-------
TABLE OF CONTENTS
1. INTRODUCTION ........................... 1-1
1.1. STRUCTURE AND CAS REGISTRY NUMBER ............. 1-1
1.2. PHYSICAL AND CHEMICAL PROPERTIES ............. 1-1
1.3. PRODUCTION DATA ...................... 1-1
1.4. USE DATA ......................... 1-1
1.5. SUMMARY .......................... 1-12
2. ENVIRONMENTAL FATE AND TRANSPORT ................. 2-1
2.1. AIR ............................ 2-1
2.1.1. Reaction with Hydroxyl Radicals ......... 2-1
2.2. WATER ........................... 2-3
2.2.1. Hydrolysis .................... 2-3
2.2.2. Oxidation .................... 2-3
2.2.3. Photolysis .................... 2-3
2.2.4. Mlcroblal Degradation .............. 2-5
2.2.5. Volatilization .................. 2-6
2.2.6. Adsorption to Sediment .............. 2-7
2.2.7. B1oconcentrat1on ................. 2-7
. • • " •
2.3. SOIL ................. .......... _2-9
2.3.1. Mlcroblal Degradation .............. 2-9
2.3.2. Chemical Degradation ............... 2-9
2.3.3. Adsorption .............. ...... 2-9
2.4. SUMMARY. . ........... ............. 2-10
3. EXPOSURE ............................. 3-1
3.1. WATER ........................... 3-1
3.2. FOOD .... ....... ........ ........ 3-1 :
...... . .. .. . .. . .. . ...... ...., ........ ... ...... 3-5
3.5'. SUMMARY. . .... . . ....... ...... . . .. . ... . . ... . 3-5
4.. AQUATIC TOXICITY. . . .! >.;..,. > .. ., ., ..,. ....... ..... . , ..... ,...—. .. 4-1
4.1. ACUTE • TOXICITY ........ ----- . . ....... ....... . . . 4-1
4.2.. CHRONIC; EFFE-CTS... .. .. . ..... . .. . „ ...... .. . .. .. .. .. 4-1
4;3v FLAW?- EWECTSr; ....... .. .- . , . . . . . ...... . .. . « 4--T-
*;.«r..- SUMMARY. . . . ..... ., ------- . ., .. . , ______ . . ,. . .. « .
X111
-------
TABLE OF CONTENTS (cont.)
Page
5. PHARMACOKINETCS 5-1
5.1. ABSORPTION 5-1
5.2. DISTRIBUTION 5-1
5.3. METABOLISM 5-3
5.4. EXCRETION 5-4
5.5. SUMMARY 5-5
6. EFFECTS 6-1
6.1. SYSTEMIC TOXICITY 6-1
6.1.1. Inhalation Exposures _^6-l
6.1.2. Oral Exposures 6-4
6.1.3. Other Relevant Information 6-10
6.2. CARCINOGENICITY 6-10
6.2.1. Inhalation 6-10
6.2.2. Oral 6-21
6.2.3. Other Relevant Information 6-26
6.3. .MUTAGENICITY 6-35
6.4. TERATOGENICITY ........ 6-35
6.5. OTHER REPRODUCTIVE EFFECTS 6-40
6.6. SUMMARY 6.-40
7. EXISTING GUIDELINES AND STANDARDS 7-1
7.1. HUMAN., =....',. ,7-1
7.2. AQUATIC -1-2
8. RISK ASSESSMENT 8-1
8.1. CARCINOGENICITY 8-1
' 8.T*T'.« InteTa;t1on.iV «.«„„„ *•„.., «•.««,«.« . ,«;... ... —, 8>I'.';'
8'a-.'?.: Or'al. . . .*'-'•.. . .... . .,., .. . . ..,..., .. ... ., ~ . . -.- 842 .
8.K3-. Other Router. . 8-3
B.T.4?. Weight of Evidence- , ^.8-4;
8.1^5?. Quantitative Risk; Assessment. .; ..8-5
8.2.: SYSTEMIC TOXICITY. . ., « ., . ., 8-11
S??:!'. *• rrih-aiTa-td'an; Efxpo'swre;-^. . ,...,:•... ., . , ., ., .... . .., 8;-1il
8.2.2. OraT E-xp'osiine . 4 - ......... .-,,. ... „., . •*
x1v
-------
TABLE OF CONTENTS (cont.)
9. REPORTABLE QUANTITIES _9-l
9.1. BASED ON SYSTEMIC TOXICITY 9-1
9.2. BASED ON CARCINOGENICITY 9-11
10. REFERENCES 10-1
APPENDIX A: LITERATURE SEARCHED A-l
APPENDIX B: CANCER DATA SHEETS FOR DERIVATION OF q^s B-l
APPENDIX C: SUMMARY TABLES FOR HALOETHERS C-l
xv
-------
LIST OF TABLES
No. Title Page
1-1 Synomyns, CAS Numbers, Empirical Formulas and Structures
of Selected Haloethers .................... 1-2
1-2 Physical Properties of the Haloethers ............ 1-6
1-3 1977 U.S. Production Data for the Haloethers ......... 1-8
1-4 Use Data for Haloethers ................... 1-11
2-1 Haloether Reaction Rates with Atmospheric Hydroxyl
Radicals ........................... 2-2
2-2 Hydrolysis Rates of Haloethers In Water ........... 2-4
2-3 Volatilization of Haloethers from Water ........... 2-8
2-4 Estimated Koc of Selected Haloethers ............. 2-11
3-1 Occurrence of Haloethers In Various Types of Waters
1n the United States ..................... 3-2
3-2 Levels of Haloethers In U.S. Waters Computed from
STORET Data Base ....................... 3-4
6-1 Acute Oral and Inhalation Toxldty of Chloroalkyl Ethers. . . 6-11
6-2- Incidences of Tumors In Male Sprague-Dawley SPF Rats :
(Spartan Substraln) and Hale Ha/ICR Mice Exposed to
bls(Chloromethyl) Ether by Inhalation for 6 Hours/Day,
5 Days/Week for 6 Months with Lifetime Observation ...... 6-13
6-3 Incidence of Respiratory Tract Tumors 1n Hale Sprague-
Dawley Rats Exposed to 0.1 ppm bls(Chloromethyl) Ether
for 6 Hours/Day, 5 Days/Week for 10-100 Exposures with
Lifetime Observation ..................... 6-16
fc-C- L'ung Career Mortality :1nf Workers Exposed to bVs(ChlORa-»;:.
methyl)" Ether 'artd? Techrtfcal -Grades Chloromethyt MethyT <•.
Ether (Selected Ep1demto.logxtcal Studies)-. ----------- ..... . .... fr-22
S-i£ Incidence of Hepatomas 1n Two Stra.Jnsi of Hleenfffiyen Oral V '
Oases jaf b1s(2-Chloroethy;l:)/ fcther u . . . ,.'•.; _,.;^ ... ~ .. ,, .„ 6*2$
6-6 i Incidence of, .Tumors;, In, B&C3F1 Mice Treated with .Technical
Grade b.1s(2-Ch)lorlo:-T^me;tWylethy;l?) -PtKer In Corn 011s by
Savage'V S-vDay^/Week foH vaa.Weetesf .„ *.>„• - ------- . . . -~r ., . . fr.-27.sf
6-7 Dermal Tumor1gen1c1ty of Haloethers 1n Female Mice ...... 6-29
xv1
-------
LIST OF TABLES (cont.)
No. Title Page
6-8 House Skin Tumor-Initiating and Tumor -Promo ting Activity
of Chloroethers ....................... 6-30
6-9 Subcutaneous Injection CardnogenlcHy Studies of
Haloethers .......................... 6-33
6-10 IntraperHoneal Injection CardnogenlcHy Studies
of Haloethers with Mice ................... 6-36
6-11 Mutagenldty and Other Short-Term Genotoxldty Assays
of Haloethers ........... ............. 6-37
9-1 Toxldty Summary for Chloroethers .............. 9-2
9-2 bls(Chloromethyl) Ether: Minimum Effective Dose (MED)
and Reportable Quantity (RQ) ................. 9-4
9-3 Composite Scores for Chloroethers .............. 9-6
9-4 Chloromethyl Methyl Ether: Minimum Effective Dose (MED)
and Reportable Quantity (RQ) ................. 9-7
9-5 .. b1s(2-Chloroethyl.) Ether: Minimum Effective Dose (MED)
and Reportable Quantity (RQ) ..... ............ 9-8
9-6 b1s(2-Chloro-l-methylethyl) Ether: Minimum Effective
Dose (MED) and Reportable Quantity (RQ) ........... 9-10
9-7 2,4,4'-Tr1chloro-2'-hydroxyphenyl) Ether: Minimum
Effective Dose(MED) and Reportable Quantity (RQ) ....... 9-12r
9-8 Derivation of Potency Factor (F) for bls(Chloromethyl)
Ether ............................ 9-13
9-9 Derivation of Potency Factor (F) for b1s(2-Chloromethyl)
Ether ... ..••... . ...„,., ..... . .. „• ,. ., . ,..., *. . .....,- ....... $-15?'
i-JOV Oen-Dvfft-ron: of Potency; Factor (iFf forr
methyTethyl) Ether (CommerdaT Grade) . . . . . ..... ... 9-T8
xv11
-------
LIST OF ABBREVIATIONS
B(a)P Benzo(a)pyrene
BCF Bloconcentratlon
bw Body weight
CAS Chemical Abstract Service
EC,. Concentration effective to 50% of recipients
GOT Glutamlc oxaloacetlc transamlnase
GPT Glutamlc pyruvlc transamlnase
KQW Octanol/water partition coefficient
LC5Q Concentration lethal to 50% of recipients
LC. Lowest lethal concentration
Lo
LD5Q Dose lethal to 50% of recipients
LOAEL Lowest-observed-adverse-effect level
MTO Maximum tolerated dose
NOAEL No-observed-adverse-effect level
NOEC No-observed-effect concentration
PEL Permissible exposure level
PMA Phorbol myMstate acetate
ppb Parts per bill loft
ppm Parts per mtlllon.
RfD Reference dose
RQ Reportable quantity
RV. Dose-rating value
RV Effect-rating value
e
STEL Short-term effect level
TLV Threshold, leve,! value
TPA T2-Q-n-te.tratfecan0y 1 pttor p4b'o;fl--T3 -acetate;
TWA* Tlme-wetghted average"
UV Ultraviolet-
xv1)1
-------
1. INTRODUCTION
1.1. STRUCTURE AND CAS REGISTRY NUMBER
Haloethers are compounds that contain an ether moiety (R-O-R) and
halogen substltuent(s) In the carbon frameworks. The structures, CAS
Registry numbers, synonyms and empirical formulas of the selected haloethers
are presented In Table 1-1.
In an ether, the numbering or lettering of the carbons begins at the
carbon next to the oxygen. Additionally, an a-haloalkyl ether 1s the same
as 1-haloalkyl ether.
1.2. PHYSICAL AND CHEMICAL PROPERTIES
The available physical properties of the selected haloethers are
presented 1n Table 1-2.
1.3. PRODUCTION DATA
Production data available for 1977 are presented In Table 1-3. SRI
(1986) lists current U.S. production of the following haloethers:
b1s(2-Chloro-l-methylethyl) ether Dow Chem., Freeport, TX
a,a-D1chloromethyl methyl ether Aldrlch Chem., Milwaukee, HI
b1s(.2-Chloroethyl) ether Buckman Labs, Memphis, TN
l,2-b1s(2-Chloroethoxy:)ethane Eastman Kodak, Batesvllle, AR
Koch Ind., Whitehall, MI
B1s(2-chloroethoxy)methane 1s produced as. an on-slte Intermediate .for the,
product-Ton; of paTysuTftde/po!Tymef$ fCllersteTnl arid; Bftrttozrt. T982J;, poTy*
sulflde polymers are currently manufactured'by Morton1 Thtoko'l tn Moss Point,
MSr (SRI, 1986).
1.4. USE. DATA
U"s,e data' for selected haloethers are: g,fyefr !n Table: 1-4.
0037d 1-1 07/07/87
-------
o
o
Oi
TABLE 1-1
Synonyms, CAS Numbers, Empirical Formulas and Structures of Selected Haloethers
Compound
Synonyms
CAS Number
Empirical
Formula
Structure
i
rsj
1,2-bls(2-Chloroethoxyjethane
bts(2-Chloroethoxy)methane
'''"
bls(2-Chloroethyl) ether
bts(a-Chloroethyl) ether
• < v ' r:
1,4-bls(Chloromethoxy)butane
1.2-bls(Ch1oromethpxy)ethane
1,6-bls(Chloromethoxy)hexane,
bls(Chloromethyl) ether
trlethylene glycol dlchlorlde.
trtglycol dlchlorlde,
l,2-bls(chloroethoxy)ethylene.
2-J2-chloroethoxy) -ethyl
2'-chloroethyl ether
ethane, l,l'-[methylene-
t)lsjo»y)]bls-l2-chloro-,
bisi^-chloroethyl) formal.
dl|2-chloroethoxy)methane,
d||2-chloroethoxy) formal.
djchjbrodlethyl formal.
2,2-dtchloroethyl formal.
jiis(B-chloroethyl) formal
' '' "-/'^ ^
ethane, 1,1' -oxybls[2-chloro-,
B.B'-dlchloroethyl ether,
jjich)ort>ethyl ether,
dichloroethyl oxide,
sym'-dlchloroethyl ether, DCEE. BCEE
• ": "• '',^5,
ethanf, l,l'-oxybls[l-chloro-,
blsjlrthloroethyl) ether,
dl-l-chloroethyl ether,
i.l'-dlchlorodlethyl ether
7 , ~
biitan'e, l,4-bls(chloromethoxy)-
bls-i,|-(chloromethoxy (ethane,
ethylene glycol bls(chloro-
ether
o
en
'*
b*$-|,|-(chlororoethoxy)hexane
" * )'.
methane, oxyblsjchloro-,
BCHE, J-(dlchloroinethyl) ether.
chlprodlmethyl ether,
dlmejihyl-1 ,1-dlchloro ether
112-26-5
C1-CH2-CH2-0-CH2-CH2-0-CH2CH2-C1
111-91-1 CsHioCl202 C1-CH2-CH2-0-CH2-0-CH2-CH2-C1
111-44-4 C4HBC120 C1-CH2-CH2-0-CH2-CH2-C1
6986-48-7 C4H8C120
CH3-CH-0-CH-CH3
I I
Cl Cl
13483-19-7 C6"l2c12°2 C1-CH2-0-CH2-CH2-CH2-CH2-0-CH2-C1
13483-18-6 C4H8C12°2 C1-CH2-0-CH2-CH2-0-CH2-C1
56894-92-9 C8H16C1202 C1-CH2-0-(CH2)6-0-CH2-C1
542-88-1 C2H4C120 C1-CH2-0-CH2-C1
CD
ca
-------
TABLE 1-1 (cont.)
Compound
Synonyms
CAS Number Empirical
Formula
Structure
2, ?'-Oxyb1s(2-chloropropane)
bts(4-Chlorophenyl) ether
2-Bromophenyl phenyl ether
3-Bromophenyl phenyl ether
b|$|?-chloro-2-methylethyl) ether.
i>jf (2-chlorotsopropyl Jether,
dl(2-ch1orolsopropyl) ether
beniene, l.l'oxybls(4-chloro-.
tltt(p-chlorophenyl)] ether.
4.V-d1chlorodlphenyl ether.
?,ja'-d!chlorodlphenyl ether
,*".. <.
ttenpene, l-bromo-2-phenoxy-.
p'-i»fonophenyl phenyl ether
beniene. l-bromo-3-phenoxy-.
p-6rpmpheny1 phenyl ether,
pi'-j>iienoxyphenyl bromide
39638-32-9 C6H1?C120
2444-89-5
702S-06-1 C12H9BrO
6876-00-2 C12H9BrO
Cl C1
CH3-{-0-i-CH3
^H3 CH3
co 2-Chloroethyl methyl ether
2-Chloroethyl vinyl ether
Chloromethyl methyl ether
2-Chlorophenyl phenyl ether
3-Chlorophenyl phenyl ether
ethane, l-chloro-2-methoxy,
2-nethoxyethyl chloride
ethene. (2-chloroethoxy)-,
O^chjoroethyl vinyl ether
2-yjjnyloxyethyl chloride
methane, chloromethoxy-. CHHE
methyl chloromethylether.
chloride
beniene, l-chloro-?-phenoxy-
ij-cljlorophenyl phenyl ether
2-cljlorodlphenyl ether
beniene. 1-chloro-3-phenoxy-
ni-ehlorophenyl phenyl ether
3-chlorodlphenyl ether
627-42-9
110-75-8
107-30-2
2689-07-8
C3H7C10
C4H7C10
C2H5C10
C,2H9C10
6452 49-9 Cj2H9C10
CH3-0-CH?-CH2-C1
C1-CH2-CH2-0-CH=CH2
C1-CH2-0-CH3
oa
4-Chlorophenyl phenyl ether
beniene, 1-chloro ^-phenoxy-.
p-cMorophenyl phenyl ether
4-chjorodlphenyl ether
7005-72-3 C12H9C10
-------
o
Gi
TABLE 1-1 (cont.)
Compound
Synonyms
CAS Number
Empirical
Formula
Structure
2,3-Dlchloro-p-dloxane
1.4-dtoxane, 2.3-dlchloro-.
p-dioxane, 2.3-dlcnloro-
95-59-0 C4H6C1202
trans-2.3-Olchloro-p-dtoxane
1.4-dtoxane, 2,3-dlchloro-, trans-
3883-43-0
a.a-Dlchloroaiethyl methyl
ether >: -,
2,3-Dlchlorotetrahydrofuran
trans-2.3-Olchlorotetrahydrofuran
•ethane, dlcMoronethoxy-
dlchlqronethyl "ethyl ether
•ethyl'dtchlorooethyl ether
|,l-dlchiprp«ethyl *ethyl ether
none
none
4885-02-3 CZH4C120
3511-19-1 C4H6C120
13129-90-3 C4H6C120
C1-CH-0-CH3
Cl
1,
p-p
o.
•j
v.
CD
Octachloro-dl-n-propyl ether
bls(2-Chloro-l-oethylethy1) ether
propane, ),}|-oxybls(2.3.3.3-tetra-
chlbrqpctachlorodlpropyl) ether.
bit(2.3.3,3-tetrachloropropyl) ether
rjonsantp 1^226
bls(2-chlorolsopropyl) ether.
dlchlQroispprqpyl ether. DCIP,
2.2J-oxyblsjV-chloropropane),
propy)ene'ch|prohydrln ether
D.P:-dtch)6r«Viopropyl ether. BC1E
127-90-2 C6H6ClflO
108-60-1 C6H|2C120
J,
Cl Cl
I I
C1-C-CH-CH2-0-CH2-CH-C-C1
II II
C1C1 C1C1
C1-CH2-CH-0-CH-CM2-C1
I I
CH3 CH3
-------
o
o
to
TABLE 1-1 (conl.)
Conpound
Synonyms
CAS Number
Empirical
Formula
Structure
2.4.4'-Tr|ch1oro-2'-hydro)cy-
dtphenyl ether
1.2.3-trts(Ch1oromethoxy)propane
phenol. 5-chloro-2-(2.4-d1chloro- 3380-34-5
eenoxy)-, Cloxlfenol. Irgasan,
xql 300, trtclosan. TCC, 1HOP.
2-hydroxy-?'.4.4'-trIchlorodl-
phenyl ether. 2.3>-oxybts(1'5-dt-
chlprophehyl-5-chlorophenol).
S-ch1oro-2-(2,4-dlch1orophenoxy)-
pheriol, 3-ch1oro-6-(2.4-d»chloro-
phenoiyjpnenol
trls-1.2.3-(ch1oronethoxy)propane 38571-73-2
glycerlp trls(chloromethyl) ether
glycerol trl(chlorooethyl) ether
i
en
C1-CH2-0-CH2-CH-CH2-0-CH2-C1
0
I
CH2
Cl
o
-j
o
«J
00
-------
TABLIE 1-2
Physical Properties of the Haloethers
0
0
CO
-J
o.
t
1
tr»
\
t\J
ox
CO •
-o
Haloether
1.2-bls(2-Chloroethoxy)ethane'
bls(2-Chloroethoxy)me thane
••'-• -'„._ -rf '
bls(2-Chloroethyl) ether
-. . "-'•--. • y. '-
bls(o,-Chloroethyl) ether
1 ,4-bli(Chloromethoxy)butan9
l,2-bls(Chloromethoxy)ethane
'"•'•" -
-------
TABU 1-2 (cont.)
O
o
O
en
cx>
Haloether
trans -2. 3-01 chloro-p-dloxanc
o.a-Olchloromethyl piethyl ether
2.3-Olchlorotetrahydrofuran
trans-2.3-Dlchlorotetrahydrgfuran
Octachloro-dl-n-propyl ether
bls(2-chloro-l-inethylethy) ether
2.4.4'-Trlchloro-2'-hydroxy-
dlphenyl ether ~:' " '
1, 2, 3-Tr1s(chloromethoxy (propane
Molecular
Weight
Ifl.Ol
JJ4.97
141.01
ML 01
3*1 •"
M?-08
289.53
231.53
Melting
Point
NA
NA
NA
NA
NA
-97C
54-57*
NA
Boiling
Point
NA
84. 5d
NA
NA
NA
189C
NA
(at 19 inn)
Density
(20"C)
(g/cro3)
NA
1.27d
NA
NA
NA
1.113d
NA
1.3575*
(17.5°C)
Mater
Solubility
(mg/l)
NA
NA
NA
NA
NA
1700° (room
temperature)
51
decomposes^
Vapor Pressure
(run Hg)
NA
NA
NA
NA
NA
0.85 (20°C)C
0.000004 (20°C)k
NA
Log Kow
•1>
1.1 38b
1.522b
1.522b
5.472b
1.614b
5.001b
1.560b
allawley. 1981
bU.S. EPA (1987) calculated value
cCaltahan et al., 1979
dOurkln et al.. 1975
•:- ' ' '. -«i'-'
eHansch and teo. I,g85
flARC, 1974. 1977
QWeast. 1985
"Verschueren, 1983
'Mabey et al.. 1981
^Branson. 1977
kUlndholz. 1983
Elites and Lopez-Ay I la, 1980
NA = Hot available
-------
o
o
CO
TABLE 1-3
1977 U.S. Production Data for the Haloethers*
Haloeth.er
Company/Location
Manufacturer/
Importer
Production Range
(pounds)
l,2-b1s(2-Chlbroethoxy)ethane
7* bjs(2-Chloroethoxy)methane
CD
b1s(2-Chloroe.thyllethejr
o
in
00
CD
3 M Co
St. Paul, HN
Muskegan Chem.
Whitehall, HI
Rohm and Haas
Philadelphia, PA
E.T. Horn Co.
LaHlrada, CA
Thlokol Chem.
Moss Point, MS
Dow Chem.
Freeport,.TX
Muskegon Chem.
Whitehall, HI
Buckman Labs
Memphis, TN
Cadet, HO
E.T. Horn
LaHlrada. CA
Fallek Chem
New York, NY
Alcolac
Baltimore, HD
Unlroyal
Naugatuck, CN
confidential
manufacturer
manufacturer
manufacturer
and Importer
Importer
manufacturer
(site-limited)
manufacturer
manufacturer
manufacturer
manufacturer
Importer
Importer
Importer
Importer
confidential
<1000
0.1-1.0 million
confidential
0.1-1.0 million
0.1-1.0 million
10-50 million
1-10 million
confidential
10-100 thousand
confidential
1-10 million
0.1-1 million
0.1-1 million
0.1-1 million
0.1-1 million
-------
TABLE 1-3 (cont.)
o
o
Gi
—4
Q.
Haloether
Company/Location
Manufacturer/
Importer
Production Range
(pounds)
l,2-b1s(Chloromethoxy)ethane
bls(Chloromethyl) ether
2,2'-Oxybls(2-chloropropane)
2-Chloroethyl methyl ether
2-Chloroethyl ylnyl ether
Chlqrpmethyl methyl ether
4-Chlorophenyl phenyl e|her
Kodak
Rochester. NY
Tennessee Eastman
Ktngsport, TN
Dow Chem
Freeport, TX
Clba-Gelgy
Cranston. RI
Alcolac
Baltimore. HD
Dow Chem.
Midland. HI
lonac Chem.
Birmingham, NJ
Rohm and Haas
Philadelphia. PA
Columbia Organlcs
Columbia. SC
Dow Chem.
Midland. HI
manufacturer
(site limited)
manufacturer
manufacturer
manufacturer
(site-limited)
manufacturer
manufacturer
manufacturer
manufacturer
manufacturer
manufacturer
confidential
0.1-1.0 million
1-10 million
none
confidential
10-50 million
0.1-1.0 million
confidential
<1000
0.1-1.0 million
o
en
ro
CD
09
-------
o
o
TABLE 1-3 (cont.)
Haloether,
Company/Location
Manufacturer/
Importer
Production Range
(pounds)
2,3-Dlchloro-p-iilgxane
a,a-Dlchloromethyl methyl ethep
bls(2-chloro-l-methylejthyl) ether
2,4,4'-Tr1ch1orp-j2'hydroxyd1phenyl ether
Hercules
Hattlesburg. MS
Kodak
... Rochester, NY
Kodak
Rochester, NY
Olln Corp.
Brandenburg, KY
Jefferson Chem.
Port neches, TX
Clba-Gelgy
Cranston, RI
Henkel Inc.
Teaneck, NJ
manufacturer
(site-limited)
manufacturer
manufacturer
manufacturer
manufacturer
manufacturer
Importer
*Source: U.S. EPA, J977
confidential
none
<1000
1-10 million
confidential
0.1-1.0 million
<1000
o
U1
09
-------
o
o
co
TABLE 1-4
Use Data for Haloethers*
Haloether
Use
Reference
o
in
CD
><•
CO
1,2-81 s (2-ch Jorpethoxy)
ethane
bt s(2-Chloroethoxy)methane
b1s(2-Chloroethyl) ether
l,2-b1s(Ch1orQmethoxy)ethane
bls(Chloromethyl) ether
2-Chloroethyl vinyl ether
Chloromethyl methyl ether
bls(2-Chloro-l-methylethyl)
ether : • ..... i.
2f4,4'-Tr1chlor72!-hydrp:xy-
(hphenyl ether
"; "•*•,. .••.&
1,2,3-Tr1s(chloi:omethoxy)-
propane
solvent for hydrocarbons, oils, etc.; extractant; Inter
mediate for resins and Insecticides; organic synthesis
Intermediate for polysulflde rubber; solvent
soil fumlgant. Insecticide, acarldde; solvent for fats,
waxes, greases; textile scouring agent; In paints,
varnishes, lacquers; In paint removers; Intermediate
does not appear to have been used commercially, but has
potential uses In synthesis of Ion-exchange resins and
light-sensitive polymers
Intermediate for Ion-exchange resins
polymer production
Intermediate, particularly for Ion-exchange resins
solvent for fats, waxes, greases; extractant; paint and
varnish removers; spotting agents and cleaning solutions
|>acter1ostat and preservative for cosmetic and
detergent preparations
does not appear to have been used commercially, but has
{potential use In resin production
Hawley. 1981
Ellersteln and
Bertozzt. 1982;
Hawley, 1981
IARC, 1975
IARC, 1977
Hawley, 1981
Vial, 1979
IARC, 1974
Hawley. 1981
Wlndholz, 1983
IARC, 1977
*Commerc1a1 use data were not located for the other haloethers.
-------
1.5. SUMMARY
Haloethers are compounds that contain an ether moiety (R-O-R) and
halogen substHuents 1n the carbon framework. With the exception of
b1s(2-chloroethoxy)methane, all the other haloethers with known water
solubility characteristics are either slightly soluble or Insoluble 1n
water, although some of the haloethers decompose 1n water (see Table 1-2).
The haloethers are also soluble 1n a wide variety of organic solvents
(Hawley, 1981; Weast, 1985; Wlndholz, 1983). Of the 27 selected haloethers,
at least nine were produced 1n quantities >0.1 million pounds 1n 1977 (see
Table 1-3). Currently, only five companies manufacture unknown amounts of
four haloethers 1n the United States (SRI, 1986). The haloethers are
generally used as chemical Intermediates, particularly for polymers and
resins, and as solvents (Hawley, 1981; IARC, 1974, 1975, 1977; Wlndholz,
1983; V1al, 1979; Ellersteln and Bertozzl, 1982).
0037d T-72 ' 05/28/87'
-------
2. ENVIRONMENTAL FATE AND TRANSPORT
Six of the selected haloethers have been classified as priority pollu-
tants by the U.S. EPA (Callahan et al., 1979). These haloethers Include
bls(chloromethyl) ether, b1s(2-chloroethyl) ether, 2-chloroethyl vinyl
ether, 4-chlorophenyl phenyl ether, b1s(2-chloroethoxy)methane and b1s(2-
chloro-1-methylethyl) ether. The majority of the available experimental
data useful 1n assessing environmental fate and transport processes pertain
to these compounds.
2.1. AIR
Based on the limited available vapor pressure data (see Table 1-2), the
selected haloethers can generally be expected to exist primarily 1n the
vapor phase In the ambient atmosphere; E1senre1ch et al. (1981) Indicated
that organlcs having vapor pressures >0.0001 mm Hg should exist almost
entirely 1n the vapor phase 1n the atmosphere. 2,4,4'-Tr1chloro-2'-hydroxy-
dlphenyl ether may exist partly sorbed to partlculate matter 1n the air
since Its vapor pressure 1s <0.0001 mm Hg.
Z'.T.T. Reaction with Hydroxyl Radicals. When released to the ambient
atmosphere 1n the vapor phase, the selected haloethers are expected to react
relatively fast with photochemically produced hydroxyl radicals. The
reaction; rate; .con$tafttsv ai«t ftalfwitve* of tlfe- Najoetherst are: presented? Vtir
Table 2-T. The rate const-ants: TVsted' Vn- Table- 2-T are estimated, values,
based, on hydrogen abstraction reactions (U.S. •>EPA,, 1987). The estimated
half-lives tndtcatr that this" reaction wVTl be the•dominant environmental •
fate, process1 1n ilre atmosphere. Although: other process'es< such as hydroTyits
1n moist air may be significant for a few compounds Including blsfchloro-
methyl) ether and 1,2-b1s(chloromethoxy)ethane (IARC, 1974, 1977), hydroly-
sis will be considerably slower 1n aAr tha.n 1n aqueous, solutVon (IARC,. 1914.),..
0038d 2-1 05/28/87
-------
TABLE 2-1
Haloether Reaction Rates with Atmospheric Hydroxyl Radicals3
Haloether Rate Constant at 25°C
(cm3/molecule-secxl012
1 ,2-b1s(2-Chloroethoxy)ethane
b1s(2-Chloroethoxy)methane
b1s(2-Chloroethyl) ether
bls(a-Chloroethyl) ether
1 ,4-b1s(chloromethoxy)butane
1 ,2-b1s(Chloromethoxy)ethane
bls(Chloromethyl) ether
b1s(4-Chlorophenyl) ether
3-Bromophenyl phenyl ether
2-Chloroethyl methyl ether
2-Chloroethyl vinyl ether
2-Chlorophenyl phenyl ether
2,3-D1chloro;-p-d1oxane
a,a-01chloromethyl methyl ether
2,3-Olchlorotetrahydrofuran
bl.sffZXhT^o^T-meth'yl^^B; «Httr»..
2,4, 4:1 -Tr 1 cbiToro-2 ' -hydr oxy-
ilRhenyl etlien
F, 2;, T-Trl s,f chrTorotnet'hoxyJ'proparre
34.9
149.8
17.9
32.5
25.5
24.6
7.38
10.2
. 22.1 .
10.7
17.0
6.5
49.5
8.3
26.5;
7M
ltt.2,
65% 5-
Half-L1feb
) (hours)
6.90
1.61
13.44
7.41
9.43
9.79
1.36
23.59
.10.89
22.47
9.00C
,1.54. ,
4:86
1.20
a.oai,
31 T2;
23.6
3.67
aSouriC«i; U.S. EPA, 1987 £
Assumes atmospheric hydroxyl radical concentr'at'lon of 8x10" molecules/cm3.
clncludes reaction with ozone at an atmospheric concentration of 6-OxlO11
molecules/cm3 (rate constant = 1.3xlO~17 cm3/molecule-sec). The rates of
this, reaction are negligible with otherrreactarTtS;V *
0038d 2-2 05/28/87
-------
CupHt (1980) reported that the anticipated atmospheric degradation
products of bls(chloromethyl) ether that result from reaction with hydroxy
radicals Include H_CO, HC1, chloromethylformate and C1HCO.
2.2. WATER
2.2.1. Hydrolysis. In general, the a-chloroalkyl ethers have extremely
short hydrolytlc half-lives In aqueous solutions and are therefore not
expected to persist for any extended period of time 1n water (U.S. EPA,
1980b). The B-chloroalkyl ethers, however, are much more stable to aqueous
hydrolysis. The available experimental hydrolysis data have been reviewed by
several authors (Durkln et al., 1975; Callahan et al., 1979; Habey et al.,
1981). Much of the available data have been generated using different
solvent systems (e.g., water:d1oxane or water:d1methylformam1de) and
variable temperatures. Table 2-2 lists rate constants and half-lives that
have been reported for 100X water at ambient temperatures.
The halogenated aromatic ethers (chlorophenyl phenyl ethers and bromo-
phenyl phenyl ethers) are not expected to hydrolyze In water (Habey et al.,
1981; Callahan et al., 1979).
2.2.2. Oxidation. With the exception of 2-chloroethyl vinyl ether,
oxidation of the haloethers 1n natural water 1s not expected to be Important.
2-Chloroethyl vinyl ether may be susceptible to oxidation because of the
presence of the caPboit-carbon doutle bond.. Rabey; e£ a TV (T98T), estimated
the rate; constant For the/'reaction-i'ofv- 2-ch,loroethyl vinyl ether - with; sing-let
oxygen In rrajtural water, to be IxTO1^ H-hour:. Assuming that the • singlet
oxygen concentration In sunlit natural wafer Is. -lxlO~" H' (Habey 'el' al.,
1981),, the half-life can; be calculated to; be;—6.9; hours.
2.2.3. Photolysis. The alky! haloethers do not strongly absorb UV 'light
and are not expected to react by means of direct photolysis In the ambient
environment (Durk,1n et/al., 1975;/Callahan et al<, 19,7.9.)...
0038d 2-3 07/07/87
-------
TABLE 2-2
0
0
co
CD
Q.
Haloether
bls(Chloromethyl) ether
"*'£ '
b1s(2-Chloroethyl) ether
2-Chloroethyl yjnyl ei\\ef
4-Chlorophenyl phenyl ether
ro - . .•£•,.-•
l :::
bl s ( 2-Chloroethoxy )me thane
Chloromethyl methyl ether
a,a-D1chloromethyl methyl
ether «*!';"' * '
bls(a-Chloroethyl) ether
Hydrolysis Rates
" '* -
Rate Constant
j).018 second"1
4.6x10"* hour"1
(estimated)
$.6x10"* hour"1
(estimated)
•";'- •- - )
4.6x10"* hour"1
(estimated)
*
-T*^ * '
<$>••
of Haloethers In
Half-Life
38 seconds
-20 years
-20 years
hydrolysis not
significant
-20 years
<1 second
<2 minutes
<2 minutes
Water
Conditions
20°C, pH 7
25°C. pH 7
25°C, pH 7
all environmental
conditions
25°C, pH 7
25°C
0°C
0°C
Reference
Callahan
et al., 1979
Habey et al. ,
1981
Habey et al. ,
1981
Habey et al..
1981
Habey et al..
1981
Durkln et al.,
1975
Durkln et al.,
1975
Durkln et al.,
1975
o
en
ro
00
co -'
-------
Choudhry et al. (1977) subjected methanollc solutions of 2- and
4-chlorophenyl phenyl ether and b1s(4-chlorophenyl) ether to Irradiation at
wavelengths >290 nm by a merry-go-round apparatus for 8 hours and found that
1.3-1.954 of the Initial concentration had reacted at the end of the exposure
period.
Dulln et al. (1986) measured the quantum yields and photolysis rates of
2- and 4-chlorophenyl phenyl ether In water. Under winter sunlight at 40° N
latitude, the measured photolysis half-lives of 2- and 4-chlorophenyl phenyl
ether were 240 and >400 days, respectively. Under summer conditions, the
photolysis half-life of 2-chlorophenyl phenyl ether was estimated to be 3.6
days; however, this estimate was based on a calculated rate constant, which
was subsequently determined to be 10 times greater than the measured rate
constant. Therefore, under summer conditions, the half-life of 2-chloro-
phenyl phenyl ether Is actually closer to 36 days. The half-life for
4-chlorophenyl phenyl ether under summer conditions was. estimated to be 200
days. All of these half-lives pertain to photolysis at surface water
conditions and are, therefore, maximum rates. As the water depth Increases,
the photolysis rate will decrease.
2.2.4. Mlcroblal Degradation. Tabak et al. (1981) examined the b1o-
degradabllUy of the organic priority pollutants In an attempt to determine
the, potential -'and condVttons for ralcrobAaTdegradation of? these com-
pounds. ., The b;iodegrada;tVon test method: Involved a, siatfc.-cuT.ture flaikr
screening procedure us1ng: a 7-day stat;.1c Incubation followed by Incubation
Vn 3'weekly subcultures ("28 total tnfcubatTon days). The concentrations of
the. tes't compound: were; 5/ and TO; ppmv and'• •& settleddomsstfc was:tewa,ter was
used as the mlcroblal Inoculum. b1s(2-Chloroethyl) ether, 2-chToroethyT
vinyl ether and b1s(2-chloro-l-methylethyl) ether were all found to have
0038d 2-5 07/07/87
-------
significant degradation with rapid adaptation. 4-Chlorophenyl phenyl ether
and b1s(2-chloroethoxy)methane did not degrade significantly under the test
conditions.
Ludzack and Ettlnger (1963) studied the breakdown of b1s(2-chloroethyl)
ether to CO- 1n Ohio River water that was supplemented with settled sewage
(1% by volume was added weekly). The authors found extensive degradation of
the chloroether after a 25- to 30-day lag period; ~85% of the theoretical
C0_ was recovered after 65 days of Incubation. Upon redoslng the test
medium with the chemical, CO- evolution occurred at rates several-fold
higher than the first time (Indicating the necessity for acclimation of the
microorganisms to the haloether). DojUdo (1979) Investigated the b1o-
degradablHty of b1s(2-chloroethyl) ether by three methods (Sapromat
resplrometer, river die-away and activated sludge unit) and found the
compound was biologically Inert under all three tests. The river die-away
test was conducted only for 18 days; as noted above 1n the Ludzack and
Ettlnger (1963) study, a lag period of 25-30 days has been observed before
Initiation of m1crob1al decomposition. *'
Voets et'al. (1976) examined the blodegradatlon of 2,4,4'-tr1chloro-2'- '"
hydroxydlphenyl ether using flask Incubation methods under both aerobic and
anaerobic conditions. No degradation was observed over a 3-week period when
av sat* extract wasr used? as* the^rolcfQbAai? litiaeuJwB^ Use?; oft at &#itta&¥c
sewage '• Inoculum1: resulted 1n[ .50% de'gr.ada'l.to.n, af£e/f;:/3I: weeM under ,b,o'th the",
aerobtc;and anaerobic conditions-.,,
2.2F.5. Volatilization". Volatilization 1s* n'ot expected to ber an Important.;
fate: ,p,r,Qce.ssf, far- the7ia-chlo'rioa?l?kyl ue;the,ri?s^ sintiei- they hyd'rpiTyie nap-Ydly; t;n?
water; T,2,3"-Tfts(chloromethoxy)propane also decomposes In* water.-
0038d " 2-6 ' 05728/87 J
-------
Table 2-3 lists estimated Henry's Law constants and estimated volatili-
zation half-lives of various non-a-chloroalkyl ethers. For 2,4,4'-tr1-
chloro-2'-hydroxyd1phenyl ether; 1 ,2-b1s(2-chloroethoxy)ethane; b1s(2-
chloroethoxy)methane and possibly 2,3-d1chloro-p-d1oxane, volatilization
from water will not be environmentally significant. Volatilization may have
some Importance for the other haloethers. 4-Chlorophenyl phenyl ether has
an estimated log K of 4.08 (see Table 1-2), which Indicates a tendency
to adsorb to sediment 1n water, which may significantly reduce Us rate of
volatilization.
2.2.6. Adsorption to Sediment. Based on their log K s (see Table
1-2), the haloalkyl ethers are not expected to partition significantly from
the water column to sediment. The only exception among the selected
haloethers Is octachloro-d1-n-propyl ether, which has an estimated log K
of 5.472.
The aromatic haloethers have estimated log K s >4.0, which suggests
that these compounds may partition significantly to organic partlculate
matter and sediment In natural water.
2.2.7. Bloconcentratlon. Based on their log K s (see Table 1-2), the
haloalkyl ethers are not expected to bloconcentrate significantly In aquatic
organisms. Velth et al. (1980) measured a BCF of 11 for b1s(2-chloroethyl)
ether I* Wueg^lT sunf tshL Lepomt sy roacrochtFOSV for; arc; exposure perVod olf 28t
days. Sasaki (1978); also found; that b1s{2-chloroethyl.) ether does not
accumulate In f1sh.; The. only haloaT;kyl ether, that; to; expected, to
bloaccumulate Is octachloro-dl-n-propyl ether which has an estimated; Tog
It of 5. 472. The BCF of: an oirg^trl'c'. cherotca'? caw tie : estimate* Frum the/
OW it'
following regression equation (Lyman et al. , 1982):
log BCF = 0.76 log K - 0.23 (2-1)
3 ow
0038d 2-7 07/07/87
-------
TABLE 2-3
g Volatll
CO
CD
O.
Haloether
b,1s(2-Chloroethyll ether
2-Chloroethyl vinyl ether
4-Chlorophenyl phenyl ether
b1sJ2-Chloro-l-methylethyl) ether
Z^jA'-Trlchloro-^'-hydroxydlphgpyl ether
a> l,2-b1s(2-Chloroe£hoxy)ethane
b1s(2-Chloroeihoxy)methane
2,3-blchloro-p-dloxane
2,3-Dlchlorotetrahydrofuran
Ization of Haloethers from Water
Estimated Henry's Law Constant
' (atm-mVmol)
1.3xlO~sb
2.5xlO--b
2.2xlO"«b
l.lxlO--b
3.1xlO~'b
9.8xlO"8C
<2.8xlO~'b
2.3xlO'6d
1.8xlO~4d
Estimated Volatilization
Half-Life*
3.4 days
6.6 hours
9.8 hours
13.8 hours
200 days
500 days
>168 days
19.7 days
9.3 hours
rvj
00
CD
aAssumes a river 1 m deep, floy/lng at a speed of 1 m/sec with a wind velocity of 3 m/sec; estimation
method outlined In Lyman et al. (1982).
^Calculated from wa.ter solubility and vapor pressure data In Table 1-2.
->- , \'^- '","-•'•
^Average of bond, and group estimation methods of Hlne and Mookerjee (1975)
dBond estimation method of Hlne fnd Mookerjee (1975)
-------
For octachloro-d1-n-propyl ether, the BCF value calculated from Equation 2-1
1s -8500, which Indicates the possibility of significant bloaccumulatlon.
The log KQWS of the aromatic haloethers range from 4.08-5.876 (see
Table 1-2). Using Equation 2-1, the estimated BCF values of the aromatic
haloethers will range from 740-17,200. Therefore, significant bloaccumula-
tlon of aromatic haloethers In aquatic organisms 1s possible.
2.3. SOIL
2.3.1. M1crob1al Degradation. Sufficient data are not available to esti-
mate the relative significance of mlcroblal degradation of the haloethers 1n
soils. As noted 1n Section 2.2.4., several of the haloethers were found to
be biodegradable under specific testing conditions while others have been
found to be resistant to degradation.
2.3.2. Chemical Degradation. Since the a-chloroalkyl ethers are
susceptible to rapid hydrolysis 1n aqueous media (see Section 2.2.1.), they
can be expected to hydrolyze rapidly 1n moist soils. There are no available
data to Indicate that the aromatic haloethers will degrade chemically )n
soil.
Wilson and Noonan (1984) examined the degradation of 2-chloroethyl vinyl;
ether In subsurface soil using microcosm tests. Comparison of autoclaved
vs. nonautoclaved samples Indicated that 2-chloroethyl vinyl ether was
degraded, by an.abiotic process in sail; however, the, degradation,• process was/
not; de.ter.nr1 ned. As noted1.n: Section 2-2.2'..,. ?-ch;l'oroethyl'. vinyl ether Vs.
susceptible to oxidation In water. It may be possible that the chemical
degradation process Involves:a free radical- oxYdatVon tnechanVsm.
2.3U3. Adsorption. Leaching? wtTT not be- Important, for the a-chlorov
aTkyT ethers since-they;are expected' to hydro^Tyze rapMly fn moist;
0038d 2-9 05/28/87
-------
Table 2-4 lists estimated KQC values of selected haloethers. The
K values for the aromatic haloethers are high and Indicate that they
will generally be Immobile 1n soil; therefore, significant leaching 1s not
likely to occur. With the exception of the highly chlorinated octachloro-
d1-n-propyl ether, the alkyl haloethers have a medium to high degree of soil
mobility, which suggests potential leaching to groundwater In the absence of
degradation processes.
Wilson et al. (1981) reported that b1s(2-chloroethyl) ether moved
readily through a sandy soil column. This agrees with the prediction of
high soil mobility from Table 2-4.
2.4. SUMMARY
The selected haloethers are not expected to be persistent atmospheric
contaminants. In the atmosphere, the haloethers will react relatively
rapidly In the vapor phase with hydroxyl.radicals at half-lives ranging from
'1.61 hours to 1.54 days (U.S. EPA, 1987). In water, the" a-chloroalkyl
ethers have extremely short hydrolytlc half-lives and are not expected to
persist for extended periods of time (U.S. EPA, 1980b). Hydrolysis Is not
environmentally Important, however, for the B-chloroalkyl ethers or the
aromatic haloethers (U.S. EPA, 1980b,c; Mabey et al., 1981; Callahan et al.,
1979). Based on their relatively high log K values (>4), the aromatic
haloethers may have a tendency to bloconcentrate In aquatic organisms and
adsorb? fa- sediment"and suspended soWds In water. VolatlTlzat-Von f-rom'water
may, be'4tf tnpartarrt transpwrt process for haiToetttePs: such a$ bts:C2>: ether,? 2vcfcloroethy.l vinyl ether,: b-ts-tZi-chtaroi-Ti-methylethy.!):' etherv
4-chTioropherryT;; Rhenyl .; ether? and: 2,3l^di1chlorotetraitTyd1raf!ura:n; howeve.r..
volatilization wtll rrof treV frnportaW fBfr^^^^^^p^cWor^^'Miydrcwydlpherfyr
ether, 1,2-b1s(2-chloroethoxy) ethane or 1,2-b1s(2-chloroethoxy)methane (see
0038d 2-10 07/07/87
-------
TABLE 2.4
o
a
01
g
Haloether
b1s(2-Chlor9ethyl) ether
bJs(2-Chloroethoxy)methan^
l,2-b1s(Chlprpmethoxy)ethane
b1s(4-Chlorophenyl) ether
Bromophenyl phenyl ether
i
=i 2-Chloroethyl vinyl ether
4r-Chloropheriyl phenyl ether.
2,3-D1chlorpTp-d1oxane
2,3-Dlchlorotetrahydrofuran
.(-, J I? ' \ • i • t - - . $:•
Octachloro-dl-p-propyl ether
b1s(2-Chlorp-)-methylethyl ethej)
2,4,4l-Trlchlo.rp-2'-hydroxyd1phenyl
Estimated Koc of Selected Haloethers
Koc Estimated from
Water Solubility3
27
9
ND
ND
ND
22
2263
ND
ND
ND
73
ether 1800
Koc Estimated
from Log KQ^
120
61
95
37,500
17,000
03
9,760
275
160
22,600
180
12,500
Soil
Mobility0
high
high
high
Immobile
Immobile
high
Immobile
medium
medium
Immobile
medium
Immobile
° Vpg
= 3.64 -
log S ()n ppm) (Lyman et al., 1982);
for S from Table 1-2
f*lpg K
00 • ' ' OC
mCSwann et a),, 1983
NO = Not determined
= Q..5IH Io9 K * i-377 (Lyman et al., 1982); values for K from Table 1-2
~~~ ' . ,' - .,»*" , ' "i*.1"' . viw
-------
Table 2-3). 2-Chloroethyl vinyl ether, the only selected haloether contain-
ing a double bond, Is susceptible to oxidation using the singlet oxygen
concentration 1n sunlit natural water (Mabey et al., 1981) and has an
estimated half-life of 69 hours. The alkyl haloethers are not expected to
undergo significant direct photolysis 1n the ambient environment (Durkln et
al., 1975; Callahan et al., 1979). The aqueous photolysis half-lives of
2- and 4-chlorophenyl phenyl ether at the surface of water under summer
sunlight conditions at 40° N latitude were estimated to be -36 and 200 days,
respectively (Dulln et al., 1986). Sufficient data are not available to
estimate the relative significance of microblal degradation of the
haloethers. Several of the haloethers have been found to be biodegradable
under specific testing conditions, while others have been found to be
resistant to degradation {Tabak et al., 1981; Ludzack and Ettlnger, 1963;
Dojlldo, 1979; Voets et al., 1976). In soil, the a-chloroalkyl ethers
will hydrolyze In the presence of moisture. Based on estimated K values
(see Table 2-4);,; the aromatic haloethers will generally be Immobile In soil
and are not expected to leach significantly. With the exception of
octachlorod1-n-propyl ether, the alkyl haloethers have a medium to high
degree of soil mobility, which suggests that these compounds are susceptible
to leaching to groundwater In the absence of degradation processes.
0038d* 2-12 07/07/87
-------
3. EXPOSURE
3.1. WATER
Chloroalkyl ethers do not occur naturally; their occurrence Is entirely
anthropogenic (U.S. EPA, 1980b). Discharges from Industrial and manufactur-
ing processes represent the major sources of these organic pollutants 1n
water.
Table 3-1 lists the selected haloethers found 1n various types of waters
In the United States. Haloethers have been detected In drinking water,
river water, groundwater and effluent wastewater.
The U.S. EPA conducted the National Organlcs Monitoring Survey of U.S.
drinking water 1n three phases between March 1976 and January 1977 (U.S.
EPA, 1980b). In phase II, the drinking water of 13/113 cities was found to
contain b1s(2-chloroethyl) ether at a mean concentration of 0.1 ppb.
b1s(2-Chloro-l-methylethyl) ether was detected In 8/113 waters at a mean
concentration of 0.17'ppb. In phase' III, 8/110 cities had detectable levels
of b1s(2-chloroethyl) ether {mean concentration 0.024 ppb) while 7/110
cities had detectable levels of b1s(2-chloro-l-methylethyl) ether (mean
concentration 0.11 ppb).
Staples et al. (1985) examined the U.S. EPA STORET'Data Base to assess
the occurrence of priority pollutants 1n U.S. waterways. The results of
this examination for selected haloethers are presented Vn Table 3-2. Cole
et a,T.. (1984) reported the preT-fmlrtary. resuTfs: of the* U.S. EPA-. Nationwide
Urban Runoff Program to assess' the occurrence of priority .pollutants In
urban stormwater runoff. None of^ the haloethers were detected In runoff
waters from 15 cities that were monitored.
3.2. FOOD
Pertinent data regarding the exposure to haloethers by food Ingestlon
could not be located 1n the available literature as cited In Appendix A. ,
0039d 3-1 07/07/87
-------
TABLE 3-1
Occurrence of Haloethers tn Waters of the United States
o
o
CO
vO
Q.
CO
1
05/28/8'
(location/Source of Water
Philadelphia. PA
Philadelphia, PA
Delaware River
Chemical plant effluent
Delaware River (downstream)
Cleveland. OH •;,
Kanawha River, WV
Chemical plant discharge
(to Ohio River)
Ohio River (Evansvllle, IN)
fvansvllle. IN
New Orleans, LA
Chemical plant discharge
River (downstream)
•-.,- •- —
Type o,l, W4tera
finished ,
drinking water
finished
drinking water
river water
wastewa.ter
river,, water
finished
drinking water
river water r
rlyer water "...
wastewatef
river water
finished
drinking water
finished
drinking w|ter
wastewatef
river wa|er
•J * ~ """"•• ' •-
Haloether Identified11
b1s(2-chloroethyl)ether
l,2-bls(2-chlor'oethoxy)ethane
bls(2-chloroethy1)ether
1 ,2-bts(2-chloroethoxy (ethane
bls{2-chloroelhyl)ether
1.2-bls(2-chloroethoxy)ethane
1.2-bls(2-chloroethoxy)ethane
1.2-bls(2-chloroethoxy)ethane
bls(2-chloro-l-methylethyl)
ether
bls(2-chloroethyl)ether
bls(2-chloro-l-melhylethyl)
ether
bls(2-chloro-l-methy1ethyl)
ether
b1s(2-ch1oro-l-methylethyl)
ethef
bls(2-chloro-l-roethylethyl)
ether
b1s(2-chloro-l~methylethyl)
ether
b1s(2-chloroethyl) ether
!'•' V
2.4,4'-trlchloro-2'-hydroxy-
dlphenyl ether
2,4.4' -tr lchloro-2' -hydroxy-
dlphenyl ether
Concentration*-
(ppb)
0.5
0.03
NO
NO
NO to trace
NO to 15
100
1
NO
NO
NO
500-35,000
0.5-5.0
0.8
0.03-0.51
0.04-0.44
6000-14,000
12-300
Comment
also not detected In
drinking water of four
other cities
2-year sampling period
(1975-1977)
August. 1976 to March,
1977 sampling
August, 1977 sampling;
suggested plant effluents
eventually reach Phila-
delphia finished drinking
water
NC
NC
NC
NC
NC
August, 1974 sampling
NC
NC
Reference
U.S. EPA. 1975
Suffet et al..
1980
Sheldon and
Hltes. 1978
Sheldon and
Hltes. 1979
SanJIvamurthy,
1978
Rosen et al. ,
1963
Kleopfer and
Falrless. 1972
Kleopfer and
Falrless. 1972
Kleopfer and
Falrless. 1972
Keith et al..
1976
Jungclaus
et al.. 1978
Jungclaus
et al.. 1978
-------
TABLE 3-1 (coot.)
O
O
co
10
o.
Location/Source of Hater
River sediment
love Canal
Wilmington. DE
Calvert City. K»
Louisville. KY.
Louisville. KV
Type of Mater3
sedlmenl
sed lmen| -water -
soil .complex
grpundwater
wastewater
wastewater
waslewa»er
Haloether Identified"
2.4,4'-trlchloro-2'-hydroxy-
dlphehyl ether
bls(2-chloroethyl)ether
bts(2-chloro-l-methylelhy1)
ether
4-chlorophenyl phenyl ether
bts(2-chloroethyl)ether
bls(4-chlorophenyl (ether
b1s(4-chlorophenyl)ether
2-chloroethyl vinyl ether
Concentration11
(ppb)
1200-5000
NQ
NQ
MQ
0.1-12.400
NQ
NQ
NQ
Comment
NC
NC
the values reflect con-
centrations of landfill
leachate (maximum) and
artesian well water
(minimum) downslope from
contaminated site
chemical plant effluents
Reference
Jungclaus
et al.. 197B
Hauser and
Bromberg. 1982
Dewalle and
Chlan. 19B1
Shackelford
and Keith.
1976
co
NQ = Not quantified,; NO = not detected; JJC = no comment
O
tn
^.
to
CO
><,
CO
-------
o
o
CO
VD
Q.
TABLE 3-2
levels of Haloethers In U.S. Waters Computed from STORET Data Base*
co
•*»
Haloether
bls(Chloromethyl) ether
bls(2-Chloroethyl) ether
2-Chloroethyl vinyl ether
4-Chlorophenyl phenyl ether
bts(2-Chloroethoxy)methane
b1s(2-Chloro-l-methylethyl) ether
Median
Concentration
(PPb)
<1.0
<10.0
<5.d
<10.0
<10.0
<10.0
Effluents
Number of
Reporting
Stations
977
1241
1291
1333
1243
1243
Ambient Water
Percent
Detectable
1.4
1.6
1.0
1.1
1.0
1.6
Median
Concentration
(PPb)
<10.0
<10.0
<10.0
<10.0
<10.0
<10.0
Number of
Reporting
Stations
317
808
929
837
834
834
Percent
Detectable
0.0
0.4
0.8
0.2
0.1
0.1
•Source: Staples et al., 1985
en
ISJ
oo
-------
3.3. INHALATION
No ambient atmospheric monitoring data were located for the selected
haloethers. Human exposure to these compounds by Inhalation may be confined
to occupational settings (U.S. EPA, 1980b). James et al. (1984)
qualitatively detected 1,2-b1s(2-chloroethoxy)ethane as a combustion product
1n an Incinerator waste gas effluent, which suggests that Incineration of
various types of refuse may release haloethers to the atmosphere.
3.4. DERMAL
Pertinent data regarding dermal exposure to haloethers could not be
located 1n the available literature as cited 1n Appendix A.
3.5. SUMMARY
Chloroalkyl ethers do not occur as such In nature; their occurrence Is
entirely anthropogenic (U.S. EPA, 1980b). Discharges from Industrial and
manufacturing processes represent the major sources of these organic pollu-
tants In the aquatic environment. Various hdloethers have been detected In
drinking water, rlverwater, groundwater and effluent wastewater (see Table
3-1). Human exposure to haloethers by Inhalation may be confined to occu-
pational settings (U.S. EPA, 1980b); however, 1,2-b1s(2-chloroethoxy) ethane
has been detected 1n an Incinerator waste gas effluent (James et al., 1984).
Sufficient data were not located to estimate dally human exposure to these
compounds.
OC39d 3-5 07/07/87
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4. AQUATIC TOXICITY
4.1. ACUTE TOXICITY
Relatively little Information was available concerning toxlclty of the
subject haloethers to aquatic organisms. U.S. EPA (1978) reported the
following 96-hour LC5_ values for bluegllls, Lepomls macrochlrus: 354
mg/a 2-chloroethyl vinyl ether and >600 mg/a b1s-(2-chloroethyl) ether.
In these studies, 96-hour NOECs were <101 mg/i 2-chloroethyl vinyl ether
and <220 mg/8, b1s-(2-chloroethyl ) ether. Buccafusco et al. (1981)
reported 96-hour LC5Q values of 350 mg/a 2-chloroethyl vinyl ether and
600 mg/8, b1s-(2-chloroethyl) ether for bluegllls. Dow Chemical Co.
(1984a) reported a 96-hour LC5Q of 184 mg/a b1s-(2-chloroethoxy) methane
for fathead minnows, Plmephales promelas. Konemann (1981) calculated a
7- to 14-day LC,.. of 54.4 mg/a. bis (2-chloroethyl ether) for gupples,
PoedHa retlculata.
The only available toxlclty data for freshwater Invertebrates applies to
Daphnla maqna. U.S. EPA (1978) reported a 48-hour EC™ of 238' mg/a and
a NOEC of <7.8 mg/i b1s-(2-chloroethyl) ether. Oow Chemical Co. (1984b)
reported a 48-hour LC5Q of 201 mg/a. b1s-(2-chloroethoxy) methane.
4.2. CHRONIC EFFECTS
In the only available chronic studies, no adverse effects occurred at
concentrations up to 19 mg/a. b1s-(2-chloroethyl) ether In the fathead
promeTas'., erabniyowTairv*T tes-f tUVff.
4*3.. PLANT EFFECTS
Pert1nen;t data regardfng effects:;. of harToethers; on aquatic pTants; couM,
no,t be located 1;n- the a.va1'labtei.T1;terature- as c1ted/1n- Appendix. A.
0040d 4-T 05728/8T
-------
4.4. SUMMARY
Data concerning toxIcHy of haloethers to aquatic biota are limited.
Studies by U.S. EPA (1978) using bluegllls and Daphnla magna Indicate that
2-chloroethyl vinyl ether and b1s-(2-chloroethyl) ether have nearly equiva-
lent acute toxldty In these two species. J). magna appeared to be more
sensitive to these compounds than bluegllls. The lowest reported acutely
toxic concentration was 184 mg/8, b1s(2-chloroethyl) ether, a 96-hour
LC-Q for fathead minnows (Dow Chemical Co., 1984a).
0040d ^ 4-2 05/28/87
-------
5. PHARMACOKINETICS
5.1. ABSORPTION
Groups of three female Charles River CD rats were given single oral
doses of 0.2 vg/kg or 3, 30 or 300 mg/kg 14C-bis-(2-chloro-l-methyl-
ethyl) ether In corn oil or Emulphor EL620-ethanol-water (1:1:8) (Smith et
al., 1977). The U.S. EPA (1980b) established that the compound was labeled
with 14C at the o- position. There was evidence of saturation of
absorption mechanisms at the highest dose, but peak concentrations of radio-
activity In the blood occurred 2-4 hours after treatment at the lower doses.
Radioactivity was detected 1n the blood after 15 minutes, the earliest
sampling time. Two rhesus monkeys that were given single oral doses of 30
mg/kg of the same 14C-labeled compound had maximum concentrations of
radioactivity In the blood after 2 hours (Smith et al., 1977). These data
Indicate that gastrointestinal absorption of b1s-(2-chloro-l-methylethyl)
ether was rapid. Lingg et al. (1982) administered single doses of
1 laC bis (2-chloroethyl) ether (40 mg/kg) and l-14C-b1s(2-chloro-l-
methylethyl) ether (90 mg/kg) In corn oil by gavage to groups of seven adult
male - Sprague-Dawley rats and measured the radioactivity 1n expired air,:
ur'mc, feces, carcass and cage wash 48 hours after treatment. Total f4C
recovery was 80.9^16.9X of the administered bis-(2-chloroethyl) ether and
73.3*1.7% of the administered bisC2.-cbloro-l-inethylethylJ ethers . F:eca,r
excretion accounted- for? 21.4% of, the-dose, of'.bis (2-chloroethyl)'. ether and
3:8% of the dose of bVs(2-chloro-1-methylethyl) ether, which suggested tthat
gastrointestinaT'absorption-was nearly" complete^
5.2. DISTRIBUTION
DTsappearaftce of radioact'ivtfy frVwirc-the PToods-of two monk'eys^fdHowIng
administration of single oral 30 mg/kg doses of l-l4C-b1s(2-chloro-l-
mcthylcthyl) ether (see Section -5.1.) was biphasic, with half -lives -.of -5
0041d . 5-1 07/07/87
-------
hours for the a or distribution phase and >2 days for the 3 or elimination
phase (Smith et al., 1977). Identical treatment of three CD rats showed a
monophaslc decline 1n blood radioactivity, with a half-life of 2 days; that
suggests that metabolism plays a more significant role than distribution 1n
the disposition of b1s(2-chloro-l-methylethyl) ether than 1n the rat. The
radioactivity die-away curves of the data from monkeys and rats were similar
after 24 hours.
In another study, rats were administered single oral doses of
14C-labeled b1s(2-chloroethyl) ether (40 mg/kg) or b1s(2-chloro-l-methyl-
ethyl) ether (90 mg/kg) as detailed In Section 5.1. (L1ngg et al., 1982).
Radioactivity determinations 48 hours after dosing showed that blood,
muscle, liver and kidney were the only tissues that had i4C levels- >0.05%
of the administered doses. The highest amounts of radioactivity from the
b1s(2-chloroethyl) ether, expressed as percent of administered dose, were In
the muscle (0.96%), kidney (0.56%) and blood (0.49%), and the highest
concentrations of radioactivity from the b1s(2-chloro-l-methylethy-l) ether
were 1n the liver (0.55%), muscle (0.50%) and blood (0.36%).
Smith et al. (1977) determined tissue distribution of radioactivity 7
days after single 30 mg/kg Injections of l-l4C-b1s(2-chloro-l-methylethyl)
ether In three female CD rats (1ntraper1toneal Injection) and one monkey
(Intravenous Injection). Distribution was widespread with the highest
amounts^ expressed as percentages ,ofadmin^s-teredl ratifaact^lv.Vty^ occurrfhg-,
In- the mustTe (2.8%), Itver tT.SXJ, fat (-0.8%! and bTood (0.7%) In" the-
monkey,. and , IB the fat (.2.Q?t)V muscle (:T.2%J;r. blood (ff.8%.y,. skin (0.7%, .
kidneys £0.7%) and liver (0.4%1 In the rats. The highest tissue, concentra-
tions «Tn rats£ p.;2^5L7 u9/
-------
found In the liver (28.8 pg/g), followed by the adrenals, kidneys, spleen
and pancreas (3.8-6.6 yg/g). With the exception of the liver In the
monkey, no tissue appeared to have a markedly greater tendency than any
other to retain radioactivity.
5.3. METABOLISM
Th1od1glycol1c add was the major urinary metabolite of l-l4C-b1s(2-
chloroethyl) ether 1n rats, accounting for -48% of a single 40 mg/kg oral
dose and 7554 of the total 48-hour urinary 14C (L1ngg et al., 1982).
Lesser metabolites Included 2-chloroethoxyacetlc add (-3.2% of the dose and
-5% of the urinary 14C) and N-acetyl-S-[2-(2-chloroethoxy)ethyl]-L-
cystelne (-4.5% of the dose and -7% of the urinary 14C). An earlier study
of the same design qualitatively Identified 2-chloroethyl-B-D-glucopyrano-
slduronlc add as another urinary metabolite of b1s(2-chloroethyl) ether
(L1ngg et al., 1979), but this 1s not considered to be a major product
(L1ngg et al., 1982). Thlodlglycollc add and S-(carboxymethyl)-L-cyste1ne
were Identified 1n the urine of rats following a single IntraperVtoneal
Injection of 100 mg/kg b1s(2-chloroethyl) ether (Mueller et al., 1979), but
the latter metabolite appeared to be an Intermediate In the. .pathway leadings
to th1od1glyco!1c add (L1ngg et al., 1982).
Urinary metabolites of single 90 mg/kg oral doses of l-l4C-b1s(2-
chloro-l-methylethyl) ether In rats Included. ZrC^chloro-t-^Bethyjlethaxx)-
pro.pana.fc .aclid; and M-^aceiy,T>S!-(!Z-hydrox;yprapy;T)-L-cystfr.t'ne (LLlnggt et al..v,
1982). These metabolites accounted for 8.9- and 17% of the administered
dose, respectively, and -36 and 19% of. the totals urinary ,14C, .respec-;
l.-Chloro.-2-propano;T (tt.,1-1.0%? aft the administered dose.)>; propy/Iene'
c [rot- quartfltatedj' and-2-(;Z^chToro:.T-«iethyTethoxyypropai»otc add (not
quantHated) were Identified as urinary metabolites In rats treated with 30
mg/kg b1s.(Z-chloro-l-methylethyl) ether by gavage,. (Smith,, etal., .19.7:7),.
0041d 5-3 07/07/87
-------
Carbon dioxide Is another Important metabolite of at least some halo-
ethers. Llngg et al. (1982) administered single oral doses of l-l4C-b1s-
(2-chloroethyl) ether (40 mg/kg) and l-14C-b1s(2-chloro-l-methylethyl)
ether (90 mg/kg) to groups of seven rats and recovered 11.5*_5.6 and
20.3*9.4% of the doses of radioactivity, respectively, as 14C02 within
48 hours.
Pertinent data regarding the metabolism of the other haloethers could
not be located 1n the available literature as cited 1n Appendix A.
5.4. EXCRETION
Elimination of 14C was examined for 48 hours following administration
of single oral doses of l-14C-b1s(2-chloroethyl) ether (40 mg/kg) and
l_i*C-b1s(2-chloro-l-methylethyl) ether (90 mg/kg) to groups of seven rats
(Llngg et al., 1982). Most of the radioactivity was excreted In the urine
and expired as C0». The percentages of administered radioactivity that
were eliminated 1n the urine, feces, expired C02 and remained 1n the
carcass after 48 hours were 64.7*_14.8, 2.4.*1.3, 11.5*5.6 and 2.3*1.2,
respectively, for b1s(2-chloroethyl) ether. The respective percentages for
b1s(2-chloro-l-methylethyl) ether were 47.5*8.1, 3.8*0.3, 20.3*9.4 and
1.7^0.5. The time to excrete one-half of the dose through urine and C0_
was determined to be 12 hours for b1s(2-chloroethyl) ether and 19 hours for
b1s(2-chloro-l-methylethyl) ether.
Urinary* excr&Ktom.of radioactivity was esseat 1 ally complete^/?4t" flours
fo&Totffng? tntripecftone&T;, tthree. rats! «r intravenous: tone monkey); tnj;ecttotr
of;-. ..*• single, 3ffi; mg/kg:' dase; of?"C^tttr(;2;-cttToi^T>methylethyl,)v ether.
although, the. ratsv excreted approximately, tw^ce; as.mucft as the, monkey (55 vs.
25X of'the administered5 dose) ;|Sm1th iet ail^ 19^7).^ Approximately 1 .aad'. 6%5
of the administered radioactivity was eliminated by the monkey and rats,
respectively, 1n the feces by 7 days> ,
0041d y 5-4 ? 07/07/87"
-------
5.5. SUMMARY
Pharmacok1net1c data are available for l4C-b1s(2-chloroethyl) ether
and l4C-b1s(2-chloro-l-methylethyl) ether (Smith et al., 1977; L1ngg et
al., 1982). Radioactivity associated with these compounds Is rapidly and
nearly completely absorbed and widely distributed throughout the body. No
tissue appears to have a tendency to retain radioactivity associated with
either of these compounds, with the exception of the liver of the monkey,
which appeared to retain 14C associated with l-l4C-b1s(2-chloro-l-
methyl-ethyl) ether (Smith et al., 1977). Th1od1glycol1c add Is the major
urinary metabolite of b1s(2-chloroethyl) ether, and urinary metabolites of
b1s(2-chloro-l-methylethyl) ether Include 2-(2-chloro-l-methylethoxy)-
propanolc acid and N-acetyl-S-(2-hydroxypropyl)-L-cyste1ne (Llngg et al.,
1982). Carbon dioxide Is an Important metabolite of both of these
haloethers 1n rats (Llngg et al., 1982). Degradation of 14C-haloethers to
single carbon units that are Incorporated readily Into endogenous substances
may account for the retention of detectable levels of radioactivity 1n the
tissues 7 days after single parenteral doses to rats and monkeys. Excretion
1s primarily through the urine and expired air. The time to. excrete
one-half of the dose of radioactivity In rats through urine and expired air
was 12 hours for l-l4C-b1s(2-chloroethyl) ether and 19 hours for
l-l*C-bU(2,-ctaoro^l-aethv. lethal) ether lUngg.;et,aU,. T9.a2)u,
004Td 5-5 07/07/87
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6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposures.
6.1.1.1. SUBCHRONIC — Groups of 25 elght-week-old male Sprague-
Oawley rats were exposed to 1 or 10 ppm (3 or 33 mg/m3) chloromethyl
methyl ether vapor, probably for 6 or 7 hours/day for 30 days (Drew et al.,
1975). Two of the rats at 1 ppm died during the exposure period; 5 were
sacrificed at the end of the exposure period; 5 were sacrificed 2 weeks
following the end of the exposure periods; and the 13 remaining rats were
maintained for life. H1stolog1cal examination of the lungs (other tissues
not examined) showed that one of the rats killed after 30 exposures had a
slight bilateral hemorrhage. H1n1mal mucosal effects occurred In the rats
that were observed for their llfespans (two with regenerative hyperplasla,
one with squamous metaplasia of the bronchial epithelium, one with trachea!
squamous metaplasia). The significance of these effects Is uncertain
because control data were not reported. Weight change In the 1 ppm rats was
not significantly different from that of an unspecified control group. Rats
that, were exposed to 10 ppm (3.3 mg/m3) chloromethyl methyl ether had high.
mortality (22/25 by exposure day 30).
Rats or hamsters' that were exposed to 1 ppm (5 mg/m3) b1s(chloro-
methyV) etherv & houns/daiy, for up to 3,0 days, also had high, mortality,, tmedlan
TTfesparfc ,af< Z3, and: 42; days-,. respecttveTy^ ftfeew; et- a,!',,. HTSjL ftTghV
Incidences of pulmonary- effectsv. Including-, bronc-hlal Vhyperplas1a In the
chloromethyl methy.T ether-expo.sed-rats* trachea!".and bronchial- hyperplasla j
and: metaplasia w
-------
Groups of four male and four female Alderly Park SPF rats (average
weight 200 g) were exposed to 20 ppm (HO mg/m3) b1s(2-chloro-l-methyl-
ethyl) ether, 6 hours/day, 5 days/week for 4 weeks (Gage, 1970). Effects on
clinical signs, body weight (measured dally), urlnalysls Indices at termina-
tion (specific gravity, pH, reducing sugars, blUrubln, protein), hematology
Indices at termination (hemoglobin, packed cell volume, mean corpuscular
hemoglobin content, total white and differential cell count, platelet count,
clotting function, urea, sodium and potassium), gross pathology or histology
(lungs, liver, kidney, spleen and adrenals) were not observed. Exposure to
70 ppm (490 mg/m3) (same groupings of animals and treatment schedule)
produced lethargy and reduced body weight gain (not quantified) but no
alterations of the blood or urine Indices or pathological effects. Eight
5-hour exposures to 350 ppm (2450 mg/m3) produced an unspecified Incidence
of lethargy, respiratory difficulty, retarded body weight gain and hlsto-
Iog1 al congestion of the liver and kidneys 1n a group of four rats of each
sex. It 1s Implied that the eight 350 ppm dally exposures were not contin-
uous (I.e., apparently 5/week).
6.1.1.2. .CHRONIC -- Groups of 120 male SPF Sprague-Dawley (Spartan
substraln) rats and 144-157 male Ha/ICR m"1ce were exposed to ff, 1, TO or TOO
ppb (0, 5, 47 or 470 vg/m3) of bls(chloromethyl) ether vapor, 6 hours/
day, 5 days/week for 6 months .an^ obseryetf for Ufe tUeong,. et al.-., 19SH*
«dd1tvtaita1:^nf(yrfla;tfofrt iregaffd'fngv:the^,«lestgm of this./study ;1s presented- tm
Section 6.2.1. Treatment-related, effects' on body weight, gain were- not;
observed1. Mortality war Increase* W ttfe- h^gh-do^e*paitsv bittr this was
attributed, to tumor, development. Absolute and r elat.tve; organ weight theart,
brain, liver, kidneys and te*te's), determined 1n four rats'/group af^fife-end
of the 6-month exposure period, did not significantly differ between the
0042d 6-2 . 05/29787
-------
treated and control groups. Comprehensive hlstologlcal examinations using
rats and limited hlstologlcal examinations using mice (nasal turblnates,
gross liver and lung lesions) did not reveal treatment-related nonneoplastlc
alterations. Hematologlcal evaluations, conducted on 10 rats from each of
the 0 and 100 ppb exposure groups at the 12th exposure week and on 4 rats
from each of the 0, 1, 10 and 100 ppb groups at the termination of the
6-month exposure period, were unremarkable; determinations Included packed
call volume, hemoglobin concentration, total red blood cell count and total
and differential white cell counts.
Seventy-four male Sprague-Oawley rats and 90 male Syrian golden hamsters
were exposed to commercial grade chloromethyl methyl ether by Inhalation at
a concentration of 1 ppm (3 mg/m3), 6 hours/day, 5 days/week for life
(Laskln et a!., 1975). Groups of 74 rats and 88 hamsters served as chamber
controls. Hlstologlcal examinations of the respiratory tract and lungs were
conducted on at least 54 of the treated rats, on at least 7'1 of the exposed
hamsters and on similar numbers of controls (numbers of animals .examined not
specifically stated). There were no treatment-related effects on weight
gain, survival or occurrence of respiratory system tumors (Section 6.2.1.).
Squamous metaplasia of the trachea occurred 1n 10% of the treated rats and
3% of the controls, but the Incidence of trachea! hyperplasla was similar In
the treated (3054) and control (2954) rats. Bronchla.l hyperplasla occurred 1n
5954 ;ofr the treated anrfV35%" of th'e. contnosT rats; but- We occurrence of
bronchiaV squaraous metaplasia was: the. same. In both treated and control rats
(13%);. Bronchoalveolar metaplasia was, noted 1n 9 exposed ,hamsters, and:
atypical appearance. o.f. the. nucle.1, of alveolar: "cells, was noted. In 10 exposed
hamsters;* atypical alveolar; cell nuclei were, observed Vn .only oite> canitraT
hamster. Presumably, bronchoalveolar metaplasia was not observed In control
hamsters.(,
0042d 6-3 07/07/87
-------
6.1.2. Oral Exposures.
6.1.2.1. SUBCHRONIC -- Groups of 10 F344 rats of each sex were admin-
istered dally gavage doses of 0, 10, 25, 50, 100 or 250 mg/kg technical
grade b1s(2-chloro-l-methylethyl) ether 1n corn oil, 7 days/week for 13
weeks 1n a range-finding study for a carclnogenlclty bloassay (NCI, 1979).
The technical grade compound was -70% pure as detailed In Section 6.2.2.
Body weight measurements conducted at the end of the study showed that there
was an adverse effect 1n the high-dose males (mean weight was 80% of the
control value). Occasional urine stains and a hunched or thin appearance
were observed occasionally during weeks 4-7 1n the high-dose males, but
treatment had no effect on survival or gross or hlstologlcal findings at any
dose In either sex. The extent of the pathological examinations was not
specified.
Groups of 10 B6C3F1 mice of each sex were given once dally gavage doses
of 0, 10, 25, 50, 100 or 250 mg/kg technical grade b1s(2-chloro-l-methyl-
ethyl) ether In corn oil for 13 weeks 1n a range-finding study for another
carclnogenlclty bloassay (NTP, 1982). The compound was -70% pure as
detailed in Section 6.2.2. There were no compound-related effects on
terminal mean body weight or survival. Comprehensive hlstopathologlcal
examinations revealed that focal pneumonHls was the only alteration; this
effect occurred at 50 mg/kg;. (3/10 males, 1/1,0, females), 100, mg/ltg (2/\&;
matfesv 3/W^ fetoafesfc-arrd 250i mg/kgj.f8y!Ttt; males?,, 4/T.O?-feraaftes.^;but,- peesum^
ab'Ty, not 1* oont ro 1 s.. -
In a^ How*-CheittVca>T. fn.d^F s^wfthi. na£*< gs^r'a^iv and? number noi.-specified)
werr-e sdnriftts-fcered; 22 doses of,-.. b-Vs-(-2i-c-h-Toro:-T-fliett.lty^ethyT )•; .either In. aH-ver-.
ol'Ttfy gavage 1rn 31 days4. The? Tdwes£ antfHighest dosages were O.OT anrf 0.27
g/kg, but the number and magnitude of Intermediate dosage levels were not
0042d. -v -. 6-4 05/29*87)
-------
Indicated. Controls were used but details were not specified. Decreased
growth rate and Increased relative liver, kidney and spleen weights occurred
at the highest dose. The Intermediate and low doses produced only decreased
growth rate. Hematologlcal Indices were normal at all doses. It was not
Indicated If pathological examinations were conducted.
2,4,4'-Tr1chloro-2'-hydroxyd1phenyl ether (purity >97%) In gum arable
was administered by gavage to groups of five male and five female white rats
(strain not specified) at doses of 0, 50, 100, 200, 500 or 1000 mg/kg, 6
days/week for 4 weeks (Lyman and Furla, 1969). Effects were noted In the
high-dose group and Included mortality (2/10) and slightly reduced weight
gain. Hlstopathologlcal examinations and blood and urine analyses were
unremarkable In all treatment groups, but the extent of these evaluations
was not Indicated. Additional Information was not reported.
6.1.2.2. CHRONIC — Groups of 26 male and 26 female Charles River CD
rats were treated with b1s(2-chloroethyl) ether of 100% purity by gavage at
doses of 25 or 50 mg/kg, twice weekly for 78 weeks, followed by a 26-week
observation period (Welsburger et al., 1981). Matched and pooled control
groups were Included In the study, but the sizes of these groups were not
reported. Mean body weights, determined weekly during the Initial month and
biweekly thereafter, were lower 1n the treated females and high-dose males
than In the corresponding, controls,. Quantitative data were not reported,
but tire effect am trotfy;, wetfgttt; f.n: the: females; was, Indicated to be; subs.tan-;
t!Va:T. Treatment-related increased Incidence of mortal 1 ty, occurred In the
high-dose females, but data were not, adequately reported. Survival at' 52"
weeks, was 6.5X In. the high-dose females, 9&-100% In the other: tneated groups/
and-97-99% 1n 'pooled controls"fromithefJenffre1 stttdyiri wttfcfc frtctfudw£ corttrtfF
groups from tests with b1s(2-chloroethyl) ether as well as numerous other
0042* 6-5 . 07/07/87
-------
compounds. Data for survival beyond 52 weeks were not reported for the
b1s(2-chloroethyl) ether-treated rats. Comprehensive pathological examina-
tions were conducted (Section 6.2.2.) but nonneoplastlc effects were not
reported.
Technical grade b1s(2-chloro-l-methylethyl) ether was administered by
gavage 1n corn oil to groups of 50 male and 50 female F344 rats at doses of
0, 100 or 200 mg/kg, 5 days/week for 103-105 weeks, followed by 1-2 weeks of
observation (NCI, 1979). Purity was -70% as detailed In Section 6.2.2.
Tox1c1ty endpolnts were the same as those routinely assessed In NCI/NTP
cardnogenlcHy bloassays. Effects Included dose-related decreased mean
body weight 1n both dose groups and sexes throughout most of the study.
Treatment-related decreased survival occurred In the high-dose males after
week 45 and 1n the low- and high-dose females after weeks 60 and 30, respec-
tively. Survival at week 78 1n the vehicle control, low- and high-dose
groups was 44/50 (88%), 46/50 (92%) and 28/50 (56%) 1n the males,-respec-
tively., and 48/50 (96%), 44/50 (88%) and 25/50 (50%) In the females, respec-
tively. An Increased Incidence of esophageal hyperkeratosls occurred 1n the
high-dose males and females; Incidences In the vehicle control, low-, and
high-dose groups were 9/50, 10/50 and 40/49 1n the males, respectively, and
13/50, 10/49 and 31/48 1n the females, respectively. A small number of
high-dose females also had esophageal acanthosAs (1/50, 0/49 and 5/48. Vn the ,
vehWfe1- contrcrtv Tow- and? tffgh-dose? groupsv, respec^tveTy;)-.;; CjeatrtlbtxtfTari
nscfosts of-i tlte>ttver was -twcrea'sed; In the h4gh-4o?re-males :. arwf females, but
there;was; no; teftec'ence to;,Ui.ts.'effect"fir; secXtans of the: report-ather "than-
an apperrdftd, data summary. Occurrence? of- other rvonneaplastlc lesions wer&
not remarkable. ' -
0042d < • 6-fc 05/29/87
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Technical grade b1s-(2-ch1oro-l-methylethyl) ether was administered by
gavage to groups of 50 male and 50 female B6C3F1 mice In a carclnogenldty
bloassay (NTP, 1982). The compound was given 1n corn oil at doses of 0, 100
or 200 mg/kg, 5 days/week for 103 weeks, followed by 1-7 weeks of observa-
tion In the males and 2-7 weeks of observation In the females. Purity was
~70% as detailed In Section 6.2.2. Clinical signs, mean body weights
(determined weekly for the first 13 weeks and monthly thereafter) and
survival were comparable between the treated and control groups of each sex.
Survival until termination of the study In the control, low- and high-dose
groups was 41/50 (82%), 44/50 (88%) and 37/50 (74%), respectively, In the
males, and 31/50 (62%), 34/50 (68%) and 28/50 (56%), respectively, 1n the
females. Treatment-related nonneoplastlc pathological effects of exposure
occurred only In the males and Included fatty metamorphosis (2/50, control;
16/50, low dose; 15/50, high dose) and chronic Inflammation of the nasal
cavity (0/50/0/50, 30/50) and nasolacMmal duct (0/50, 0/50, 28/50).
Unpublished results of a mouse study (NCI, 1978), which appears to have
been conducted with the NCI (1979) rat bloassay, are summarized In U.S. EPA
(1980b). An unspecified number of mice of unspecified strain were treated
with 0, 10 or 25 mg/kg of b1s(2-chloro-l-methylethyl) ether by gavage, 5
days/week for 728 days. The primary systemic effect was centrllobular
necrosis of the liver,, which occurred \n veh.j£le control, the low-dose and
the'hlglf-dosegrouprs at Incidence*of 2, 27 and 0%, respectTveTy, 1n the
male mice, and 0, 19 and 6%, respectively, 1n the female mice. The In-
creased Incidence of centrllobular necrosis, In the Tow-dose groups was not
explained.. Incidences of pulmonary, hemorrhage (&,, 2, 14%) and esophageal
VnfTammatloTi -(&„ Z>; 5%) were slightly Trtcreasech tnr ttref tftgfl-dotfe males.•,
0042d 6-7 07/07/87
-------
Additional Information regarding the design or results of this study (e.g.,
chemical composition, survival data) were not reported. It appears that the
Inexplicable lack of centMlobular necrosis 1n the high-dose groups may be
the reason for exclusion of this study from the NCI (1979) report and the
basis for apparent retestlng by the NTP (1982).
MHsumoM et al. (1979) administered b1s(2-chloro-l-methylethyl) ether
of high purity (98.5%) to groups of 56 male and 56 female SPF-ICR mice In
the diet at concentrations of 0, 80, 400, 2000 or 10,000 ppm. Seven
mice/dose/sex were sacrificed at weeks 13, 26 and 52, six mice/dose/sex were
sacrificed at week 78, and the remaining surviving mice were sacrificed at
week 104. Body weight and food consumption were measured monthly throughout
the study, and comprehensive hematologlcal, blood biochemical and urlnalysls
determinations were performed at the Interim and terminal sacrifices, and on
mice, sacrificed .when .moribund. Comprehensive gross and hlstologlcal
examinations were conducted on all animals at th'e scheduled sacrifices and
on those that were moribund or died.'
Markedly decreased mean body weight, food consumption and food effi-
ciency, and Increased mortality, which was due to consequent starvation^
occurred at 10,000 ppm in both sexes (MHsumorl et al., 1979). Water
consumption also was decreased In the 10,000 ppm females. The hematologlcal
and hlstologlcal examinations revealed effects. Indicative of anemia, at weeks.
13ri 26,atvd- 52r 1n th«>TO,.000 ppm,matesr amfc females.;, ttres'efncladed.^.decreased'.
erv;thro>c-y.te. count,, hema.tocrTt and hemo.glob1n,r Increased, polychromatic
er-y;throcytesv spTertte1 hemosftJerlrT deposition and: extra-medullary
hematopqlesTs of. the sp/leem (latter ,.effect only 1n males at week Tl^
Splenic hemosiidefln; deposltiYatf; was?,tKe;{ oalya one? .of these*; effects that was?
evident at 104 weeks, occurring 1n 34/112 treated mice of both sexes vs.
3/112 controls. Similar, but less ..pronounced effects, (slight. reduction 1n ,
0042dv . 6-8 £ 07/07^875
-------
mean body weight, mild decreased In erythrocyte count and hemoglobin
concentration and Increased polychromatic erythrocytes) occurred at 2000 ppm
In the females. Effects consistent with anemia also occurred at 80 and 400
ppm but only In males at 13 weeks. These Included decreased erythrocyte
count, hematocrU and hemoglobin, but there were no splenic histologlcal
alterations. The hematologlcal examinations also revealed mild leukopenla
(reflecting decreased lymphocytes and Increased polymorphonuclear
neutrophlls) during the first half of the study, primarily in the 2000 and
10,000 ppm groups, but this was attributed to malnutrition. Treatment-
related effects Including Increased plasma GOT and GPT, Increased urea
nitrogen, Increased alkaline phosphatase, decreased total protein and
decreased blood glucose, occurred In the 10,000 ppm male and female groups
at weeks 13, 26 and 52. The urlnalyses were unremarkable. Absolute and
relative organ weight measurements at week 104 were unremarkable; slight
decreases occurred In the weights of various organs, but they corresponded
to the decreased body weight. Treatment-related nonneoplastlc pathological
effects other than the splenic alterations discussed above were not observed.
Although the effects described above primarily occurred during the first-
half of the study and were mild In degree, the hematologlcal and histo-
loglcal evidence was concluded to be Indicative of treatment-related eryth-
rocyte destruction (MUsuraorl et al... (.ia794. The, anenla was corisAdereA to-
bev toxIcoTogicaTTyi yTgrrfffcawt a"t<- TO',;000:V ppnr frr both sexes and' at* 2000 ppm
In the females,, and:, maximum, na-effeet levels (actuaTTy, NOAEls) were, con-
cluded to be 2000 ppm (198 mg/kg: bw/day;, determined byT,Investigators)'in the:
male mice and 400 ppm, 13.5..8. mg/kg^ bw/day). 1:n the female, mice,..
0042d 6-9 07/07/87
-------
6.1.3. Other Relevant Information. The acute oral and Inhalation
toxldty of various chloroalkyl ethers are summarized 1n Table 6-1. These
data Indicate that the a-chloroalkyl ethers [bls(chloromethyl) ether and
chloromethyl methyl ether] are more acutely toxic than the B-chloroalkyl
ethers [b1s(2-chloroethyl) ether and b1s(2-chloro-l-methylethyl) ether] by
Inhalation exposure but not by oral exposure. This appears to be related to
reduced toxic potential resulting from extremely short lifetimes of the
a-chloroalkyl ethers 1n aqueous solution (U.S. EPA, 1980b).
The primary acute toxic effect of Inhaled bls(chloromethyl) ether Is
Irritation of the respiratory passages and lungs (U.S. EPA, 1980b). This
appears to be attributable to decomposition Into hydrogen chloride and
formaldehyde In the presence of water.
6.2. CARCINOGENICITY
6.2.1. Inhalation. Groups of 120 male SPF Sprague-Oawley (Spartan sub-
strain) rats- and 144-157 male Ha/ICR mice were'exposed to 0, 1, 10 or 100
p,pb. (0, 5, 47:. or 470 yg/m3) of bls(chloromethyl) ether vapor, 6; hours/
day, 5 days/week for 6 months and observed for the duration of their life-
span (Leong et al., 1981). Body weights were determined once a week for the
Initial 3 months of the study and monthly thereafter. Gross necropsies and
comprehensive hlstologlcal examinations were conducted on four rats/group
that were sacrificed for pulmonary exfollatlve cytologlcal evaluation on,
post,erxp,o.sure period/day 1, on f,ttur< ratsVgroup that.'were :,sacrtfIced?on* potst-
expasune; period day. i for cytogenetlc evaluation {Section 6*3,.),: and .on. all
rats-,:th£t dited spontaneously or- werfr satr^f^cedi"wh'en - moirstbiwd^ during rth"e.
observation: period. Necropsies .also were; conducted on. all mice, that died
during/ theT exposure or observation.: pentads.; or.4'were" s,acr?,ifVced .whewmoribund
during the observation period, but complete histology was not performed on
0042d 6-10 ' - ' 07/07/87
-------
1 I\J
TABLE 6-1
Acute Oral and Inhalation Toxlclty of Chloroalkyl Ethers3
Compound
Species
Route
tethal Dose or Concentration
Reference
Chlofomethyl methyl ether
btsJChloromethyl) ether
bls(2-Chloroethyl) ether
Transr2,3-dlchloro-p-dloxane
rat
hamster
ra|"
haasier
ra|
bls(2-Chloro-l-methyJethyl| ether rat
2-Chloroethyl vinyl ether
ral
oral
Inhalation
Inhalation
oral
Inhalation
Inhalation
Inhalation
oral
Inhalation
Inhalation
oral
Inhalation
oral
Inhalation
oral
1050 - 817 ng/kg
LCso = 55 ppn (181 mg/m*) for 7 hours
LC$o - 65 ppra (214 mg/ra») for 7 hours
LD50 = 0.21 ml/kgb
LCjo = 7 ppra (33 rog/m*) for 7 hours
LCjo = ?*> n>g/n>* for 6 hours
7 ppn (33 mg/ra*) for 7 hours
75 ng/kg
1000 ppm (S.8 g/ra») for 45 minutes
ppm (1460 rag/ro1) for 4 hours
•= 105 ppm (614 mg/m1) for 250 minutes
LOjo * 240 rog/kg
LC^Q = 700 ppm (490 mg/m') for 5 hours
LD$o = 250 mg/kg
LC^o -= 250 ppm (1090 mg/m*) for 4 hours
LOSO =1.41 ml/kgc
1050
LC|.o =
or 250
N10SH. 1974
Drew et al.. 1975
Drew et al.. 1975
Smyth et al.. 1969
Drew et al.. 1975
Leong et al.. 1971
Drew et al.. 1975
Smyth and Carpenter. 1948
Smyth and Carpenter, 1948;
Carpenter et al.. 1949
Schrenk et al.. 1933
Smyth et al.. 1951
Gage. 1970
Smyth et al.. 1949
Carpenter et al., 1949
Smyth et al.. 1969
'Source: U.S. EPA.19800
Equivalent to 278 mg/kg (U.S. EPA. 1980b)
'Equivalent dosage expressed as rog/kg cannot be estimated because density of compound was not available (see Table 1-2).
CO
-------
all mice, because an ascending urinary tract Infection caused early
mortality. H1stolog1cal examinations using the mice were limited to grossly
recognized liver and lung lesions, which suggests a tumorous process, and on
nasal turblnates from 208 mice.
There were no significant differences 1n body weight gain between the
control and treated rats, but tumor-related mortality was significantly
Increased In the high-dose rats after the seventh experimental month (1
month postexposure) (Leong et al., 1981). Atypical or neoplastlc cells were
not detected by the pulmonary exfollatlve cytology examinations, but 96/111
(86.5%) of the rats exposed to 100 ppb developed nasal esthesloneuro-
epHhellomas) (Table 6-2). These tumors arose from the olfactory epithelium
and some had metastases. During months 7-12 and 13-18 of the study, 67/76
and 27/31 moribund or dead rats, respectively, that had been exposed to 100
ppb had gross and microscopic evidence of the esthes1oneuroep1thel1oma for-
mation. Pulmonary adenomas occurred 1n 4/111 (3.6%) of the 100 ppb exposed
rats, an Incidence that Is almost statistically slgnflcant (p=0.059). The
majority of rats exposed to 10, 1 or 0 ppb bls(chloromethyl) ether died of
spontaneous or age-related diseases after the 16th experimental month;, some
survived as long as 28 months.
Mean body weights of the treated groups of mice were comparable with
those of the .contrail mice? throughout ther expje^tiwititi: lU«»ng; ,e# a;L ,/138&l;. ;
MoctarTitty; that was. due, .to, an, ascteitd'Tng;.urinary tract fnfecttan occurred?., fnv,
the majority: of the treated and control mice but may.have bee^ aggravated by
treatment "as, onset-'.was.- earlier fat the treated ffllte ~f~T ;montfy, of exposure vs.
3 months1 Vn? thecontrols). The' ftrcildenee oTrpuT'irojiary; tumors ^adeyiomas, and ;•
adenocardnomas) was Increased In 'the ^high-dose mTce, but the Increase was <•
statistically significant only when mice that survived beyond the Initial
6-month exposure period were considered (see Table 6-2). - 5
0042d 6-12 07/07/87^
-------
o
o
TABLE 6-2
Tumor Incidences In Male Sprague-Dawley SPF Rats (Spartan Substraln) and Hale Ha/ICR Mice
Exposed to b1s(Chlop:pmethyl) Ether by Inhalation 6 Hours/Day, 5 Days/Week for 6 Months
. , , with Lifetime Observation3
OJ
Species Concentration
(ppm)
Rat 100
10
t
P
100
10
]
0
Mouse 100
10
Tj
0
100
IP
1
0
Duration
$f Study** Target Tumor Type
(months) Organ •
19C nose esthesloneuroeplthelloma
28
28
28
19C lung adenoma
28
28
28
25 lungs adenomas or adenocarclnomas
25
25
25
25 lungs adenomas or adenocarclnomas
25
25
25
Tumor Incidence
(p Value)
96/111 (p<0.005)d'e
0/111
0/113
0/112
4/111 (p=0.059)d
0/111
0/113
0/112
10/144f (p>0.05)d
3/143f
7/138f
10/157f
8/279 (p<0.05)d
3/379
5/459
9/869
cb
-------
o
o
ro
o.
TABLE 6-2 (cont.)
QUALITY OF EVIDENCE
The compound was administered by a natural route of exposure to large groups of two
species at three dose levels. The animals were observed for life and comprehensive
hlstologjcal examinations were conducted on the rats.
Strengths of study:
Weaknesses of study: The exppsure duration was relatively short and females were not tested. Comprehensive
h)stolpg1caj examinations of the mice were precluded by early mortality because of a
urinary Infection that was not treatment-related. Animal ages and compound purity
were not Deported; animals were ambient rather than sham-exposed.
Overall adequacy:
Adequate
: Leong et al., 1981
from survival curves
cNasal tumor development caused e^rly mortality.
dF1sher Exact tes|
eHetastas1s of esthesloneuroeplthelloma to regional lymph nodes occurred In 5/111 rats (p<0.05)
^ !; fiw i; ,1.1 s, '£.?'• J_
fIncidences of tumors In all mjce In the study.
^Incidences of tumors In mice tha,| survived past the 6-month exposure period.
o
~j
\
o
-J
3
-------
In an earlier study, groups of 20-50 male Sprague-Dawley rats were
exposed to 0.1 ppm (0.5 mg/m3) bls(chloromethyl) ether vapor, 6 hours/day,
5 days/week for 10, 20, 40, 60, 80 or 100 exposures and observed for life
(Kuschner et al., 1975). As detailed 1n Table 6-3, nasal esthesloneuro-
epHhellomas and lung squamous cell carcinomas were Induced by the expo-
sures. Determination of statistical significances of the tumor Incidences
reported In Table 6-3 1s precluded by a lack of Incidence data for the
control group, which consisted of 240 unspecified animals that appear to
have been used only for llfespan comparisons. The cardnogenlcHy of
b1s(chloromethyl)ether Is demonstrated clearly, however, by the total number
of treated rats with malignant nasal tumors (26/200, Including 17/200 with
esthesloneuroepHhellomas) and lung tumors (14/220, Including 13/220 with
squamous cell carcinomas) and a slgmoldal exposure-response curve for
combined tumors 1n survivors beyond 210 days that was linear upon problt
transformation. Compound purity was not specified, however, and the
respiratory system was the only site subjected to pathologic examinations.
Preliminary results of this study were reported by Laskln et al. (1971).
Dulak and Snyder (1980) reported that respiratory tract tumors developed
1n -35% of an unspecified number of male Sprague-Dawley rats exposed to 0.1
ppm (0.5 mg/m8) bls(chloromethyl) ether vapor, 6 hours/day, 5 days/week
foe 3.Q exposures. The rats were observed for life and, the first tumors were
observed- after 350 days; the types of tumors were not spec/If led an* addi-
tion* 1 1nf orraa11on was not reported.
A group of 50 male Strain A/Heston mice were exposed to' fndustrtal grade
b1:s(ch^oromethy.l) ether vapor at a. concentration of 0.005, mg/iv (.5,
mg/rn*),1 6 htwrs/
-------
TABLE 6-3
o
o
incidence of Respiratory Tract Tumors In Hale Sprague-Dawley Rats Exposed to 0.1 ppm
bls(Ch)or.pmethyl) itiiejf, 6 Hours/Day. 5 Days/Week for 10-100 Exposures with Lifetime Observation3
Number of
Exposures
Hedjaq
LVfespan
(weeks)
Target Organ
Tumor Type
Tumor Incidence
100
80
60
40
20
5ft
43
nose
lung
respiratory tract
nose
lung
respiratory tract
nose
lung
respiratory tract
nose
lung
respiratory tract
nose
lung
respiratory tract
esthesloneuroeplthelloma
squamous cell carcinoma
total malignant tumors
esthesloneuroeplthelloma
squamous cell carcinoma
total malignant tumors
esthesloneuroeplthelloma
squamous cell carcinoma
total malignant tumors
esthesloneuroeplthelloma
squamous cell carcinoma
total malignant tumors
esthesloneuroeplthelloma
squamous cell carcinoma
total malignant tumors
3/30
8/30
12/20b
9/50c
3/5QC
15/34b
2/20
2/20
4/18b
2/20
0/20
4/18b
1/50
0/50
3/46b
o
01
10
\
CO
-------
TABLE 6-3 (cont.)
§
Median
Number of Ltfespan
Exposures (weeks)
10 69
0 66
Target Organ
nose
lung
respiratory tract
NR
Tumor Type
esthes loneuroepHhel Ionia
squamous cell carcinoma
total malignant tumors
NR
Tumor Incidence
0/50
0/50
l/41b
NR
a§purce: Kuschner et al., 1375
bAnimals surviving beyond 21Q days
^ cTwenty of the rats Included In this tabulation were exposed In an earlier experiment.
NR = Not reported
Q
th
INJ
US
CO
-------
examination of the lungs at conclusion of exposure showed that 26/47 surviv-
ing mice had lung tumors, with an average of 2.9 tumors/mouse. Lung tumors
were found In 20/49 untreated chamber control mice observed for 130 days
(average 0.9 tumors/mouse) and 46/49 positive controls (500 mg/m3
urethane, 6 hours/day for 130 days 1n 28 weeks) (average 54.2 tumors/mouse).
Bls(chloromethyl) ether was considered to be a tumorlgen 1n this assay on
the basis of the Increased mean number of tumors/mouse In the treated group.
Kuschner et al. (1975) exposed 100 male Syrian golden hamsters to 0.1
ppm (0.5 mg/m3) bls(chloromethyl) ether by Inhalation, 6 hours/day, 5
days/week for life. A single undlfferentlated carcinoma of the lung was
observed 1n one hamster that died on day 501 after 334 exposures. A
survival curve Indicated that there was significant mortality In the treated
hamsters after 20 weeks, with 100% mortality after -75 weeks. This survival
curve 1s similar to curves for data In rats exposed to 0.1 ppm b1s(chloro-
methyl) ether, which reflected mortality from respiratory' system tumor
development (Kuschner et al., 1975). The mortality In the hamsters Is
difficult to evaluate, however, as no cause was Indicated, sites other than
the respiratory system were not subjected to gross or hlstologlcalv
examinations and because colony controls rather than sham-exposed controls
were used.
Laskln et al. (1975) exposed 74 male Sprague-Dawley rats and, 90 male
SyrTani golden hamsitersr:' ta commercial igrade c.lKlo.raime.thyfE: methylt -either: by;:
f nh&U&f on--*t a concertlratlorv of 7 ppm i3'rug/m*);. & hours/day,. 5 days/week
foe: T.1«feL, Group* of 74 nat:s and. 88 hamsters served* as? chamber/controls^
HTs'toTogical evaluations,- of v the- respiratory vferactC-ainxk Tungs: werer conducted-
on at least 54 "of t he! v treatedvratsv ort atn'teas^B loCvthe^expcsetf hamsters:
and on similar numbers of controls (exact numbers of animals examined not
0042d 6-18 07/07/87
-------
specified). Although not stated specifically, the results of this study
Indicate that hlstologlcal examinations of gross abnormalities In other
tissues were also conducted. Mortality and weight gain were similar among
the rat and hamster treatment and control groups. Tumors of the respiratory
tract, found In two of the treated rats, Included a squamous cell carcinoma
of the lung that metastaslzed to the kidneys, and an esthesloneuro-
epHhelloma that originated 1n the olfactory epithelium. Another exposed
rat had an undlfferentlated pituitary tumor. One treated hamster had an
adenocarclnoma of the lung and another had a squamous papllloma of the
trachea. Although the Incidences of these tumors are not statistically
significant, the authors speculated that the tumors might be attributable to
bls(chloromethyl) ether, which could have been present In the commercial
grade chloromethyl methyl ether tested 1n this experiment.
A group of 50 male Strain A/Heston mice were exposed to Industrial-grade
chloromethyl methyl ether vapor at a concentration of 0.006 mg/s. (6
mg/m3), 6 hours/day, 5 days/week for 101 days 1n 21 weeks (Leong et al.,
1971). Gross examination of the lungs after exposure showed that 25/50 mice
had lung tumors, with an average of 1.5 tumors/mouse. Lung tumors were
found 1n 20/49 untreated chamber control mice observed for 130 days (average
0.9 tumors/mouse) and 46/49 positive controls (500 mg/m3 urethane, 6
hours/day, ,5; days/week for .130 days In 28 weeks), (average S4..2 tumors/
mouse:). The results- of th-ls. pulmonary; tumor assay, were considered to be.
Inconclusive as bls(chloromethyl) ether occurred as a contaminant In .the
test material at concentrations that Increased from 0.3-2.6X during, the-
experlmenta,! period.
U;.S>. EPA; fT980b) concluded that unequivocal evidence * exists that
bls(chloromethyl) ether and, for practical purposes, chloromethyl methyl
0042d 6-T9 07/07/87
-------
ether, are human respiratory carcinogens. The conclusion regarding the
cardnogenlcHy of chloromethyl methyl ether Is based on the facts that
commercial grade chloromethyl methyl ether typically contains
bls(chloromethyl) ether as an Impurity, generally 1-8% (IARC, 1979), and
Insufficient ep1dem1olog1cal evidence Is available to separate the carcino-
genic effects of these two compounds. IARC (1979) has also concluded that
bls(chloromethyl) ether and technical grade chloromethyl methyl ether are
carcinogenic for humans.
Respiratory cancers have been Identified 1n workers that were exposed to
commercial grade chloromethyl methyl ether In a Philadelphia chemical plant
where 1t was used as an alkylatlng agent (Flgueroa et a!., 1973; Weiss and
Boucot, 1975; Weiss, 1976; Weiss and Flgueroa, 1976; OeFonso and Kelton,
1976; Weiss et al., 1979; Albert et al., 1975; Pasternack et al., 1977); to
bls(chloromethyl) ether when used as a contaminant In a California
an1on-exchang«.- resin" manufacturing plant' (Lemen et al., 1976); to b1s-
(chloromethyl) ether In a Japanese dyestuff factory (Sakabe, 1973); and to
bls(chloromethyl) ether In the testing laboratory and production operation
of a German chemical plant (Thless et al., 1973). Heavy -exposures =~to-
bls(chloromethyl) ether and chloromethyl methyl ether have been Identified
as the cause of lung adenocardnomas In two German research chemists
(Bettendorf, 1976; Reznlk et al., 1977).. Two studies ^have shown a
association betVeeff abnorma-T puTmorvary; cytolo'gy and} Vxpp sure' to
mefthy-T) ether, which was \ not related to cigarette smoking (Frost e;t; asl«,
1973;" Lemen :et~:a:ir, TaTtff. Irr tataTc, Attf appears; that, at leasit 4;Z cases of1
lump cancer have, been associated wtt ft exposure to bTs(.chloromethyT};: ether
and oommercitai; ch
-------
predominant hlstologlcal type has been small cell-undlfferentlated or oat
cell carcinomas. Several of the studies demonstrated that the occurrence of
lung cancer was related to the Intensity and duration of exposure.
The ep1dem1olog1cal studies of bls(chloromethyl) ether or chloromethyl
methyl ether-exposed workers cannot be used as a basis for quantitative risk
estimation for either of these compounds because quantitative exposure data
were not reported and because exposures cannot be attributed solely to
either compound. Also, since U.S. EPA (1980b) considered the studies to
provide unequivocal evidence of human cardnogenldty (U.S. EPA, 1980b;
IARC, 1979), they will not be reviewed or evaluated comprehensively. An
overview of several of the more extensive studies 1s presented 1n Table 6-4.
6.2.2. Oral. Commercial grade b1s(2-chloroethyl) ether was administered
orally to groups of 18 male and 18 female B6C3F1 and 18 male and 18 female
B6AKF1 mice (BRL, 1968; Innes et a!., 1969). These hybrid strains were
designated (C57BL/6xC3H/Anf )F] and (C57BL/6xAKR)F1, respectively. In the
Innes et al. (1969) report. The oral treatment schedule consisted of dally
Intubation of 100 mg/kg of the compound In distilled water from days 7-28 of
life, followed by administration In the diet at a concentration of 300 ppm
until 80'weeks of age. The gavage dose represented the MTD (determined 1n
preliminary subchronlc studies), and was not adjusted to changing body
weight during the 3 weeks, of treatment.. The diet coAceatratloB WAS ca,\cu-.
Tatetf to? prwfde1 approx^matfeTy>;: thff sai&rl^:'.vs-fn$--\ttieiwif4W^' the*,TWA dosage for the entire* study^s; 4^^
mg/kg/day. Negative control groups consisted of four untreated groups and
Q0*2d: 6-2T 07/07/87
-------
TABLE 6-4
Lung Cancer Mortality |n Workers fxppsed to Unspecified Concentrations of bts(Ch)oromethyl) Ether and Technical Grade Chloromethyl Methyl Ether
IVJ
o
—I
o
~J
•s.
00
Exposed
Population
669 Philadelphia
chemical plant
workers3
1446 Philadelphia
chemical plant
workers3 * • :.
(465 exposed)
721 Chemical
plant workers6
136 California
anlon-exchange
plant workers?
Control
Population
1616 unexposed
workers from the
same plant ' r'
general . -
population
(Philadelphia)
1815 unexposed
workers^ from the
same plant ;
general
population
(Connecticut)
Duration of Exposure
<1 year,1? (n=398)
1 to <5 years'* (n=170)
>5 years6 (n=101)
«12 year.;!*
m *e3n
£5 years
Type of Lung Cancer
(predominant)
NR
small cell carcinoma
NR
small cell carcinoma
(undifferenttated) '.
Number of Number of
Observed Expected
Cancer Deaths Cancer Deaths
19 5.0
39 18.1
23 4.5
5 0.54
Increased Risk
[ Obser ved/E xpec t ed ]
(p value)
3.8' (p<0.01)
2.15c'd (p<0.001)
5. 1C (p<0.05)
9.24 (p<0.01)
Reference
DeFonso and
Kelton, 1976
Weiss
et al.. 1979
Pasternack
et al., 1977f
Lemen
et al.. 1976
3Chloromethyl methyl ether was used as an aljcylatlng agent In the manufacture of organic compounds. This plant was the subject of eplderolologlcal studies
by flgueroa et al. (1973). Weiss and Boucot (1975). Weiss (1976), Weiss and Ftgueroa (1976). DeFonso and Kelton (1976) and Weiss et al. (1979).
DA qualitative exposure rating system was used to approximate relative exposure concentrations and duration times.
'Increased risk was shown to be dependent on the duration and Intensity of exposure.
dstgntfIcantly Increased risk occurred only, among workers with moderate and heavy exposure. The Increased risk was 6.9 In 97 moderately exposed workers
(9 observed cases vs. 1.3f expected) and 30 In heavily exposed workers (9 observed cases vs. 0.3 expected).
eThls appears to be the same plant that was studied by DeFonso and Kelton (1976) and Weiss et al. (1979).
^Preliminaryresults were reported by Albert et al. (1975) and Nelson (1976).
9bls(Chlorpfnethyl) ether was a contaminant In a manufacturing process that produced anlon-exchange resins.
NR = Not reported '-.« .#,.
-------
one group that was treated with 0.5% gelatin; each of these groups consisted
of 18 mice/strain/sex. Following the treatment period, all surviving mice
were dissected and grossly examined, and tissue samples from the chest
contents, liver, spleen, kidneys, adrenals, stomach, Intestines and genitals
were microscopically examined. Moribund mice were sacrificed and subjected
to gross pathological examinations, but hlstologlcal examinations were
performed only when deemed appropriate (criteria not specified). As
detailed 1n Table 6-5, the Incidences of hepatomas In males of both strains
and females of one strain were statistically higher than In the pooled
control group. All unmetastaslzlng hepatic-cell tumors were diagnosed as
"hepatomas."
b1s(2-Chloroethyl) ether of 100% purity was administered 1n SSV vehicle
to groups of 26 Charles River CD rats of both sexes by gavage at doses of 25
or 50 mg/kg, twice weekly for 78 weeks, followed by a 26-week observation
period (Welsburger et a!., 1981). These doses were Intended to represent
the MTD and one-half the HTD as determined 1n a subchronlc study. Matched
and pooled control groups were used but the sizes of these groups were not
reported. Necropsies that Included comprehensive hlstologlcal examinations
were conducted on all rats (Including those that were moribund during the
study) that developed palpable tissue masses during the study and on five
rats of;" each sex* tit the telgtr-dose' group, at the end, of: the 18:-week.( treatment
period. The authorr. concluded: that b1s(2-chToroethyl) ether; was not
carcinogenic,,, but the results of the pathological • examination were not;
specifically reported. Compound-reTated decreased body weight occurred In'
th'e treated! females and h1gh;-dose mal;es,v and. survival was/Tower. In; the
high-dose females' (see Section 6.1.2.7.). The authors1 suggested ;an; fff'e -;
basis of the survival data that the doses for the males may not have been
sufficient to eHcH a carcinogenic response.
0042d 6-23 07/07/87
-------
TABLE 6-5
Incidence of Hepatpmas 1n Two Strains of Mice Given
Oral Doses of b1s{2-Chloroethyl) Ether3.b
Strain
B6C3F1
B6AKF1
Sex
M
F
M
F
Dosec
(mg/kg/day)
0
41.3
0
41.3
0
41.3
0
41.3
Hepatoma Incidence
(p value)
8/79d
14/16 (p<0.01
0/87d
4/18 (p<0.01
5/90d (p<0.01
9/17
l/82d (NS)
0/18
)e
)e
)e
QUALITY OF EVIDENCE
Strengths of study: Both sexes of two strain of mice were exposed by a
natural route for a significant portion of the life-
span.
Weaknesses of study: Multiple species and doses were not tested and group
sizes were relatively small. Extensive histologlcal
examinations were not conducted.
Overall adequacy: /Adequate
aSource: BRL, 1968; Innes et al., 1969
bCommercJa,l grade, test chemical
CTWA dose; reflect-Trfg- TOO mg/Kg/xta-y -gava.ge treatment "for ^ week*antf 300'ppm
diet treatment for the next 76iweeks*. A-da1:ly dose was calculated from the
300 ppm diet, concentration by assuming that mouse food,consumption 1s equiv-
alents' to l;3%£o£.body :weifgh|t/
-------
Groups of 50 F344 rats of each sex were treated by gavage with technical
grade b1s(2-chloro-l-methylethyl) ether In corn oil at doses of 0 (vehicle
control), 100 or 200 mg/kg, 5 days/week for 103 weeks, and maintained for an
additional 1-2 weeks (NCI, 1979). The technical grade compound was obtained
from three different sources and contained -2% b1s(2-chloro-n-propyl) ether
and 28.5% 2-chloro-l-methylethyl(2-chloropropyl) ether. Dose-related
decreased mean body weight occurred 1n both sexes, and treatment-related
decreased survival occurred In the high-dose males and high- and low-dose
females (see Section 6.1.2.2.). Almost all of the high-dose group rats died
by the end of the bloassay. Comprehensive gross and hlstologlcal examina-
tions that were conducted on dead, moribund and surviving animals (47-50/
group examined) did not reveal treatment-related Increased Incidences of
tumors 1n either sex. Expression of tumoMgenlcHy, however, may have been
complicated by the low survival 1n the high-dose group, as Insufficient
• • * •
numbers of high-dose rats of each sex were considered at risk for develop-
ment of late-developing tumors.
Technical grade b1s(2-chloro-l-methylethyl) ether In corn oil was also
administered by gavage to groups of 50 B6C3F1 mice of each sex at doses of
0,-~100 or 200-mg/kg/day, 5 days/week for 103 weeks, followed by 1-7 weeks-of
observation (NTP, 1982). The technical grade product was -70% pure, con-
talnWf- -26-28.5%; 2-chloFo-4-(Bethylethyl (2,-chloropjrapKU *U«r aM 2.1-2.;6Jfc;
b-1s (-2-chloropropyl) e-ther. Ra-ts a-Tso- were- treated, but; tnTs study. was
aborted when a dosing error after 7T weeks; caused (;a. Targe number of deaths;;,
details;, were not reported. There-were no compound-related; effects-on body
we;Vgh*sr- or- survival; ksee Sectlonv 6..T..&2.;}:;,-. Treatment was; carcinogenic,/
however, Inducing ' stattsffca-TTy significant" Increased ? Incidences "• of
alveolar/bronchlolar adenomas 1n both sexes and hepatocellular carcinomas
0042d 6-25 07/07/87
-------
with lung metastases In the males (Table 6-6). A low Incidence of squamous
cell papHlomas or carcinomas occurred In the stomach or forestomach of the
female mice. Since these stomach tumors are rare In B6C3F1 mice, 1t was
concluded that the occurrence was probably treatment-related.
b1s(2-Chloro-l-methylethyl) ether of high purity (98.5%) was adminis-
tered to groups of 56 male and 56 female SPF-ICR mice In the diet at
concentrations of 0, 80, 400, 2000 or 10,000 ppm (MHsumorl et al., 1979).
Comprehensive gross and hlstologlcal examinations were conducted on seven
mice/dose/sex after 13, 26 and 52 weeks of treatment, on six mice/dose/sex
after 78 weeks of treatment, on remaining surviving mice after 104 weeks of
treatment, as well as on moribund and dead mice. Treatment-related
neoplastlc lesions were not observed. Expression of tumor1gen1dty 1n the
high-dose group, however, may have been complicated by low survival (see
Section 6.1.2.2.). Average dally Intake In the 10,000 ppm dose groups was
reported to be 961 mg/kg/day 1n the males and 927 mg/kg/day In the females.
6.2.3. Other Relevant Information. The cutaneous cardnogenldty of
various chloroethers was evaluated 1n mice (Van Duuren et al., 1968, 1969,
1974, 197-5; Lyman and Furla, 1969). These Devaluations Included long-term
thrice weekly dermal application studies and Initiation-promotion studies
(Tables 6-7 and 6-8). The skin application studies showed that b1s(chloro-
•ethyH? 'ftther;*.1 T.Z^M st^ftw^t^^ha^.aml; poistfcJx , tcU^a^cltforo;-
methoxy.)propane- were active as complete carcl-nogem,. Bre1n1t1at1on-
pr.amrt.Von itudles* which teste4var.tou5? chJapoe.thelrs as tiatii Initiators ar\4;
promotensv showed," that: fctsfchlororaethyl) ether was- actVv# as * tumor
promo:ter; Fonilowtng;- Initiation with " stinger dosesr of B;fa"pL fftlter; situdi^es-T
v>
showed that bls(chloromethyl) ether was active also as a mouse sktn burner
Initiator when TPA was used as the promoter (Zajdela et al., 1980).
0042d 6-26 07/07/87
-------
a
2
rvi
ex
TABLE 6-6
Incidence of Tumors In B6C3F1 Nice Treated with Technical Grade b1s(2-Chloro-l-methylethyl) Ether
"In Corn Oil by Gavage, 5 Days/Week for 103 Weeks3
09
Sex Dose
(pig/kg)
» 0
100
200
P
100
200
0
100
?oo
0
100
200
0
100
200
f 0
100
£00
0
100
200
Duration
of Study
(weeks)
104-110
104rllO
104-110
104-110
104-110
105.110
105-JlO
Target Organ
lung
lung
liver
liver
stomach or
forestomach
lung
lung
Tumor Type
alveolar /bronchlolar
adenoma or carcinoma
alveolar/bronchlolar
adenoma
hepatocellular adenomas
and carcinomas?
hepatocellular carcinoma
squamous cell papllloma
alveolar/bronchlolar
adenoma or carcinoma
alveolar/bronchlolar
adenoma
Tumor Incidence
(p value)b
6/50 (p>0.05)c»d
15/50 (p=0.02)c-d
13/50 (p>0.05)c»d
5/50 (p>0.05)C.d
13/50 (p=0.03)c»d
11/50 (p>0.05)e.f
13/50 (p<0.01)c»d
23/50 (p=0.03)d'e
27/50 (p<0.01)c'd
5/50 (p<0.01)c»d
13/50 (p=0.03)d»e
17/50 (p<0.01)c.d
0/49 (p>0.05)e.f
1/50 {p>0.05)e'f.h
1/50 (p>0.05)e'f."
1/50 (p<0.01)c'd
4/50 (p>0.05)e.f
10/50 (p<0.01)c«d
1/50 (p=0.01)c'd
4/50 (p>0.05)e«f
8/50 (p=0.02)c-d
-------
TABLE 6-6 (cqnt.)
Sex
f
Dose
(mg/kg)
0
100
200
Duration
of Study
(weeks)
105-1J0..
Target Organ
stomach or
forestomach
Tumor Type
squamous cell papllloma
or carcinoma
Tumor Incidence
(p value)*5
0/50 (p>0.05)e»f
0/49 (P>0.05)e»f
3/49 (p>0.05)e«f'n
er>
&
CD
Strengths of study:
QUALITY OF EVIDENCE
Adequate numbers of animals of both sexes were exposed by a natural route at two
doses for the majority of their llfespan. Adequate numbers of animals survived to
be at risk for late-developing tumors and comprehensive hlstologlcal examinations
were.conducted.
Weaknesses of study: Jechnlcal grade compound of 70% purity was tested. Although only one species was
' " '" ' Jested^ the results of rats tested with essentially the same protocol and the same
Overall adequacy:
batches of chemicals were reported earlier (NCI, 1979)
Adequat^
o
in
oo
Source: NTP, 1902
p value for the CochrjnTArm1tage test for linear trend Is shown next to the control Incidence; the
yalue for the Fisher Exact test Is shown next to the Incidences In the treated groups.
cp<0.05 In j|fe table analysis
p<0.05 In Incidental tumor test
": ' . / *, *" .J *• - r
ep>0.05 1n Ijfs table analysis
c •''<•- *•''.""•' .,*••*.
r3 p>0.05 In Incidental tumor test
etastases |o the lung occurred In 1/50 control, 4/50 low dose and 3/50 high dose male mice.
was concluded that these tumors were probably related to treatment since they are rarely observed In
vehicle control and untreated control B6C3F1 mice.
-------
TABLE 6-7
Dermal lumorlgenlclty of Haloethers In Female Nice
rv»
a.
Chemical
Chloromethyl methyl ether
bls(Chloromethyl) ether
a.a-Dtchloromethyl
methyl ether
Octachloro-dt-n-propyl
^ ether
2,3-Dlchloro-p'dloxano
l,2-bls(Chloromethoxy|
ethane' ' '
1.4-b1s(Chloromethoxy)
butane • '•-, ,
1 .6-bts(Chlorornethoxy^
hexane %. '•
1 ,2.3-Tr Is(Chloromethoxy)
propane ; .*•;''
2.4.4'-TMchloro-2'-
hydroxydtphenyl ether
o
^ aVehtcle control data given
Strain
ICR/IU
Swiss
ICR/Ha
Swiss
ICR/Ha
ICR/Ha
Swiss
Swiss-
Hlllerton
Swiss-
Hi! ler ton
ICR/Ha
Swiss
ICR/Ha
Swiss
ICR/Ha
Swiss
ICR/Ha
Swiss
ICR/Ha
Swiss
Charles
River
Swiss
In parentheses
Pose
(vehicle)
(benzene)
28 mg
(benzene)
2.Q mg
(benzene)
2.0 mg
jjjenzene
(benzene)
\.0 mg
(benzene)
0,5 mg
'(acetone)
J:P ""a
(cyclohexane)
(cyclohexane)
1.0 mg
(cyclohexane)
1.0 mg
(cyclohexane)
Q.I rot of O.S
or l.OX acetone
solution
Application
3 times/week
3 times/week
for 325 days
3 times/week
3 times/week
3 times/week
3 times/week
3 times/week
3 times/week
3 times/week
3 times/week
3 times/week
3 times/week
, Statistical evaluations conducted
Duration
329 days
540 days
329 days
325 days
450 days
450 days
580 days
502 days
503 days
503 days
502 days
19 months
Median
Survival
llmea
(days)
NR
>540 (>540)
313 (NR)
313 (>540)
>450 (>450)
>450 (>450)
478 (543)
>502 (>504)
473 (>504)
484 |>504)
493 (>504)
NR
only on carcinoma Incidences
Incidence of
Papllloroas3
0/20 (0/20)
0/20 (0/20)
13/20 (0/20)
13/20 (0/20)
0/20 (0/20)
0/20 (0/20)
2/50 (0/50)
4/50 (0/50)
1/50 (0/50)
0/50 (0/50)
6/50 (0/50)
NRd
In the Van Duuren
Incidence of
Carcinomas'1
0/20 (0/20)
0/20 (0/20)
12/20 (0/20)
12/20 (0/20)
0/20 (0/20)
0/20 (0/20)
0/50 (0/50)
4/50b (0/50)
1/50C (0/50)
0/50 (0/50)
3/50c (0/50)
NRd
et al. (1975) study
Reference
Van Duuren
et al.. 1968
Van Duuren
et al.. 1969
Van Duuren
et al.. 1968
Van Duuren
et al.. 1969
Van Duuren
et al.. 1969
Van Duuren
et al.. 1969
Van Duuren
et al.. 1974
Van Duuren
et al.. 1975
Van Duuren
et al.. 1975
Van Duuren
et al.. 1975
Van Duuren
et al.. 1975
Lyman and
Furla, 1969
.
f\J • h
us b
, p<0.05
S Vo.qs
Tumor Incidences not reported but were similar In treated and control groups.
-------
o
o
ro
o.
Chemical
Chloromethyl methyl
ether
i
CJ
o
bls(Chloromethyl) ether
o
o
\ a.-ci-Dlchloromethyl
3 methyl ether"
TABLE 6-8
House Skin Tumor-Inlt latlng and Tumor -Promo ting Activity of Chloroethers3
Strain
'*»««)
ICR/Ha
Swiss |F)
ICR/Ha
$*'« (F)
ICR/Ha.
Swiss (F)
ICR/Ha
Swiss (F)
Charles
River
CDI (F)
ICR/Ha
Swiss (F)
ICR/Ha
Swiss (f)
XVIlnc/Z
K
ICR/Ha
Swiss (F|
ICfl/Ha
Swiss (fj
Charles
CDI (F)
Swiss-
Nil ler ton
(f) •.-.
Initiation/ Promotion (3 times
.Single Dose weekly beginning 14
l01^ days after primary
" treatment)11
1.0 0.025 rag croton
resin
1.0 0.025 mg phorbol
ester
0-15 B(a)P 2.0 mg
0.15 B|a)P 2.0 mg
10.1 0.2 ml of 0.25X
'' :• croton olle
1.0 0.025 ng croton
resin
1.0 0.025 mg phorbol
ester
1.0 2.0 ng TPA
0.15 fl(a)P 2.0 mg .
0.15 B(a)P 2.0 mg
2.1 0.2 ml of 0.25X
croton oil6
l.Q 0.025 ng phorbol
ester
Median Survival
Treatment Time
or Study (days)d
Duration0
329 days NR
540 days 468 (>450)
329 days NR
325 days >540 (540)
30 weeks NR
329 days NR
540 days 474 (NR)
590 days NR
325 days NR
325 days 315 (540)
30 weeks NR
450 days >450 (>450)
Incidence of
Pap111omasd
3/20 (2/20)
5/20 (2/20)
0/20 (0/20)
1/20 (0/20)
NRf
4/20 (2/20)
5/20 (0/20)
12/289 (4/28)9
12/20 (0/20)
13/20 (0/20)
NRn
3/20 (2/20)
Incidence of
Carcinomas''
0/20 (0/20)
1/20 (0/20)
0/20 (0/20)
0/20 (0/20)
NR
0/20 (0/20)
2/20 (0/20)
3/28 (0/28)
11/20 (0/20)
12/20 (0/20)
NR
1/20 (0/20)
Reference
Van Duuren
et al.. 1968
Van Duuren
et al.. 1969
Van Duuren
et al.. 1968
Van Duuren
et al.. 1969
Slaga
et al.. 1973
Van Duuren
et al.. 1968
Van Duuren
et al.. 1969
Zajdela
et al.. 1980
Van Duuren
et al.. 1968
Van Duuren
et al.. 1969
Slaga
et al.. 1973
Van Duuren
el al.. 1969
-------
1ABLE 6-8 (cont.)
Chemical
o.o-Dtchloromethyl
methyl ether'
bts(a-Chloroethyl)
ether ,
bls(2-Chloroethyl)
ether
Octachloro-dl-n-propyl
ether ;
2,3-Dlchloro-p-dloxane
: . •"• '
Initiation/ Promotion (3 tiroes Median Survival
Strain Single Dose weekly beginning 14 Treatment Time Incidence of
(sex) (mg) day$ after primary or Study (days)d Paplllomasd
:"- : treatment)" Duration0
Swiss- 0.15 BlaJP 1.0 mg 450 days >450 (>450) 0/20 (0/20)
HUlerton
in "'
ICR/Ha 1.0 2.5 ng PHA 590 days 414(485) 7/20 (2/20)
Swiss (F)
JCR/Ha 1.0 2.5 ng/PHA 590 days 459(485) 3/20 (2/20)
Swiss (F|
Swiss- 1.0 0.025 mg phorbol 450 days >450 (>450) 3/20 (2/20)
filler ton ' ester
}n
Swiss- 0.15 Q(a)P 1.0 mg 450 days >450 (>450) 1/20 (0/20)
HUlerton : -
(n »-.-
ICR/Ha 0.5 2.5 Mg/PHA 385 days 385 (NR) 8/30 (3/30)
Swiss |f)
Incidence of Reference
Carclnomasd
0/20 (0/20) Van Duuren
et al., 1969
0/20 (0/20) Van Duuren
et al.. 1972
0/20 (0/20) Van Duuren
et al.. 1972
1/20 (0/20) Van Duuren
et al.. 1969
0/20 (0/20) Van Duuren
et al.. 1969
2/30 (0/30) Van Duuren
et al.. 1974
alf more than one dose was (tested In a particular study, data are given for the highest dose If Inactive and for the lowest dose If active.
••""-• " " . . '*" •
bProfiwtlon for duration of study In the Van Ouuren,et al. (1968, 1969. 1972, 1974) studies. Promotion for 42 weeks In the Zajdela et al. (1980) study.
cDuratlon from beginning of promotion phase
•^Vehicle (benzene) control data In parenlhesetj untreated and positive control data reported but not presented In this table. Acetone was used as the
vehicle for 2,3-dlchlord-p-dloxane. ' '•'".
• . -, • , ..v ' • '•" •• . •
eTwlce weekly applications for 29 weeks beginning 1 week after Initiation.
fThere were 0.2 paplllomas/treated mouse vs. 0/qouse In controls (26 treated and 29 controls tested).
QTotal Incidence of paptllqmas; Incidences of persistent paplllomas were 4/28 tn treated and 1/28 In controls.
"There were 0.6 paplllomas/lreated mouse vs. O/qtpufe In controls (28 treated and 30 controls tested).
o
tn
-------
2,3-D1chloro-p-d1oxane showed possible activity as an Initiating agent with
PMA as the promoter (Van Duuren et al., 1972).
The cardnogenlcHy of various chloroethers was also evaluated 1n mice
and rats that were treated by weekly subcutaneous Injections for life
(Gargus et al., 1969; Van Ouuren et al., 1969, 1971, 1972, 1974, 1975;
Zajdela et al., 1980). These studies, which are summarized 1n Table 6-9,
Indicate that chloromethyl methyl ether, b1s(2-chloroethyl) ether, 2,3-d1-
chloro-p-d1oxane, 1,2-b1s(chloromethoxy)ethane, 1,2,3-tr1s(chloromethoxy)-
propane and possibly bls(a-chloroethyl) ether Induced Injection-site
sarcomas In mice. Hlstologlcal examination of abnormally appearing tissues
did not reveal treatment-related distant tumors 1n these studies.
Groups of 48-51 male and female newborn ICR Swiss mice were given single
subcutaneous Injections of predetermined MTDs of Industrial grade
bls(chloromethyl) ether (12.5 yl/kg) or chloromethyl methyl ether (125
vl/kg) In peanut oil and observed for 6 months (Gargus et al., 1969).
Growth and survival of these mice were comparable with those of vehicle
controls. Dissecting microscopic examination of the lungs showed that
45/100 mice treated with bls(chloromethyl) ether and 17/99 treated wtth
chloromethyl methyl ether developed adenomas; the mean numbers of tumors/
treated mice were 0.64 and 0.21, respectively. Seven of 50 vehicle controls
(30 males, 20 females) had lung tumors (0.14 tumors/mouse). These data were.
Interpreted- a& Indtcatfng a s:Vgn1:f 1 caret-tumor4"gen^Vc: effect; afr b;1.s;(chToro-;
me:tlry:Tj ether: tri this, assay, sy/stemv; Iti was suggested that the/sraaTT
tncreaiie 1w tumors \m the ohlorometby.tvn«,tiiy:Yether? group may be attributed;
to. b1;s/(ichToromethy''l'); ether,vWhtch: occurred asKa;0;.3% contaminant.!';
Weekly 1ntraper1toneal Injections of; b;1'S(ch'Tonometh;yl)K,fttheF> T,:2-b,ils->
(chloromethoxy)ethane and 1.2,3-tr1s(chloromethoxy)propane for life produced
significantly Increased Incidences, of 1nject1on-s.1te sarcomas In female:
0042d - 6-32 07/07/87 *
-------
• TABLE 6-9
Subcutaneous Injection Carctnoijenlclty Studies of Haloethers
Q.
Chemical
Chloromethyl methyl ether
-
bls(Chloromethyl) ether
i
CO
bls(a-Chloroethyl) ether
bls(2-Chloroethyl) ether
2,3-01chloro-p-dloxane
o -"•* '""•-
tfl
•^ • 2.3-Olchlorotetrahydrofuran
ift.
Species/Strain
rat/Sprague-
Dawley -..
mouse/ICR/Ha
Swiss
roouse/ICR/Ha
Swiss ;
mouse/ICR Swiss
(newborn)
rat/Spraque-
Dawlev. '
piouse/ICR/Ha
Swiss '•"••'.
mouse/»y|lnc/Z
mouse/KVIlnc/Z
mouse/|CR/Swlss
(newborn)
mouse/ICR/Ha
Swiss * -
mouse/|CR/Ha
Swiss '•'"•''•'•''•••'•
mouse/ICR/Ha
Swiss !;•',.
mouse/|CR/Ha
Swiss ~ V
Sex
F
F
F
H.F
F
F
H
F
M.F
F
F
F
F
Dose and Schedule
3 nig/ Inject I on/weekb
0.3 rag/Injection week
for 26 weeksb
0.3 mg/lnjectlon/weekb
125 nt/kg (132.6 mg/kg).
single Injection
3 mg/ Inject Ion/week for
first 114 daysb;
subsequently 1 mg/
Injection/week1*
0.3 mg/lnject1on/weekb
0.3 rag/Inject lonb, 32
Injections in 42 weeks
0.3 mg/1nject1onb, 32
Injections In 42 weeks
125 yl/kg (132.6 rog/kg).
single Injection
0.3 mg/1nject1on/weekb
1 mg/1njectlon/weekb
0.5 mg/ Inject! on/week6
0.3 mg/lnjectlon weekb
Hedlan
Duration Survival
Time
(days)a
515 days 478 (496)
644 days 497 (497)
life 496 (643)
6 months NR
515 days 325 (496)
371 days 260 (443)
549 days NR
549 days NR
6 months NR
life 649 (643)
life 656 (643)
580 days 444 (523)
life >685 (643)
Injection-Site
Sarcomas8
1/20
5/30
10/30
0/99C
5/20
21/50d
12/27d
10/24d
1/100C
4/30
2/30
17/50d-f
1/30
(0/20)
(0/30)
(0/30)
(NR)
(0/20)
(1/50)
(0/30)
(NR)
(NR)
(0/30)
(0/30)
(0/50)
(0/30)
Reference
Van Duuren
et al.. 1969
Van Duuren
et al.. 1971
Van Duuren
et al.. 1972
Gargus
et al.. 1969
Van Duuren
et al.. 1969
Van Duuren
et al.. 1975
Zajdela
et al.. 1980
Zajdela
et al., 1980
Gargus
et al., 1969
Van Duuren
et al.. 1972
Van Duuren
et al.. 1972
Van Duuren
et al.. 1974
Van Duuren
et al.. 1972
-------
TABLE 69 (cont.)
o
o
CJ
Chemical
),2-b1s(Chloromethoxy)ethane
1.4-b1s(Chloromethpxy)butane
1.6-b1s(Chloromethoxy)hexane
,?•;"'_" '. •:••:•!
1.2,3-tr1s(Chloromethoxy]|
propane
'\
Species/Strain
•»• '-.-, •-•?,,.
mouse/ICR/Ha
SyM>'
muuse/ICR/Ha
*W.*:
mouse/ICR/Ha
s-JsiS-;
nibuse/lCR/Ha
•SMiSr^"-
'. '. J i* ' ' •
Sex Dose and Schedule
* •" .
F 0.3 rag/ Injection/week0
F 0.3 mg/1njecllon/weekc
F 0.3 ing/Inject lon/weekc
F 0.3 mg/1njecilon/weekc
Duration
S69 days
569 days
S69 days
569 days
Hedlan
Survival
Time
(days)*
362 (436)
443 (436)
440 (436)
349 (436)
InJectlon-Stte
Sarcomas3
9/50d (0/50)
0/50 (0/50)
1/50 (0/50)
10/50d-9 (0/50)
Reference
Van Duuren
et al.. 1975
Van Duuren
et al., 1975
Van Duuren
et al.. 1975
Van Duuren
et al.. 1975
aVehlcle control data given In parentheses. Statistical evaluation conducted only In the Van Duuren et al. (1975) and Zajdela et al. (19BO)
studies. ''^r-s^.
bNujo1 vehicle
'Pulmonary tumors jvlso occurred In treaied rats.
?jp<0.01 i-iv'"
' •"'•li. " .
fJr.lcapryltn vehicle
'Total local malignant tumors; Includes ^4 sarcomas. 1 squamous cell carcinoma and 2 adenocarclnomas
9Two additional animals had carcinomas s'
oo
-------
ICR/Ha Swiss mice (Van Ouuren et a!., 1975) (Table 6-10). Necropsies that
Included hlstologlcal examinations of abnormally appearing tissues did not
reveal treatment-related distant tumors. Thrice weekly Intraperltoneal
Injections of b1s(2-chloroethyl) ether at doses of 8-40 mg/kg for up to 24
Injections did not produce treatment-related Increased Incidences of lung
adenomas In Strain A mice (Thless et al., 1977).
6.3. MUTAGENICITY
Hutagenlclty and genotoxldty data for the chloroethers are summarized
In Table 6-11. Ijn vitro assays with various strains of Salmonella typhl-
murlum. Bacillus subtnis. Escherlchla coll and Saccharomyces cerevlslae
have yielded positive responses In b1s(2-chloroethyl) ether and b1s(2-
chloro-1-methylethyl) ether without metabolic activation preparation, which
Indicates that these chloroethers may be direct-acting mutagens.
b1s(2-Chloro-l-methylethyl) ether also produced chromosome aberrations and
slsterchromatld exchanges In cultured Chinese hamster ovary cells (NTP,
1982). Dally gavage administration for 8 weeks of b1s-(2-chloroethyl) ether
and b1s(2-chloro-l-methylethyl) ether at three unspecified dose levels did
not , produce a, detectable Increase In heritable translocatlons In mice
(Jorgenson et al., 1977, 1978) (see Section 6.3.). However, the sample size
used was so small that only an Increase of 100 times the spontaneous level
of translacafcton* could, have? teea detected;.,- 2.»4,4'-Tr\chlor.o^l-^ydFoxx-
dfptfenyT ether did.not ^produce somatic mutation* (for, color alterations^ ft*
the offspring of mice treated by Intraperltoneal Injection during gestation
(spot test) (Russell and Montgomery, 1980).,. Although the available data are
Indicative of mu.tagen1c.tty. of b1s(:2:-ch:loroethy,l);: ether and bis. (-2-ch;Torff-l>
methylethyl) ether' In -Yn vitro mfcrobfal- assays, much*' of
-------
TABLE 6-10
Inlraper Honeal Injection Carctnogentclty Studies of llaloethers with Hlcea
Chemical
bls(Chloromethyl) ether
2,3-Dlchloro-p-dloxane
1.2-b1s(Chloromethoxy)ethane
t,4-b1s(Chloromethoxy)butane
. •••''".'*'.*
1 ,6-bls(Chloromethoxy)hexane
1 .2,3-tr1s(Chloromethoxy)propane
-""*•• •:—1-"
Bose and Schedule
p. 02 rag/ Injection/week0
(M rag/ Inject Ion/week*1
0,3 mg/lnjectlon/weekd
0.) »g/ Injection/week*1
0.3 i«g/ Injection/week11
i
0.9 ng/lnject Ion/week*1
Exposure
Duration
(days)
424
450
546
567
567
532
Median
Survival lime
(days)"1
287 (441)
NR
481 (513)
478 (513)
472 (513)
428 (513)
Injection-Site
Sarcomas'1
4/30c (0/30)
0/30e (1/30)
2/30M (0/30)
0/30 (0/30)
0/30 (0/30)
5/30h (0/30)
Incidence of
Papillary Tumors
of Lungs'1
NR
12/30 (10/30)
NR
NR
NR
NR
Reference
Van Duuren
et al.. 1975
Van Duuren
et al.. 1974
Van Duuren
et al., 1975
Van Duuren
et al., 1975
Van Duuren
et al., 1975
Van Duuren
et al., 1975
"Female ICR/Ha Swiss mice' '
''Vehicle control dala given In parenthesg$.
cNuJol vehicle
dTr1capry!1n vehicle
eOne treated mouse had a local undlfJe.renHated malignant tumor.
9jwo additional mice had local undlfftjrenjfated malignant tumors.
,".p<0.02 ^
o
in
\
TO
ip
CD
-------
TABLE 6-11
Hiitagenlclty and Other Short-Term Gcnotoxlclty Assays of HaToethers
, >-..'.
Chemical
bls(Chlorqmethyl) ether
*• \ i
o> b1s(2-Chloroethy1) ether,
CJ
-^i
0
«j
*^
o •
-J
*^ '•
00
~J
Assay
reverse mutation
chromosome
aberration
rey.erse mutation
reverse mutation
reverse mutation
reverse mutation
reverse mutation
reverse mutation
reverse mutation
reverse mutatlpn
Indicator
Organism
Salmonella
typhlrourluni
TA1S35
TA1S38
TA9B
TA100
Sprague-Dauley
Spartan rat
bone marrow
cells
S. typhlmurlum
(strains NR)
S. typhlmurlum
TA100
TAT 535
S. typhlmurlma
(strain NR)
S. typhlmurlmi
TA100
TA1535
TA1538
TA98
S. typjilmurlum
TA100
S. typhlmurluni
(strains NR)
S. typhlmurlum
(unspecified
TR strains)
Escherlchla
coll HP2
Application
plate Incorporation
vapor exposure
hi vivo; evaluation
conducted 5 days
postexposure
plate Incorporation
suspension
suspension
vapor exposure
(desiccator)
vapor exposure
(desiccator)
host -mediated
(unspecified species)
NR
plate Incorporation
Concentration
or Dose
NR
NR
NR
20 pg/plate
1-100 ppb,
(5-470 ng/m»)
6 hours/day,
5 days/week
for 6 months
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
Activating Response
System
*
f
»
t +
NA
NR
NR +
NR f
¥
NR »
NR f
NR » (weak)
NR t (weak)
t-
NA
*a
NR
Reference
Anderson and
Styles, 1976
Leong
et al.. 1981
Simmon et
al.. 1977a
Simmon et
al., 1977a
Simmon et
al.. 1977b
Simmon et
al.. 1977a
Simmon et
al.. 1977b
Simmon et
al.. T977a
Shlrasu
et al.. 1975
Simmon et
al.. 1977a
-------
(ABLE 6-11 (cunt.)
g Chemical i ' Assay -'•
bls(2-Chloroethyl) ether reverse mutation
reverse mutation
rec-assay ,;
NR
heritable
trarislocatlon
bls(?-Chloro-l-methylethyl) reverse muta)}on
0, ethei- .-"•••;'••• --^ - ":;-:' -'*^~
reverse mytgiton
'.' ' - ; !• ' "y. F
.-T-; : ••".
reverse mu;tat)on
reverse mutation
'•. •' . • *' «v'*V' .
-: *3 • ** ^ *
C3 NO
tn ^.M,
* '• " "• °"f\. ^'":->
CO
Indicator ' Application
Organism .
E. coll NR
WP? B/rhcr*.
WP? hcr-
Baclllus NR
subtllls
GSY 1035
B. subtllls NR
(strain NR)
Saccharomyces suspension
cerevlslae D3
mouse dally gavage for 8
(strain NR) weeks *
S. typhlmur lum plate Incorporation
TA100
TA1535
S. typhlmur lum suspension
TA100
TA1535
S. typhlrourluni vapor (desiccator)
TA100
TA1535
E. coll WP? plate Incorporation
'''-•• vapor desiccator
S. cerevlslae suspension
D3
Concentration Activating Response
or Dose System
NR - •*
NR - fa
NR - *a
NR NR t
NR NA
(three dose
levels)
NR -
> f (weak)
NR
f » (weak)
NR *
NR - +
NR - * (weak)
f »
NR - » (weak)
NR
^
NR
t f (weak)
NR NR i
Reference
Shlrasu
et al.. 1975
Shlrasu
et al.. 1975
Shlrasu
et al.. 1975
Simmon et
al.. 1977a
Jorgenson et
al.. 1977.
1978
Simmon
et al.. 1978
Simmon et
al.. 1978^
Simmon et
al.. 1978b
Simmon
et al.. 1978
Simmon
et al.. 1978
-------
TABLE 6-11 (cent.)
o :
o Chemical
r\>
Q.
b1s(2-CMoro-l-methylethyl)
ether ' '
2.4.V-Tr1chloro-2'-hydroxy-
dlphenyl ether
"*•»
heritable
trans location
chromosome
aberration
sister -chroroat Id
exchange
spot test
(raelanbcytes)
Indicator
Organism
mouse
(strain NR)
Chinese hamster
ovary cells
Chinese hamster
ovary cells
offspring of
Inbred C57BL/E
female mice with
multiple reces-
sive T-stock
males
Application
dally gavage for 8
weeks
unspecified In vitro
unspecified In vitro
Intraper Itoneal In-
jection on post-
conception days 9.25
or 10,25
Concentration
or Dose
NR
(3 dose
levels)
NR
NR
1-25 rag/kg
Activating Response
System
NA
NR *
NR f
NA
Reference
Jorgenson et
al.. 1977.
1978
NTP. 1982C
NTP. 1982C
Russell and
Montgomery.
1980
'Although not stated specifically, positive responses In all four assay systems by these Investigators Is Implied.
to bSome of these results also reported by Simmon et al. (1977b)
• rt - . i' • • i > *,.•"-"'•.'*'
vO
cUnpubl1shed results
NR =. Nqt reported; NA. = not applicable
o
en
10
S;
00
-------
6.4. TERATOGENICITY
Pertinent data regarding the teratogenldty of the haloethers that are
the subject of this report could not be located In the available literature
as cited 1n Appendix A.
6.5. OTHER REPRODUCTIVE EFFECTS
Inbred C57B1/E female mice that had been bred to multiple recessive
T-stock males were treated by 1ntraper1toneal Injection of 2,4,4'-tr1chloro-
2'-hydroxyd1phenyl ether at doses of -3, 8 or 25 mg/kg on postconceptlon
days 9.25 or 10.25 (Russell and Montgomery, 1980). This test 1s an \n_ vivo
somatic mutation assay (spot test) (see Section 6.3.) and the compound was
99.7% pure and administered In methanol. Reduced prenatal survival, as
Indicated by reduced litter size, occurred at 25 mg/kg In both treated
groups; this effect was attributed to maternal toxlclty. Postnatal survival
(between birth and 12 days) was significantly reduced at 8 and 25 mg/kg In
the day 9.25 treatment group and at all doses 1n the day 10.25 treatment
group.
6.6. SUMMARY
Rats exposed to 1 or 10 (3 or 33 mg/m3) chloromethyl methyl ether, 6-7 ?•
hours/day for up to 30 days, and rats and hamsters exposed to 1 ppm (5
mg/m3) b1s{chloromethyl) ether, 6 hours/day for up to 30 days experienced
mortality and hlstopathologlcal alterations of the respiratory tract.
L|fe^ftnief'' exposure of .-> ratsfc aadl twns^eirs to 1 ^Bpmpia* - mg/n»»%, :ch^^cowethyf
mettty-T ether, 6: hours/day,,. 5 dayr/week .produced.".hr-TTtaTogtcan changes:: In the'
respiratory*; tract". iLasklnC et? aT.i, IStffff. Stfrv1vaT= was flat atffekrtetf.
Inhalation exposure", to 20 or 70 ppm (140 or 490 mg/m3.) b1s(2-chloro-T-
methyl-et'hyiT)'. ether, W tfours/daVi* S; days/week for 4"weeks did no.t protiuce
altered blood or urine Indices, or tissue histology; however, reduced weight
gain was rated at 70 ppm (Gage, 1970).
0042* fr-40i 08/26/87
-------
Dally oral exposure to b1s(2-chloro-l-methylethyl) ether for 13 weeks
produced reduced body weight In rats at 250 mg/kg but not at lower doses (no
hlstologlcal effects at any doses) (NCI, 1979), and focal pneumonHls at >50
mg/kg 1n mice (NTP, 1982). Subchronlc oral exposure to 10 mg b1s(2-chloro-
1-methylethyl) ether (22 doses 1n 31 days) produced decreased growth In rats
(Dow Chemical, n.d.) and Increased relative liver, kidney and spleen weights
at 200 mg/kg. Oral exposure to 2,4,4'-tr1chloro-2'-d1hydroxyd1phenyl ether
on 6 days/week for 4 weeks caused reduced weight gain and mortality In rats
at 1000 mg/kg but not at lower doses (Lyman and Furla, 1969). Nasal tumors
developed 1n rats and possibly lung tumors developed In mice that were
exposed to bls(chloromethyl) ether by Inhalation at concentrations of 100
ppb (5 vg/m3), 6 hours/day, 5 days/week for 6 months with lifetime
observation (Leong et a!., 1981) and nasal tumors In rats exposed to 0.1 ppm
(0.5 mg/m3) for 6 hours/day, 5 days/week for 40-100 exposures with
lifetime observation (Kuschner et al., 1975).
Another study Indicated that treament-related respiratory tumors of an
unspecified type developed 1n rats exposed to 0.1 ppm (0.5 mg/m3) b1s-
(chloromethyl) ether vapor, 6 hours/day, 5 days/week for 30 exposures, with,
lifetime observation (Dulak and Snyder, 1980). bls(Chloromethyl) ether also
produced an Increased Incidence and frequency of lung adenomas 1n strain A
mice, exposed to 1 ppm,. (£ ng/aH*. ft hour's/day for 82 days im 2J weeks
(Leong, et-aT., 1311)... .
Commercial grade ;ch-loromethy.V. methy,7; ether vapor did not produce
significantly Increased Incidences "of respiratory system1tumors In rats;, or
hamsters' exposed to? 1. ppnr• .|3 mq/m'-f for &', hmirs/tfffyv 5?< da.y,s'/we;ek». but
there were Increased Incidences of squamous metaplasia of "the trachea and
bronchial hyperplasla In the rats (Laskln et al., 1975). Strain A mice
0042d 6-41 08/26/87
-------
exposed to 2 ppm (6 mg/m3) chloromethyl methyl ether vapor, 6 hours/day, 5
days/week for 101 days In 21 weeks also developed lung tumors, but the
results were Judged Inconclusive because the test material was contaminated
with bls(chloromethyl) ether (Leong et al., 1971). Ep1dem1olog1cal studies
of workers exposed to b1s(chloromethyl) ether and commercial chloromethyl
methyl ether have demonstrated exposure-related occurrence of lung tumors,
predominantly small cell-undlfferentlated or oat-cell carcinomas (see
Section 6.2.1.1.)- Because Industrial grade chloromethyl methyl ether
contains carcinogenic bls(chloromethyl) ether as a contaminant, and because
there 1s Insufficient ep1dem1olog1cal evidence to separate the carcinogenic
effects of these compounds, there Is sufficient evidence to conclude that
bls(chloromethyl) ether and Industrial grade chloromethyl methyl ether are
human carcinogens (IARC, 1979; U.S. EPA, 1980b).
Dally Intubation- with commercial grade b1s(2-chloroethyl) ether at a
dose of 100 mg/kg on days .7-28 of life followed by administration In the
diet at a concentration of "300 ppm for the next 76 weeks produced signifi-
cantly Increased Incidences of hepatomas In male and female B6C3F1 mice and
male B6AKF1 mice (BRL. 1968; Innes et al., 1969); the TWA dose was 41.3
mg/kg/day. Twice weekly administration of 100% pure b1s(2-chloroethyl)
ether by gavage at doses of 25 or 50 mg/kg for 78 weeks, followed by a
26-week observation period, was not carcinogenic In Charles. River CO rats;
but caused* reduced weight gain at both doses and mortality fft the; fctgtp dose
(.We1 sburger, e-t? afU* 19&EK
Carcfrragerttettfy bfoassays of! tecnntfcat;grade ftfsf2-cltTor.a-T:-methyTethyT)
ether were conducted Irr wfrtch groups: .of. 50- F!344: ratsTof.' each' .sex- (NCT, T'9'79)
and 50 B6C3F1 mice of each sex (NTP, 1982) were treated by gavage at doses
of 100 or 200 mg/kg, 5 days/week for 103 weeks. The technical grade chemi-
cal was -70% pure, containing -28.5% 2-chloro-l-methylethyl(2^chloroprQpyl)
0042d 6-42 08/26/87
-------
ether and 2% b1s(2-chloro-n-propyl) ether. The rats were observed for 1-2
weeks following treatment. Increased Incidence of tumors did not occur In
the rats but there were nonneoplastlc effects Including reduced weight gain
and decreased survival (both doses), centrllobular necrosis (high dose) and
esophageal hyperkeratosls (high dose). The mice were observed for 1-7 weeks
following treatment and developed significantly Increased Incidences of
alveolar/bronchlolar adenomas (both sexes), hepatocellular carcinomas
(males) and low Incidences of squamous cell paplllomas or carcinomas 1n the
stomach or forestomach (high-dose females). Nonneoplastlc effects occurred
In the male mice, Including fatty metamorphosis and chronic Inflammation of
the nasal cavity and nasoYacrlmal duct. High purity (98.5%) b1s(2-chloro-l-
methylethyl) ether was not carcinogenic to SPF-ICR mice when concentrations
of 80, 400, 2000 or 10,000 ppm were administered In the diet to groups of 56
ro1ce/sex at for durations as long as 104 weeks (MHsumorl et al., 1979).
The average dally Intake of chemical by the 10,000 ppm group was higher (961
mg/kg/day by males; 927 mg/kg/day by females) than that given to the mice In
the NTP (1982) bloassay. Toxic effects Included mild anemia. Increased
polychromatic erythrocytes and splenic hemoslderln deposition: at the: high
dose In both sexes primarily during the first half of the study. Similar
effects also occurred at 2000 ppm In the females and only at 13 weeks at 80
and 4^0 ppm In the males....
The cardrtogenlcity* of'numerous; chToroethers h'as been evaluated In
dermal application, dermal Initiation-promotion, subcutaneous Injection and
IntraperttoneaT Insertion stutffes. Most of these studies were conducted' by
Van Quurerv efc. a'*. (1968^ W&S:,,. T;9^i;.r, TS72* T$£*> T9.75){r. wna a'dnrtnVster-ed; the-
compounds thrice weekly (dermal studies') or once weekly (tnjectton studies)
to mice for life. bls(Chloromethyl) ether was tumorlgenlc In all of the
0042d 6-43 08/26/87
-------
aforementioned types of studies, Including mouse skin assays In which
bls(chloromethyl) ether was active as an Initiator or promoter. l,2-b1s-
(Chloromethoxy) ethane and 1,2,3-tr1s(ch1oromethoxy)propane were tumoMgenlc
In dermal application, subcutaneous Injection and Intraperltoneal Injec-
tion studies. Chloromethyl methyl ether, bls(a-chloroethyl) ether and
1,2,3-tr1s(chloromethoxy)propane were tumorlgenlc by subcutaneous Injection.
Positive responses have been produced by bls(chloromethyl) ether,
b1s(2-chloroethyl) ether and b1s(2-chloro-l-methylethyl) ether 1n In vitro
assays with various strains of S. typhlmurlum. B_. subtnis. £. coll and S.
cerevlslae without metabolic activation (Shlrasu et al., 1975; Simmon et
a!., 1977a,b, 1978; Anderson and Styles, 1978), which Indicates that these
chloroethers may be direct-acting mutagens. b1s(2-Chloroethyl) ether also
produced chromosome aberrations and slster-chromatld exchanges In cultured
.Chinese hamster ovary cells (NTP, 1982). bls(Chloromethyl) ether did not
produce chromosome aberrations In the bone marrow cells of mice exposed by
Inhalation (Leong et al., 1981). 2,2,4'-Tr1chloro-2'-hydroxyd1phenyl ether
was^ negative- In the In vivo spot test with mice (Russell and Montgomery,
1980).
Pertinent data regarding the teratogenldty of the chloroethers could
not be located 1n the available literature as cited 1n Appendix A. Intra-
per 1 toneal tnjectVaa of 2,4,4' -tr 1 chlono-2,' -hydroxyd 1 phenyl e.ther to'jftVcft,;ore'
po.s,tcQnce,pMotfc. day T0:.25. .caused^ r,editce& Hfcter sires:, largely-:b«cause: of-
maternal to*totty at 25 mg/Kg and retfucetiyp0$trtaf«r? stirv^va^rat; 3-25Vmg/kgK
CiRusseTT and:Montgomery, T98Q).;
0042d 6-44 08/26/87
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUNAN
bls(Chloromethyl) ether and chloromethyl methyl ether are regulated as
carcinogens by OSHA without PELs (OSHA, 1985). The ACGIH (1986) recognizes
bls(chloromethyl) ether as a human carcinogen and recommends a TLV-TWA
concentration for a normal 8-hour workday and a 40-hour workweek of 0.001
ppm (0.005 mg/m3). Chloromethyl methyl ether 1s listed as an Industrial
substance suspect. of carcinogenic potential for man by ACGIH (1986) and Is
not assigned a TLV. An ambient water quality criterion was derived for
bls(chloromethyl) ether by the U.S. EPA (1980b) on the basis of Induction of
malignant respiratory tumors In male rats (Kuschner et al., 1975). A water
concentration of 0.038 ng/8. was calculated to keep the Individual lifetime
cancer risk <10~5. The rapid hydrolysis of bis(chloromethyl) ether In
water precludes a realistic estimation of exposure and that the criterion
was calculated 1n the event that levels are monitored In water.
ACGIH (1986) recommended a TLV-TWA of 5 ppm (30 mg/m') and a TLV-STEL
of 10 ppm (60 mg/ma) for dlchloroethyl ether [b1s(2-chloroethyl) ether],
and noted that skin exposure may contribute to overall exposure. 'An ambient
water quality criterion of 0.3 yg/l was based on the Induction of
hepatomas 1n male mice (Innes et al., 1969) to keep the Individual lifetime
cancer rtsk of &Vs!*^MaroetnyT)r ether XKT5 (.U.:S» EPA> ISMfel..
Ant InterTm toxlcity-based ambient water quality cr1ter-Ton of 34-.7
vg/t for bis(2-chloro-T-methylethyl);ether was derived from the LOAEL
for, centrllobular necrosis in. mtce of. 10: mg/kg/day (NCI:, 1S78}. by: the U.S.
EPA friasOtoU IkSv EPA (BBQb:) tncorxect% named; Ms,t2-ch1;oro^-me(thyl^thy;Tr
ether bts(2-chToro1sopropyT) ether and vused the abbreviation BCIEV The
00*30* 7-1 07/07/87
-------
criterion of 34.7 vq/i was considered an Interim criterion because the
quality of data was Inadequate; positive carc1nogen1dty data (NTP, 1982}
were available subsequent to preparation of the U.S. EPA (1980b) document.
7.2. AQUATIC
U.S. EPA (1980c) summarized the available data concerning toxlclty of
haloethers to aquatic biota and concluded that acute and chronic toxldty to
freshwater biota occurred at concentrations as low as 0.360 and 0.122
mg/a, respectively, and would occur at lower concentrations among species
that are more sensitive than those tested. U.S. EPA (1980b) noted that
acute toxlclty of chloroalkyl ethers to freshwater aquatic life occurred at
concentrations as low as 238 mg/a, and would occur at lower concentrations
among species more sensitive than those tested.
OM3
-------
8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Inhalation cardnogenldty data are available for
bls(chloromethyl) ether and chloromethyl methyl ether. As detailed 1n
ctlon 6.2.1., bls(chloromethyl) ether Induced nasal olfactory epthellum tumo
rs (esthes1oneuroep1thel1omas) and possibly pulmonary tumors 1n rats exposed
to 100 ppb (5 yg/m3), 6 hours/day, 5 days/week for 6 months with
lifetime observation (Leong et al., 1981) and nasal tumors at 0.1 ppm (0.5
mg/m3), 6 hours/day, 5 days/week for 40-100 exposures with lifetime obser-
vation (Kuschner et al., 1975). Another study Indicated that treatment-
related respiratory tumors of an unspecified type developed In rats exposed
to 0.1 ppm bls(chloromethyl) ether vapor, 6 hours/day, 5 days/week for 30
exposures with lifetime observation (Dulak and Snyder, 1980). At 100 ppb (5
vg/m3) b1s(chloromethyl) ether, 5 days/week for 6 months with lifetime
observation, an Increase was observed 1n the Incidence of lung adenomas and
carcinomas 1n mice {Leong et al., 1981). bls(Chloromethyl) ether also
produced an Increased frequency of lung adenomas 1n strain A mice that were
exposed- to 1 ppm (S^mg/m3), 6 hours/day on 82 days In 27 weeks (Leong et*
al., 1971).
Commercial or Industrial grade chloromethyl methyl ether vapor did not
produce; iVgnlBcaatl^ I'ncrea&eif/ trifcVdeiice* or respiratortf system; tumors, fir
rats or hamsters exposed t"o 1 ppm (3;mg/m*)," £ hours/day, 5 days/week! for;.
life (Laskln et al., 1975), or In strain:A mice exposed, to 2" ppm (6.; mg/m3);^
& hours/day, 5 days/week for 'TOT days; In 21 weeds' (Leeng-et »T.. 197T£.
EpTdem1oTogfca.T studies? of worker's exposed; to'. bts;('chTor,oroe£hyl| ether, and"
chloromethyl methyl ether have demonstrated exposure-related occurrence ofv
lung tumors, predominantly small cell undlfferentlated or oat-cell carcinoma
0044d 8-1 07'/08/87"
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(see Section 6.2.1.1.)- Because Industrial grade chloromethyl methyl ether
contains carcinogenic bls(chloromethyl) ether as a contaminant, and because
there 1s Insufficient ep1dem1olog1cal evidence to separate the carcinogenic
effects of these compounds, there 1s sufficient evidence to conclude that
bls(chloromethyl) ether and technical grade chloromethyl methyl ether are
human carcinogens (IARC, 1979; U.S. EPA, 1980b).
8.1.2. Oral. The cardnogenlcHy of b1s(2-chloroethyl) ether and
b1s(2-chloro-l-methylethyl) ether has been evaluated 1n oral administration
studies.
Dally Intubation with commercial grade b1s(2-chloroethyl) ether at a
dose of 100 mg/kg on days 7-28 of life, followed by administration 1n the
diet at a concentration of 300 ppm for the next 76 weeks produced signifi-
cantly Increased Incidences of hepatomas In male and female B6C3F1 mice and
male B6AKF1 mice (BRL, 1968; Innes et.al., 1969) (see Section 6.2.2.); the
TWA dose Is 41.3 mg/kg/day. Twice weekly administration of 100X pure
b1s(2-chloroethyl) ether by gavage at doses of 25 or 50 mg/kg for 78 weeks,
followed by a 26-week observation period, was not carcinogenic In male or
female Charles RIverCD rats (Welsburger et a*., 1981).
CardnogenlcHy bloassays of technical grade b1s(2-chloro-l-methylethyl)
ether were conducted In which groups of 50 F344 rats/sex (NCI, 1979) and 50
B6C3F1 mice/sex (NTP, 1982), were treated by^ gavag* at doses of> 1!(H£ w 200T
. S rfay.s/week for 103: weeks. The,VtechnrYcal grade chemical was -70X
%, Z^TTfZ^hlorQpr,o,p,y:l) e.yier and 2%
ethef. The-rat?were; observed for^T-2-weeks follow-
ing treatment. Increased ; Incidences iof. tumors did /no.t'occur xln any;,of- the
treatment groups; the low survival rate significantly decreased the
Incidence of male and female high-dose rats at risk for development of late
0044d 8-2 07/08/87
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appearing tumors. The mice, observed for 1-7 weeks following treatment,
developed significantly Increased Incidences of alveolar/bronchlolar
adenomas (both sexes) and hepatocellular carcinomas (males) {see Table
6-5). A low nonstatlstlcally significant Incidence of squamous cell
paplllomas or carcinomas In the stomach or forestomach of the high-dose
female mice was also observed. Stomach tumors In B6C3F1 mice were rare;
therefore, occurrence of tumors was probably treatment-related. Dietary
administration of high purity (98.554) b1s(2-chloro-l-methylethyl) ether was
not carcinogenic to SPF-ICR mice (MltsumoM et al., 1979). In this study,
groups of 56 mice/sex were treated at dietary levels of 80, 400, 2000 or
10,000 ppm for durations as long as 104 weeks. The average dally Intake of
chemical by the 10,000 ppm group was higher (961 mg/kg/day by males, 927
mg/kg/day by females) than that given to the mice In the NTP (1982) bloassay.
8.1.3. Other Routes. The cardnogenlclty of numerous chloroethers has
been evaluated In dermal application, dermal Initiation-promotion, sub-
cutaneous Injection and 1ntraper1toneal Injection studies. Most of these
studies were conducted by Van Duuren et al. (1968, 1969, 1971, 1972, 1974,
1975), who administered the compounds thrice weekly (dermal studies) or once
weekly (Injection studies) to mice for life. As detailed 1n Section 6.2.3.
and Tables 6-7 to 6-10, bls(chloromethyl) ether was tumorlgenk In all of
the aforementioned types of studies. Including mouse skin assays In which
b;t's;fchToromethyT) ether; was" active as; an Initiator or promoter. T,2-bTs>
(ChToromethoxy)ethane' and 1,2,3-tr1s(;cnloromethoxy.)pr;opane: were tumorlgenlc
In? dermal application, subcutaneous. Injection- and'.Intraperltorteal Inrjec-
tl'on, studies1.. ChTorcmiethyiT methyl; ether, K1is:;(:a-cMoroeth-y,T)y ether aredr
1,2,3-trVs {chloromethoxyyproparre^werev tumorIgerrtcvby subcutaneous ffffeetlorr.
8-3 07/08/87
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8.1.4. Weight of Evidence. Inhalation exposure to bls(chloromethyl)
ether and commercial chloromethyl methyl ether Is associated with the
Induction of lung tumors In humans (see Section 6.2.1.), and Inhalation of
bls(chloromethyl) ether has produced nasal and lung tumors 1n rats and mice
(Leong et al., 1981; Kuschner et al., 1975; Dulak and Snyder, 1980). Since
IARC (1979) and U.S. EPA (1980b) have concluded that bls(chloromethyl) ether
and technical grade chloromethyl methyl ether are human carcinogens (see
Section 8.1.1.). the appropriate U.S. EPA (1986b) classification for these
chemicals 1s Group A - human carcinogen.
Commercial grade b1s(2-chloroethyl) ether produced Increased Incidences
of hepatomas 1n two strains of mice when administered orally (BRL, 1968;
Innes et al., 1969), but 100% pure b1s(2-chloroethyl) ether was not
carcinogenic 1n rats when administered by gavage (Welsburger et al., 1981).
Although hepatomas In mice often occur spontaneously and are difficult to
classify, the high Incidences and occurrence 1n two strains and sexes
Indicate that the hepatomas 1n the BRL (1968) and Innes et al. (1969)
studies were treatment-related and the. animal data constitute sufficient
evidence for carc1nogen1c1ty. On the basis :of these data supplemented by
predominantly positive responses In mutagenldty assays and because human
data are lacking, b1s(2-chloroethyl) ether 1s most appropriately classified
1n EPA Group 82 - probable human carcinogen. ;,
Ch'ronte,gavtfge?arimltotfstratfait of, coraraericVal grade" £-TOX$; BtfsfZ^-ehToro-
ethfer was- not tumoriTgwfcl In' F:3$4". rafti; af either sex (NCL;
^Q
-------
Chronic dietary administration of high purity (98.5%) b1s(2-chloro-l-
methylethyl) ether was not tumorlgenlc to SPF-ICR mice (MHsumorl et al.,
1979). Although there Is evidence of carc1nogen1dty 1n B6C3F1 mice (NTP,
1982), the effect cannot be attributed definitely to b1s(2-chloro-l-
methylethyl) ether because 1t cannot be determined If H 1s due to compound
Impurity or mouse strain sensitivity. The evidence for carc1nogen1c1ty 1n
animals Is best considered limited. Since there are no human data,
b1s(2-chloro-l-methylethyl) ether 1s classified 1n EPA Group C - possible
human carcinogen.
The other chloroethers that are the subject of this report should be
classified 1n EPA Group D - not classifiable as to human cardnogenlclty.
Although 1,2-b1s(chloromethoxy)ethane, 1,2,3-tr1s(chloromethoxy)propane and
bls(a-chloroethyl) ether were tumorlgenlc 1n dermal, subcutaneous and
IntraperHoneal administration 1n mice, overall evidence for carclnogenldty
of these compounds 1n animals 1s best considered Inadequate. Other chloro-
ethers yielded negative results In these specialized tests and still others
have not been tested.
8.1.5. Quantitative Risk Estimates.
8.1.5.1. INHALATION — b1s(Chloromethyl) ether and commercial chloro-
methyl methyl ether are recognized as human respiratory carcinogens, but
data suitable for, quantitative risk estimation are available only, for bis-
(chloromethy.T):' ether {:see Section 6.2..K)/. * The; most appropriate basts for
derivation of a q,* for Inhalation exposure Is the study by Leong e,t al.
fcl 9.8.1. U: 1n which, exposure1 to 100. ppb (,4?& jtg/mai bistchloronethyl} ethers
vapovr, 6- hours/day., 5, days/weeK for & months produced; nose es.thestoneuro-
epHheTlomas 1n 96/T1T rats (see Tab'Te .6-2)'. t, Respiratory .tract :tumorsv
Including esthesloneuroeplthellomas and lung carcinomas, also were produced
00440* 8-5 . 07/08/87'
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1n Sprague-Oawley rats exposed to 0.1 ppm (0.5 mg/m3) bls(chloromethyl)
ether, 6 hours/day, 5 days/week for 10-100 exposure (Kuschner et al., 1975)
(see Table 6-3). This study provides a less adequate basis than the Leong
et al. (1981) study for calculation of a q,* because treatment duration
was variable and shorter (20 weeks maximum), a single exposure level was
used, tumor Incidences were lower (particularly when not pooled), and
control group Incidences were not reported. Respiratory tract tumors also
were Induced In Sprague-Dawley rats exposed to 0.1 ppm, 6 hours/day, 5
days/week for 30 exposures (Dulak and Snyder, 1980), but this report Is
limited by Inadequate reporting and most of the deficiencies associated with
the Kuschner et al. (1975) study.
To derive the Inhalation q * from the Leong et al. (1981) study, the
exposure concentrations of 0, 1, 10 and 100 ppb (0, 5, 47 and 470 yg/m3)
are adjusted to continuous concentrations by multiplying by the proportion
of dally exposure (6 hours/24 hours) and weekly exposure (5 days/7 days).
The contlauous concentrations are transformed to mg/kg/day doses of 0,
0.0002, 0.0023 and. 0.0345 by multiplying by the reference rat Inhalation
rate (0.223 mVday), dividing by reference rat body weight (0.35 kg) and
adjusting for average dally dose over the experimental period by multiplying
by the ratio of treatment duration to experiment duration (6 months/28
months except 6 months/19 months. 1n the high-dose group). .Using the
transformed; s doses; wlit'nJ the, corresponding- 'esthesVoneurdepftheXfamSr-' tumor:
incidence*' and the comp,u.ter1z,«l muTtt stage model ^eyeTop-edfby Howe and1 Crump:
the* aaadi'ttstwt <> I*. cafcutete* SOK, He KQAa<; fog/kg/day T1
(Appendix BT)v The human qw=*y which ~1sr c&TouJated^btf multiplying,
unadjusted q^ by the cutfe root aft; ttfe>: ratttr oft assumed"' human1 body ^weight '
(70 kg) to assumed rat body weight (0.35 kg), Is 59.5 (mg/kg/day)'1. If
It Is assumed that humans we-lgh 70 kg and Inhale. 20 m3/day;of a1r,.the;
0044d . 8-6 x 07/08/87
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concentrations of bls(chloromethyl) ether 1n air associated with Increased
lifetime risk of cancer at risk levels of 10~5, 10~6 and 10~7 are
5.9xlO~7, 5.9xlO~8 and 5.9xlO~9 mg/m3, respectively.
A q * for Inhalation exposure to b1s(2-chloroethyl) ether can be
calculated from the oral q * (Section 8.1.5.2.) by assuming equal potency
by both routes. Since appropriate pharmacoklnetlc data are not available,
1t can be assumed that absorption by the Inhalation and oral routes 1s 50
and 10054, respectively. Multiplication of the oral q * of 2.46
(mg/kg/dayr1, derived from the BRL (1968) and Innes et al. (1969)
studies, by the ratio of the percentage absorption by the Inhalation route
to the percentage absorption by the oral route gives an Inhalation q,* of
1.23 {mg/kg/day)"1. If 1t Is assumed that humans weigh 70 kg and Inhale
20 mVday of air, the concentrations of b1s(2-chloroethyl) ether In air
associated with Increased lifetime risk of cancer at risk levels of 10~s,
10"* and 10~7 are 2.8xlO"5, 2.8xlO~6 and 2.8xlO"7 mg/m3,
respectively.
A q.* for Inhalation exposure to technical b1s(2-chloro-l-methylethyl)
ether can be calculated from the oral q,* (Section 8.1.5.2.) using the *
same approach as for b1s(2-chloroethyl) ether. Multiplication of the* oral
q.j* of 6.97xlO"2 (mg/kg/day)"1, derived from the NTP (1982) study, by
the ratio of assumed percentage of absorption by, the tnhalatVon route: (50%),
to assumed percentage of absorption by. the oral route (100%), gives an
inhalation q* of 3.49xlO~2 (mg/kg/day)"1. If H- 1s assumed that
humans weigh 70 kg and inhale 20 mVday of air, the concentrations of
b1s('2-chloro-l-me.thylethyl). ether Vn: air associated with an increased;-
lifetime risk of cancer ' at rtsk -levels of TOT*. T0~* and TO"7, are
l.OxlO"3, l.OxlO"4 and l.OxlO"5 mg/m3, respectively.
8-7 07/08/87
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8.1.5.2. ORAL — Oral cardnogenldty data are not available for
bls(chloromethyl) ether or chloromethyl methyl ether, which are recognized
as carcinogenic for humans by Inhalation. It Is possible to use the q *
for Inhalation exposure to b1s(chloromethyl) ether (see Section 8.1.5.1.) as
the oral q.*, however, by assuming equal potency by both routes and recog-
nizing the mode of carcinogenic action. The Induction of nasal epithelial
tumors (esthesloneuroepHhellomas) by Inhalation Indicates that b1s(chloro-
methyl) ether 1s a contact carcinogen that exerts Its effects at the site of
contact Independent of systemic absorption. Since 1t 1s reasonable to
expect that bls(chloromethyl) ether may also be carcinogenic at the site of
exposure following oral administration, the Inhalation q * of 59.5
(mg/kg/day)~a can be adopted as the oral q * without adjustment for oral
absorption. If 1t 1s assumed that a 70 kg human consumes 2 I/day, the
concentrations of bls(chloromethyl). ether associated with Increased lifetime
risk of cancer at risk levels of 10~5, 10"6 and 10~7 are 5.9x10"*,
5..9xTO~7 and 5.9xlO~8 mg/i, -respectively. These levels cannot be used
for practical purposes, however, as rapid hydrolysis of bls(chloromethyl)
ether 1n water precludes exposure (U.S. EPA, 1980b).
The U.S. EPA (1980b) ambient water quality criterion for b1s(chloro-
methyl) ether, however, Is based on a q * of 9299.8 (mg/kg/day)"1,
calculated from the, Kus.chner, et al. (1975) Inhalation study. As 4e:UVle4, in
Section 6'.:Z.T.,v rat's were.exposed ;-to .Oil- ppmy 6 hours/day, "5 .days/week for
TOVI.OO exposures. this. s?tudy w^lKnot; be.; usejd) fior, caiTcuTat:tan;a£ an. inhala-
fforr or-oraT .q"=* Because tfi* Le^g* *f'«T. PT981) stutfy-:Twh1ch was not
available- for ',considerafclorr by?,.Ul.S. ;:EPW. (IWOb^I used
-------
(1980b), as H Is reported that the rats were given 100 exposures of various
concentrations of bls(chloromethyl) ether rather than 10-100 exposures of a
single concentration. This statement Is consistent with the doses used In
the U.S. EPA (1980b) evaluation, but the origin of the doses, which was not
reported by Kuschner et al. (1975), was not Indicated. An exposure duration
of 728 days and an assumed tumor Incidence of 0/240 1n colony controls were
also used without explanation.
A q * for oral exposure to b1s(2-chloroethyl) ether can be based on
the Induction of hepatomas 1n mice that were treated by gavage at a dose of
100 mg/kg/day on days 7-28 of life, and subsequently 1n the diet at a con-
centration of 300 ppm- for the next 76 weeks (BRL, 1968; Innes et al.,
1969). If 1t 1s assumed that mouse food consumption Is equivalent to 1354 of
body weight/day, then the dosage during the dietary part of the study 1s 39
mg/kg/day and the TWA dosage for the entire study Is 41.3 mg/kg/day.- Using
this dosage, the hepatoma Incidence 1n the 66C3F1 strain males and the
computerized multistage model developed by Howe and Crump (1982), the
unadjusted q * Is calculated to be 8.14xlO~2 (mg/kg/day)'1 (Appendix
B2). This q,* may be somewhat conservative, . however, as the? number: of •
treated animals used 1n the calculation was relatively small. The human
q,* calculated by multiplying the unadjusted q,* by the cube root of the
ratVo of reference human body weight 170 kg) to reference mousfr; body weight
£07.0$ k"g;)and by t-fte. cube of the-. raWo oF. assumed mouse: Hfespan (T0'4 weeks):
to experiment duration (79 weeks); 1s 2.46 (mg/kg/day)'1. Assuming that a
70 kg human consumes 2 a/day, the concentrations' of t>T?f2-chToroethyl)
ether Vn drinking, water associated; with. Incr.eaisedv.VlfebVme rVstf o.f cancer a.t
risk levels of TO~V 10"«> antf TO"^ are 1.4xTO~4, 1.4xlO"5 land '
1.4xlO~7 mg/a, respectively.
0044d ' 8-9 07/08J/87 '
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U.S. EPA (1980b) used the same study (BRL, 1968; Innes et al., 1969) and
tumor Incidences used to calculate a human q * of 1.144 (mg/kg/day)'1
for b1s(2-chloroethyl) ether. This q * Is lower than the q * calculated
above because the U.S. EPA (1980b) computation used a different dose and a
Hfespan that was the same as the treatment/study duration (560 days), which
obviated the Hfespan correction. The dose used by U.S. EPA (1980b) was 39
mg/kg/day, which does not account for the period of gavage treatment.
Gavage administration of technical grade b1s(2-chloro-l-methylethyl)
ether at doses of 100 or 200 mg/kg, 5 days/week for 103 weeks produced
hepatocellular carcinomas or adenomas and alveolar/bronchlolar adenomas or
carcinomas 1n B6C3F1 mice (NTP, 1982) but was not tumorlgenlc In F344 rats
(NCI, 1979). Dietary administration of high purity (98.5%) b1s(2-chloro-l-
methylethyl) ether at concentrations of 80-10,000 ppm (927 or 961 mg/kg/day
at the high dose) for 104 weeks was not tumorlgenlc 1n SPF-ICR mice
(Mltsumorl et al., 1979). Since 1t Is probable that most human exposure to
b1s(2-chloro-l-methylethyl) ether 1s to; technical grade compound, 1t Is
appropriate to use the NTP (1982) carc1nogen1c1ty data to derive an oral
q * Using doses adjusted for partial weekly exposure, the liver hepato-
cellular adenomas or carcinomas 1n the male mice and the computerized
multistage model developed by Howe and Crump (1982), the unadjusted q * 1s
calculated to be 5.78jclO~3 (mg/kg/day)"1 (Appendix B31-, The human; q,.*-
calculated* by; mu-Ttfprl-y^ng the unadjusted- cu**v by tfter cttte, roat of the; ratio-
of reference; human bo'dy wel'ght (70' k;g)~ to eitf ma ted. average,, mouse/ body
wetgtrt'.|0,0^ feg),/ rr fr,97xia"» (ing/kg/dayr*. ' Assuming ttttt a TO kg
human; consumes 2 I/day, the concentrations o'fi .technical b1s|2>chTona~W
methylethyl) ether In drinking water associated wTth 'Increased lifetime
-------
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) -- Mortality and
hlstopathologlc lesions of the respiratory epithelium were observed 1n rats
exposed to chloromethyl methyl ether at 1 or 10 ppm (3 or 33 mg/m3), prob-
ably for 6 or 7 hours/day for 30 days (Drew et al., 1975). High mortality
was also observed 1n rats and hamsters exposed to bls(chloromethyl) ether at
1 ppm (5. mg/m3), 6 hours/day for up to 30 days (Drew et al., 1975).
Hyperplasla and metaplasia with atypical appearance of the nuclei were
observed 1n tracheal and bronchial epithelium In the rats and hamsters
exposed to bls(chloromethyl) ether. Gage (1970) exposed rats to b1s(2-
chloro-1-methylethyl) ether at 20 or 70 ppm (140-490 mg/m3), 6 hours/day,
5 days/week for 4 weeks. Exposure to 70 ppm was associated with lethargy
and reduced body weight gain, but there were no effects on hematology,
urlnalysls or gross or microscopic pathology. There were no effects at 20
ppm. RfDs for subchronlc Inhalation exposure to these chloroethers will not
be derived because they have been shown to be carcinogenic.
8.2.1.2.. CHRONIC EXPOSURES — Leong et al. (1981) exposed male rats
and mice by Inhalation to bls(chloromethyl) ether at 0, 1, 10 or 100 ppb (0,
5, 47 or 470 vg/m3), 6 hours/day, 5 days/week for 6 months with lifetime
observation. High concentration group rats had Increased mortality
attributed to tumor development. There appeared to be no significant non-
neoplastlc hlstopathologlc effects and no effects on; hematology. No effects
were reported tn mice.
In a, lifetime exposure study,. Laskln- et a.!.; {1.9,75)" exposed male,, rats and^
hamsters to chloromethyl methyl ether at 1 ppm (3 mg/m3), 6 hours/day, 5
days/week. The Incidence of metaplastlc or hyperplastlc lesions In the
ep1.thel1um of various segments of the respiratory- tract appeared ., to be
0044d 8-11 07/08/87
-------
Increased In both species compared with controls. Because both b1s(chloro-
methyl) ether and chloromethyl methyl ether are EPA Group A carcinogens, no
attempt Is made to calculate RfDs for chronic Inhalation exposure to these
compounds.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) — NCI (1979)
administered b1s(2-chloro-l-methylethyl) ether by gavage to rats at 0, 10,
25, 50, 100 or 250 mg/kg, 7 days/week for 13 weeks. There were no effects
on survival, gross or hlstopathologlcal appearance at any dosages. High-
dose males had a hunched or thin appearance and occasional urine stains. In
an Identical study using mice (NTP, 1982), focal pneumonltis occurred at >50
mg/kg. Because b1s(2-chloro-l-methylethyl) ether Is carcinogenic, no RfD
will be derived for subchronlc oral exposure to this chemical.
Groups of five rats/sex (unspecified strain) were treated with
2,4,4'-tr1chloro-2'-hydroxyd1phenyl ether 1n gum arable by gavage at doses
of 0, 5.0V 100, 200, 500 or 1000 mg/kg, 6 days/week for 4 weeks (Lyman and
Furla, 1969). Mortality -(2/10 rats) and slightly reduced weight gain (not
quantified) reportedly occurred at 0000 mg/kg'. Unspecified? hfcto^oglca;!'
examinations and unspecified blood and urine analyses were unremarkable 1n
all of the treatment groups. Although this study 1s limited by undetailed
report 1 ng,,,*ho*t> duration aiiut.anSyFT? grou& s^t«sj,, fft cast fei used? *r the1:bases,
o£ a suttchrontc' RfDV for 2v4,4:t-tr1chlora-2l^hydroxyd1phenyl ether. The
htfgttestl NGE.U. Vs. 500 mg/kg, whichsTs,;. eqUjtyalent .to 429, tng/kg/day when multi-
plied by 6 tf*y$/7days --ttfadjust' for' part'tolweekly exposure. Dit-VHVoft of
the adjusted NOElr by an^ uncertainty factor of AvTOO' (10 for farters'pec-fesv
extrapolation and TO to* protect the*most sensitive humans") gives an RfD for
subchronlc exposure of 4 mg/kg/day, or 300 mg/day for a 70 kg human.
0044d: 8-12 ^ 07/08/87
-------
Although adequate parameters appear to have been evaluated 1n this study,
confidence 1n the RfD should be regarded as low because the study was short
and limited In scope. In addition, only a factor of 2 exists between the
NOEL and a dosage associated with mortality.
8.2.2.2. CHRONIC EXPOSURES — Welsburger et al. (1981) administered
b1s(2-chloroethyl) ether to rats by gavage at 25 or 50 mg/kg, twice weekly
for 78 weeks, followed by a 26-week observation period. Mean body weights
were reduced 1n treated females and high-dose males, and Increased mortality
occurred 1n high-dose females.
Chronic cancer experiments were conducted with rats (NCI, 1979) and mice
(NTP, 1982) 1n which b1s(2-chloro-l-methylethyl) ether was administered by
gavage at 0, 100 or 200 mg/kg, 5 days/week for 103-105 weeks. Survival was
reduced In high-dose male rats and both treated groups of female rats.
High-dose rats of both sexes had esophageal lesions and high-dose male rats
had centrllobular liver necrosis. There were no effects on survival of
mice. The only nonneoplastlc lesions In mice occurred 1n both treated
groups of males and Included fatty changes and chronic Inflammation of the
nasal epithelium. ; Because b1s(2-chloroethyl) ether and b1s(2-chlor-o^l;--
methylethyl) ether are carcinogens, RfDs will not be calculated for chronic
oral exposure to these compounds.
The Lymin and Furt* fl969>}' gavage studx with rats was used as the- basis
for calcuTtfflon of an: Rffffor•• s-ubc.hr on Tc oraT'exposure to- 2,"4,4!-tr1chloro--
2'-hydroxyd1phenyl ether (see Section 8.2.2.1.); however,, given the Inade-
quate study duration (4 weefcsj, 1t Is inappropriate'to use.v the NOEL from-*
this study to calculate,, an RfD ""fair chromic oral exposurev:
0044d 8-13' OT/08/8T
-------
9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
The Inhalation and oral toxldty of bls(chloromethyl) ether, chloro-
methyl methyl ether, b1s(2-chloroethyl) ether, b1s(2-chloro-l-methylethyl)
ether and 2,4,4'-tr1chloro-2'-hydroxyd1phenyl ether are discussed 1n
Sections 6.1.1. and 6.1.2., and dose-response data for these chemicals are
summarized 1n Table 9-1.
Inhalation exposure to b1s(chloromethyl) ether at a concentration of 1
ppm, 6 hours/day for 30 days caused mortality and bronchial hyperplasla and
metaplasia with atypla 1n rats and hamsters (Drew et al., 1975). Rats
exposed by Inhalation to 100 ppb b1s(chloromethyl) ether, 6 hours/day, 5
days/week for 6 months died from nasal tumors (Leong et al., 1981). The
subchronlc data are Inappropriate for derivation of an RQ because the
chronic data Indicate that the. hyperplasla and metaplasia are likely to be
preneoplastlc alterations, and because division of the subchronlc equivalent
human doses by an uncertainty factor of 10 (to approximate chronic exposure)
gives the same equivalent human dose as that associated with the carcino-
genic response 1n the Leong et al. (1981) study. Adequate data for the
derivation of a toxlclty-based RQ for bls(chloromethyl) ether are therefore
not available (Table 9-2).
Chronic (Laskln et al., 1975) and subchronlc (Drew et al., 1975), Inhala-
tion; studies wtth -ra-ts prav-Tde toxTclty data for.:xhTorometnyt methyl, ether.
Chronic exposure produced squamous metaplasia 1n the' trachea and bronchial
hyperplasla; at an equivalent human dose of Q..Q5- mg/kg/day :• (-s.ee Table-9-1)..
S.1m,1lar trachea1!, and. bronchial h1:stolog1,c4T alterations and mortality were
associated with subchronlc exposures ta- .a>TO-foW'. higher cancentrattom of
chloromethyl methyl ether. Although the most severe effect was mortality
0045;d: 9-1 05/29/87
-------
TABLE 9-1
loxlclty Summary for Chloroethers
en
Q.
10
1
ro
05/29/8
Chemical/Vehicle/
Purity
bls(Chlpromethyl)
ether/air/NP
Chloromethyl methyl
ether/alr/NB
Chlororaethyl methyl
ether/air /commer-
cial grade
b1s(2-Chloroethyl)
ether/SSy/lOOX
b1s(2-Chloro-l-
methylejhyl) ether/
alr/NR' ;
bts(2-Chloro-l-
methylethyl) ether/
corn p^l/technlcal
grade* "'' ' '.
Route
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
oral
(gavage)
Inhalation
oral
(gavage)
oral
(gajrage)
Species/. No. at
Strain/Sex Start
rat/Sprague, 50
Dawley/N .'
hamster/ 50
Syrlan/N
rat/SPf 120
Sprague-Dawley
Spartan/M
rat/Sprague- 25
Dawley/H
rat/Sprague- 74
Oawley/M
rat/Charles 26/sex
illyer.CD/M.f
'--?' "is, •
rat/SPf 4/sex
Park/M.f
rat/F344/M.f 10/sex
j :M- '. • " ;- .;'"•
r,al/F344/N,£ 50/sex
Avera'ge
Body
Weight
(kg)
.. *•*
0.35b
0.1 4b
0.35b
0.35b
0.35b
0.35b
0.35b
0.35b
0.20 (F)f
Exposure Transformed
Animal Dose
(mg/kg/day)
1 ppm (5 mg/m1) 0.8C
6 hours/day for
30 days
1 ppm (5 mg/m') 1.2C
6 hours/day for
30 days
100 ppb (0.47 0.05C
rag/re"), 6 hours/
day, 5 days/week
for 6 months
1 ppm (3 mg/m»). 0.5C
6-7 hours/day for
30 days
1 ppm (3 mg/m»). 0.3e
6 hours/day, 5
days/week for life
50 ing/kg, twice 14
weekly for 78
weeks
70 ppm (490 55.8
mg/m"), 6 hours/
day, 5 days/week
for 4 weeks
250 ng/kg/day. 7 250
days/week for 13
weeks
100 rag/kg, 5 71.4
days/week .for
103-105 weeks
Equivalent
Human Dose3
(mg/kg/day)
0.01d
0.02d
0.01
0.009d
0.05
2.4
0.954d
4.3d
10.1
Response
Mortality, tracheal and
bronchial hyperplasla
and metaplasia with
atypla
Same as above
Mortality resulting
from nasal tumor
development
Mortality, minimal
tracheal /bronchial
hyperplasla or meta-
plasia
Tracheal squamous meta-
plasia and bronchial
hyperplasla
Mortality and decreased
body weight gain In the
females
Reduced weight gain
and lethargy
Reduced weight gain In
males
Reduced weight gain In
both sexes, decreased
survival In females
Reference
Drew et al.
1975
Drew et al.
1975
t
•
Leong
et al.. 1981
Drew et al.
1975
»
Laskln
et al.. 1975
Welsburger
et al.. 1981
Gage. 1970
NCI. 1979
NCI. 1979
-------
TABLE 9-1 (cent.)
W *rr—
o
ex Chemical/Vehicle/
Purity
bls(2-Ch)oro-l-
methylethyl) ether/
olive oIl/NR
bts(2-Chloro-l-
Rp.ule
oral
Species/
Straln/Seii
rat/NR/NR
Average
No. at Body " Exposure
Start Weight
(kg)
NR 0.35b 10 rog/kg. 22
Transformed
Animal Dose
(mg/kg/day)
7.1
Equivalent
Human Oosea
(mg/kg/day)
Response
O.ld Decreased
growth rate
(gavage) doses In 31 days
ora)
methylethyl) ether/(gavage)
corn oil/technical
grade* ..-. '
^ ,*
"\
oral
( gavage |
mouse/
B6C3F1/M
mouse/
B6C3F1/M.F
10/sex 0.03 (N)b SO mg/kg/day.
days/week for
weeks
50/sex 0.04 (M)f 100 mg/kg/day
days /week for
7 50
13
. 5 71.4
103
0.38d Focal
5.92 Fatty
liver
pneuroonltls
metamorphosis of
In
males
Reference
Dow
Chemical.
n.d.
NTP,
NTP.
1982
1982
bls(2-Chloro-l- oral
raethylethyl) ether/ (gavage)
NR/NR -•• .:'•'"
05
I
weeks
npuse/NR/N.f NR 0.03b 10 rog/kg. 5
'" days/week for
728 days
mouse/SPF-ICR/ 56/sex 0.04|F)f 2000 ppm for
7.1 0.5 Centrllobular necrosis NCI. 19789
of liver In both sexes
194h 16.1 Reduced weight gain. Hltsumort
methylethyl) ether/
diet/98. SX
2,4.4'-Tr1chloro-
2' -hydroxydlphenyl
ether/gun arablc/>97X
ora|
(gavage)
H.F
rat/NR/H.F 5/sex 0.35b
104 weeks
1000 rog/kg
days/week
weeks
. 6 857.1 1'
for 4
anemia, polychromatic
erythrocytes In females
*.7d Mortality and reduced
weight gain
et al.. 1979
lyman and
Furla. 1969
00
dCalcu1ated by multiplying the animal transformed dose by the cube root of the ratio of the animal body weight to the human body weight.
"Reference body weight (U.|, EPA, 1985)
^Calculated by multiplying the concentration by the number of hours/day, number of exposures/duration of study and by the animal dally Inhalation rate and
by dividing by the animal.body weight. Inhalation rates of 0.223 nVday for rats and 0.131 a*/day for hamsters were used.
dThe dose was "divided by an uncertainty factor of 10 to approximate chronic exposure.
e~70X pure as detailed If) Section 6.2.2
fEstimated froa growth CMrye
^Unpublished data sunroarlzed by U.S. EPA (1980b)
"Intake estimated by Investigators
NR = Not reported
-------
TABLE 9-2
bls(Chloromethyl) Ether
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route:
Dose:
Effect:
Reference:
RVd:
RVe:.
Comppslte Score:
RQ: -t. Data ararnot sufficient for deriving an;RQ
Off45d}. 9^4'*.* 05/29/87
-------
resulting from the subchronlc exposure, this 1s an inappropriate basis for
derivation of an RQ because mortality 1s an acute affect and because
adequate chronic data are available. Therefore, 0.05 mg/kg/day represents a
MED for tracheal and bronchial alterations. Multiplication of this dose by
70 kg yields a human MED of 3.5 mg/day (Table 9-3). The RVd corresponding
to the human MED 1s 4.7. The most appropriate RV for the more severe
respiratory tract alteration, squamous metaplasia of the trachea, 1s 7.
Multiplication of the RVrf and the RV gives a CS of 32.9, which corre-
sponds to an RQ of 100 (Table 9-4). A CS of 30.4 was calculated by the U.S.
EPA (1983b) using earlier methodology 1n which the human MED was calculated
by assuming equivalent absorbed doses among species.
Twice weekly gavage administration of 50 mg/kg b1s(2-chloroethyl) ether
for up to 78 weeks caused treatment-related mortality 1n rats (Helsburger et
al., 1981). The equivalent human dose 1s 2.4 mg/kg/day (see Table 9-1) and
the human MED 1s 168 mg/day (see Table 9-3). Multiplication of the RVg
for this MED (2.2) and the RVg for mortality (10) results In a CS of 22,
which corresponds to an RQ of 100 (Table 9-5).
Several subchronlc and chronic oral studies provide toxldty data for
b1s(2-chloro-l-methylethyl) ether 1n rats and mice (see Table 9-1). Sub-
chronic Inhalation toxlclty data for rats are also available (Gage, 1970).
The most suitable bases for possible RQ derivation are the chronic studVes
because- of the1 more appropriate treatment durations and more severe effects-;
The primary effect Identified tn the subcnronic studies with rats (NCI,
19.75; Dow Chemical, .n.d.). V* decreased! growth. Focal pneumonttVs occurred
ttr mice; as: a resuTt of daily- subchroniiog.avage: treatment (rNTP*. t982)>
Chronic gavage treatment with technical grade compound caused decreased
survival In rats (NCI, 1979) at an equivalent human dose of 10.1 mg/kg/day
0045d 9-5 07/08/87
-------
o
o
tn
o.
TABLE 9-3
Composite Scores for Chloroethers
Chemical
Chloromefhyl methyl
ether .
b1s(2-Chlo>oethyl)
ether '"^ >"
b1s(2-Chloro-l-
roethyle'thyl) ether*1
bls(2-Ch)oro-l-
methyletjjyl) ether**
bls(2-Chloro-l-
raethylethyl) ether*
2.4.4|-lr»«:hloro-
2'-hydroi(ydlphenyl
etljgr , ]'"'•'-
^ ^^ s<
Route
Inhalation
oral
&*
ocal
oral
oral
• f-
oral
<*' * '• ;~
Species Animal Dose
, :-'^ (mg/kg/day)
rat 0.3
) * *
ral 14
**•?-
rat 71.4
mouse 71.4
mouse 194
rat 857.1
' * h
Chronic
Human MED^ RVd Effect RVe
(mg/day)
3.5 4.7 squamous metaplasia of 7
the trachea
168 2.2 mortality 10
.......
707 1.2 mortality 10
414 -- 1.6 fatty metamorphosis In 5
the liver
1127 1 anemia, polychromatic 5
erythrocytes. reduced
weight gain
1029 1 mortality 10
CS RQ Reference
32.9 100 Laskln
et al.. 1975
22 100 Welsburger
et al.. 1981
12.0 1000 NCI. 1979
8 1000 NTP. 1982
5 5000 Nltsuroorl
et al.. 1979
10 1000 Lyman and
Furla. 1969
dOer|yed by multiplying the equivalent human dose expressed In terms of mg/kg/day In Table 9-1 by 70 kg to express the chronic human NED In
terjis of rag/day for 4 70 kg human.
blec|;nlcal grade (-7QJI p.ure) ;• ••*-••-•>•-
£9fl.5X pure
o
00
-------
TABLE 9-4
Chloromethyl Methyl Ether
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: Inhalation
Dose3: 3.5 mg/day
Effect: squamous metaplasia of the trachea
Reference: Laskln et al., 1975
RVd: 4.7
RVe: 7
Composite Score: 32.9b
RQ: 100
Equivalent human dose
bA composite score of 30.4 was calculated by U.S. EPA (1983b) using
different, methodology »t '
00*5d y-7 07/08/87
-------
TABLE 9-5
b1s(2-Chloroethyl) Ether
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route:
Dose*:
Effect:
Reference:
RVd:
RVe:
Composite Score:
oral
168 mg/day
mortality
Welsburger et al., 1981
2.2
10
22
100
*E'qv#v*Tertfc human;
0045d-
$-fl!'-':
05729/87
-------
(see Table 9-1). The human MED Is 707 mg/day, the RVd Is 1.2, the RVg
for life shortening 1s 10 and the CS 1s 12 (see Table 9-3). Chronic gavage
treatment with technical grade compound produced fatty metamorphosis In the
livers of mice (NTP, 1982) at an equivalent human dose of 5.92 mg/kg/day
(see Table 9-1). The human MED 1s 414 mg/day, the RVd 1s 1.6, the RVg
for fatty alterations Is 5 and the CS Is 8 (see Table 9-3). Unpublished NCI
(1978) data reported by the U.S. EPA (1980b) showed that chronic exposure
produced centrllobular necrosis 1n mice at a lower equivalent human dose
(0.5 mg/kg/day) than the one producing fatty metamorphosis, but this Is an
Inappropriate basis for RQ derivation because of apparent data Inadequacies
(see Section 6.1.2.2.). Chronic dietary administration of high purity
b1s(2-chloro-l-methylethyl) ether caused reduced weight gain and effects
Indicative of erythrocyte destruction 1n mice (M1tsumor1 et al., 1979) at an
equivalent human dose of 16.1 mg/kg/day (see Table 9-1). These effects are
consistent with an RV of 5 (reversible cellular changes) because the
erythrocyte alterations were most prevalent during the first half of the
study (see Section 6.1.2.2.). The CS derived from the HHsumorl et al.
(1'9X9) data 1s 5.0 (see Table 9-3). The NCI (1979) tox1c1ty data, there-
fore, are the most appropriate basis for the RQ because they yield the
highest CS (12.0), which corresponds to an RQ of 1000 (Table 9-6). The
derivation of this RQ 4s VdervUcal tor thatprevlou&YY; reported b&lLS/. EPAr
(;T983c%
Subchronlc. gavage administration of 2,4t4':-trTchToro-2l-hydroxyd1pheny,t
ether produced reduced weight gain and some mortality 1n rats at an equiva-
lent human, dose at 14.7; mg/kg/day when adjusted to approximate chronlt
exposure with an uncertainty facto'r of*' TO (Lyman and FuMa, 1969)" (see Table
9-1). This study 1s limited by small group sizes, short treatment duration
and undetailed reporting but can be used to calculate an RQ./; The human MED
0045tf 9-9 07/08/87
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TABLE 9-6
b1s(2-Chloro-l-methylethyl) Ether
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route:
Dose*:
Effect:
Reference:
RVd:
RVe:
Composite Score:
RQ:.
oral
707 mg/day
mortality
NCI, 1979
1.2
10
12
1000
*Bqiu.ttai-1ertt human dose
0045d
9-10
05/29V87
-------
1s 1029 mg/day, the RVd Is 1, the RVg associated with mortality Is 10
and the CS Is 10 {see Table 9-3), which corresponds to an RQ of 1000
(Table 9-7).
9.2. BASED ON CARCINOGENICITY
Inhalation exposure to b1s(chloromethyl) ether and commercial chloro-
methyl methyl ether 1s associated with the Induction of lung tumors In
humans (see Section 6.2.1.), and Inhalation of bls(chloromethyl) ether has
produced nasal and lung tumors 1n rats and mice (Leong et al., 1981;
Kuschner et al., 1975; Dulak and Snyder, 1980) (see Section 6.2.1. and
Tables 6-2 and 6-3). These data are sufficient to classify b1s(chloro-
methyl) ether and commercial chloromethyl methyl ether In EPA Group A (see
Section 8.1.4.). Although both these haloethers are recognized as carcino-
gens, suitable data for quantitative risk estimation are available only for
bls(chloromethyl) ether.
Using the reasoning applied 1n the derivation of a q,* (see Section
8.1.5.1.), the most appropriate basis for calculation of an F Factor for
bls(chloromethyl) ether 1s the study of Leong et al. (1981) 1n which
exposure to 100 ppb vapor, 6 hours/day, 5 days/week for 6 months produced
nasal esthesloneuroepHhellomas 1n 96/111 mice (see Table 6-2). To derive
the F factor, the exposure concentrations of 0, 1, 10 and 100 ppb are trans-
formed; to, doses/ of Q*. (UQQftl, 0.00-11 and a.OV69 mg/kg^/(Uyy 4v detaVTe* in:
Secttbrr ff.T.5'.?. Usrttog' ttfeste dose* wTtif' the--corresponding esthes 1-one.uro-
ep.tthelloma tumor Incidences and the computerized multistage !modeT .developed
by. Howe and Crump ^1982), the ^unadjusted 1/E01(J t? caTcuTated to be' 15*
(mg/kg/dayrr (Table :9:-8;)'. Th:e. adjusted^ l/Ettjg,(,F Factor) caTcuIa;ted; by.-,
multlplylng the unadjusted 1/ED,0 byvthe.cube root of the ra'tlo of assumed
human body weight (70 kg) to assumed mouse body weight (0.03 kg), Is 924
0045d ' 9-11 07/08/87
-------
TABLE 9-7
2,4,4'-Tr1chloro-2'-hydroxyd1phenyl Ether
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route:
Dose*:
Effect:
Reference:
RVd:
RVe:
Composite Score:
RQ:
oral
1029 mg/day
mortality
Lyman and FuMa, 1969
1
10
10
1000
*Equ,fva-Ten.t .human dose.-:
0045d
9-T2 :
05/29/87
-------
TABLE 9-8
Derivation of Potency Factor (F) for b1s(Chloromethyl) Ether
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight:
Duration of treatment:
Duration of study:
Ufespan of animal:
Target organ:
Tumor type:
Experimental doses/exposures (ppb):
Transformed doses (mg/kg/day):
Tumor Incidence:,
Unadjusted*' T/EDro:
Adjusted 1/EDio (f factor):
Leong et al., 1981
Inhalation
rat
Sprague-Dawley
male
vapor
0.35 kg*
6 months
28 months (control, low and middle
dose); 19 months (high dose)
28 months control, low and middle
dose); 19 months (high dose)
nose
esthesloneuroepltheHoma
0 1 10
0 0.0001 0.0011
0/D2 Q/1W
T58 (mg/kg/day)"1
924 mg/kg/day)"1"
100
0.0169
*Reference value.
0045d>
9-T3 ;••
05/29787'
-------
(mg/kg/day)"1. This F factor places bls(chloromethyl) ether In Potency
Group 2. An EPA Group A chemical that 1s 1n Potency Group 2 ranks HIGH 1n
the Hazard Ranking Scheme under CERCLA. A HIGH hazard ranking Is assigned
an RQ of 1.
Commercial grade b1s(2-chloroethyl) ether {composition not specified)
produced Increased Incidences of hepatomas 1n males of two strains of mice
and In females of one strain when administered predominantly 1n the diet
(BRL, 1968; Innes et al., 1969) (see Table 6-5), but 100% pure
b1s(2-chloroethyl) ether was not carcinogenic In rats when administered by
gavage (Welsburger et al., 1981) (see Section 6.2.2.). Although hepatomas
1n mice often occur spontaneously and are difficult to classify, the high
Incidences and occurrence In two strains and sexes Indicate that the
hepatomas In the BRL (1968) and Innes et al. (1969) studies were
treatment-related. On the basis of these data and predominantly positive
responses 1n mutagenlclty assays (see Section 6.3.), b1s(2-chloroethyl)
ether can be classified 1n EPA Group B2.
The hepatomas were Induced by treatment by gavage at a dose of : 100
mg/kg/day on days 7-28 of life and subsequently by diet at a concentrations
of 300 ppm for the next 76 weeks (BRL, 1968; Innes et al., 1969); the TWA
dose for the entire study 1s 41.3 mg/kg/day. Using this dose, the highest
Incidence of hepatooas (B6C3F1 strain males), and the^ compeer lied multistage
model developed < by Howe- antf Crump1, (T982;jj,, ttte^unadjustedT/CD^g. Is
calculated td be 0.453 (mg/kg/day,),'1 tTafrte M)U tttfs T/E01(J,. may, be
ssmewhat conservative,., haweverv as the number of treated animals useditm the;
caTctr.Tat 1 on was' relativeTyl smaTT. ., The; adjusted- 1:/ED,0 pF; Fatetor);, calc;u;-<
lated by multiplying the unadjusted kl/ED10 by the cube root of the ra*1o '-••
of assumed human body weight (70 kg) to assumed mouse body weight (0.03 kg)
and by the cube of the . ratio of; assumed' mouse Hfespan, (104 weeks\to
0045d ' 9-14 ' " <• • 071/08/87-
-------
TABLE 9-9
Derivation of Potency Factor (F) for b1s(2-Chloroethyl) Ether
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight:
Duration of treatment:
Duration of study:
Llfespan of animal:
Target organ:
Tumor type:
Experimental doses/exposures:
Transformed doses:
Tumor Incidence:
Adjusted T/EDTO- f F- factor h-
BRL, 1968; Innes et al., 1969
oral
mouse
B6C3F1
male
water (gavage) and diet*
0.03 kg*
79 weeks
79 weeks
104 weeks
liver
hepatomas
0, 41.3 mg/kg/day TWA*
0, 41.3 mg/kg/day
8/79, 14.16
13°. 7 mg/lcg/day ) ~*
^Treatment- consisted of, dally Intubation", of TOO .'rag/leg" \n distilled water on:
days 7-28 of life, followed by dietary administration of 300 ppm until 80
weeks of age. Mouse food consumption was assumed to b.e. equivalent to. 13%'
of body we1ght/da^ for. calculation of, the 'TWA dose:.
(HKSd? .
9-T5
a5/29/87
-------
experiment duration (79 weeks), 1s 13.7 (mg/kg/day)"1. This F factor
places b1s(2-chloroethyl) ether 1n Potency Group 2. An EPA Group B2 chemi-
cal that Is In Potency Group 2 ranks MEDIUM In the Hazard Ranking Scheme
under CERCLA. A MEDIUM Hazard ranking 1s assigned an RQ of 10.
Chronic gavage administration of commercial grade b1s(2-chloro-l-methy1-
ethyl) ether, which was -70% pure containing -28.5% 2-chloro-l-methylethyl-
(2-chloropropyl) ether and 2% bls(2-chloro-n-propyl) ether, was not tumorl-
genic 1n F344 rats of either sex (NCI, 1979), but 1t produced Increased
Incidences of alveolar/bronchlolar adenomas In male and female B6C3F1 mice
and hepatocellular carcinomas In male B6C3F1 mice (NTP, 1982) (see Table
6-6). A low Incidence of stomach or forestomach squamous cell papHlomas or
carcinomas 1n the high-dose female mice was considered to be probably
related to treatment because of the rarity of stomach tumors In B6C3F1
mice. Chronic dietary administration of high purity (98.5%)
b1s(2-chloro-l-methylethyl) ether was not tumorlgenlc to SPF-ICR mice
*
(MHsumorl et al., 1979) (see Section 6.2.2.). Although there Is evidence
of carclnogenldty In the B6C3F1 mice (NTP, 1982), the effect cannot be
attributed definitely to b1s(2-chloro-l-methylethyl) ether because 1t cannot
be determined If 1t Is due to compound Impurity or mouse strain
sensitivity. b1s(2-Chloro-l-methylethyl) ether Is therefore classified 1n
EPA Group C. .....
Settee ft- fspro&ab'Te tha-t" most human' exposure'to b^stZ-chToro-T^ffiethyT-
ethyl) ether Vsr to: commercta:!: grade, compound;,. It ts appropriate .to- use;the
NTP (1982)i carcinogen 1 city data itas derive* an^F* {•'actor.: Ttte ortce were
exposed'? by; gavage: at doses of 1QQ or 200 imgyfkgr 5 days/weeK .for 103:'weeks.
Using these doses adjusted for partial 'weekly exposure, the corresponding
liver tumor Incidences and the computerized multistage model developed by
Howe and Crump (1982), the unadjusted 1/ED-m 1s = calculated: to be,
0045d 9-W: 07/08/8*
-------
3.48xlO'2 (mg/kg/day)'1 (Table 9-10). The adjusted 1/ED10 (F factor),
calculated by multiplying the unadjusted T/ED,Q by the cube root of the
ratio of assumed human body weight (70 kg) to measured average mouse body
weight (0.04 kg) 1s 4.19X10'1 (mg/kg/day)'1. This F factor places b1s-
(2-chloro-l-methylethyl) ether In Potency Group 3: An EPA Group C chemical
that Is 1n Potency Group 3 ranks LOW 1n the Hazard Ranking Scheme under
CERCLA. A LOW hazard ranking 1s assigned an RQ of 100.
IARC (1979) and U.S. EPA (1980b) considered chloromethyl methyl ether to
be a human carcinogen on the basis of occupational data, and the chemical
was assigned to EPA Group A (see Section 8.1.4.). Data were not sufficient
for derivation of a Potency (F) factor, and It appears most appropriate to
assign chloromethyl methyl ether to Potency Group 2. An EPA Group A com-
pound 1n Potency Group 2 ranks HIGH 1n the CERCLA Hazard Ranking Scheme for
RQs. A HIGH hazard ranking corresponds to an RQ of 1.
Hazard ranking based on cardnogenldty Is not possible for the other
haloethers that are the subject of this report.
0045d 9-17 07/08/87
-------
TABLE 9-10
Derivation of Potency Factor (F) for b1s(2-Chloro-l-methylethyl) Ether
(Commercial Grade)
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight:
Duration of treatment:
Duration of study:
Llfespan of animal:
Target organ:-
Tumor-type: •;.
Experimental- doses/exposures (mg/kg):
Transformed doses {mg/kg):
Tumor Incidence:
Unadjusted 1/ED]0:
Adjusted l/E&io (F factor): ,
NTP, 1982
oral (gavage)
mouse
B6C3F1
male
corn oil
0.04 kga
103 weeks
107 weeksb
107 weeks
liver
hepatocellular adenoma or
carcinoma
0
0
13/50
100
68.8
23/50
200
27/50
3.48xlO-2 (mg/kg/day)~l
4.19xlO~1 (mg/kg/dayr1
a'E-s.ttmate«t. from graphic data provided by:, InventVgator ,
0045d
OS/Z9/87v.
-------
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0046d Tff-10 07/09/87
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0046d 10-12 07/09/87
-------
Simmon, 'V.F., K. Kauhanen and R.G. Tardlff. 1977b. Mutagenk activity of
chemicals Identified In drinking water. Dev. Toxlcol. Environ. Sc1. 2:
249-258.
Simmon, V.F., L. Hedden, D. Poole and R. Tardlff. 1978. Mutagenlc assays
with b1s-(2-chlorod!1sopropyl) ether. Mutat. Res. 53: 261-262.
Slaga, T.J., G.T. Bowden, B.G. Shapas and R.K. Boutwell. 1973. Macro-
molecular synthesis following a single application of alkylatlng agents used
as Initiators of mouse skin tumorlgenesls. Cancer Res. 33: 769-776.
Smith, C.C., R.D. L1ngg and R.G. Tardlff. 1977. Comparative metabolism of
haloethers. Ann. N.Y. Acad. Sc1. 298: 111-123.
Smyth, H.F., Jr. and C.P. Carpenter. 1948. Further experience with the
range finding test 1n the Industrial toxicology laboratory. J. Ind. Hyg.
Toxlcol. 30: 63. (Cited 1n U.S. EPA, 1980b)
Smyth, H.F., Jr., et al. 1949. Range-finding toxldty data; List III. J.
Ind. Hyg. Toxlcol. 31: 60. (CHed In U.S. EPA, 1980b)
Smyth,. H-.F.,. Jr..., at sT. TOST.. Range-find.^ .toxfolty -..da**;- Us* IV. I.,
Ind. Hyg ., Occup,. Med- ,4s- lift, dttted \n U.S.. EP/W mob);,
Smyth;, OL,- Jr., etr.aiK. T96*. Rarcge-f.1fnd*ngr ' to»terty.> teta-;, L1:s* VIL.
Ind. Hyg. Assoc.. ! 31: 60. (Cited In If.S. EPrA, T980b)
0046d 10-13 07/09/87
-------
SRI (Stanford Research Institute). 1986. 1986 Directory of Chemical
Producers: United States of America. SRI International, Menlo Park, CA.
p. 503, 587, 856, 1069.
Staples, C.A., A. Werner and T. Hoogheem. 1985. Assessment of priority
pollutant concentrations In the United States using STORE! database.
Environ. Toxlcol. Chem. 4: 131-142.
Suffet, I.H., L. Brenner and P.R. Cairo. 1980. Gas chromatography-mass
spectrometry Identification of trace organlcs 1n Philadelphia, Pennsylvania,
USA drinking water during a two year period. Water Res. 14: 853-867.
Tabak, H.H., S.A. Quave, C.I. Mashnl and E.F. Barth. 1981. B1odegradab1l1ty
studies with organic priority pollutant compounds. J. Water Pollut. Control
Fed. 53: 1503-1518.
Thless, A.M., et al. 1973. Zur Tox1kolog1e von Dlchlorodlmethylather-
Verdacht auf kanzerogene Wlrkung auch belm Menschen. Zbl. Arbeltsmed. 23:
97. (Cited In U.S. EPA. 1980b)
Thless.iJ-C., e.t al. 1977* Test for carclnogenldty ,of organ,Vcv contanrt-
narvt^af- OnTt"etf. Sit'&tes:
-------
U.S. EPA. 1975. Preliminary Assessment of Suspected Carcinogens In Drink-
Ing Water. Interim Report to Congress, June, 1975. U.S. EPA, Washington,
DC.
U.S. EPA. 1977. Computer print-out of non-confidential production data
from TSCA Inventory. OPTS, CID, U.S. EPA, Washington, DC.
U.S. EPA. 1978. In-Depth Studies on Health and Environmental Impacts of
Selected Water Pollutants. U.S. EPA, Washington, DC. Contract No.
68-01-4646.
U.S. EPA. 1980a. Guidelines and Methodology Used 1n the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 49347-49357.
U.S. EPA. 1980b. Ambient Water Quality Criteria Document for Haloethers.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and-. Assessment Office, Cincinnati, OH for the Office of Water
Regulations and Standards, Washington, DC. EPA 440/5-80-050. NTIS
PB81-117616.
U.S. EPA'. T980c. Ambient Water QuaTTfy Criteria Document for .ChfToroalkyT-
Ethers.: Prepared by, the. Office of.."Health.' and Envlr.onmenta.T Assessment,,
Environmental- Criteria and Assessment" Off-tee.-. CtnclrmatV, ;OH for the- Office
of Water Regulations and Standards, Washington, DC. EPA, 440/5-80-0:30.. MTIS;
PB81-117418.
0046d 10-T5 07/09/87
-------
U.S. EPA. 1983a. Methodology and Guidelines for Reportable Quantity
Determinations Based on Chronic Toxldty Data. Prepared by the Office of
Health and Environmental Assessment, Environmental Criteria and Assessment
Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA, 1983b. Reportable Quantity Document for Chloromethyl Methyl
Ether. Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for the Office
of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1983c. Reportable Quantity Document for b1s(2-Chloro1sopropyl)
Ether. Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for the Office
of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1985. Reference Values for Risk Assessment. Prepared by the
Office*-of Health and Environmental ^Assessment, Environmental Criteria '.and
Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington, *
DC.
U.S.; EP.A^' I.;9i86av,~ Hethadotagy;' for' • Exalu&tftigt Paten,Ua:T; rCarcinogentclty tny
Support of Repair table Qjtanmy, Ad},ustmeivls, Pursuant .to CERCLA Section *T02.. ,-
Prepared" by-, tnV Office- of: He*TtW antf-En^v-Trenraental- A'ss;essment. Carcinogen
Assessment Gr'oup, ^asMrcgtoni;,; D[Cvfor-th:e Offices, af>So;11d Waste and,,Emergency
Response, Washington, DC.
0046d 10-16 07/09/87
-------
U.S. EPA. 1986. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
U.S. EPA. 1987. Graphical Exposure Modeling System (GEMS). Octanol-Water
Partition Coefficient (CLOGP) and/or Fate of Atmospheric Pollutants (FAP)
computer data systems. U.S. EPA, Research Triangle Park, NC.
Van Duuren, B.L., 8.M. Goldschmldt, C. Katz, L. Langseth, G. Mercado and A.
S1vak. 1968. Alpha-halo ethers a new type of alkylatlng carcinogen. Arch.
Environ. Health. 16(4): 472-476.
Van Duuren, B.L., A. Slvak, B.M. Goldschmldt, C. Katz and S. Melchlonne.
1969. CardnogenlcHy of haloethers. J. Natl. Cancer Inst. 43(2): 481-486.
Van Duuren, B.L., S. Melchlonne, R. Blair, B.M. Goldschmldt and C. Katz.
1971. CardnogenlcHy of Isoesters of epoxldes and lactones: Azlrldlne
ethanol, propane sulfone and related compounds. J. Natl. Cancer Inst. 46:
143.
Van Duuren, B.L., C. Katz, B.M. Goldschmldt, K. Frenkel and A. Slvak. 1972.
CarcAnogBn^clitjt; of ;halo-ether;S?.v llv £trvctun.£*$cttvttjj relation- of: analogs;
of bVs^Wxjromethyi'H) ether. IJ-RatT...''Cancer Inst. ffttSfc U31:-l:439..
Varv Duuren, ff.L., B-.H. GbTdschmlrftY Cv Katr.. I. Seldman and J;.S. Paul.
T974. Carcinogenic acttvl'ty of alkyTa.tfrtg' agervts. !„ NatT;. Cancer Inst.
53(3): 695-700.
0046d 10-17 07/09/87
-------
Van Duuren, B.L., B.M. GoldschmVdt and I. Seldman. 1975. Carcinogenic
activity of d1- and trlfunctlonal alpha-chloro ethers and of 1,4-d1chloro-
butene 2 In ICR/Ha Swiss mice. Cancer Res. 35(9): 2553-2557.
Velth, G.D., K.J. Hacek, S.R. Petrocelll and 3. Carroll. 1980. An evalua-
tion of using partition coefficients and water solubility to estimate bio-
concentration factors for organic chemicals In fish. In; Aquatic Toxicology,
J.G. Easton, et al., Ed. Am Soc. Tes. Mater, Philadelphia, PA. p. 116-129.
ASTM STP 707.
Verschueren, K. 1983. Handbook of Environmental Data on Organic Chemicals,
2nd ed. Van Nostrand Relnhold Co., New York, NY.
V1al, T.M. 1979. Elastomers, synthetic (acrylic). In: K1rk-0thmer
Encyclopedia of Chemical Technology, Vol. 8, 3rd ed., M. Grayson and D.
Eckroth, Ed. John Wiley and Sons, Inc., New York. p. 463.
Voets, J.P., P. P1pyn, R. Van Lancker and W. Verstraete. 19-76? Degradation
of mlcroblddes under different environmental conditions. J. Appl.
Bacterlol. 40: 67-72.
Heas?t. R'.C-.,. Ed. H8&: CRC.; Handbook- afr Chemt.s,try. and::".Physics.. 66thred.,
CRC Press, Inc.;» Boca Ra.tonv,FL» p. C-2QS,., C-24&,*
Welsb'urger,, &..K., ,&:»-;. UllaM,. H-H;: Nam, J.j;." Garland -HXJ. Welsburger.
1981. Carc1nogen1c1ty tests' of certain environmental and Industrial chemi-
cals. J. Natl. Cancer Inst. 67(1): 75-88.
0046d 10-18 Of/09/87
-------
Weiss, W. 1976. Chloromethyl ethers, cigarettes, cough and cancer. J.
Occup. .Hed. 18: 194. (Cited In U.S. EPA, 1980D)
Weiss, W. and K.R. Boucot. 1975. Respiratory effects of Chloromethyl
methyl ether. J. Am. Med. Assoc. 234(15): 1139-1142.
Weiss, W. and W.G. Flgueroa. 1976. The characteristics of lung cancer due
to Chloromethyl ethers. J. Occup. Med. 18: 623-627.
Weiss, W., R.L. Moser and 0. Auerbach. 1979. Lung cancer 1n Chloromethyl
ether workers. Am. Rev. Resplr. 01s. 129(5): 1031-1037.
Wilson, J. and M.J. Noonan. 1984. M1crob1al Activity In Model Aquifer
Systems.. Robert S. Kerr Environ. Res. Lab. 35 p. EPA 600/D-84-136. NTIS
PB84-194893.
Wilson, J.T., C.G. Enfleld, W.3. Dunlap, R.L. Cosby, D.A. Foster and L.B.
Baskln. 1981. Transport and fate of selected organic pollutants 1n a sandy
soil. J. Environ. Qual. 10: 501-506.
W1ndho,U. M., W. 1983. The Merck Index, 10th ed. Merck & Co.» Inc..
Rahway. NJ. p. T38T.
Zajdete,. F.r. A.. Cro,tsy-r A--. Barfctn>. £:„ MalaveVVle, \~ Tomatts aiwt H. Bartsct»v
1980. Caretno.genI'dty, o;f chloroethyTene, ox.l:de, an, uTt'lmat'e, reacMve metabo'-.
IHe of vinyl chloride and b1s(chloromethyT)v ether after subcutaneous admfn-
Istratlon and 1n Initiation-promotion experiments with mice. Cancer Res.
40: 352-35,6,
0046d TO-19" 07/09/87
-------
APPENDIX A
LITERATURE SEARCHED
This HEED 1s based on data Identified by computerized literature
searches of the following:
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXBACK 76
TOXBACK 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
These searches were conducted 1n February, 1987. In addition, hand searches
were made of Chemical Abstracts (Collective Indices 5-9), and the following
secondary sources should be reviewed:
ACGIH (American Conference of Governmental Industrial Hyg1en1sts);.
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1986-1987. TLVs: Threshold Limit Values for Chemical Substances In
the Work Environment adopted by ACGIH with Intended Changes for
1>98S-198,7;. ' Cincinnati*, QHv
Clayton, G.D': and F.E. Clayton, Etf. T987. Party's Indus trTal.
Hygiene and Toxicology;, 3rd rev. ed.. Vol. 2A~ John lit ley and
Sonsf, NY. 2878Lp.
Clayton, G.D. and F.E. Clayton, Ed. . T98T. Patty's Industrial
Hygiene, and; Toxicology;,, 3rd, rev-, ed,.,. Vol. 2.B.-.. John Wiley and
su NY.. pr
Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2C. 3ohn WHey and
Sons, NY. p. 3817-5112.
A-!-
-------
Grayson, M. and D. Eckroth, Ed. 1978-1984. K1rk-0thmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. WHO, IARC, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. L1eu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
SRI International, Menlo Park, CA. EPA 600/6-84-010. NTIS
PB84-243906.
NTP (National Toxicology Program). 1986. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Reinhold Co., NY.
SRI (Stanford Research Institute). 1986. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report 1n the Special Review
Program, Registration Standards Program and the Data CalV 1n
Programs. Registration Standards and the Data Call In Programs.
Office of Pesticide Programs, Washington, DC.
U.:S. EPA-. 1985. CSB Existing Chemical Assessment Tracking ^
Name and CAS Number Ordered Indexes. Office of Toxic Substances,
Washington, DC.
USITC (U.S. International Trade Commission). 1985. Synthetic
Organic Chemicals. U.S. .Production and Sales, 1984, USITC Publ.
ws.
Vetscttueren , - Kv 1383L Handbook of EriVflronrnerrtatf". Qatat on:. Organic.
Cherolca-ls, 2nd ed.; .Van Nostrand Relnhold Co. , NY.
Wfndholz, 4*.;. Erf. ' BS^::TOe:Rercle:\rrKteKK. Tffth;ed.
Inc., Rahway, *NJ'.
Worthing:, C.R. ,and;S.B;v Walker-, Ed. 19831: -. TCfe -Pes-tfo1.de Manual.
BrHUsh Crop Protection Council,.- ; 6,95 p.,.*/--'.,'
A-2-..
-------
In addition, approximately 30 compendia of aquatic toxlclty data were
reviewed, Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute Toxldty
of Chemicals to Fish and Aquatic Invertebrates. Summaries of
Toxldty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Oept. Interior, F1sh and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
A-3
-------
APPENDIX Bl
Cancer Data Sheet for Derivation of q-|*
Compound: b1s(chloromethyl) ether
Reference: Leong et al., 1981
Spec1es/strain/sex: rat/Sprague-Daw!ey/male
Body weight = 0.35 kg (assumed)
Control Low Dose
Length of exposure (le) NA 6
(months)
Length of experiment (Le) = 28 28
(months)
Llfespan of animal (L) = 28 28
(months)
Tumor site and type: nose, esthes1oneuroep1thel1oma
Route: Inhalation
Mid Dose
6
28
28
High Dose
6
19
19
Experimental Doses
or Exposure3
(ppb)
Transformed Doseb
(mg/kg/day)
Incidence
No. Responding/No. Tested
0
1
10
100
Unadjusted qj*"
Human q-j* = 59
0
0.0001
0.0011
0.0169
». T. 0*801 58 (nrg/kg/day)"1 '.
.5339 ( mg/kg/day )~l
0/112
0/113
0/111
96/ail
Exposures were 6 hours/day, ;5 days/week for 6 months.
Exposures: expressed, as , mg/m3: were; multiplied; by, 6 hours/24 hours., by 5y
days/'?;, days; c byj; reference; i?a-t^ 1;nhatfa£1ioa rate:; of: Qi.223* ra*/ awE
divided by reference rat body'weight of "0.35" kg. Result' was multiplied by
le/Le to expand exposures for duration of experiment.
B-l
-------
APPENDIX 82
Cancer Data Sheet for Derivation of q-|*
Compound: b1s(2-chloroethyl) ether
Reference: BRL, 1968; Innes et al., 1969
Specles/strain/sex: mouse/B6C3Fl/male
Body weight = 0.03 kg (assumed)
Length of exposure (le) = 79 weeks
Length of experiment (Le) = 79 weeks
Llfespan of animal (L) = 104 weeks
Tumor site and type: liver, hepatomas
Route/vehicle: oral/gavage and diet"!"
Experimental Doses
or Exposure
(mg/kg/day)
Transformed Dose
(mg/kg/day)
Unadjusted q-|* = 8.14xlO~2 (mg/kg/day)'1
Human q-j* = 2.46 (mg/kg/day)~* ; ^
Incidence
No. Responding/No. Tested
0
41.3 (TWA dosejt >
0
41.3
8/79
14/16
"Treatment consisted of dally Intubation w1th>*TOO mg/k£ In distilled
water on days 7-28 of life:,, followed :t*y dietary adm1n1str;atton\of; 300 ppm
uret1.li!80. weeks, of age. Mou-se footi caKsurtpWan wa,s assumed.to be;, equlival enf:
to: V3#. of body, weight/day- fror ca-Jculatton: tff the HWA*
-------
APPENDIX B3
Cancer Data Sheet for Derivation of q-j*
Compound: b1s(2-chloro-l-methylethyl) ether (technical grade)
Reference: NTP, 1982
Spec1es/strain/sex: mouse/B6C3Fl/male
Body weight = 0.04 kg (estimated from graphic data provided by 1ngest1gator)
Length of exposure (le) = 103 weeks
Length of experiment (Le) = 104-110 (107) weeks
Llfespan of animal (L) = 107 weeks
Tumor site and type: liver, hepatocellular adenomas or carcinomas
Route/vehicle: gavage/corn oil
Experimental Doses or Exposure Transformed Dose • Incidence
(mg/kg) (mg/kg/day) No. Responding/No. Tested
100
200
x 5/7
x,5/7
days
days
0
X
X
103/107
103/107
weekst
weeks*
0
68
137
.8
.5
13/50
23/50
27/50 "
Unadjusted
5.78x10'?- ( mg/kg/day J,T
^Length of experiment assumed to be 107 weeks (midpoint of reported rangej...
B-S
-------
APPENDIX Cl
Summary Table for bls(Chloromethyl) Ether
r>
Species
Inhalation Exposure
Subchronlc NA
Chronic NA
Carclnogenlctty rat
Oral Exposure
Subchronlc " NA
Chronic. NA
Carclnogenlctty rat
RE PORTABL E QUANT 1 T 1 E S
Based on chronic tqxlclty:
Based on Carclnogenlctty:
Exposure Effect RfD or qj'
•'•
NA NA NA
NA NA NA
1, 10 or 100 ppb, 6 hours/day, nasal estheslo- 59. S (mg/kg/day)"1
6 days/week for life neuroeplthelloma
NA NA NA
NA NA NA
1. 10 or 100 ppb, 6 hours/day, nasal estheslo- S9.5 (mg/kg/day)"1
5 days/week for life neuroeplthelloma
ID
1
Reference
NA
NA
Leong et al.,
1981
NA
NA
Leong et al.,
1981
ID
Leong et al. ,
1981
(0 > Insufficient data; NA c not applicable
-------
APPENDIX C2
Summary Table for b1s(2-Chloroethyl) Ether
«!*
inhalation Exposure
Subchronlc '% N/\
Chronic NA
Carclnogenlclty mouse
Oral Exposure
n .-,•••• . " ' 1 "*•••'''
\
™ Subchronlc NA
':* '— 'V
Chronic . NA
Carclnogenlclty mouse
REPORTABLE QUANTITIES
Based on chronic toxlclty:
Based on Carclnogenlclty:
Exposure
NA
NA
41.3 mg/kg/day (TWA)
for 79 weeks
NA
NA
41.3 mg/kg/day (TWA)
for 79 weeks
>,
100
10
Effect RfD or qi* Reference
NA NA NA
NA NA NA
hepatomas 1.23 (mg/kg/day)'1 BRL, 1968; Innes
et al.. 1969
NA NA NA
NA NA NA
hepatomas 2.46 (mg/kg/day)'1 BRL, 1968;
Innes et al. ,
1969
Welsburger
et al., 1961
BRL, 1968; Innes
et al.. 1969
|D = Insufficient data; NA = not applicable
-------
APPENDIX C3
Summary Table for b1s(2-Chloro-l-methylethyl) Ether (Technical Grade)
Species
Inhalation Exposure
Subchronlc NA
Chronic HA
Carclnogenlclty mouse
Oral Exposure
°* Subchronlc NA
.Chronic NA
Cardnogenlclty mouse
- - - ;-j -- . T — r~~ . "•-" =
REPORTABLE QUANTITIES
Based on chronic toxIcHy:
Based on carclnogenlclty:
Exposure Effect
NA NA
NA NA
100 or 200 mg/kg, hepatocellular adenomas
5 days/week for or carcinomas
104-110 weeks
NA NA
NA NA
100 or 200 mg/kg, hepatocellular adenomas
5 days/week for or carcinomas
104-110 weeks
1000
100
RfD or q^* Reference
NA NA
NA NA
3.49xlO~2 NTP, 1982
(mg/kg/day)"1
NA NA
NA NA
6.97xlO~2 NTP, 1982
(mg/kg/day) *
NCI, 1979
NTP, 1982
ID = Insufficient data; NA = not applicable
-------
APPENDIX C4
Summary Table for 2,4,4'-Tr1chloro-2'-hydroxyd1phenyl Ether
" '' ' V, : - ' *•» f "*"
..- Species
Inhalation Exposure .
Subchronlc ID
Chronic ID
Carcinogenic! J. y jg
Oral Exposure
Subchronlc rat
Chronic , IQi
Carclnogenlclty ID
REPORTABLi QUANTITIES
Based on chronic toxlclty:
Based on carclnogenlclty:
Exposure
ID
ID
ID
500 mg/kg,
6 days/week
for 4 weeks
ID
ID
1000
ID
Effect RfD or q^* Reference
ID ID ID
ID ID ID
ID ID ID
reduced weight 300 mg/day Lyman
gain and mortality Furla
at a higher dose
ID ID ID
ID ID ID
Lyman
Furla
ID
and
, 1969
and
, 1969
10 = Insufficient data
-------
APPENDIX C5
Summary Table for Chloromethyl Methyl Ether
i^> t - ,- - • • - . _-*> % .-- -
Species
Inhalation Exposure
Subchronlc ID
Chronic ID
Carclnogenjclty ID
Oral Exposure
i Subchronjc ID
Chronic " ID
Carclnogenlclty ID
REPORTABlt QUANTITIES
Based on chronic toxIcUy:
"^ *•".•* . it **-,'•' *. ' , *"
Based on carc1nogen,1c1ty:
Exposure Effect RfD or q-|* Reference
ID ID ID ID
ID ID ID ID
ID ID ID ID
ID ID ID ID
ID ID ID ID
ID ID ID ID
100 Laskln
et al.. 1975
1 ID*
'This chemical was assign^ to Potency Group 2.
ID = Insufficient data
-------