Environmental Health Perspectives

Vol. 57, pp. 75-84, 1984

Experimental Studies on Toxicity of

Ethylene Glycol Alkyl Ethers in Japan

by Kasuke Nagano,* Eiki Nakayama,* Hisao Oobayashi,*

Tomoshi Nishizawa,* Hirokazu Okudat and

Kazunori Yamazaki*

Past studies on the toxicological effects of ethylene glycol alkyl ethers as well as the recent data on these

chemicals in Japan are reviewed. Only a few researchers have participated in the study of ethylene glycol

alkyl ethers in Japan. The effects of ethylene glycol alkyl ethers on testis and embryotoxic effects of

ethylene glycol monomethyl ether (EGM) have been studied, as has the teratogenicity of ethylene glycol

dimethyl ether (EGdM). Studies on ethylene glycol alkyl ethers and related compounds administered to

mice by oral gavage revealed the occurrence of testicular atrophy and decreased white blood cell count by

EGM, EGdM, ethylene glycol monomethyl ether acetate, ethylene glycol monoethyl ether and ethylene

glycol monoethyl ether acetate, and the toxicity was related to their chemical structure. On the other hand,

ethylene glycol, ethylene glycol monopropyl ether, ethylene glycol monobutyl ether, ethylene glycol

monophenyl ether, ethylene glycol monoacetate or ethylene glycol diacetate showed no such an effect.

Studies on EGM using hamsters or guinea pigs revealed the occurrence of testicular atrophy similar to that

observed in mice. In regard to the methyl ethers of other glycols, there is no convincing evidence that

propylene glycol monomethyl ether, diethylene glycol monomethyl ether or diethylene glycol dimethyl

ether causes testicular atrophy in mice. Teratological studies of EGM and EGdM revealed embryotoxic

effects in mice.

Introduction

In Japan, ethylene glycol ethers have been widely

used as industrial solvents for resins, lacquers and dyes,

but there are no available data on their use. The

production of ethylene glycol ethers in Japan in 1980 is

estimated to be 43,048 tons (1). The total amount of the

ethers imported in 1980 was reported to be 8,121 tons,

94.5% of which came from the U.S. (2). Only a few

researchers have participated in studies on the toxicity

of ethylene glycol ethers in Japan. Since 1976, we have

studied the effects of ethylene glycol alkyl ethers on the

testis to define the possible relation between their

chemical structures and the effects on the testis, and to

elucidate the pathogenesis of testicular lesions (3).

In addition, Uemura reported teratogenic effects of

ethylene glycol dimethyl ether in mice in 1980 (4);

we also reported embryotoxic effects of ethylene glycol

monomethyl ether in mice in 1981 (5). Past studies on

*Japan Bioassay Laboratory, Japan Industrial Safety and Health

Association, 2445 Ohshibahara, Hirasawa, Hadano Kanagawa, 257

Japan.

tOccupational Health Service Center, Japan Industrial Safety

and Health Association, 35, Shiha 5-chome, Minato-ku, Tokyo;

108 Japan.

the toxicological effects of ethylene glycol alkyl ethers

as well as recent data on these chemicals in Japan are

reviewed in this paper.

Testicular Atrophy Induced by

Ethylene Glycol Alkyl Ethers

Three experiments were conducted to evaluate the

toxicity of ethylene glycol alkyl ethers to the testis: (1)

Testicular changes in mice given ethylene glycol alkyl

ethers and related compounds; (2) the effects of ethylene

glycol monomethyl ether on the testis of hamsters and

guinea pigs; (3) The effects of alkyl ethers of other

glycols on the testis of mice.

We attempted to determine the possible relation

between their chemical structures and the effects on the

testis, and the pathogenesis of testicular lesions in

these experiments.

Testicular Changes in Mice Given

Ethylene Glycol Alkyl Ethers and

Related Compounds

Materials andMethods. Male JCL-ICR mice (Japan

CLEA Co.), 6 weeks of age, were used. The materials
NAGANO ET AL.

0,8

0-

ae

(U

L.

0

.0

m

0,

D

:0

0

-

%._

4._

n

FIGURE 1. Testicular atrophy induced by EGM. Dose-dependent

decrease in testis size is shown.

tested were ethylene glycol (E

monomethyl ether (EGM), ethyle

ether (EGE), ethylene glycol mono

ethylene glycol monobutyl ether (E

monophenyl ether (EGPh), ethyler

ether acetate (EGMA), ethylene gi

acetate (EGEA), ethylene glycol

ethylene glycol diacetate (EGdA)

dimethyl ether (EGdM). EGPr and

from Tokyo Kasei Kogyo Co., EGA

Co. and the rest from Wako Cher

CH27OH

CH2-OH

(EG)

CH2-0-CH3 CH2-O-C2H5 CH2-O-C3H7

ICI H I

CH270H CH270H CH270H

(EGE) (EGPr)

CH27OH

CH2-OOC

(EGEA) (EGA)

,G), ethylene glycol

ne glycol monoethyl

opropyl ether (EGPr),

;GB), ethylene glycol

no 041r"Al mnnmamthulr

Daily dose (mg/kg)

FIGURE 2. Relation between daily doses (expressed as mg/kg body

weight) and testis weight of mice which were treated with ethylene

glycol alkyl ethers and related compounds: (h-[ ) EG; (o-o)

EGM; (-@*) EGE; (A---A) EGPr; (A-A) EGB; (A-A)

EGPh; (o---o) EGMA; (A---e) EGEA; (U---.) EGA; (u--_)

EGdA; (o---o) EGdM. Testis body weight ratio are expressed

as the mean of the values from five mice at each dose.

ka IIIVU £WRlulAllylAJ Gastric intubation was employed for administration of

Lycol monoethyl ether each material because of the necessity of administering monoacetate (EGA), accurate amount of materials. Each of the samples was Iand ethylene glycol diluted with water or olive oil and given orally by EGdA were obtained stomach tube 5 days per week for 5 weeks. The daily from Kanto Chemical doses were 4000, 2000, 1000 and 500 mg/kg body weight mical Co. for EG, EGE and EGEA; 2000, 1000, 500, 250, 125 and

62.5 mg/kg body weight for EGM and EGMA; 2000,

1000 and 500 mg/kg body weight for EGPr, EGB, EGA

and EGdA; 1000, 500 and 250 mg/kg body weight for

EGdM. The control mice were given water by the same

CH2-O-C4H9 CH2-OC,H5 method. On the following day of the final administration,

12 1 animals were necropsied under pentobarbital sodium

CH2-OH CH2-OH anesthesia. The testes were weighed and the combined (EGB) (EGPh) weight of seminal vesicles and coagulating gland was

also measured. Tissue specimens for histopathological CH2-OOCCH3 examination were fixed in 10% buffered formalin

XH3 CH2-OOCCH3 solution, embedded in paraffin, sectioned, and stained

(EGdA) with hematoxylin and eosin. Blood for hematological

studies was taken from the posterior vena cava at the

time of necropsy.

Results. Gross observation showed that the testes

of mice given some of the ethylene glycol alkyl ethers

0,6

0,4

0,2

I I I a I . p

62,5 125 250 500 1000 2000 4000

(EGM)

CH2-O-CH3 CH2-O-C2H5

CH2-OOCCH3 CH2-0OCCH3

(EGMA)

CH2-O-CH3

CH2-0-CH3

(EGdM)

L

76

-
ETHYLENE GLYCOL ALKYL ETHERS TOXICITY

were decreased in size (Fig. 1). The weight of the testes

(expressed as testis-body weight ratio) of mice

administered ethylene glycol alkyl ethers or related

compounds for 5 weeks is shown in Figure 2. In animals

0,8 -

0,6 F

0,4 r

0,2 F

0,5 1 5 10

Daily dose (m mol/kg)

FIGURE 3. Relation between daily doses (mmole/kg body weight)

and testis weight of mice which were treated with ethylene glycol

alkyl ethers and related compounds. Symbols as in Fig. 2.

given EGM, EGE, EGMA, EGEA and EGdM, dosedependent decreases in testicular weight were observed.

Considering toxic effects on the testis based on

testicular weight and daily dose, as weight per body

weight, EGM seemed to be most toxic, followed by

EGdM, EGMA, EGE and EGEA, in that order.

Esterification appeared to lessen the testicular atrophy

effect in both the methyl and ethyl ethers of ethylene

glycol, and dimethyl ethers had such toxicity less than

monomethyl ethers. Examination of the testicular

weight and daily molar dose per body weight (Fig. 3)

showed that testicular atrophy was greater for EGM,

EGMA and EGdM than for EGE and EGMA. The

reduction in testicular toxicity by esterification or

dimethylation when daily dose was expressed as weight

per body weight was due to the difference in molecular

weight of these compounds.

No significant difference in weight of the testis was

found in EG, EGPr, EGB, EGPh, EGA or EGdA groups

as compared with that of control animals. A slight

decrease in the combined weight of the seminal vesicles

and the coagulating gland was seen only in groups

receiving higher doses of EGM, EGMA and EGdM.

Histopathological examinations of the testis from

mice given EGM, EGE, EGMA, EGEA and EGdM

revealed dose-related atrophy of the seminiferous

epithelium at various degrees. Sertoli cells remained

normal up to later stage. Leydig cells were normal

in appearance, though infrequently proliferative (Fig.

4-13).

In the hematological examination, the decrease in

white blood cell was the most prominent change. EGM,

EGE, EGMA. EGEA and EGdM caused a significant

decrease in white blood cell count, and the order of toxic

ZL '. ,, ,*

M -M

S>;* *X -s.

FIGURE 4. Testis of control mouse. H&E.

-

e

0-

0

._

C

D

0

0

4._

I-0

77
NAGANO ET AL.

FIGURE 5. Testis of mouse treated with 2000 mg/kg/day of EGM. Seminiferous tubules are decreased in size and irregularly shaped.

Spermiogenic cells have disappeared completely. H&E.

FIGURE 6. Testis of mouse treated with 1000 mg/kg/day of EGM. Small tubules with disappearance of spermiogenic cell cells are shown. H&E.

effect on leukocyte by these chemicals resembled that

on testicular weight (Fig. 14). The change in red blood

cells was slighter than leukocyte changes, and red cell

count, packed cell volume and/or hemoglobin content

decreased at the higher dose levels of EGM, EGMA,

EGEA and EGdM. For EGB-treated mice, a decrease

in red cell count was noted in 500 mg/kg or higher

dose groups.

Effects of Ethylene Glycol Monomethyl

Ether on Testis of Hamsters and

Guinea Pigs

Since the effect of ethylene glycol alkyl ethers on the

testis of other animal species was not known, we carried

out preliminary studies of the toxic effect of EGM on

the testis of hamsters and guinea pigs.

78
ETHYLENE GLYCOL ALKYL ETHERS TOXICITY

FIGURE 7. Same testis as in Fig. 6. Sertoli cells (A) and spermatogonia (B) are shown in the basal layer. H&E.

FIGURE 8. Testis of mouse treated with 500 mg/kg/day of EGM. Some spermatogonia (A) and spermatocytes (B) are preserved. Leydig cells (C)

are proliferative. H&E.

Materials and Methods. Adult male Syrian golden

hamsters and guinea pigs were used. EGM was diluted

with water, and given orally with stomach tube 5 days

per week for 5 weeks. The daily doses were 500, 250,

125 and 62.5 mg/kg body weight for hamsters, and 500

and 250 mg/kg for guinea pigs. The control animals were

given water by the same method. On the following day

of the final administration, animals were necropsied

under pentobarbital sodium anesthesia. The testes were

weighed and the combined weight of the seminal

vesicles and coagulating gland was also measured.

Blood for white blood cell count was taken from the

posterior vena cava at the time of necropsy.

Results. A decrease in testicular weight was seen in

all dose groups of hamsters (500, 250, 125 and 62.5

mg/kg body weight group), while neither the combined

weight of the seminal vesicles and coagulating gland nor

white blood cell count was affected (Table 1).

79
NAGANO ET AL.

FIGURE 9. Testis of mouse treated with 250 mg/kg/day of EGM. Some tubules contain spermatozoa (A), but other tubules are atrophic (B).

H&E.

FIGURE 10. Testis of mouse treated with 1000 mg/kg/day of EGMA. Sertoli cells and a few spermatogonia are shown. H&E.

Table 1. Effects of ethylene glycol monomethyl ether on hamsters.

Mean seminal vesicle and

Daily dose, No. animals/ Mean body Mean testis weight coagulating gland weight Mean WBC/

mg/kg group weight, g mg %a mg %a mm3

500 4 112 652t 0.58t 1172 1.03 4000

250 4 121 748t 0.62t 1543 1.29 4762

125 4 124 1299t 1.06t 1643 1.33 4675

62.5 4 131 3559 2.63* 1795 1.38 5433

Control 4 131 3715 2.84 1769 1.36 4925

aOrgan/body weight ratio.

*Significantly different (p < 0.05) from the control group.

tSignificantly different (p < 0.01) from the control group.

80
ETHYLENE GLYCOL ALKYL ETHERS TOXICITY

FIGURE 11. Testis of mouse treated with 1000 mg/kg/day of EGdM. Spermiogenic cells have disappeared. H&E.

FIGURE 12. Testis of mouse treated with 2000 mg/kg/day of EGE. Some spermiogenic cells are preserved. H&E.

Table 2. Effects of ethylene glycol monomethyl ether on guinea pigs.a

Mean seminal vesicle and

Daily dose, No. animals/ Mean body Mean testis weight coagulating gland weight Mean WBC/

mg/kg group weight, g mg %a mg %b mm3

500 3 782 927 0.12 4109 0.525 4000

250 3 755 946 0.13 3635 0.481 4100

Control 3 749 3889 0.52 3883 0.518 9180

aStatistical examination was not carried out.

bOrgan/body weight ratio.

81
NAGANO ET AL.

FIGURE 13. Testis of mouse treated with 4000 mg/kg/day of EGMA. Sertoli cells and some spermatogonia are preserved. H&E.

5000

4000

E

E"I

0

0

0

0

.0

la

3000 _

2000 _

1000

EGM

62,5 125 250 500 1000 2000 4000

Daily dose (mg/kg)

FIGURE 14. Relation between daily dose (expressed as mg/kg body

weight) and white blood cell count of mice which were treated with

ethylene glycol alkyl ethers and related compounds.(G-o); EGM;

(o-o) EGE; (o---o) EGMA; ( ---e) EGEA; (o---o) EGdM.

White blood cell count is expressed as the mean of the values from

five mice at each daily dose.

The testicular weight in all dose groups of guinea pigs

(500 and 250 mg/kg) decreased to one-fourth of that in

the control group, while the combined weight of seminal

vesicles and coagulating gland was not affected. White

blood cell count in all dose groups was decreased to

one-half of that in the control group (Thble 2).

From these results, it appears that oral administration of EGM causes testicular atrophy in hamsters and

guinea pigs in the same manner as observed in mice.

Effects of Alkyl Ethers of Other Glycols

on the Testis of Mice

Some alkyl ethers of ethylene glycols induce testicular

atrophy in some animal species. In this experiment, we

describe the possible effect of the methyl ether of

propylene and diethylene glycol on the testis.

Materials andMethods. Male JCL-ICR mice (Japan

CLEA Co.), 6 weeks of age, were used. The materials

used were propylene glycol monomethyl ether (PGM),

diethylene glycol monomethyl ether (dEGM) and diethylene glycol dimethyl ether (dEGdM), and EGM

and EGE, as positive control. PGM was obtained from

Tokyo Kasei Kogyo Co., and other chemicals from Wako

Chemical Co. PGM, dEGM and dEGdM were administered to mice for 25 days in the drinking water at a

level of 2% and EGM and EGE for 18 days at a level of

2.5%. Control mice were allowed water ad libitum.

Animals were necropsied under pentobarbital anesthesia

at the end of administration. Testicular weight and the

combined weight of seminal vesicles and coagulating

gland were measured. Blood for white blood cell count

was taken from the posterior vena cava at the time of

necropsy.

82
ETHYLENE GLYCOL ALKYL ETHERS TOXICITY

Table 3. Effects of alkyl ethers of other glycols on mice.

Mean seminal vesicle and

Concen- Duration of No. animals/ Mean body Mean testis weight coagulating gland weight Mean WBC/

Compound tration, %a dosing, days group weight, g mg gb %b mm3

PGM 2.0 25 5 41.2 322 0.78 397 0.97 4530

dEGM 2.0 25 5 38.6 237 0.62 420 1.09 4690

dEGdM 2.0 25 4 41.0 218 0.53 381 0.93 3934

Control 0 25 5 40.6 290 0.71 441 1.09 3270

EGM 2.5 18 8 26.2t 47t 0.18k 191t 0.72 538t

EGE 2.5 18 8 33.7* 122t 0.36t 260 0.77 1506

Control 0 18 4 39.0 221 0.57 242 0.62 1740

a% in drinking water.

bOrgan/body weight ratio.

*Significantly different (p < 0.05) from the control group.

tSignificantly different (p < 0.01) from the control group.

Results. No significant difference was noted between PGM-, dEGM- or dEGdM-treated groups and

control (in the testicular weight, the combined weight of

seminal vesicles and coagulating gland or white blood

cell count). In dEGM and dEGdM groups, a slight

decrease in testicular weight was observed, but these

decreases were due to one animal of each group and are

statistically not significant. However, a decrease in

testicular weight and/or white blood cell count was

observed in both EGM-and EGE-treated groups. Under

these experimental conditions, we can not indicate that

PGM, dEGM or dEGdM causes any testicular atrophy

(Table 3).

Embryotoxic Effects of Ethylene

Glycol Monomethyl Ether and

Ethylene Glycol Dimethyl Ether

in Mice

It is well known that alkylating agents such as

Busulphan inhibit cell proliferation and cause testicular

atrophy and leukopenia. These chemicals produce a

lethal effect or damage to the fetuses (6). The effects of

ethylene glycol alkyl ethers on testis and leukocyte

resembled those of alkylating agents. Consequently,

ethylene glycol alkyl ethers which cause testicular

atrophy and leukopenia may have also embryotoxic

effects.

We studied the embryotoxic effects of EGM, and

Uemura studied those of EGdM. These studies are

summarized here.

Materials and Methods

Ethylene Glycol Monomethyl Ether (EGM). Female JCL-ICR mice (Japan CLEA Co.) were housed

overnight with males of the same stock, and the day on

which a vaginal plug was observed was designated day 0

of gestation. On days 7 to 14 of gestation, EGM at

various daily doses (1000, 500, 250, 125, 62.5 and 31.25

mg/kg body weight) dissolved in water was given by

gastric intubation. The group administered vehicle only

served as the control. On day 18 of gestation, mice were

sacrificed. Litter values and gross abnormalities were

recorded. Blood was taken from dams for white blood

cell count. Living fetuses with no external malformations or with only abnormal digits were examined for

skeletal abnormalities and the degree of ossification.

Ethylene Glycol Dimethyl Ether (EGdM). Female

CRJ:CD-1 mice (Charles River Japan Inc., 12 weeks of

age) were housed overnight with same stock males (14

weeks of age), and the day on which a vaginal plug was

observed was designated day 0 of gestation. On days 7

to 10 of gestation, EGdM at various daily doses (490,

350 and 250 mg/kg body weight) dissolved in water was

given by gastric intutabion. The group administered

vehicle only served as the control. On day 18 of

gestation, mice were sacrificed. Litter values and gross

abnormalities were examined. Fetuses were examined

for their skeletal abnormalities and the degree of

ossification.

Results

EGM. All fetuses except one of the 500 mg/kg

group were dead in the 1000 and 500 mg/kg group, and

there was an increase in the incidence of dead fetuses in

the 250 mg/kg group. Gross abnormalities, such as

Although the significant maternal toxicity was not

observed, both EGM and EGdM induced marked and

dose-related embryotoxic effects. A summary of the

results is given in Figure 15.

exencephaly, umbilical hernia or abnormal digits, were

observed in the 250 mg/kg group. Reduction in fetal

weight was seen in the 125 mg/kg and higher dose

groups. Skeletal malformations including fusion and

agenesis of either ribs or vertebrae were observed in

62.5 mg/kg or higher dose groups. Skeletal variations

such as bifurcated or split cervical vertebrae and

retardation of skeletal ossification in fetuses were noted

in all treated groups (250-31.25 mg/kg).

83
84 NAGANO ET AL.

EON Leucopenla of dams

Fetal death

Gross anomiles

Fetal body weight loss

Skeletal malformations

Skeletal variations

Retardation of ossification

31,25 62,5 125 250 500 1000

Daily dose of EGO (mg/kg)

EGdS Fetal death

Gross anomalies

Fetal body Welght loss

Skeletal malformations

Skeletal variations

Retardation of ossification

250 350 490

Daily dose of E1dM (mg/kg)

FIGURE 15. Summary of study on embryotoxic effects of EGM and

EGdM.

EGdM. There was an increase in the incidence of

dead fetuses in the 490 mg/kg group. An increase in

number of gross abnormalities, such as exencephaly,

caudal defect and umbilical hernia, were observed in the

350 mg/kg and higher dose groups. In all treated

groups, increased incidence of skeletal malformations

such as fused ribs and vertebrae, skeletal variations

such as extra ribs and retardation of skeletal ossification

was noted.

Discussion

Past studies and recent data on the toxicological

effects of ethylene glycol ethers in Japan were reviewed.

Testicular atrophy in mice, hamsters and guinea pigs

were observed on administration of some ethylene

glycol alkyl ethers, i.e., EGM, EGE, EGMA, EGEA

and EGdM. A correlation between chemical structures

and their effects on testis was observed. Testicular

atrophy was induced by EGM, EGE, EGMA, EGEA

and EGdM, and the atrophy was greater for EGM,

EGMA and EGdM than EGE and EGEA, when dose

level is expressed as mole/body weight. However, no

significant effect on the testis was seen in the groups

treated with EG, EGPr, EGB, EGPh, EGA and EGdA.

Alkyl ethers of other glycols, i.e., PGM, dEGM and

dEGdM, did not show any significant evidence on the

induction of testicular atrophy in mice.

From the above findings it can be concluded that

there is a correlation between chemical structures of

ethylene glycol alkyl ethers and their ability to induce

testicular atrophy. Both methyl and ethyl ethers of

ethylene glycols cause testicular atrophy. Methyl ethers

have a greater effect than ethyl ethers. Esterification of

these chemicals does not affect the potency of the

toxicity. Dimethyl ethers of ethylene glycols have

quantitatively the same testicular toxicity as monomethyl ethers. Alkyl ethers of other glycols such as

propylene glycol and diethylene glycol have no significant

effect on the testis.

Ethylene glycol alkyl ethers can be concluded to

induce testicular atrophy by affecting dividing cells of

some kinds and inhibiting cell proliferation from the

following reasons. Alkylating agents induce leukopenia

as well as testicular atrophy by affecting cell division

(7). Similarly, EGM, EGE, EGMA, EGEA and EGdM

cause leukopenia at the same degree as for testicular

atrophy. However, histopathologically, Leydig cells and

Sertoli cells were found to be normal even at higher dose

levels. Only a slight decrease in weight was recorded for

the seminal vesicle and the coagulating gland at

extremely higher dose levels. By these findings, testicular changes induced by ethylene glycol alkyl ethers

can be distinguished from those induced by hormonal

substances (e.g., 17 3-estradiol) or vasoactive substances (e.g., cadmium chloride) (8). Substances showing inhibitory effect on cell proliferation are known to

produce a lethal effect on or damage to the fetus when

given to pregnant animals (6). EGM and EGdM exhibit

marked embryotoxic effects. This fact also supports the

conclusion that ethylene glycol alkyl ethers have an

inhibitory effect on cell proliferation.

From the results of the present animal experiments,

it can be concluded that some ethylene glycol alkyl

ethers have toxic effects on the testis and fetus.

The authors are indebted to Dr. M. Enomoto, Dr. K. Uemura,

Mr. Y. Koshima and Mr. Y. Kurakata for help in the presentation of

this paper and many useful suggestions for its improvement.

REFERENCES

1. Ministry of International Trade and Industry. Year Book of

Chemical Industrial Statistics, Research Institute of International

Trade and Industry, Tokyo, 1981.

2. Japan Tariff Association. Japan Export and Import. Japan Tariff

Association, Tokyo, 1981.

3. Nagano, K., Nakayama, E., Koyano, M., Oobayashi, H., Adachi,

H., and Yamada, T. Testicular atrophy of mice induced by ethylene

glycol mono alkyl ethers. Japan. J. Ind. Health 21: 29-35 (1979).

4. Uemura, K. The teratogenic effects of ethylene glycol dimethyl

ether on mouse. Acta Obst. Gynaec. Japan. 32: 113-121 (1980).

5. Nagano, K., Nakayama, E., Oobayashi, H., Yamada, T., Adachi,

H., Nishizawa, T., Ozawa, H., Nakaichi, M., Okuda, H., Minami,

K., and Yamazaki, K. Embryotoxic effects of ethylene glycol

monomethyl ether in mice. Toxicology 20: 335-343 (1981).

6. Hemsworth, B. N., and Jackson, H. Embryopathies induced by

cytotoxic substances. In: A Symposium on Embryopathic Activity

of Drugs (J. M. Robson, Ed.), Churchill, London, 1965, pp.

116-137.

7. Patanelli, D. J. Suppression of fertility in the male. In:

Endocrinology, Vol. 5 (R. 0. Greep and E. B. Astwood, Eds.),

American Physiological Society, Washington, DC, 1975.

8. Zshauer, A., and Hodel, C. Drug-induced histological changes in

rat seminiferous tubular epithelium. Arch. Ibxicol. (Suppl.) 4:

466-470 (1980).