PR85-101772
EPA-600/D-84-234
September 1984
TOXICOLOGICAL EVALUATION OF SELECTED
CHLORINATED PHENOLS
Joseph F. Borzelleca, Lyman W. Condie
and Johnnie R. Hayes
Department of Pharmacology and Toxicology
Division of Toxicology
Medical College of Virginia
Richmond, VA
and
U.S. Environmental Protection Agency
26 W. St. Clair St.
Cincinnati, OH
Supported by U.S.E.P.A. Grant R-808861010
HEALTH EFFECTS RESEARCH LABORATORY
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
RESEARCH TRIANGLE PARK, NC 27711
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TFCHN1CAL REPORT DATA
(PU CSc tea J /tiifrat t'Oo* <*n tlu triers* bi fori d'^tpU tiny
1 «fc*»OR7 NO 2
I.PA h00/n-8 : -25-1
3 RECIPIENT S ACCESS CN' NO
P3S 5 1017 7?
Af*d SUBTlTU^
Toxlcologlcal evaluation of Selected Chlorinated
Phenols
S REPORT DAT£
Septr-ihrr 1 <-)Ki
6 PERFORMING ORGANIZATION CODE
'"ifc^rzeYfeca, Condie*, and Hayes
8 PERFORMING ORGANIZATION RtPOHT NO
V PERFORMING ORGANIZATION NAME AND AOORtSS
Dept. Pharmacology and Toxicology, Medical College of
Virginia, Richmond, VA 23298
*TOTB/TMD/HERL/ORD/USEPA, 26 West St. Clair Street,
Cincinnati, OH 45268
10 program Element no
ABMC1A
11 CONTRACT/GRANT NO
CR808861
12. SPONSORING AGENCY NAME AND ADDRESS
HERL/ORD/USEPA
Research Triangle Park, NC 27711
JL3 TYPE OF REPORT and PERIOD COvEREC .
Proceedings
14 SPONSORING AGENCY CODE
EPA-600/11
15 SUPPLE ME NT AP v t*OTE£.
)
16 VKtRJKT '
Toxicology studies were conducted with the mono-, di-, and pentachlorophenols (CP).
Chlorophenols (except PC) denonstrate a relatively low order of toxicity. The order
of toxicity in mice and rats (most to least) is: PCP > tetra CPs > mono CPs > tri
CPs > di CPs. Short-term (14 days) repeated exposure to 2-CP at (gavage) doses of
35, 69, or 175 mg/kg/day (approximately 1/10, 1/5, 1/2 the acute oral LD50) resulted
in 1002 lethality at the highest dose and no biologically significant compound
related effects at the lower doses. Short-term (14 days) repeated exposure to 2,4-DCP
at (gavage) doses of 64, 128, or 638 mg/kg/day (approximately, 1/20, 1/10, 1/2 the
acute oral LD50) failed to induce significant compound related toxicity. The liver
waB identified as a possible target organ. Subchronic exposure to 2,4-DCP at drinking
water concentrations of 0.2, 0.6, and 2.0 ng/ml (limit of solubility and acceptability
was 2.0 mg/ml) for 90 days (approximate doses of 50, 150, 500 ng/kg/day) failed to
induce significant compound related toxicity. The data presented and a review of the
available literature support the relatively low order of toxicity of most chlorinated
phenols ingested orally (except PCP).
17. KEY WORDS AND DOCUMENT ANALYSIS
1 DESCRIPTORS
b. IOENTIF IERS/OPEN ENDED TERMS
c. cosati Field/Croup
H DISTRIBUTION STATEMENT
Release to public
19. SECURITY CLASS (Thu Report)
unclassified
21. NO. or PAGES
22
20 SECURITY CLASS fTlutptfti
unclassified
22 PRICE
CPA Fx* 2230-1 (¦». 4-T7I
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NOTICE
This document has been reviewed in accordance with
U.S. Environmental Protection Agency policy and
approved for publication. Mention of trade names
or commercial products does not constitute endorse-
ment or recommendation for use.
ii
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INTRODUCTION
Chlorinated phenols (CPs) have been used as chemical intermediates in the
manufacture of many products. Some have been used as antiseptics since 1893,
whereas others are used as fungicides and preservatives 1n non-food Items.
The U.S.E.P.A. and other regulatory bodies and organizations Involved with
the safety of drinking water are Interested in these compounds because they are
sometimes found in finished water and because there 1s a relative paucity of
toxicolbgical data concerning them. They do not appear to be a severe problem
in drinking water for a number of reasons: (1) organoleptic properties - they
affect the taste of the water and Intake would be self-limiting; (2) the
United solubility of some of these compounds 1n water; (3) available toxico-
loglcal data suggest that they generally are not highly toxic.
The CPs are formed from the breakdown of chlorobenzenes and from the
chlorination of water containing phenol. The medicinal odor and taste of
water is often due to CPs.
In conjuction with the U.S.E.P.A., selected literature was reviewed and
a series of Investigations were conducted to evaluate the acute and subchronic
toxicity of a selected number of chlorinated phenols. The physical and chemi-
cal characteristics of a series of chlorinated phenols and those Investigated
1n our program are listed 1n Table 1.
Experimental Design
The basic experimental design consisted of an evaluation of the effects of
orally administered chlorinated phenols 1n mice and rats. These socles were
1
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selected because of their sensitivity to xenoblotlcs, size, cost and ease of
handling. The agents tested were selected by the U.S.E.P.A. Exposures were
either acute, repeated or subchronic and by either gavage or 1n drinking water.
Details of the major procedures used are summarized in Tables 2, 3 and 4 and
In Figure 1.
RESULTS
The acute oral toxicity data are summarized in Table 5. These data Indicate
that pentachlorophenol 1s the most toxic and the dichlorophenols the least
toxic.
2-Chlorophenol was evaluated following 14 days of exposure at doses of 35,
69 and 175 mg/kg/day administered by stomach tube. The data are summarized 1n
Table 6. 2,4-D1chlorophenol was evaluated following 14 and 90 days of
exposure. The exposure levels for the repeated dosing 14-day study were 64,
128, and 638 mg/kg/day and for the subchronic study they were 50, 150, and
500 mg/kg/day. The test compounds were administered by gavage for the 14-day
study and in the drinking water for the subchronic study. Thfe data are
summarized 1n Tables 7 and 8.
At the termination of the 2,4-DCP subchronic exposure study, 10 males and
10 females per group were randomly selected for an 1n vivo fertility study.
Dosing was continued throughout mating and gestation. Eighteen days after
mating, all females were sacrificed and the following parameters were measured
or calculated:
2
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Total Implants
Total resorptions
Total number live pups
Weight of individual pups
Fertility Index
The data are summarized on Table 9. The increased resorption rate at the mid
dose is not statistically different from the vehicle control. There were no
consistent adverse compound related effects.
In vitro reproductive data are summarized 1n Table 10.
The effects of exposure to selected chlorinated phenols on sister
chromatid exchange (SCE) are summarized in Table 11.
DISCUSSION
Acute Toxicity. Available acute oral toxicity data of phenol and chlorinated
phenols in mice and rats are summarized in Table 12. These compounds are not
highly toxic, with the exception of pentachlorophenol. The order of toxicity
(most to least) is: PCP > tetrachlorophenols > monochlorophenols > trichloro-
phenol s > dichlorophenols. The order is similar 1n both nice and rats and
suggests similar species sensitivity. The effects produced by these compounds,
in both species and in both sexes, are also similar suggesting similar mecha-
nisms of action. Increased respiration, motor weakness, tremors, CNS depres-
sion, convulsions, dyspnea, coma and then death were observed. Body tempera-
ture was decreased with the mono- and di-chlorophenols but was increased with
the other chlorophenols.
3
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Short Tern Repeated Dosing. 2-CP at a dose of 175 mg/kg/day was lethal.
At doses of 35 and 69 mg/kg/day, slight toxic effects were noted among the
females only. The 2,4-DCP data essentially confirm and extend the findings
of Kobayashi £t aj_. (7) whose mice received 667 mg 2,4-DCP/kg b.w. for 10
days without evidence of any adverse effect. The liver appeared to be a
target organ 1n both studies.
Subchronic Toxicity. The data presented confirm and extend the earlier work
of Kobayashi et al_. (7). They exposed mice for 6 months to doses of 45, 100
or 230 mg/kg/day. The only effect reported was non-specific microscopic liver
changes. In the studies from our laboratories, the highest concentration that
the animals would accept was 2.0 mg/ml using 10 JEmulphor as the vehicle
(resulting 1n a dose of 500 mg/kg/day). No significant biological effects
were observed.
In Vitro Reproductive Effects. Eight chlorophenols were evaluated. Penetra-
tion was depressed by the 2,5-DCP, 3,4-DCP and 3,5-DCP at the highest concen-
N
tration tested (1.0 mM). 2,4-DCP was Inactive in vitro. Sperm and ova were
removed fron the animals exposed subchronically and evaluated. There were no
effects on penetration. The 1n vivo findings confirm the in vitro effects.
Sister Chromatid Exchange. There were no adverse effects on SCE of mice
exposed either acutely or for 14 or 90 days.
4
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SUMMARY AND CONCLUSIONS
1. Chiorophenols (except pentachorophenol) demonstrate a relatively low order
of toxicity.
2. The order of toxicity in nice and rats (most to least) is:
PCP > tetra CPs > mono CPs > tri CPs > di CPs.
3. Short term (14 days) repeated exposure to 2-CP at (gavage) doses of 35,
69 or 175 mg/kg/day (approximately 1/10, 1/5, 1/2 the acute oral LD^q)
resulted in 100^ lethality at the highest dose and no biologically
significant compound related effects at the lower doses.
4. Short term (14 days) repeated exposure to 2,4-DCP at (gavage) doses of 64,
128 or 638 mg/kg/day (approximately 1/20, 1/10, 1/2 the acute oral LD^)
failed to Induce significant compound related toxicity. The liver was
Identified as a possible target organ.
5. Subchronic exposure to 2,4-DCP at drinking water concentrations of 0.2,
0.6 and 2.0 mg/ml (limit of solubility and acceptability was 2.0 mg/ml)
for 90 days (approximate doses of 50, 150, 500 mg/kg/day) failed to induce
significant conpound related toxicity.
6. The data presented and a review of the available literature support the
relatively low order of toxicity of most chlorinated phenols ingested
orally (except PCP).
5
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Table 1
PHYSICAL AND CHEMICAL PROPERTIES OF PHENOL AND CHLORINATED PHENOLS
Fonnula
M.W.
Physical
State
S.G.
M.P.*C
B.P.'C
Solubility
Water Ale.
(pph)
Ether
pKa
Phenol
C ,H OH
b b
94.11
Crystals
1.072
41
182
8.2 at 15*
at 63.3*
s
VS
9.89
2-CP
ClCcH,OH
6 4
128.56
Liquid
1.241
(18/15*C)
a -7; b -0;
Y -4.1
175-6
2.85
s
S-alk
8.65
3-CP
cic6h4oh
128.56
Needles
1.268 (25*C)
32-33
214
2.6
s
S
8-12
4-CP
C1C,H-0H
6 4
128.56
Needles
1.306
(20/4*C)
41-43
217
2.7
vs
VS
9.37
2,3-DCP
C12C6H3OH
163.01
Needles
1.383
(60/25*)
45
209-10
0.45
YS
VS
2,4-DCP
C1?C6H30H
163.01
Hexagonal
Needles
45
206-208
SS
VS
VS
7.85
2,5-DCP
ci2c6h3oh
163.01
Pr1 sms
59
211*
SS
VS
VS
7.50
2,6-DCP
CI2C6H30H
163.01
Needles
68-69
219-220
»
vs
VS
6.91
3,4-DCP
Cl2CgH3OH
163.01
Needles
68
253.5
~
8.58
3,5-DCP
ci2c6h3oh
163.01
Prisms
68
233*
SS
V
Continued on next page
>
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Table 1: PHYSICAL AMD CHEMICAL PROPERTIES OF PHENOL AND CHLORINATED PHENOLS (Continued)
3,4,5-TCP
Physical Solubility
Formula M.W. State S.G. M.P.#C B.P.'C Water Ale. Ether pKa
(pph)
2,3,5-TCP Cl3CgH2OH 197.46 Needles
2.4.5-TCP C13C6H20H 197.46 Needles
2.3.6-TCP C13C6H20H 197.46 Needles
2,4,6-TCP C13C6H20H 197.46 Needles
C13C6H20H 197-46 Needles
55
61-63
58*
68-69
101
2,3,4,5-TCP C14C6H0H 231.90 Needles 1.6 (60/4*C) 69-70
2,3,4,6-TCP CI4C6H0H 231.90 Needles
2,3,5,6-TCP C14C6H0H 231.90 Leaflets
2,3,4,5,6-PCP ClgCgOH 266.35 Solid 1.85 (22#C) 188-89
70
115'
249-50 Sl.S. S
252
246
271-277
164
150
310
0.09 VS
Sl.S VS
VS
VS
7.07
5.98
6.62
7.83
5.46
5.00
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Table 2
EXPERIMENTAL DESIGN
Acute Oral Toxicity Study
Animals:
Adult male and fenale CD-I ICR mice; healthy, acclimated, randomized
Adult male and female CD rats; healthy, acclimated, randomized
Overnight (18 hours) fast (water, no food)
10 males, 10 females per dosage level; 5 levels
Housing: 1/plastic shoebox cage with hardwood sawdust bedding
Feed: Purina Rodent Chow No. 5001; delonlzed water (1n bottles)
Environmental Conditions:
Rooms: 22° * 2°C; relative humidity: 40-60*
Light Cycle: 12 light/12 dark (7:00 a.m. - 7:00 p.m.)
Test Material:
Identity confirmed
Prepared day of administration
Administered by gavage (stomach tube)
Volume: 10 ml/kg body weight
Specific Conditions:
Food withheld for 2 hours after dosing
Continuous observations for 1 hour after dosing, hourly for next 4 hours
and twice dally for the next 14 days
Cageside observations Include changes in behavior, respiration,
circulation, skin and fur, eyes, mucous membranes; evidence of
tremors or convulsions, lethargy, sleep, coma, salivation, diarrhea;
time of onset of changes and duration; time of death
All animals that died during the observation period and the survivors
were necropsied
Calculations of LD50:
Log Probit Analysis of Finney (1)
L1tchf1 eld-W1Icoxon (2)
8
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Table 3
EXPERIMENTAL DESIGN
Short Term (14-days) Repeated Oral Dosing Study
Animals:
Adult male and female CD-I ICR mice; healthy, acclimated, randomized;
earpunched for identification
Adult male and female CD rats; healthy, acclimated, randomized
10 males, 10 females per dosage level; 5 levels
Housing: 1/plastic shoebox cage with hardwood sawdust bedding
Feed: Purina Rodent Chow No. 5001; deionized water (in bottles)
Environmental Conditions:
Rooms: 22° * 2°C; relative humidity: 40-60^
Light Cycle: 12 11 ght/12 dark (7:00 a.m. - 7:00 p.m.)
Test Material:
Identity confirmed
Prepared day of administration (gavage) or twice weekly (drinking water)
Vehicles: water, corn oil, Emulphor
Gavage: 10 ml/kg/body weight; Drinking Water: chemical, toxicological or
palatability limit
Specific Conditions:
Groups: Controls: naive, vehicle, positive (occasionally);
3 treated groups, at least 20 males and 20 females per group
Cageside observations: twice daily; behavior, morbidity; mortality;
exceptions noted
Body weights: onset, days 8 and 15 and at necropsy r
Fluid consumption: twice weekly (unless gavaged)
Hematology: blood collected at necropsy; wbc (total, differential);
rbc, platelets, HCrt, Hb, coagulation
Serum chemistries: LDH, SGPT, SGOT, SAP, BUN, bilirubin, protein,
glucose, cholesterol, ALB/GLOB, P, Ca, Na, CI, K
Liver microsomal activities: cytochrome P450» cytochrome B5,
microsomal protein, aminopyrine demethylase, aniline
hydroxylase, arylhydrocarbon hydroxylase
Imune response
Genetic toxicology: testicular DNA synthesis and sperm morphology;
SCE (testes, bone marrow); mitotic Index (bone marrow)
Reproductive toxicology: in vitro penetration, fertilization,
blastula formation
Activity and behavioral measurements
Necropsy: gross observations; organ weights
Statistical Analysis: appropriate tests including Bartlett's Test
for Homogeneity, Parametric ANOVA, Dunnett's Multirange Test,
Wilcoxon Non-Parametric Test; Significance: p < 0.05
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Table 4
EXPERIMENTAL DESIGN
Subchronlc Oral Toxicity Study (90-Days)
Animals:
Adult male and female CD-I ICR mice; healthy, acclimated, randomized;
earpunched for identification
10 males, 10 females per dosage level; 5 levels
Housing: l/plast1c shoebox cage with hardwood sawdust bedding
Feed: Purina Rodent Chow No. 5001; deionized water (1n bottles)
Environmental Conditions:
Rooms: 22° * 2°C; relative humidity: 40-60%
Light Cycle: 12 light/12 dark (7:00 a.m. - 7:00 p.m.)
Test Material:
2,4-dichlorophenol
Identity confirmed
Prepared twice weekly (drinking water)
Vehicle: Emulphor (10T.t aqueous)
Specific Conditions:
Groups: Controls: naive, vehicle, positive (cyclophosphamide);
3 treated groups, at least 20 males and 20 females per group
Cageside observations: twice daily; behavior, morbidity, mortality,
exceptions noted
Body weights: onset, once weekly and at necropsy
Fluid consumption: twice weekly
Hematology: blood collected at necropsy; wbc (total, differential);
rbc, platelets, HCrt, Hb, coagulation
Serum chemistries: LDH, SGPT, SGOT, SAP, BUN, bilirubin, protein,
glucose, cholesterol, ALB/GLOB, P, Ca, Na, CI, K
Liver microsomal activities: cytochrome P45o» cytochrome B5,
microsomal protein, aminopyrine demethylase, aniline
hydroxylase, arylhydrocarbon hydroxylase, ethoxycoumarln-0-
deethylase, testosterone hydroxylation, cytochrome c reductase
Genetic toxicology: testicular DNA synthesis and sperm morphology;
SCE (testes, bone marrow); mitotic index (bone marrow)
Reproductive toxicology: in vitro penetration, fertilization,
blastula formation
Activity and behavioral measurements
Necropsy: gross observations; organ weights
Statistical Analysis: appropriate tests Including Bartlett's Test
for Homogeneity, Parametric ANOVA, Dunnett's Multirange Test,
Wilcoxon Non-Paranetric Test; Significance: p < 0.05
10
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Figure 1
IN VITRO PENETRATION AND FERTILIZATION SCHEME
Tine
(Hours)
24
Control Male
Cauda Epididymides
1
Epldidymal Sperm
I
Capacitation Medium A
15 minutes
Evaluate Motility, Viability
Control Female
(62 hr - PMSG)
(24 hr - HCG)
Oviducts
I
Ova 1n Cumulus Mass
1
Capacitation Medium B
Insemination Medium
5f, C02
(3 mi n.)
Incubator (5- CO2)
4-5 hours
Wash Ova
Insemination Medium
4
Mount on Slide
(20- 30 ova/sl ide)
1
Fixati ve
(G1utaraldehyde, Formaldehyde)
4
Stai n
I
*PMSG: Pregnant Mare Serun
Gonadotronhi n
HCG: Human Chorionic Gor.adotroohi n
Score
11
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Table 5
ACUTE ORAL TOXICITY OF CHLOROPHENOLS
IN CD-I MICE
Acute Oral LD50
(mg/kg)
Conoound
Molecular
Weight
Puri ty
Yehicle/
Sol vent
Male
Feoale
2-Chiorophenol
128.56
98* .
Dei oni zed
Water
347 .
(239-393)
(321-381)7
3-Chlorophenol
128.56
99-
Deioni zed
Water
521
(463-586)
533
(468-601)
4 Chiorophenol
128.56
99*<-
Corn Oil
1373
(1191-1583)
1422
(1333-1518)
2,3-Dichlorophenol
163.00
98:.
Corn Oil
25tf5
(2046-3266)
2376
(2186-2585)
2,4-Dichlorophenol
163.00
99'
Corn Oil
1276
(982-1569)
1352
( 1094-1670)
2,5-Di chlorophenol
163.00
98
Corn Oil
1600
(1233-2075)
946
(623-1438)
2,6-Dichlorophenol
163.00
99
Corn Oil
2198
(1727-2797)
2120
(1799-2498)
3,4-Dichlorophenol
163.00
99 :
Corn Oil
1685
(1504-1887)
2046
(1472-2846)
3,5-Di chlorophenol
163.00
991
Corn Oil
2643
(2269-3078)
2389
(1829-3120)
Pentachlorophenol
226.34
99*"
10 Emulphor
177
(125-252)
117
(65-212)
l/Confidence limits
12
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Table 6
SHORT-TERM REPEATED DOSING (14 DAYS)
2-CP, MICE
Animals: 12 males, 12 females per group
Exposure Levels: Naive control; vehicle control (corn oil);
35, 69, 175 nig/kg/day; positive control
(cyclophosphamide, 25 mg/kg)
Body Weights: Days 1, 8, 15; lower at 69 mg/kg
Mortality: All died at 175 mg/kg
Organ Weights and Ratios: Females only - + brain, liver, spleen
Hematology: NCRE*
Clinical Chemistry: NCRE
Hepatic Microsomal f-FO Activity: NCRE
Immune Response, cell mediated and humoral: NCRE
Behavioral Parameters: Hyperactivity at both doses
Sister Chromatid Exchange: NCRE
Gross Pathological Findings: None
*NCRE - No biologically or statistically significant compound
related adverse effects
13
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Table 7
SHORT-TERM REPEATED DOSING (14 DAYS)
2,4-DCP, MICE
Animals: 12 males, 12 females per group
Exposure Levels: Naive control; vehicle control (corn oil);
64, 128, 638 mg/kg/day; positive control
(cyclophosphamide, 25 mg/kg)
Body Weights: Days 1, 8, 15 - NCRE*
Mortality: 1 male at the 638 mg/kg level - NCRE
Organ Weights and Ratios: NCRE
Hematology: NCRE ( t in platelets at 638 mg/kg)
Clinical Chemistry: ~ bilirubin among all treated females only;
slight t in SGOT, SGPT in male mice at mid dose
Hepatic Microsomal ^0 Activity: + glutathione, * microsomal protein,
+ cytochrome bs among females and males at
638 mg/kg dose
Behavioral Parameters: NCRE
Sister Chromatid Exchange: NCRE
Gross Pathological Findings: None
~NCRE - No biologically or statistically significant compound
related adverse effects.
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Table 8
SU3-CHR0NIC ORAL TOXICITY (90 DAYS)
2,4-DCP, MICE
Animals: 20 males, 20 fenales per group
Exposure Levels: Naive control (deionized water); vehicle control
(101 emulphor); 0.2, 0.6, 2.0 mg/ml drinking solution
(equivalent to 50, 150, 500 mg/kg b.w./day)
Fluid Consumption: Measured twice weekly - naive controls (M and F)
had highest fluid intake; treated females consumed
more than vehicle controls
Body Weights: Weekly - NCRE*
Mortality: 1 at 150 mg/kg - NCRE
Organ Weights and Ratios: NCRE
Hematology: NCRE
Clinical Chemistry: NCRE
Hepatic Microsomal ^0 Activity: NCRE
Sister Chromatid Exchange: NCRE
Behavioral Parameters: NCRE
Gross Pathological Findings: None
In vitro Penetration: NCRE ,
Reproductive Effects: NCRE
*NCRE - No biologically or statistically significant compound
related adverse effects.
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Table 9
REPRODUCTIVE EFFECTS OF 90-DAY TREATMENT
WITH 2,4OICHL0R0PHEN9L
Total No. Total No. Total No. Mean Mean Pup
F.I.* Implants Resorptions Live Pups Litter Size Wt. (grams)
Control (naive) 90 198 5 193 11 1.08
10* Emulphor 75 166 12 154 10 1.09
0.2 mg/ml 80 181 1 180 11 1.01
0.6 ng/ml 90 198 16 182 10 1.13
2.0 mg/ml 65 160 1 159 12 1.11
v
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Table 10
PERCENT PENETRATION {MEAN * S.E.M.) OF MOUSE OVA FOLLOWING EXPOSURE
TO VARIOUS CHLOROPHENOLS AT THREE CONCENTRATIONS
COMPOUND
Treatment
2-CP
3-CPd
2,3-DCP
2,4-DCP
2,5-DCP
2,6-DCP
3,4-DCP
3,5-DCP
CdCI 2
Control
65 * 6
58
68 * 5
76 * 5
75 * 3
78 * 4
78 * 4
62 * 0
66 * 6
(90)
(41)
(158)*
(128)
(135)
(190)
(218)
(181)
(393)
0.1 itM
65 * 1
82
74 * 1
74 * 10
82 * 5
83 * 5
71 * 14
66 * 2
58 * 7
(57)
(40)
(131)
(100)
(90)
(132)
(140)
(115)
(427)
0.3 mM
65 * 5
50
82 ± 6
57 * 6
79 * 5
78 * 3
64 * 9
53 * 3
26 * 7b
(94)
(20)
(95)
(112)
(155)
(145)
(163)
(121)
(219)
1.0 rtl
65 * 1
60
78 * 3
60 * 8
50 * 3b
67 * 5
8 * 7b
7 * 3b
4 * 2b.c
(91)
(28)
(104)
(124)
(131)
(150)
(138)
(109)
(156)
F-Value
1.41
1.36
1.22
5.00a
1.85
8.243
18.68^
11.01*
*Tota1 ova observed in 4-5 experiments.
aThis F-value is significant at P £0.05. -
^Significantly different from control.
Concentration of CdCl? is 0.6 nil in this experiment,
d
One experiment.
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Table 11
SISTER CHROMATID EXCHANGE RESPONSE
FOLLOWING EXPOSURE TO CHLORINATED PHENOLS*
Compound
Route of Adninistrati on
Duration
Response
2,3-DCP
I.P.
24 hrs
__ **
2,4-DCP
I.P.
24 hrs
__ *+
2,4-DCP
Drinking Water
24 hrs
**
2,5-DCP
I.P.
24 hrs
± irk*
2,6-DCP
I.P.
24 hrs
3,4-DCP
I.P.
24 hrs
PCP
I.P.
24 hrs
*I.P. injections are routinely employed as a standard pre-
drinking water exposure screen. This may become important
when pharmacokinetic considerations are brought to bear on
the problem. To date, a descrepency between the data
obtained by either route of exposure has not been found.
**The compound was negative 1n the SCE assay.
**"*In order to be considered a positive compound in the SCE
assay, the results must exhibit a dose response relationship
and be two times greater than background. With 2,5-DCP a
dose response was established but we were unable to achieve
a two-fold increase 1n the SCE level due to toxicity.
18
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Table 12
ACUTE ORAL TOXICITY (L050) OF PHENOL AND CHLORINATED PHENOLS
Mouse (mg/kg) Rat (mg/kg)
Male
Female
Male
Female
Phenol
300
(3)*
_ _ _
530 ( 4)
2-CP
347
(5), 670 (6)
345
(5)
670 (7)
3-CP
521
(5)
530
(5)
570 (7)
4-CP
1373
(5)
1422
(5)
670 (7),
261 (8)
2,3-DCP
2585
(5)
2376
(5)
2,4-DCP
1276
(5), 1630 (10)
1352
(5)
580 (7),
28 30 (10). 4000 ( 9)
2,5-DCP
1GOO
(5)
946
(5)
2,6-DCP
2193
(5)
2120
(5)
2940 (8)
3,4-DCP
1685
(5)
2046
(5)
3,5-DCP
2643
(5)
2389
(5)
2,3,5-TCP
2,4,5-TCP
820 (7),
1620 (8)
2,3,6-TCP
2,4,6-TCP
820 (8)
3,4,5-TCP
-
^ «
2,3,4,5-TCP
400
(8)
140 (7)
2,3,4,6-TCP
2,3,5,6-TCP
109
(8)
PCP
177
(5)
117
(5)
80 (7),
78 (10), 146 (11)
175 (11)
~Reference
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REFERENCES
1. Finney, D.G.: Problt Analysts, 3rd Edition, Cambridge University Press,
London, 1971.
2. Litchfield, J.T., Jr. and Wilcoxon, F.: J. Pharmacol. Exper. Therap.
96:99-113, 1949.
3. von Oettingen, W.F. and Sharpless, N.E.: J. Pharmacol. Exper. Therap.
88 : 400, 19 4 6.
4. Diechmann, W.B. and Witherup, S.: J. Pharmacol. Exper. Therap. 80: 233,
1944.
5. Borzelleca, J.F., Hayes, J.R., Condie, L.W. and Egle, J.L., Jr.: Toxicol.
Appl. Pharmacol, (in press).
6. Bubnov, V.D.: Tr. Vses. Nauchno-Issled. Inst. Vet. Savll. 33: 258, 1969,
cited in EPA Ambient Water Quality Criteria Document for 2-Uilorophenol,
1980.
7. Deichnann, W.B.: Fed. Proc. 2: 76, 1943.
8. Lewis, R.J., Jr. and Tatkew, R.L.: Registry of Toxic Effects of Chemical
Substances, 1979.
9. Kobayashi, S., Tolda, S., Kawamura, H., Chang, H.W., Fubuda, T. and
Kawaguchi, K.: J. Med. Soc. Toho, Japan, JL9: 356, 1972, cited 1n EPA
Ambient Water Quality Criteria Document for 2,4-Dichlorophenol, 1980.
10. Vernot, E.H., MacEwen, J.D., Haun, C.C. and Kikhead, E.R.,: Toxicol.
Appl. Pharmacol. ^2: 417, 1977.
11. Gaines, T.B.: Toxicol. Appl. Pharmacol. 14: 515, 1969.
JO
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