of each species after a 2-h fumigation (Burditt et al.,
1963).
Diglyme is a strong teratogen. Developmental

effects occur at low concentrations without maternal
toxicity. Effects on fetal weights, an increased number
of resorptions, and an increased incidence of variations/
malformations in a wide variety of tissues and organ
Frankfurt am Main, Hoechst AG, 2 pp. (unpublished test

results).
20
systems have been found. A LOAEL of 25 ppm

(140 mg/m3) has been identified in rats for the inhalation
route, and a NOAEL of 25 mg/kg body weight has been
identified in rabbits for the oral route. Maternal toxicity
indicated by reduced weight gain was rather low. The
relevance of these findings for humans is shown by the
fact that they are found in three different species rats,
rabbits, and mice and also by different routes of
exposure (inhalation and oral).
body weight. Applying safety factors of 10 for interindividual variability and 10 for interspecies variation, a
guidance value of 0.25 mg/kg body weight would be
obtained.
11.1.3
Assuming that exposure concentrations for

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

in two large epidemiological studies of female workers in
the semiconductor industry with exposure to EGEs
including diglyme. One of these studies also examined
the risk to wives of male employees with EGE exposure.
The studies found an association of the risk of spontaneous abortion with occupational exposure to EGEs. One
of these studies found evidence of a doseresponse
relationship. The risk of spontaneous abortion from
exposure to diglyme alone could not be evaluated.
In conclusion, from the sample risk characterization

for the workplace, there is high concern for possible
human health effects. No information is available on the
presence or concentrations of diglyme in cosmetics;
because of its reprotoxic potency, all exposure of the
general public to diglyme should be avoided.
The effect of EGEs on conception rates in exposed

female workers is not clear. The conception rate was
assessed in two prospective studies. One study found
slightly decreased rates; no effects were observed in the
other.
Painters exposed to the solvent 2-methoxyethanol,
which is also a metabolite of diglyme, were found to
have an increased prevalence of oligospermia and
azoospermia. The painters were also exposed to numerous other substances, including organic solvents and
metals, however.
11.1.2
Sample risk characterization
11.1.4
Uncertainties in the evaluation of human

health effects
There is a high degree of confidence that the

reproductive system is the target of the toxicity of
diglyme. This is concluded from consistent results from
experiments in several animal species with different
routes of application. Epidemiological studies indicate a
risk for humans as well.
Criteria for setting tolerable intakes/

concentrations or guidance values for
diglyme
A guidance value for uptake of diglyme via

inhalation according to EHC 170 (IPCS, 1994) can be
based on the developmental toxicity study in rats
(DuPont, 1988a; Driscoll et al., 1998), which gave a
LOAEL of 25 ppm (140 mg/m3). As the LOAEL of 25 ppm
(140 mg/m3) is, according to the authors, at the bottom
end of the doseresponse curve, a safety factor of 2
seems to be sufficient to extrapolate to a NOAEL.
Applying further a safety factor of 10 for interindividual
variability and 10 for interspecies variation, a guidance
value of about 0.1 ppm (0.6 mg/m3) would be obtained.
No long-term animal studies have been conducted

with diglyme. Therefore, not all end-points could be
reliably assessed, and there is some uncertainty concerning the NOAELs derived from short-term studies.
No data are available for the possible use of
diglyme in cosmetics, which may be an important source
of consumer exposure.
11.2
Evaluation of environmental effects
Diglyme releases into the environment are to be

expected from its use as a solvent, reaction medium, and
separating agent in industrial processes. A minor contribution from diglyme-containing consumer products
(cosmetics, water-based paints) is possible but cannot
be quantified with the available data.
For the oral route, no NOAEL from a reliable

repeated-dose toxicity study is available. If one assumes,
however, that, as in inhalation studies, developmental
toxicity is the most relevant end-point, one could use the
study with rabbits, which gave a NOAEL of 25 mg/kg
21
The main target compartment of diglyme is the

hydrosphere. The chemical is inherently biodegradable
with a rather long log phase and significant adsorption
to activated sludge. Bioaccumulation and
geoaccumulation are of minor importance.
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25
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26
APPENDIX 1 SOURCE DOCUMENTS
APPENDIX 2 CICAD PEER REVIEW
The draft CICAD on diglyme was sent for review to institutions and organizations identified by IPCS after contact with
IPCS national contact points and Participating Institutions, as
well as to identified experts. Comments were received from:
BUA (1993a) Diethylene glycol dimethyl ether

(bis(2-methoxyethyl)-ether). GDCh Advisory
Committee on Existing Chemicals of Environmental Relevance (BUA). Stuttgart, Hirzel, pp.
164 (BUA Report 67)
M. Baril, International Programme on Chemical Safety/

Institut de Recherche en Sant et en Scurit du Travail
du Qubec, Canada
For the BUA review process, the company that is in charge

of writing the report (usually the largest producer in Germany)
prepares a draft report using literature from an extensive
literature search as well as internal company studies. This draft is
subject to a peer review in several readings of a working group
consisting of representatives from government agencies, the
scientific community, and industry.
R. Benson, Drinking Water Program, US Environmental

Protection Agency, USA
R. Cary, Health and Safety Executive, United Kingdom
R. Chhabra, National Institute of Environmental Health
Sciences, National Institutes of Health, USA
The original German version of this report was published

in 1991.
J. Gift, National Center for Environmental Assessment, US

Environmental Protection Agency, USA
Greim H, ed. (1994) Diethylene glycol dimethyl

ether. In: Occupational toxicants. Critical data
evaluation for MAK values and classification of
carcinogens. Weinheim, Wiley-VCH, pp. 4150
R. Hertel, Federal Institute for Health Protection of

Consumers and Veterinary Medicine, Germany
C. Hiremath, National Center for Environmental
Assessment, US Environmental Protection Agency, USA
The scientific documentations of the German Commission

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

Kingdom
G. Johanson, National Institute for Working Life, Sweden
S. Kristensen, National Industrial Chemicals Notification
and Assessment Scheme, Australia
J. Montelius, National Institute for Working Life, Sweden
H. Savolainen, Ministry of Social Affairs and Health,
Finland
K. Ziegler-Skylakakis, Commission of the European
Communities/European Union, Luxembourg
27
Professor M. van den Berg, Environmental Sciences and

Toxicology, Institute for Risk Assessment Sciences, University of
Utrecht, Utrecht, The Netherlands
APPENDIX 3 CICAD FINAL REVIEW

BOARD
Geneva, Switzerland, 812 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, Universit 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 (ViceChairperson)
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
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,
Dr M. Younes, International Programme on Chemical Safety,
29
1357
October 2000
CAS No: 111-96-6

RTECS No: KN3339000
UN No: 1993
Bis(2-methoxyethyl) ether
Diglyme
1,1'-Oxybis(2-methoxyethane)
Dimethyl carbitol
C6H14O3 / (CH3OCH2CH2)2O
Molecular mass: 134.2
TYPES OF
HAZARD/
EXPOSURE
ACUTE HAZARDS/SYMPTOMS
PREVENTION
FIRST AID/FIRE FIGHTING
FIRE
Flammable.
NO open flames, NO sparks, and

NO smoking.
Powder, water spray, foam, carbon

dioxide.
EXPLOSION
Above 51C explosive vapour/air

mixtures may be formed.
Above 51C use a closed system,

ventilation.
In case of fire: keep drums, etc.,

cool by spraying with water.
EXPOSURE
AVOID EXPOSURE OF
(PREGNANT) WOMEN!
Inhalation
Cough. Shortness of breath.
Ventilation, local exhaust, or

breathing protection.
Fresh air, rest.
Skin
MAY BE ABSORBED! Redness.
Protective gloves. Protective

clothing.
Remove contaminated clothes.

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

work.
Rinse mouth.
SPILLAGE DISPOSAL
PACKAGING & LABELLING
Ventilation. Collect leaking liquid in sealable

containers. Absorb remaining liquid in sand or inert
absorbent and remove to safe place. (Extra
personal protection: filter respirator for organic
gases and vapours).
UN Hazard Class: 3
UN Pack Group: III
EMERGENCY RESPONSE
STORAGE
NFPA Code: H1; F2; R1
Fireproof. Separated from strong oxidants, strong bases, and strong acids.
IPCS
International
Programme on
Chemical Safety
Prepared in the context of cooperation between the International

Programme on Chemical Safety and the European Commission
IPCS 2000
SEE IMPORTANT INFORMATION ON THE BACK.
1357

IMPORTANT DATA
Physical State; Appearance

COLOURLESS LIQUID, WITH CHARACTERISTIC ODOUR.
Chemical dangers
The substance can form explosive peroxides. Reacts with
strong acids, strong bases, and strong oxidants.
Occupational exposure limits
TLV not established.
MAK: 5 ppm; 27 mg/m3; H (1999)
MAK: class II,1 (1999)
Routes of exposure
The substance can be absorbed into the body by inhalation of
its vapour and through the skin.
Inhalation risk
A harmful contamination of the air can be reached rather
quickly on evaporation of this substance at 20C.
Effects of short-term exposure
The substance irritates the eyes, the skin and the respiratory
tract.
Effects of long-term or repeated exposure
May cause reproductive toxicity in humans.
PHYSICAL PROPERTIES
Relative density of the vapour/air-mixture at 20C (air = 1): 1.01
Flash point: 51C c.c.
Auto-ignition temperature: 190C
Explosive limits, vol% in air: 1.5-17.4
Octanol/water partition coefficient as log Pow: -0.36
Boiling point: 162C

Melting point: -68C
Relative density (water = 1): 0.95
Solubility in water: miscible
Vapour pressure, kPa at 20C: 0.33
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
Il est lgrement irritant pour la peau et la

muqueuse oculaire. On ne dispose daucune tude sur
leffet sensibilisant de ce compos.
RSUM DORIENTATION
Le prsent CICAD consacr lther dimthylique

de dithylne-glycol (dsign sous le nom de diglyme
dans ce qui suit) a t prpar par lInstitut Fraunhofer
de recherche sur la toxicologie et les arosols, de
Hanovre (Allemagne). La dcision dinclure le diglyme
dans la srie des CICAD a t prise en raison de la
crainte que lon peut avoir au sujet dventuels effets de
ce compos sur la sant humaine, notamment en ce qui
concerne la fonction de reproduction. Ce CICAD repose
sur un certain nombre de rapports tablis par le Comit
consultatif GDCh sur les substances chimiques dimportance cologique (BUA, 1993a) ainsi que par la MAKKomission allemande (Greim, 1994). Il a t procd en
mars 2000 un dpouillement bibliographique exhaustif
des bases de donnes existantes, afin de rechercher des
rfrences des publications postrieures aux rapports
en question. Des informations sur la prparation et
lexamen par des pairs des sources documentaires
utilises sont donnes lappendice 1. Lappendice 2
fournit des renseignements sur lexamen par des pairs du
prsent CICAD. Ce CICAD a t approuv en tant
quvaluation internationale lors dune runion du
Comit dvaluation finale qui sest tenue Genve du 8
au 12 janvier 2001. La liste des participants cette
runion figure lappendice 3. La Fiche internationale
sur la scurit chimique du diglyme (ICSC 1357), tablie
par le Programme international sur la scurit chimique
(IPCS, 2000), est galement reproduite dans le prsent
document.
Lexprimentation animale montre que chez le mle,

cest principalement lappareil reproducteur qui est
touch aprs exposition rpte. Lors dune tude au
cours de laquelle on a fait inhaler du diglyme pendant
2 semaines des rats mles, on a observ une diminution
du poids du testicule, de lpididyme, de la prostate et
des vsicules sminales. Les testicules taient atrophis
et on a constat une atteinte des spermatocytes. Ces
tudes ont permis de fixer 30 ppm (167 mg/m3) la
concentration sans effet nocif observable (NOAEL) et
100 ppm (558 mg/m3) la concentration la plus faible
produisant un effet observable (LOAEL). Des tudes sur
la souris ont rvl des anomalies morphologiques
affectant les spermatozodes et consistant principalement
dans la prsence dune tte amorphe, aprs exposition
1000 ppm (5580 mg/m3). Aprs avoir t exposs par la
voie respiratoire de fortes concentrations de diglyme,
mles et femelles ont galement prsent des anomalies
affectant le systme hmatopotique et consistant
notamment en une modification du nombre de
leucocytes et une atrophie splnique et thymique.
On ne dispose daucune tude long terme sur le
diglyme; il nest donc pas possible dvaluer tous les
points daboutissement ventuels de son action toxique.
Aucune gnotoxicit na t mise en vidence in vitro,
que ce soit par divers tests dAmes ou par recherche
dune synthse non programme de lADN. In vivo, on
ne constate pas non plus daugmentation du nombre des
aberrations chromosomiques dans les cellules de la
moelle osseuse.
Le diglyme (No CAS 111-96-6) se prsente sous la

forme dun liquide incolore dgageant une odeur lgre
et agrable. Il est miscible leau et un certain nombre
de solvants organiques courants. Il peut donner
naissance des peroxydes en prsence doxydants.
Comme il est dipolaire et aprotique, on lutilise
principalement comme solvant (dans lindustrie des
semi-conducteurs, en synthse chimique et dans les
laques), comme milieu ractionnel inerte en synthse et
pour certaines sparations par distillation.
Des tests de ltalit dominante effectus sur des

rats ont montr que le nombre de gravidits tait
sensiblement rduit chez le rat aprs exposition
1000 ppm (5580 mg/m3), mais pas la concentration de
250 ppm (1395 mg/m3). Les rsultats positifs de ces tests
pourraient sexpliquer par une action du diglyme sur la
fertilit.
Les tudes de tratognicit effectues sur des
rats, des lapins et des souris ont rvl des effets
dpendant de la dose sur le poids foetal, le nombre de
rsorptions et lincidence des anomalies et des
malformations affectant un grand nombre de tissus et
dorganes des concentrations par ailleurs non toxiques
pour les mres. Lors dune tude consacre aux effets
sur le dveloppement avec exposition par la voie
respiratoire, on a trouv une LOAEL gale 25 ppm (140
mg/m3); dans le cas dune exposition par voie orale, la
NOAEL tait de 25 mg/kg de poids corporel pour le lapin
A ltat liquide ou sous forme de vapeurs, le

diglyme est facilement absorb quelle que soit la voie
dexposition, puis mtabolis et excrt dans les urines.
Son principal mtabolite est lacide 2-mthoxythoxyactique, lacide 2-mthoxyactique tant un mtabolite
secondaire. Chez le rat, il est prsent dans la proportion
de 5 15 % dans les urines.
Aprs exposition par voie orale ou respiratoire, le
diglyme ne prsente quune faible toxicit aigu.
32
Selon les donnes disponibles, lexposition au

diglyme nimplique pas de risque important pour les
organismes aquatiques. Comme on ne connat pas les
niveaux dexposition, il nest pas possible de donner une
caractrisation reprsentative du risque couru par les
organismes terrestres. Toutefois, compte tenu du mode
dutilisation du diglyme, il ny a pas lieu de craindre une
exposition importante.
et de 62,5 mg/kg de poids corporel pour la souris. Les

effets toxique du diglyme sur la fonction de reproduction
sont attribus son mtabolite secondaire, lacide 2mthoxyactique.
Des tudes pidmiologiques sur des femmes
travaillant dans lindustrie des semi-conducteurs et
exposes de par leur profession des thers thyliques
de glycol, dont le diglyme, ont mis en vidence un
accroissement du risque davortement spontan et une
baisse de la fcondit. Dune faon gnrale, les travailleurs de lindustrie des semi-conducteurs sont exposs
un certain nombre de substances potentiellement toxiques pour la fonction de reproduction, notamment des
thers thyliques de glycol. Ces donnes ne permettent
pas de dterminer quelle est la part du diglyme dans cet
accroissement du risque deffets gnsiques nocifs.
Chez des peintres exposs divers mtaux, solvants
organiques et autres substances chimiques, parmi
lesquels le 2-mthoxythanol (qui est galement un
mtabolite du diglyme), mais pas au diglyme lui-mme,
on a constat un accroissement du risque
doligospermie.
Dans lenvironnement, cest principalement dans
lhydrosphre que le diglyme se rassemble. Le compos
resiste lhydrolyse. Le calcul montre que le t 1/2 de la
raction du diglyme avec les radicaux hydroxyles
atmosphriques est de 19 h environ. Le diglyme est
intrinsquement biodgradable avec une phase logarithmique relativement longue est une adsorption notable
aux boues actives. Compte tenu de la valeur de son
coefficient de partage entre le n-octanol et leau et de sa
miscibilit leau, il semble que le potentiel de bioaccumulation et de goaccumulation du diglyme soit
ngligeable.
Les rsultats exprimentaux valables dont on peut
disposer au sujet de la toxicit du diglyme vis--vis de
divers organismes aquatiques, permettent de considrer
ce compos comme prsentant une faible toxicit aigu
pour les biotes de lhydrosphre. La CE0 48 h pour la
daphnie (Daphnia magna) et la CE10 72 h pour les
algues (Scenedesmus subspicatus) sont $1000 mg/litre
(concentration maximale mesure). Dans le cas de lide
rouge (Leuciscus idus), on a trouv une CL0 96 h de
$2000 mg/litre. On ne dispose que de quelques tudes
concernant la toxicit du diglyme pour les espces
terrestres. Le seuil de toxicit pour un champignon,
Cladosporium resinae, est denviron 9,4 g/litre.
Daprs les exemples reprsentatifs de caractrisation du risque sur le lieu de travail, il y a amplement lieu
de craindre des effets sur la sant humaine. Il faut donc
viter que la population soit expose au diglyme.
33
El destino principal en los animales machos tras

ingestas repetidas de diglime son los rganos reproductores. En estudios de inhalacin de dos semanas en ratas
macho, se observ una reduccin dependiente de la
dosis del peso de los testculos, el epiddimo, la prstata
y las vesculas seminales. Se atrofiaron los testculos y
se detectaron daos en los espermatocitos. La
concentracin sin efectos adversos observados
(NOAEL) en estos estudios fue de 30 ppm (167 mg/m3);
la concentracin ms baja con efectos adversos
observados (LOAEL) fue de 100 ppm (558 mg/m3). En los
experimentos con ratones se puso de manifiesto una
alteracin morfolgica del esperma, principalmente con
cabezas amorfas, tras la exposicin a 1000 ppm
(5580 mg/m3). Tras la exposicin por inhalacin a
concentraciones elevadas, tambin se observaron
efectos en el sistema hematopoytico de los animales
machos y hembras, por ejemplo cambios en el recuento
de leucocitos y atrofia del bazo y el timo.
RESUMEN DE ORIENTACIN
Este CICAD relativo al ter de dietilenglicoldimetilo

(denominado en lo sucesivo diglime) fue preparado por
el Instituto Fraunhofer de Toxicologa y de Investigacin
sobre los Aerosoles de Hannover, Alemania. Se
seleccion el diglime para someterlo a examen en la serie
de los CICAD debido a las preocupaciones que
suscitaba en relacin con la salud humana, en particular
sus posibles efectos reproductivos. El CICAD se basa
en los informes compilados por el Comit Consultivo
Alemn sobre las Sustancias Qumicas Importantes para
el Medio Ambiente (BUA, 1993a) y la MAK-Kommission
alemana (Greim, 1994). En marzo de 2000 se realiz una
investigacin bibliogrfica amplia de bases de datos
pertinentes para buscar cualquier referencia publicada
con posterioridad a las incorporadas a estos informes. La
informacin sobre la preparacin de los documentos
originales y su examen colegiado figura en el Apndice
1. La informacin acerca del examen colegiado de este
CICAD se presenta en el Apndice 2. Este CICAD se
aprob como evaluacin internacional en una reunin de
la Junta de Evaluacin Final celebrada en Ginebra (Suiza)
del 8 al 12 de enero de 2001. La lista de participantes en
esta reunin figura en el Apndice 3. La Ficha
internacional de seguridad qumica (ICSC 1357) para el
diglime, preparada por el Programa Internacional de
Seguridad de las Sustancias Qumicas (IPCS, 2000),
tambin se reproduce en el presente documento.
No hay estudios prolongados disponibles del

diglime; por consiguiente, no se pueden evaluar de
manera fidedigna todos los efectos finales. En varias
pruebas de Ames y en una prueba de sntesis de ADN
no programado no apareci ningn posible efecto genotxico del diglime in vitro. Tampoco se observ un
aumento del nmero de aberraciones cromosmicas en
las clulas de la mdula sea in vivo.
En una prueba de dominancia letal con ratas, el
nmero de gestaciones se redujo significativamente tras
la exposicin a 1000 ppm (5580 mg/m3), pero no con
250 ppm (1395 mg/m3). Los resultados positivos pueden
deberse a los efectos del diglime en la fecundidad.
El diglime (CAS N 111-96-6) es un lquido incoloro

ligeramente aromtico. Es miscible en agua y en algunos
disolventes orgnicos comunes. En presencia de
agentes oxidantes, puede formar perxido. Debido a sus
propiedades aprticas dipolares, el diglime se utiliza
principalmente como disolvente (industria de los semiconductores, sntesis qumica, barnices), como medio de
reaccin inerte en la sntesis qumica y como agente
separador en las destilaciones.
En estudios de teratogenicidad con ratas, conejos

y ratones se detectaron efectos del diglime dependientes
de la dosis en el peso fetal, el nmero de resorciones y la
incidencia de variaciones y malformaciones en una
amplia variedad de tejidos y sistemas de rganos a
concentraciones que no eran txicas para la madre. En
un estudio de inhalacin en ratas, la LOAEL para los
efectos en el desarrollo fue de 25 ppm (140 mg/m3); la
NOAEL para la va oral fue de 25 mg/kg de peso corporal
en conejos y de 62,5 mg/kg de peso corporal en ratones.
La toxicidad reproductiva del diglime se atribuye al cido
2-metoxiactico, que es un metabolito secundario.
El diglime, en forma lquida o de vapor, se absorbe

fcilmente por todas las vas de exposicin, se metaboliza y se excreta principalmente en la orina. El metabolito
ms importante es el cido 2-metoxietoxiactico. El cido
2-metoxiactico es un metabolito secundario; en ratas,
alcanza un valor aproximado del 5-15% en la orina.
En estudios epidemiolgicos de trabajadoras de la

industria de los semiconductores expuestas en el lugar
de trabajo a los teres de etilenglicol, incluido el diglime,
se ha registrado un aumento del nmero de abortos
espontneos y una reduccin de la fecundidad. Sin
embargo, los trabajadores de esta industria estn
expuestos a varias sustancias con posible toxicidad
La toxicidad aguda del diglime es baja tras la

exposicin oral o por inhalacin.
El diglime es ligeramente irritante de la piel o los
ojos. No se dispone de investigaciones sobre sus
efectos de sensibilizacin.
34
reproductiva, entre ellas los teres de etilenglicol y otras.

A partir de estos datos, no es posible determinar la
contribucin del diglime al aumento del riesgo de efectos
reproductivos adversos. Se observ que los pintores
expuestos a diversos metales, disolventes orgnicos y
otros productos qumicos, 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
qumica presenta estabilidad hidroltica. La semivida en
el aire para la reaccin del diglime con los radicales
hidroxilo se calcula en unas 19 horas. El diglime es
bsicamente biodegradable, con una fase logartmica
larga y una adsorcin 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 bioacumulacin y la
geoacumulacin.
Teniendo en cuenta los resultados de pruebas
vlidas disponibles sobre la toxicidad del diglime para
diversos organismos acuticos, este compuesto se
puede clasificar como sustancia con una toxicidad aguda
baja en el compartimento acutico. 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 concentracin medida ms alta).
Para el cacho (Leuciscus idus), se determin 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 mostr una concentracin umbral txica de unos
9,4 g/litro.
Los resultados de la caracterizacin del riesgo de
muestra para el lugar de trabajo suscitan una gran
preocupacin por sus posibles efectos en la salud
humana. Se debe evitar la exposicin de la poblacin
general al diglime.
Los datos disponibles no indican un riesgo
importante asociado con la exposicin de los organismos
acuticos a esta sustancia. Debido a la falta de
mediciones de los niveles de exposicin, no se puede
realizar una caracterizacin del riesgo de muestra para los
organismos terrestres. Sin embargo, teniendo en cuenta
las pautas de uso del diglime, no cabe esperar una
exposicin 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)
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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)
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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)
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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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