FINAL DRAFT
United States
Env^onmenta, Protect-on 5QOECAOCING01 5
Research and
Development
HEA1TH AND ENVIRONMENTS EFFECTS DOCUMENT
FOR P-HYDRQQUINQNE
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268 U.S. Environmental Protection
Region V, Library
230 south Dearborn Street &r
Chicago, Illinois 60604 x^
DRAFT: DO NOT CITE OR QUOTE
NOTICE
This document Is a preliminary draft. It has not been formally released
by the U.S. Environmental Protection Agency and should not at this stage be
construed to represent Agency policy. It Is being circulated for comments
on Its technical accuracy and policy Implications.
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DISCLAIMER
This report 1s an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
Health and Environmental Effects Documents (HEEDs) are prepared for the
Office of Solid Haste and Emergency Response (OSWER). This document series
Is Intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for emer-
gency and remedial actions under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). Both published literature and
Information obtained from Agency Program Office files are evaluated as they
pertain to potential human health, aquatic life and environmental effects of
hazardous waste constituents. The literature searched for In this document
and the dates searched are Included In "Appendix: Literature Searched."
Literature search material 1s current up to 8 months previous to the final
draft date listed on the front cover. Final draft document dates (front
cover) reflect the date the document 1s sent to the Program Officer (OSWER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include Reference doses {RfDs)
for chronic and subchronlc exposures for both the Inhalation and oral
exposures. The subchronlc or partial lifetime RfD, Is an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval, for example, one that does
not constitute a significant portion of the Hfespan. This type of exposure
estimate has not been extensively used, or rigorously defined as previous
risk assessment efforts have focused primarily on lifetime exposure
scenarios. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchronlc RfDs Is the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
In the cas° of suspected carcinogens, RfDs are not estimated. A
carcinogenic potency factor, or q-|* (U.S. EPA, 1980), Is provided Instead.
These potency estimates are derived for both oral and Inhalation exposures
where possible. In addition, unit risk estimates for air and drinking water
are presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxldty and carclno-
genlclty are derived. The RQ Is used to determine the quantity of a hazar-
dous substance for which notification 1s required 1n the event of a release
as specified under the CERCLA. These two RQs (chronic toxldty and cardno-
genldty) represent two of six scores developed (the remaining four reflect
IgnltablHty, reactivity, aquatic toxldty, and acute mammalian toxlclty).
Chemical-specific RQs reflect the lowest of these six primary criteria. The
methodology for chronic toxldty and cancer-based RQs are defined In U.S.
EPA, 1983 and 1986a, respectively.
111
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EXECUTIVE SUMMARY
p-Hydroqu1none Is a white crystalline solid at room temperature; It Is
soluble In water and a variety of organic solvents (Hawley, 1981; Varagnat,
13,81). It Is currently produced by two U.S. manufacturers (Eastman Kodak
and Goodyear), with a combined annual production capacity of 34 million
pounds (SRI, 1986), p-Hydroqulnone and Its derivatives are used as
developers 1n black-and-wh1te photography and 1n other applications such as
lithography and x-ray films (Varagnat, 1381). It Is also used as an Inter-
mediate to produce antloxldants for rubber and food. p-Hydroqulnone 1s added
to a number of Industrial monomers to Inhibit polymerization during
shipping, storage and processing (Varagnat, 1981).
p-Hydroqulnone Is not a persistent compound 1n the environment. In the
atmosphere, p-hydroqu1none will react In the vapor-phase with hydroxyl
radicals at an estimated half-life of -14' hours. In the aquatic environ-
ment, photooxldatlon of p-hydroquinone can be expected to be a major removal
process 1n sunlit natural waters. The half-lives for the oxidation of
p-hydroqu1none by hydroxyl radicals and by peroxy radicals are 20 hours and
12 minutes, respectively, 1n typical natural water (Mill and Mabey, 1985).
p-Hydroqu1none has been found to be biodegradable In aquatic media (Harbison
and Kelly, 1982). Hydrolysis, volatilization, adsorption to sediment and
bloconcentratlon are not expected to be Important. In soil, p-hydroqu1none
may be susceptible to free radical oxidation (Dragun and Helling, 1985).
Estimated K values (10-50) Indicate that leaching 1n soil may be
significant. Leaching through soil to groundwater is possible in the
absence of significant degradation processes. In a laboratory
1v
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experiment, the persistence of p-hydroqu1none 1n a chernozem soil was found
to be only 1 day at a concentration of 500 lag/leg (Medvedev and Oavldov,
1981a,b).
A National Occupational Hazard Survey conducted between 1972 and 1976
estimated that 378,028 U.S. workers In 132 occupational categories were
possibly exposed to p-hydroqulnone annually (NIOSH, 1984). More recently,
NIOSH estimated that -470,000 U.S. workers In 137 occupations may be exposed
to p-hydroqu1none annually (U.S. EPA, 1984). p-Hydroqulnone has been
detected In wastewater effluents frora chemical plants (Shackelford and
Keith, 1976), coal-tar chemical production (IARC, T977) and coal
gasification processes (Mohr and King, 1985). p-Hydroqu1none has also been
detected 1n cigarette smoke and 1n dlesel engine exhausts (IARC, 1977;
Graedel, 1978). Adequate data were not available to permit estimation of
the average dally human exposure to this compound.
The lowest reported toxic concentrations for freshwater fishes. Inverte-
brates and bacteria are all -0.04 mg/8. p-hydroqulnone. The data for
freshwater plant species are highly variable but seem to Indicate that
plants are somewhat less sensitive, with the lowest reported toxic concen-
trations close to 1 mg/i. There Is too Uttle Information about p-hydro-
qulnone effects on marine species to draw any conclusions.
Pharmacoklnetlc studies Indicate that following oral administration,
p-hydroqulnone Is absorbed rapidly, conjugated with sulfate and glucuro-
nlde, and excreted In the urine. These results have been found In humans
(Fassett and Roudabush, 1952), rabbits (Garton and Williams, 1949) and rats
(D1v1ncenzo et al., 1984). Cats metabolize p-hydroqu1none primarily to
p-hydroqu1none sulfate (Miller et al., 1976).
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Davis (1979) did not find p-hydroqu1none In the blood of rats 15 minutes
to 6 hours after they were given oral doses of p-hydroqu1none. In distri-
bution studies of radlolabeled p-hydroqu1none Injected Into rats, Greenlee
et al. (1981a,b) found that residual radioactivity associated with
A4C-laJbeled p-hydroqu1none was concentrated 1n the bone marrow and
lymphoid organs.
At physiologic ptt, p-hydroqulnoas autoxldl^es to qu1no*i {Greenlee et
al., 1981b). However, this reaction has not been shown to occur In vivo.
Women who used cosmetic p-hydroqu1none ointments excreted higher concen-
trations of urinary volatile phenols than women who did, not yse the oint-
ments (Kahambwe et al., 1986).
Eye lesions have been reported In workers exposed to p-hydroqu1none dust
and qulnone vapor (Sterner et al., 1947; Anderson, 1947; Miller, 1954). The
severity of eye lesions Increased with the length of exposure, and the
lesions can progress even after exposure has ended. Concentrations found 1n
a plant where eye Injuries were observed were 0.044-14.1 mg/m3 qulnone and
20-36 mg/m3 p-hydroqu1none (Oglesby et al., 1947). At these levels, no
signs of systemic Intoxication were noted In workers with or without eye
lesions (Sterner et al., 1947).
In a subchronlc toxldty study, Carlson and Brewer (1953) found that
rats fed a diet containing 5% p-hydroqu1none for 9 weeks ate less, lost
weight and developed aplastlc anemia. Atrophy of the bone marrow and other
tissues, and superficial ulceratlon and hemorrhage of the stomach were
noted. No changes were observed In dogs fed p-hydroqu1none at up to a TWA
dose of 25.1 mg/kg/day for 80 weeks or 100 mg/kg/day for 26 weeks (Carlson
and Brewer, 1953). Blood analyses and urlnalyses revealed no effects
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In humans fed p-hydroqulnone at 300-500 mg/day for 3-5 months (Carlson and
Brewer, 1953). No effects were noted In Syrian hamsters fed p-hydroqu1none
In the diet at 0.5% for 20 weeks (Hlrose et al., 1986).
Mozhayev et al. (1966) found that rats treated with p-hydroqulnone' In
the drinking water at 100 rag/kg/day gained weight slower than controls.
Rats treated at 50 mg/kg/day or more exhibited a decrease In the number of
erythrocytes, and an Increase In the number of leukocytes and dystrophlc
changes 1n the small Intestines, liver, kidneys and myocardium. Nakamura
(1982) found lowered heraatocrlt and a decrease In the number of bone marrow
cells In »1c* provided with p-toydroqo1none In the drinking water at 4 g/J,
(4000 ppm) for 4 weeks.
Delcambre et al. (1962) observed blood effects 1n rats treated by gavage
with p-hydroqu1none at 15 mg/kg, 6 days/week for 40 days. These effects
were not observed 1n rats treated at 7.5 mg/kg/day for 40 days, or In rats
treated at 5 and 10 mg/kg, 6 days/week for 4 months. Mortality was high In
the 10 mg/kg group. Rats treated orally at 156 mg/kg for 30 days showed
Increased liver weights, decreased hepatic glycogen and vitamin C content
and decreased blood serum protein levels (Anlkeeva, 1974).
In an 8-week study (Christian et al., 1980), a depression In body weight
was observed 1n rats treated with p-hydroqu1none In the drinking water at
>470 mg/kg/day. Changes 1n relative organ weights were observed 1n rats
treated at >390 mg/kg/day. There were no effects at <270 mg/kg/day. In a
15-week study (Christian et al., 1980), the only significant change was an
Increase In relative liver and kidney weights In rats provided with p-hydro-
qulnone 1n the drinking water at >110 mg/kg/day.
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The NTP sponsored a 13-week gavage study (Keller, 1982; Bloassay Systems
Corp., 1981a) 1n which rats died at >200 mg/kg/day. Survivors were lethar-
gic, and toxic nephropathy and squaraous hyperplasla and acanthosls of the
stomach were observed. There were no effects at <100 mg/kg/day. The NTP
13-week gavage study using alee (Keller, 1982; Bloassay Systems Corp.,
198113) resulted In death at >200 mg/kg/day. Males treated dally at >25
mg/kg and females at >H3Q mg/kg wer-e lethargic, and hunched posture was
observed at >200 mg/kg. The only significant hlstopathologlc effects were
forestomach lesions at >200 mg/kg/day.
In a oral toxlclty study [Vtoodard, 1951), no changes In body weight gain
or blood counts were observed 1n dogs treated with p-hydroqu1none In TWA
doses of 21.5 and 42.9 mg/kg/day for 810 days. Hyperplasla of the bone
marrow and excessive pigment deposits In the spleens were observed In all
dogs. No changes In hematologlcal parameters or hlstopathology were noted
In rats fed p-hydroqu1none In the diet at concentrations up to 1% for 103
weeks (Carlson and Brewer, 1953).
Gastrointestinal disease attributed to p-hydroqu1none was reported In
crewmen aboard a navy vessel (Hooper et al., 1978). Other symptoms noted In
humans Ingesting p-hydroqulnone at relatively large doses, Include acldosls,
anemia, erosion of the gastric mucosa, edema of Internal organs, convul-
sions, coma and death (NIOSH, 1978).
A review of all the p-hydroqu1none toxldty data by the Cosmetic
Toiletry and Fragrance Assoc. (1986) concluded that p-hydroqu1none Is "safe
for cosmetic use at concentrations of <1.0/4 1n formulations designed for
discontinuous, brief use followed by rinsing from the skin and hair."
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In a 14-day gavage study sponsored by NTP (Davis, 1979), doses of 1000
and 500 rag/kg were lethal to rats, while 500 and 250 mg/kg doses were lethal
to mice. Rats at all doses (>63 mg/kg/day) lost weight. Gross pathology
revealed no consistent changes In either rats or mice.
The acute oral LD5Q ranged from -200-1200 mg/kg In rats, dogs, mice
and guinea pigs depending on the solvent of p-hydroquinone (Anlkeeva, 1974;
Carlson and Brewer, 1953; Lehman et a!., 1951). The compound Is more toxic
to cats, with an oral L05Q of 42-86 rog/kg (Carlson and Brewer, 1953).
No studies concerning the carclnogenlclty of p-hydroqu1none by either
the Initiation or oral routes of exposure were located. A gavage study of
the carclnogenlclty of p-hydroqu1none has been completed but the data are
not yet available (NTP, 1987).
An Increased tumor Incidence was observed 1n mice In which cholesterol
pellets containing 20% p-hydroqu1none were Implanted 1n the bladder (Boyland
et al., 1964). In an 18-week study, no Increased skin tumor Incidences were
observed In mice treated weekly with p-hydroqulnone and croton oil (Roe and
Salaman, 1955). Boutwell and Bosch (1959) concluded that p-hydroqu1none was
Inactive as a promoter In mouse skin following a single application of DHBA.
Holmberg et al. (1986) found that after an 1ntraper1toneal dose of DENA,
p-hydroqulnone administered orally to rats at 100 mg/kg resulted In a
significant elevation of y-glutamyl-transpeptldase positive foci 1n the
liver. p-Hydroqu1none Injected Into laboratory animals results In arrested
metaphase (Parmentler and Dustln, 1948; Parmentler, 1953; Rosin and
Doljanske, 1953).
p-Hydroqu1none Injected subcutaneously Into mice with melanoma Increased
survival (Chavln et al., 1980).
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p-Hydroqu1none tested positive for reverse mutation 1n £. typhlmuMum on
ZLM medium but was negative on VB medium {Gocke et al., 1981). The remain-
ing Ames type assays have been negative (Goodyear Tire and Rubber Co., 1982;
Sakal et al., 1985). DNA damage was observed when p-hydroqu1none was tested
E.. coll (Goodyear Tire and Rubber Co., 1982).
Negative results have been found 1n studies of sex-1Inked recessive
lethal mutations In J). melanoqaster (Gocke et al., 1981; Goodyear Tire and
Rubber Co., 1982) ami 1n a test for DNA damage In mouse lymphoma cells
(Pel lack-Walker and Sluraer, 1986). p-Hydroqu1none did not transform
BaW3T3 wous* cells (Goodyear "Hre and Rubber Co., 1982). Post «t al.
(1984), Penney et al. (1984) and Painter and Howard (1982) have shown that
p-hydroqu1none Inhibits DNA and RNA synthesis. p-Hydroqu1none has been
shown shown to Increase the rate of SCE 1n human lymphocytes (MoMmoto and
Wolff, 1980; Knadle, 1985; Erexson et al., 1985).
p-Hydroqu1none tested positive In 'a mouse mlcronucleus test (Gocke et
al., 1981). A spot test In mice was negative (Gocke et al., 1983). Jowa et
al. (1986) found that _^n_ vitro. p-hydroqu1none reacts with deoxyguanoslne
and DNA to form two adducts.
An Increase In the resorptlon rate was observed In rats fed a total of
0.5 g of p-hydroqu1none throughout gestation (Telford et al., 1962). The
only effects noted In rats dosed by gavage with p-hydroqulnone on gestation
days 6-15 at doses of 300 mg/kg, were decreased maternal weight gain and
decreased female fetal weights (Krasavage, 1985). No effects were observed
at <100 mg/kg.
The number of young produced In two successive Utters by male and
female rats fed p-hydroqulnone 1n their diet for 6 months at levels up to 1%
were similar to controls (Carlson and Brewer, 1953). Female rats fed
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p-hydroqulnone In the diet at concentrations up to 0.3% for 10 days before
mating and throughout gestation showed no changes In reproductive parameters
(Ames et al., 1956).
Racz et al. (1959) found that oral administration of p-hydroqulnone at
200 mg/kg/day and possibly at 50 and 100 mg/kg/day for 2 weeks prolonged
estrus In female rats. In a study by Skalka (1964), reduced fertility was
observed 1n male rats subcutaneously Injected with p-hydroqu1none at 100
mg/kg/day for 51 days before mating. Other effects noted were decreased
testes, ep1d1dym1des, seminal vesicle and suprarenal gland weights.
Data regarding ttw carcinogenItIty of p-foydroqtJltvone were Inatteqnate to
perform quantitative risk assessments based on carclnogenlcHy. p-Hydro-
qulnone, therefore, was classified as an EPA Group D chemical.
An RfD of 0.4 mg/kg/day or 30 mg/day for a 70 kg human for subchronlc
oral exposure and of 0.04 mg/kg/day or 3 mg/day for chronic oral exposure
were derived based on a NOAEL of 300 mg/day (4.3 mg/kg/day) for 3-5 months
1n humans In the study by Carlson and Brewer (1953). An uncertainty factor
of 10 for the protection of the most sensitive Individuals was used for the
subchronlc oral RfD. An uncertainty factor of 100 (an additional factor of
10 for the use of a subchronlc NOAEL) was used for the chronic oral RfD.
Confidence 1n the chronic oral RfD Is medium to low because the study was
subchronlc 1n humans and examined urine and blood parameters, also an
assessment of the potential cardnogenldty of the chemical 1s pending the
results of the NTP bloassay.
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TABLE OF CONTENTS
Page
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS REGISTRY NUMBER. 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 2
1.5. SUMMARY 4
2. ENVIRONMENTAL FATE AND TRANSPORT , 5
2.1. AIR 5
2,2. UATJ-B 5
2.2.1. Hydrolysis 5
2.2.2. Photoox1dat1on 5
2.2.3. Mlcroblal Degradation 6
2.2.4. Volatilization 6
2.2.5. Adsorption 6
2.2.6. 81oconcentrat1on 6
2.3. SOIL 9
2.3.1. Chemical Degradation 9
2.3.2. Mlcroblal Degradation 9
2.3.3. Adsorption 9
2.3.4. Persistence -. . . 10
2.4. SUMMARY 10
3. EXPOSURE 11
3.1. WATER 11
3.2. FOOD 11
3.3. INHALATION 11
3.4. DERMAL 12
3.5. SUMMARY 12
4. AQUATIC TOXICITY 13
4.1. ACUTE TOXICITY 13
4.2. CHRONIC EFFECTS 13
4.3. PLANT EFFECTS 16
4.4. SUMMARY 16
5. PHARMACOKINETCS 19
5.1. ABSORPTION 19
5.2. DISTRIBUTION 19
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TABLE OF CONTENTS (cont.)
Page
5.3. METABOLISM . 20
5.4. EXCRETION 22
5.5. SUMMARY 22
6, EFFECTS 24
6.1. SYSTEMIC TOXICITY 24
6,1.1. Inhalation Exposures 24
6.1.2. Oral Exposures 26
6.1.3. Other Relevant Information 33
6.2. CARCINQGENICITY . . . . 39
fc.2.1. Inhalation. 39
6.2.2. Oral 39
6.2.3. Other Relevant Information 40
6.3. MUTAGENICITY 41
6.4. TERATOGENICITY 45
6.5. OTHER REPRODUCTIVE EFFECTS 46
6.6. SUMMARY 48
7. EXISTING GUIDELINES AND STANDARDS 53
7.1. HUMAN 53
7.2. AQUATIC 53
8. RISK ASSESSMENT 54
8.1. CARCINOGENICITY 54
8.1.1. Inhalation 54
8.1.2. Oral 54
8.1.3. Other Routes 54
8.1.4. Weight of Evidence 55
8.1.5. Quantitative Risk Estimates 55
8.2. SYSTEMIC TOXICITY 55
8.2.1. Inhalation Exposure 55
8.2.2. Oral Exposure 57
9. REPORTA8LE QUANTITIES 61
9.1. BASED ON SYSTEMIC TOXICITY 61
9.2. BASED ON CARCINOGENICITY 65
10. REFERENCES 67
APPENDIX A: LITERATURE SEARCHED 87
APPENDIX B: SUMMARY TABLE FOR p-HYDRIQUINONE 90
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LIST OF TABLES
No. TUIe Page
1-1 p-Hydraqu1none Production Data for 1977 3
2-1 81odegradat1on Test Results for p-Hydroqu1none 7
4-1 Acute Toxldty of p-Hydroqu1none to Freshwater F1sh 14
4-2 Acute Toxldty of p-Hydroqu1none to Aquatic
Invertebrates 15
4-3 Acute ToxIcHy of p-Hy
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LIST OF ABBREVIATIONS
BCf B1oconcentrat1on factor
BHA Butylated hydroxyanlsole
bw Body weight
CAS Chemical Abstract Service
CNS Central nervous system
COO Chemical oxygen demand
CS Composite score
0£MA N,N~d1ethyln1trosaralne
OHBA Dlmethylbenzanthracene
DNA Deoxyrlbonuclelc acid
DOC Dissolved organic carbon
ECso Concentration effective to 50/4 of recipients
(and all other subscripted concentration levels)
Koc Soil sorptlon coefficient standardized
with respect to organic carbon
Kow Octanol/water partition coefficient
Concentration lethal to 50% of recipients
(and all other subscripted dose levels)
Dose lethal to 50% of recipients
LOAEL Lowest-observed-adverse-effect level
MED Minimum effective dose
NMR Nuclear magnetic resonance
NOAEL No-observed-adverse-effect level
NOEC No-observed-effect concentration
PEL Permissible exposure limit
ppm Parts per million
RBC Red blood cell
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LIST OF ABBREVIATIONS (cont.)
RfD Reference dose
RNA Rlbonucleic add
RQ Reportable quantity
RVjj Dose-rating value
RVe Effect-rating value
SCE Slster-chromaild exchange
ThOO Theoretical oxygen demand
TLV Threshold limit value
TWA Time-weighted average
UV Ultraviolet
W8C White blood cell
xv1
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1. INTRODUCTION
1,1. STRUCTURE AND CAS REGISTRY NUMBER
p-Hydroqu1none Is the common chemical name, but this compound Is also
known as 1,4-benzened1ol, 1,4-d1hydroxybenzene, hydroqulnol, p-d1hydroxy-
benzene and p-hydroxyphenol (U.S. EPA, 19865). The structure, molecular
weight, empirical formula and CAS Registry number for p-hydroqu1none are as
follows:
H
H
Molecular weight: 110.06
Empirical formula: C^H^O-
CAS Registry number: 123-31-9
1.2. PHYSICAL AND CHEMICAL PROPERTIES
p-Hydroqu1none 1s a white crystalline solid (Hawley, 1981) that Is
soluble 1n water, alcohol, ether, acetone and carbon tetrachlorlde, but only
slightly soluble 1n benzene (Varagnat, 1981). Selected physical properties
are listed below:
Melting point:
Boiling point:
Specific gravity:
g/cm3 (15/4°C)
Water solubility:
at 15'C
at 25°C
at 60°C
Vapor pressure:
at 25°C
at 132°C
172°C
287°C
1.332
59,000 ppm
70,000 ppm
260,000 ppm
0.000019 mm Kg
1.0 mm Hg
Varagnat, 1981
Varagnat, 1981
Varagnat, 1981
Verschueren, 1983
Verschueren, 1983
Varagnat, 1981
Jones, 1960
Perry and Green, 1984
0049d
-1-
07/14/87
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Log Kow:, 0.59 Hansch and Leo, 1981
pKa at 30*C: 9.914 Varagnat, 1981
Flash point: 165*C (closed cup) Varagnat, 1981
A1r conversion
factor at 25°C: 1 ppm = 4.50 mg/m3 Verschueren, 1983
Chemically, p-hydroqu1none undergoes the typical reactions of phenols
(Varagnat, 1981). It undergoes the normal esierlfIcatlon and etherlfIcatlon
reactions, giving rise to mono- and dlesters and ethers. It 1s autooxldlzed
tn aqueous solutions by reacting with oxygen and 1s easily tialogenated and
sulfonated. Oxidation, which becomes rapid In the presence of alkali,
causes solutions of p-hydroqulnone to turn brown In air (Wlndholz, 1983).
1.3. PRODUCTION DATA
Production data available from the public portion of the U.S. EPA TSCA
Production File for 1977 1s presented In Table 1-1. p-Hydroqu1none 1s
currently manufactured by Eastman Kodak (Tennessee Eastman) In Klngsport,
TN, and by Goodyear T1re 1n Bayport, TX (SRI, 1986); their combined annual
production capacity Is 34 million pounds. In 1983, 0.433 million pounds of
p-hydroqu1none was Imported through principal U.S. customs districts (USITC,
1984).
p-Hydroqu1none Is manufactured 1n the United States by either the
oxidation of aniline or by the hydroperoxldatlon of d11sopropylbenzene
(Varagnat, 1981). Eastman Kodak uses the aniline process while Goodyear
uses the d11sopropylbenzene process (SRI, 1986).
1.4. USE DATA
The estimated domestic use pattern of p-hydroqu1none Is as follows
(Varagnat, 1981): photographic developers, 45%; antloxldants and polymeri-
zation Inhibitors, 50%; other, 5%. p-Hydroqulnone and Us derivatives are
0049d -2- 07/14/87
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TABLE 1-1
p-Hydroqu1none Production Data for 1977*
Company
Manufacturer/Importer
Production Range
(pounds)
Tennessee Eastman
fioody«ar T1re & Rubber
Haven Chem.
Carcus Chem.
EM Laboratories
Fallek Chem.
Agfa-Gevaett.Inc.
SPS Technologies
Sakal Trading NY
MHsul & Co.
Phlllpp Br1s. Chem.
Holtrachem. Inc.
Rhone-Poulenc, Inc.
Confidential
manufacturer
manufacturer
manufacturer
manufacturer
Importer
Importer
Importer
Importer
Importer
Importer
Importer
Importer
confidential
confidential
10-50 million
1-10 «mion
1-10 thousand
confidential
confidential
1-10 thousand
10-100 thousand
<1000
none
10-100 thousand
confidential
none
1-10 thousand
0.1-1.0 million
*Source: U.S. EPA, 1977
0049d
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06/02/87
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used as developers In black-and-white photography and In a variety of other
applications such as lithography and x-ray films {Varagnat, 1981). p-Hydro-
qulTKjne 1s used as an Intermediate to produce antloxldants for rubber and
food (Varagnat, 1981); the main food antioxldant Is BHA. p-Hydroqu1none Is
added to a number of industrial monomers to Inhibit polymerization during
shipping, storage and processing and Is also used as a chemical Intermediate
{Varagnat, 1981).
1.5. SUMMARY
p-Hydroqulnone Is a white crystalline solid at room temperature; It 1s
soluble 1n water and a variety of organic solvents (Hawley, 1981; Varagnat,
1981). It 1s currently produced by two U.S. manufacturers (Eastman Kodak
and Goodyear), with a combined annual production capacity of 34 million
pounds (SRI, 1986). p-Hydroqu1none and Us derivatives are used as
developers 1n black-and-white photography and In other applications such as
lithography and x-ray films (Varagnat, 1981). It Is also used as an Inter-
mediate to produce antloxldants for rubber and food. p-Hydroqulnone 1s added
to a number of Industrial monomers to Inhibit polymerization during
shipping, storage and processing (Varagnat, 1981).
0049d -4- 07/14/87
-------
2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
The vapor pressure of p-hydroqu1none (0.0130013 nro Hg at 25*t, see
Section 1.2.) suggests that It may exist In both the vapor- and participate
adsorbed-phases 1n the ambient atmosphere (Elsenrelch et al., 1981). In the
vapor-phase, p-hydroqu1none win degrade quite rapidly. The estimated rate
constant for the vapor-phase reaction of p-hydroquinone with photochemical!y
produced hydroxyl radicals In the atmosphere 1s 1.7xlO~ai cm3/molecule-
sec at 258C (U.S. EPA, 1987). Giving a typical atmospheric hydroxyl radical
concentration of S.OxlQ3 molecules/cm*, the estimated half-life Is ~14
hours for this reaction (U.S. EPA, 1987).
p-Hydroqulnone absorbs light significantly at wavelengths >290 nm
(Sadtler, 1966) and has been shown to photomlnerallze to carbon dioxide when
adsorbed to silica gel and exposed to light (Kotzlas et al., 1979). There-
fore, p-hydroqu1none adsorbed to partlculates 1n the atmosphere, may be 'sus-
ceptible to photolysis; however, this 1s likely to depend on the nature of
the adsorbing substrate. Partlculates 1n the atmosphere may be physically
removed by wet and dry deposition.
2.2. WATER
2.2.1. Hydrolysis. Since p-hydroqu1none does not contain functional
chemical groups that are susceptible to environmental hydrolysis, hydrolysis
Is not expected to be Important.
2.2.2. Photoox1dat1on. Photoox1dat1on of p-hydroqu1none 1s expected to
be a major removal process In sunlit natural waters. The half-lives for the
oxidation of p-hydroqu1none by photochemlcally produced hydroxyl radicals
and by peroxy radicals are 20 hours and 12 minutes, respectively, 1n typical
natural water (Mill and Mabey, 1985).
0049d -5- 06/02/87
-------
2.2.3. M1crob1al Degradation. The b1odegradabH1ty of p-hydroqu1none has
been studied by a number of Investigators. Table 2-1 presents the results
of selected blodegradatlon tests, which demonstrate that p-hydroqulnone may
be biodegradable in natural waters.
Harbison and Kelly (1982) reviewed literature, pertaining to the
blodegradatlon of p-hydroqu1none. In general, Warburg resplrometer studies
have shown that p-hydroquinone requires an acclimation period when exposed
to activated sludges. In addition, Inhibitory effects can occur 1n unaccll-
mated sludge systems exposed to concentrations >50~100 ppm. The authors
experimentally tJenonstrated ttiat p-tiydroqu1none present 1n a synthetic
photographic waste stream at a concentration of 100 ppm was readily degraded
by an acclimated activated sludge.
p-Hydroqu1none has also been shown to be biodegradable under anaerobic
conditions (Young and Rivera, 1985; Szewzyk et al, 1985; Speece, 1983; Chou
et al.t 1979).
2.2.4. Volatilization. Based on a water solubility of 70,000 ppm and a
vapor pressure of 0.000019 mm Hg at 25°C (see Section 1.2.), the Henry's Law
constant for p-hydroqulnone is estimated to be 3.9xlO~10 atm-m3/mol.
This value of Henry's Law constant Indicates that volatilization from water
1s not environmentally Important (Lyman et al., 1982).
2.2.5. Adsorption. Based on a relatively high water solubility (70,000
ppm at 25°C) and low log K (0.59), adsorption to sediments in the
aquatic environment 1s not likely to be important.
2.2.6. B1oconcentrat1on. The 8CF for p-hydroqulnone in goldfish was
experimentally determined to be 40 in a 3-day static system test (Freltag et
al., 1984). In a 1-day static system test, a BCF of 40-65 was determined
for p-hydroqu1none 1n algae (Freltag et al., 1984; Geyer et al., 1981).
0049d -6- 06/02/87
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The BCF of an organic chemical can be estimated from the following
regression equations (Lyman et a"!., 1982):
log BCF = 0.76 log KQW - 0.23 (2-1)
log BCF = 2.791-0.564 log WS (In ppra) (2-2)
For p-hydroqulnone, the BCf values calculated from Equations 2-1 and 2-2 are
-2 and 1, respectively, based on a Tog K of 0.59 and a water solubility
of 70,000 ppffl. These BCF values and the experimental BCF values Indicate
that p-hydroqu1none Is not expected to bloconcentrate significantly In
aquatic organisms.
2.3. SOIL
2.3.1. Chemical Degradation. Dragun and Helling (1985) listed p-hydro-
qulnone as an organic compound that can be oxidized at soil and clay
surfaces by free radical mechanisms. Oxidation causes aqueous solutions of
p-hydroqu1none to turn brown In air; the process becomes very rapid In the
presence of alkali (Wlndholz, 1983). It Ys therefore likely that p-hydro-
qulnone will undergo oxidation 1n soils, particularly at higher soil pHs.
2.3.2. M1crob1al Degradation. p-Hydroqulnone Is biodegradable under both
aerobic and anaerobic conditions (see Section 2.2.3.). The quantitative
significance of blodegradatlon In soil Is not clear, however, from the
available data.
2.3.3. Adsorption. The K of an organic chemical can be estimated
from the following regression equations (Lyman et al., 1982):
log KQC = 3.64-0.55 Log WS (In ppm) (2-3)
Log KQC = 0.544 Log KQW * 1.377 (2-4)
For p-hydroqu1none, the K values calculated from Equations 2-3 and 2-4
are -10 and 50, respectively, based on a water solubility of 70,000 ppm and
a log KQw of 0.59. These K values Indicate very high to high soil
0049d -9- 07/14/87
-------
mobility (Swann et a"!., 1983). Therefore, p-hydroqu1none Is susceptible to
significant leaching from soil to groundwater In the absence of significant
degradation processes.
2.3.4. Persistence. Hedvedev and Davidov (1981a,b) examined the rate of
degradation of .p-hydroquInane in chernozem soil (.554 humus content) at 19°C
1n laboratory tests. p-Hydroqu1none 1n the soil at an Initial concentration
of 500 rag/kg persisted for only 1 day,
2.4. SUMMARY
p-Hydroqu1none 1s not a persistent compound In the environment. In the
atmosphere, p-hytfroqu1none will react In the vapor-phase with hydroxyl
radicals at an estimated half-life of -14 hours. In the aquatic environ-
ment, photooxldatlon of p-hydroqu1none can be expected to be a major removal
process 1n sunlit natural waters. The half-lives for the oxidation of
p-hydroqu1none by hydroxyl radicals and by peroxy radicals are 20 hours and
12 minutes, respectively, 1n typical natural water (Mill and Mabey, 1985).
p-Hydroqu1none has been found to be biodegradable 1n aquatic media (see
Table 2-1) (Harbison and Kelly, 1982). Hydrolysis, volatilization, adsorp-
tion to sediment and bloconcentratlon are not expected to be Important. In
soil, p-hydroqu1none may be susceptible to free radical oxidation (Dragun
and Helling, 1985). Estimated K values (10-50) Indicate that leaching
1n soil may be significant. Leaching through soil to groundwater 1s
possible 1n the absence of significant degradation processes. In a labora-
tory experiment, the persistence of p-hydroqu1none 1n a chernozem soil was
found to be only 1 day at a concentration of 500 mg/kg (Hedvedev and
Oavldov, 1981a,b).
0049d -10- 06/02/87
-------
3. EXPOSURE
A National Occupational Hazard Survey conducted between 1972 and 1976
estimated that 378,028 U.S. workers in 132 occupational categories might
have been exposed to p-hydroqu1none (NIOSH, 1984). More recently, NIOSH
estimated that potentially -470,000 U.S. workers in 137 occupations might be
exposed to p-hydroqu1none annually (U.S. EPA, 1984).
3.1. WATER
p-Hydroqu1none was detected In a wastewater effluent from a chemical
plant 1n Ra1*1gh, Nt, 1n 1974 (SJwclcelford and Keith, 1976). It was
detected in effluents from the production of coal-tar chemicals (IARC, 1977)
and 1n effluents from coal gasification processes (Mohr and King, 1985).
The U.S. EPA STORET Data Base contained no data on p-hydroqu1none.
p-Hydroquinone might be released to the aquatic environment from a
variety of wastewater effluents resulting from industrial applications.
Disposal of used photographic developing solutions containing p-hydroquinone
is one possible source (Dynamac Corp., 1982).
3.2. FOOD
Pertinent food monitoring data could not be located in the available
literature as cited in Appendix A.
3.3. INHALATION
p-Hydroquinone has been detected 1n cigarette smoke and in diesel engine
exhausts (IARC, 1977; Graedel, 1978). No ambient atmospheric monitoring
data were located, although this compound is known to be released to the
atmosphere during methyl methacrylate manufacture and production of coal tar
chemicals (Dynamac Corp., 1982).
0049d -11- 06/02/87
-------
3.4. DERMAL
- Pertinent data regarding dermal exposure could not be located 1n the
available literature as cited In Appendix A; however, dermal exposure would
seem to be possible during use of photographic developing solutions contain-
ing p-hydroqulnone.
3.5. SUMMARY
A National Occupational Hazard Survey conducted between 1972 and 1976
estimated that 378,028 U.S. workers In 132 occupational categories were
possibly exposed to p-hydroqu1none annually (NIOSR* 1984). More recently,
HIOSH estimated that -470.000 U.S. workers In 137 occupations way be exposed
to p-hydroqu1none annually (U.S. EPA, 1984). p-Hydroqulnone was detected 1n
wastewater effluents from chemical plants (Shackelford and Keith, 1976),
coal-tar chemical production (IARC, 1977) and coal gasification processes
(Mohr and King, 1985). p-Hydroqu1none was detected In cigarette smoke and
1n dlesel engine* exhausts '(IARC, 1977; Graedel, 1978). Adequate data were
not available to permit estimation of the average dally human exposure to
this compound.
0049d -12- 07/14/87
-------
4. AQUATIC TOXICITY
4.1. ACUTE
The available data concerning acute toxIcHy of p-hydroquinone to fresh-
water fishes are presented in Table 4-1. The lowest reported toxic concen-
tration was 0.044 mg/l, a 96-hour LCrQ for fathead minnows, Pimephales
promelas (Degraeve et al., 1980). Additional data were provided by
Applegate et al. (1957), who reported that 5 mg/s, was lethal to rainbow
trout, Salmo qairdnerl. bluegllls, Leporols macrochirus, and larval sea
lampreys, Petroaiyzon marinus. Bandt (1955) reported that 0.2 rog/a was a
toxic threshold for carp, Cvorlnus carpio, perch, Perta sp., and stickle-
back, Gasterosteus sp. No data on marine fish species were found.
Acute toxicity data for Invertebrates are presented in Table 4-2. The
lowest reported toxic concentration was 0.05 mg/d, a 96-hour LC50 for
Daphnia magna (NAPM, 1974). Among the freshwater species tested, the clado-
cerans Daphnia magna and Daphnia pullcaria appeared to be more sensitive
than the other freshwater Invertebrates tested, i.e., three species of
protozoa and one rotifer (see Table 4-2). The only data available for
marine invertebrates was a lethal threshold of 0.83 for shrimp, Cranqon
septemspinosa (McLeese et al., 1979).
4.2. CHRONIC
Pertinent data regarding chronic toxicity of p-hydroquinone to aquatic
organisms could not be located in the available literature as cited in
Appendix A.
0049d -13- 06/02/87
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4.3. PLANT EFFECTS
Information concerning effects of p-hydroqu1none on aquatic plants and
bacteria 1s presented In Table 4-3. The data for aquatic plants show a
great deal of variability, with the lowest reported toxic concentration
being 0.93 mg/l, a threshold for Inhibition of cell multiplication In the
green alga, Scenedesmus quadrlcauda (Brlngmann and Kuehn, 1980). Among
bacteria, the lowest reported toxic concentration was 0.0382 mg/i, a
30-m1nute EC5Q for Inhibition of luminescence In Photobacterlum
phosphoreum.
4.4. SUHNAJTC
The lowest reported toxic concentrations for freshwater fishes, Inverte-
brates and bacteria are all -0.04 mg/l p-hydroqulnone. The data for
freshwater plant species are highly variable but seem to Indicate that
plants are somewhat less sensitive, with the lowest reported toxic concen-
trations close to 1 mg/i. There Is too Uttle Information about p-hydro-
qulnone effects on marine species to draw any conclusions.
0049d -16- 07/14/87
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5. PHARMACOKINETICS
5.1. ABSORPTION
Recovery of p-hydroqulnone and Its conjugates 1n the urine following
oral exposure Indicate that It Is readily absorbed from the gastrointestinal
tract. Fassett and Roudabush (1952) recovered 40-45% of a 250 or 500 mg/kg
oral dose of p-hydroqu1none In the urine of a human subject collected over
22 hours. About 73% of a 100-230 mg/kg oral dose of p-hydroqu1none given to
rabbits was recovered In the urine collected over 24 hours (Garton and
Williams, 1943), while 92-100% of oral doses of p-nydroqulnone {5-200 mg/kg)
were recovered In the urine of rats collected over 48 or 96 hours
(Dlvlncenzo et al., 1984).
5.2. DISTRIBUTION
No p-hydroqu1none was found In the blood of rats at periods of 15
minutes to 6 hours after the rats were treated by gavage with doses of 250
or 500 mg/lcg (Davis, 1979).
Dlvlncenzo et al. (1984) examined the distribution of radioactivity In
tissues of rats 48 and 96 hours after they were dosed by gavage with
[14C]-labeled p-hydroqu1none at 200 mg/kg. The results showed concentra-
tions of radioactivity of <0.2% of the dose In the liver and kidneys.
Radioactivity concentrations were lower In the lung, heart, brain and fat.
At 96 hours after dosing, concentrations of radioactivity were lower than at
48 hours. Radioactivity 1n the bone marrow was not determined.
Greenlee et al. (1981a) studied the distribution of p-hydroqulnone In
rats. Control or Aroclor 1254 pretreated male F344 rats were given a single
Injection of 14C-labeled p-hydroqu1none (100 yd, 1.3 mg/kg) In the
lateral tall vein. The rats were sacrificed 2 hours later and the distri-
bution of radioactivity was determined by whole body autoradlography. The
0049d -19- 07/14/87
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results showed that radioactivity associated with 14C-labeled p-hydro-
qulnone was concentrated In the bone marrow and lymphold organs. A decrease
\n total circulating radioactivity and 1n the uptake of radioactivity by
bone marrow and lymphold organs was noted in the Aroclor pretreated rats.
In a similar study by Greenlee et al. (1981b), control or Aroclor
pretreated rats were given a single Injection of 14 mg/kg 1*C-labeled
p-hydroquinone (100 jaC1) in the lateral tall vein. The rats were sacri-
ficed 2 or 24 hours later, and soluble and tovalently bound radioactivity 1n
the liver, spleen, thymus and bone marrow were determined using a scintilla-
tion counter. Tne results showed that {i*C3p-hydroquJno«e»der1ved soluble
radioactivity was retained 1n the bone marrow for at least 24 hours, but was
not retained 1n the liver or thymus. In contrast, covalently bound radio-
activity was Increased at 24 hours in all tissues, with the greatest
Increase noted in bone marrow. Aroclor pretreatment depressed covalent
bonding of radioactivity in the liver, white blood cells and bone marrow.
5.3. METABOLISM
About 10-15% of a 250 ur 500 mg/kg dose ingested by a human was found in
the urine collected over 22 hours as unchanged p-hydroquinone (Fassett and
Roudabush, 1952). Approximately 38-42% of the dose was found as conjugates
in the urine.
Garton and Williams (1949) dosed rabbits by gavage with p-hydroquinone
at 100-230 mg/kg and collected the urine for 24 hours. Analysis of the
urine revealed a recovery of 30% of the dose as p-hydroquinone ethereal
monosulfate, 43% p-hydroquinone monoglucuronlde and a trace (0.065%) of free
p-hydroquinone.
Divincenzo et al. (1984) dosed groups of four male Sprague-Oawley rats
by gavage with either a single dose of 200 mg/kg [14C]p-hydroquinone, or
0049d -20- 06/02/87
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with four dally doses of 200 mg/kg unlabeled p-hydroquinone followed by a
single 200 rag/kg dose of Jl4C]p-hydroqu1none. Most of the administered
radioactivity was recovered In the urine. In the single dose experiment,
56.4% of the radioactivity in the urine was a glucuronlc acid conjugate,
42.3% a sulfurlc add conjugate and 1.1% was unchanged p-hydroquinone. In
the multiple dose experiment, 72.2, 23.2 and 1.3% of the urinary radio-
activity was glucuronic add conjugate, sulfuric add conjugate and
unchanged p-hydroqulnone, respectively.
Miller et al. (1976) dosed one male and one female domestic cat intra-
venously with 2,3.5«6-1*t labeled p-tiydroqulnone at 20 ng/kg. Six tours
after the compound was administered, -87% of the dose was recovered 1n the
urine as p-hydroqu1none sulfate, 10% as unmetabollzed p-hydroqulnone and 3%
as a glucuronlc add conjugate. The Investigators noted that sulfate conju-
gation 1s the only detoxification mechanism available to the cat, presumably
because cats are deficient In glucuronlc add conjugating pathways.
Greenlee et al. (1981b) found that at physiologic pH (7.4), p-hydroqul-
none autoxldlzes to a product with a UV absorption maximum of 248 nm. The
product was most likely qulnone, and the authors proposed the following
oxidatlve pathway:
p-hydroqu1none + 20- -> qulnone * 201 * 2H*
20~ * 2H* -» H202 + 02
The latter reaction was catalyzed by superoxlde dlsmutase. The rate of
autoxldatlon of p-hydroqulnone was enhanced 5-fold by 250 units of super-
oxide dismutase. Metabolism studies do not clearly indicate that this
reaction occurs in vivo.
0049d -21- 06/02/87
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5.4. EXCRETION
Approximately 40-45'/. of a 250 or 500 rag/kg dose of p-hydroqu1none was
excreted 1n the urine 22 hours after It was Ingested by a human subject
(Fassett and Roudabush, 1952).
Xaharabwe et al. (1986) found that women who used cosmetic p-hydroqu1none
ointments excreted urinary volatile phenols at a level of 71.5 mg/i
compared with 39 mg/i in Individuals who did not use ike ointments. It 1s
not clear 1f the phenols are metabolites of p-hydroqu1none.
Olvlncenzo et al. (1984) examined the excretion of radioactivity after
groups of 2-4 male Spr ague-Daw! ey rats were dosed by gavatje with
[l4C]p-hydroqu1none at a single dose of 5-200 mg/kg, or four doses of
unlabeled p-hydroqulnone (200 mg/kg/day) followed by a single dose of
[l4C]p-hydroqu1none (200 mg/kg). The results showed that -87% of the
administered radioactivity was excreted In the urine during the first 24
hours, while almost all of the radioactivity was excreted In the urine
within 96 hours. Radioactivity eliminated In expired air and feces ranged
from 0.1-5.8% of the dose, while <1.3% of the dose remained In the carcass
and excised tissue. Throughout the experiment, total recovery reached
92-102% at 48-96 hours after dosing.
5.5. SUMMARY
Pharmacok1net1c studies Indicate that following oral administration,
p-hydroqu1none Is absorbed rapidly, conjugated with sulfate or glucuro-
nlde, and excreted In the urine. These results have been found 1n humans
(Fassett and Roudabush, 1952), rabbits (Garton and Williams, 1949) and rats
(Olvlncenzo et al.f 1984). Cats metabolize p-hydroqu1none primarily to
p-hydroqu1none sulfate (Miller et al., 1976).
0049d -22- 07/14/87
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Davis (1979) did not find p-hydroqu1none 1n the blood of rats 15 minutes
to 6 hours after they were given oral doses of p-hydroqu1none. In distri-
bution studies of radlolabeled p-hydroqu1none Injected Into rats, Greenlee
et al. (1981a,b) found that residual radioactivity associated with
14C-labeled p-hydroqu1none was concentrated in the bone marrow and
lymphold organs.
At physiologic pH, p-hydroquinone autoxldlzes to quinone (Greenlee et
al., 1981b). This reaction has not been shown to occur 14 vivo.
Women who used cosmetic p-hydroqu1none ointments excreted higher concen-
trations of urinary volatile phenols tnan women who did not use the oint-
ments (Kahambwe et al., 1986).
0049d -23- 06/02/87
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6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposures.
6.1.1.1. SUBCHRONIC Pertinent data regarding the toxldty of
p-hydroqulnone following subchronlc Inhalation exposure could not be located
In the available literature as cited 1n Appendix A.
6.1.1,2. CHRONIC Occupational exposure to p-hydroqulmwie dust and
qulnone vapor has resulted In eye lesions. Sterner et al. (1947) found that
94/201 workers Involved In the manufacture of p-hydroqulnone had eye
Injuries, which varied from mild Irritation and staining of conjunctlvae and
cornea, to changes In the thickness and curvature of the cornea, loss of
corneal luster and Impaired vision. The severity of the eye Injury tended
to Increase with length of exposure.
Oglesby et al. (1947) reported exposure concentrations In the plant
where eye Injuries' were observed. The qulnone vapor concentration ranged
from 0.01-3.2 ppm (0.045-14.4 mg/m3) and the concentration of p-hydro-
qulnone dust ranged from 20-35 mg/m3.
Anderson (1947) and Miller (1954) reported that ocular lesions developed
1n Individuals Involved In the manufacture of p-hydroqulnone. These studies
agree that prolonged exposure (>5 years) Is required for the development of
severe ocular effects.
In 1955 and 1956, Anderson and Oglesby (1958) examined the eyes of
workers who had not been exposed for 3-5 years. Although conjunctiva!
staining had disappeared, corneal effects progressed 1n some Individuals.
Naumann (1966) examined microscopic changes 1n corneal specimens from
three workers exposed to p-hydroqu1none for 9, 9 and 11 years. The speci-
mens were obtained when corneal transplant operations were performed to
Improve vision 7-20 years after qu1none/p-hydroqu1none exposure had ended.
0049d -24- 07/14/87
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Microscopic examinations of the specimens revealed two types of abnormal
pigment. The first, a diffuse brown pigment, found 1n the epithelial layer
tested Iron-positive. The second pigment, a fine granular material, was
located In the most damaged part of the corneal stroma and stained similar
to melanin. Nauman (1966} stated that the loss of vision was likely a
result of lost keratocytes and marked stromal damage, which was demonstrated
by the loss of birefringence of the collagen fibers with polarized light.
In addition. Bowman's membrane was Irregularly thickened or absent In places.
All studies describing eye lesions Involve exposure to both qulnone
vapor and p-hydroqu1none dust. The relative contributions of the two com-
pounds In causing eye Injury 1s uncertain. Oglesby et al. (1947) suggested
that p-hydroqulnone may have a greater role. Qulnone vapor 1s only slightly
soluble 1n aqueous solvents so that compared with qulnone, p-hydroqu1none
dust may stay 1n contact with the eye for longer periods of time. The
authors- also suggested that the more Irritating qulnone vapor may be a
greater stimulant of lacrlmatlon so that qulnone 1s more likely to be
diluted and washed away.
Sterner et al. (1947) examined p-hydroqu1none workers with eye Injury
for evidence of systemic absorption and Intoxication. Physical examinations
and laboratory tests Including hemoglobin, RBC, WBC and differential counts,
hematocrlt, sedimentation rate, Icteric Index and the ratio of Inorganic
sulfate to total sulfate 1n the urine, were performed. During 1943 and
1945, three groups of workers were examined. The first group consisted of
47 p-hydroqu1none workers with some degree of eye Injury. The second group
of 100 Individuals, Included all workers Involved 1n the manufacture of
p-hydroqu1none. The control group consisted of 1018 workers from the same
0049d -25- 07/14/87
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plant with no exposure to harmful materials. Exposure concentrations were
0.045-14.4 rag/ra3 quinone vapor and 20-35 mg/m3 p-hydroqu1none dust
(Oglesby et al., 1947).
The results of the study Indicated no significant differences between
the controls and workers with eye Injury or workers engaged In the manufac-
ture of p-hydroqulnone. According to NIOSH (1978), the most nearly signifi-
cant differences from control values were the percent of lymphocytes 1n the
blood for all exposed employees and those with eye Injuries In 1943, 1n the
Icterus Index of the employees with eye Injuries 1n 1945, and 1n the percent
of basophlls 1n the blood of exposed workers 1n 1943. Ho significant
differences were noted between workers with eye Injuries and the entire
exposed population of workers. Sterner et al. (1947) concluded that the
exposure to qu1none/p-hydroqu1none of the order sufficient to produce eye
Injuries Is not sufficient to produce systemic effects as measured by
physical examinations and laboratory tests.
6.1.2. Oral Exposures.
6.1.2.1. SUBCHRONIC -- Carlson and Brewer (1953) fed a group of 14
adult Sprague-Oawley rats diets containing 5% p-hydroqu1none for 9 weeks. A
similar group, fed the basal diet, was maintained as controls. During the
9-week study, the treated rats experienced a 46% loss 1n weight and
developed aplastlc anemia. Microscopic examination of the bone marrow
showed a decrease 1n cellularlty with marked atrophy of the hematopoletlc
elements. Atrophy of the liver cord cells, lymphold tissue of the spleen,
adipose tissue and striated muscle, and superficial ulceratlon and hemor-
rhage of the stomach mucosa were also noted. The authors stated that the
adverse findings were due In part to reduced food Intake.
0049d -26- 06/02/87
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Carlson and Brewer (1953) also fed 4-month-old male and female mongrel
pups p-hydroqu1none In sugar-coated tablets mixed 1n the diet for 80 weeks.
One pup was fed 16 mg/kg/day for 80 weeks, two pups were-fed 1.6 mg/kg/day
for 31 weeks and then 40 mg/kg/day for 49 weeks (TWA=25.1 mg/kg/day), and
two pups were maintained as controls. In a second experiment, five adult
male dogs were fed diets containing p-hydroqu1none at 100 mg/kg/day for 26
weeks. Ur1nalys1s, hematologlcal analyses and hlstopathologlcal examina-
tions of major organs and tissues revealed no changes compared with controls.
In a study of p-hydroqulnone toxlclty In humans (Carlson and Brewer,
1953), 2 wen ^twjestetJ 500 ing/day for 5 months and 17 men and women Ingested
300 mg/day for 3-5 months. The total dally doses were Ingested In three
doses with meals. Results of blood analyses and urlnalyses conducted 1
month before the study and during the study revealed no abnormal findings.
The blood analysis Included % hemoglobin, hematocrlt or RBC count, differen-
tial WBC count, sedimentation*'rate, platelet count, coagulation time and
Icteric Index. The urine parameters examined were albumin, reducing sugars,
white and red cell counts, casts and urobHlnogen.
Hlrose et al. (1986) found that p-hydroqulnone In the diets of 15 Syrian
Golden hamsters at 0.5% for 20 weeks did not result In significant changes
in body weight or Hver weight when compared with controls. In addition, no
hlstopathologlc changes In the liver, kidneys, cheek pouch, stomach,
esophagus, lung, pancreas or bladder were observed.
Mozhayev et al. (1966) treated rats for 6 months with p-hydroqu1none
added to the drinking water. The compound was added to the water at concen-
trations designed to provide doses of 0.025, 0.05, 0.25, 0.5, 5, 50 or 100
mg/kg/day. The number, age and sex of the rats used in the study were not
0049d -27- 07/14/87
-------
reported. The parameters examined were body weight, hemoglobin concentra-
tion, and RBC and WBC counts. At sacrifice, the "liver, spleen, kidneys,
small Intestine and brain were examined microscopically.
Rats treated with p-hydroqulnone at TOO mg/kg/day showed a significantly
(p<0.05) slower weight gain than controls. Weight gain changes were not
observed 1n the other treatment groups. Treatment of rats at >50 mg/kg
resulted 1n a slight decrease 1n hemoglobin (p<0.1), a decrease 1n the
number of erythrocytes (p
-------
abnormalities, but one 15 mg/kg rat developed slight anemia with decreased
neutrophlls, anlsocytosls, severe polychromatophma and numerous erythro-
blasts. On day 40, one control rat showed anlsocytosls and erythroblastosls
and one 7.5 mg/kg rat also had erythroblastosls. In the 15 mg/kg group,
four rats had anlsocytosls, five had definite polychromatophllla and four
had erythroblasts In the peripheral blood.
In another study by Delcarobre et al. (1962), two groups of 15 rats were
dosed with a solution of p-hydroqu1none 1n water by stomach tube at 5 or 10
mg/kg, 6 days/week for 4 months. Fifteen rats dose
-------
of treatment revealed no abnormalities. Kidney and liver weights relative
to body weights were Increased 1n rats at the 5000 and 10,000 mg/i
levels. Microscopic examinations of the heart, aorta, lungs, liver, spleen,
kidney, stomach, duodenum, pylorus, Heum, colon, urtnary bladder, prostate
and testes, ovary and uterus, pancreas, thyroids, adrenal, pituitary, brain,
spinal cord, eye, skeletal muscle and skin revealed no compound-related
pathological changes.
Christian et al. (1980) also conducted a 15-week study using Carworth
Farm weanling rats. Groups of 15 rats/sex were provided with drinking water
containing p-hydroquVnone at 0, 1000, 2000 or 4000 mg/i. Based on water
consumption data provided by the authors, the male rats consumed p-hydro-
qulnone at -110, 200 and 360 mg/kg/day and the females at 140, 240 and 430
mg/kg/da.y. Water Intake In this study also decreased with Increasing
p-hydroqulnone concentration. Terminal body weights were slightly depressed
1n hrgh dose males but were similar or higher than controls 1n other groups.
Hemoglobin levels were slightly reduced In males at 200 and 360 mg/kg/day
after 5 and 10 weeks of treatment but were normal after 14 weeks of treat-
ment. No change 1n the total number of leukocytes or 1n the distribution of
leukocytes was noted. A statistically significant Increase (p<0.001) In the
ratio of I1ver-to-body weight was noted In all dose groups. Relative kidney
weights were also Increased (p<0.01) 1n all groups except the 140 mg/kg/day
females. Microscopic examination of the same organs and tissues as examined
in the 8-week study revealed no compound-related changes. In addition,
measurement of spontaneous locomotor activity with running wheels and
activity platforms showed no discernible effects on the CNS.
An abstract of a Russian study (Anlkeeva, 1974) reported that dally oral
administration of p-hydroqu1none at 156 mg/kg to rats for 30 days resulted
In Increased Hver weights, decreased hepatic glycogen and vitamin C
0049d -30- 07/14/87
-------
content, and decreased blood serum protein levels. p-Hydroqu1none treatment
also Inhibited pseudochollnesterase activity. Additional details of this
study were not available.
In preparation for an NTP 2-year cardnogenlcHy study of p-hydroqulnone
using F344 rats and B6C3F1 mice, a 13-week gavage study was conducted
(Keller,, 1982; Bloassay Systems Corporation, 1981a,b). Groups of 10 males
and 10 females of each species were treated by gavage with p-hydroqulnone
(>97% pure) suspended 1n corn oil, 5 days/week for 13 weeks at doses of 0,
25, 50, 100, 200 or 400 mg/kg/day. Major organs of rats and mice In the
control, 400 and 200 tng/kg/day group.; «er« examined microscopically.
All rats treated at 400 mg/kg/day died. Except for three females at 200
mg/kg/day, all other rats survived the 13-week study period. Clinical signs
of toxldty Included tremors and convulsions 1n rats that died, and lethargy
In survivors at 200 mg/kg/day. At 100 mg/kg/day, weight gain was 14 and 10%
below controls In males and females, respectively. Hlstopathologlc examina-
tions revealed toxic nephropathy In 7/10 males and 6/10 females and focal
squamous hyperplasla and acanthosls of the stomach 1n two males dosed at 200
mg/kg/day (Bloassay Systems Corporation, 1981a).
In mice (Bloassay Systems Corporation, 1981b), eight males and eight
females died at dally doses of 400 mg/kg/day, and two males died at 200
mg/kg/day. Clinical signs In mice that died were similar to those described
for rats. Lethargy was observed 1n the 25, 50, 100, 200 and 400 mg/kg/day
males and the 100, 200 and 400 mg/kg/day females. Hunched posture was noted
in the 400 mg/kg males and females and the 200 mg/kg/day males. Males at
400 and 200 mg/kg/day showed a decrease 1n body weight gain. The only
significant hlstopathologlc effects noted were forestomach lesions Including
mucosal ulceratlon, Inflammation and squamous hyperplasla In three males and
two females at 400 mg/kg/day and one female at 200 mg/kg/day.
0049d -31- 07/14/87
-------
Two male and two female young mongrel dogs (6.1-8.4 kg) were given
single doses of p-hydroqulnone by stomach tube at 100 mg/kg (Woodard,
1951). After this Initial dose, the dogs were divided Into two groups of
one male and one female and treated with p-hydroqulnone in gelatin capsules
at 25 or 50 mg/kg/day, 6 days/week for 809 days (TWA doses 21.5 and 42.9
lag/kg/day). Two untreated dogs served as controls. Throughout the study,
body weights were monitored and blood counts were performed, p-Hydroqu1none
treatment was suspended on days 20-73 for one 25 mg/kg dog because of weight
loss and on days 238-309 for all dogs to study effects on body weight. At
ttte end of the experiment, the dogs were sacrificed for gross and
microscopic examinations of Internal organs.
The results of the experiment showed no significant changes In weight
gain or blood counts. Microscopic examinations revealed hyperplasla of the
bone marrow and excessive pigment deposits 1n the spleens of all dogs. It
Is not clear 1f these lesions were also observed In controls.
6.1.2.2. CHRONIC -- Carlson and Brewer (1953) examined the chronic
toxldty of p-hydroqulnone in groups of 10 male and 10 female Sprague-Oawley
rats fed diets containing p-hydroqu1none at 0, 0.1, 0.5 or 1.0% for 103
weeks. In a second 103-week experiment, groups of 16-23 rats of each sex
were fed diets containing p-hydroqulnone that had been heated with lard at
190°C for 30 minutes before being Incorporated into the diet at 0, 0.1, 0.25
or 0.5%. Throughout the study, body weights of the rats were recorded, and
hematologlcal parameters Including RBC, % hemoglobin and differential WBC
were determined. At the end of the study, hlstopathologlcal examinations of
major organs and tissues were completed.
0049d -32- 07/14/87
-------
The results of the study showed a significant decrease (p<0.05) in the
growth rate of rats fed 0.5 and 1.0% p-hydroqu1none during the first month
of the study. The final body weights of treated rats were not significantly
different from controls. This effect was not observed In rats treated with
p-hydroqu1none Incorporated Into lard. No changes were noted In hemato-
loglcal parameters or In hlstopathologlcal examinations of rats from either
study.
6.1.3. Other Relevant Information* Hooper et al. {1978) studied an out-
break of gastrointestinal disease 1n 544 crewmen who were exposed to
p-tiydroquTnon* In the water supply aboard a navy vessel. Symptoms of the
Illness Included nausea, vomiting, abdominal cramps and diarrhea, which
usually ended 1n 12-36 hours. Levels of p-hydroqulnone 1n the water were
not determined, but p-hydroqu1none was Identified (>0.1 pg/ma) In the
serum of 3/6 111 patients, and 1t was not found 1n the serum of 6/6 healthy
controls.
NIOSH (1978) reported a number of cases 1n which people Ingested
p-hydroqu1none or photographic developer containing p-hydroqulnone.
p-Hydroqu1none caused mild to severe systemic effects 1n humans. Depending
on the dose, symptoms noted Included addosls, anemia, erosion of the
gastric mucosa, edema of Internal organs, convulsions, coma and death.
p-Hydroqu1none 1s used 1n cosmetic formulations designed to lighten skin
and In oxldatlve hair dyes. Because of these uses, the toxldty of p-hydro-
qulnone following skin application has been examined. These studies,
reviewed by the Cosmetic Toiletry and Fragrance Assoc. (1986), revealed no
systemic effects following the skin application of p-hydroqu1none, although
at concentrations >3X, the studies Indicate that p-hydroqu1none 1s a skin
Irritant. The Cosmetic Toiletry and Fragrance Assoc. (1986) concluded that
0049d -33- 07/14/87
-------
p-hydroqulnone Is "safe for cosmetic use at concentrations of 1.0% and less
1n formulations designed for discontinuous, brief use followed by rinsing
from the skin and hair."
Sterner et al. (1947) tried repeatedly to develop eye lesions in rabbits
similar to those observed In humans. Rabbits were exposed to qulnone vapor
up to concentrations where corneal edema and ulceratlon were observed. In
addition, subconjunctlval Injections of qulnone did not result 1n ttve
development of the characteristic lesions. Ferraris des Gaspare (1949)
exposed rabbits to finely powdered p-hydroqti1none (concentration not
provided) for 2 aontlis. The rabbits developed eye lesions similar to ttiose
observed 1n humans; a brown pigmentation first on the conjunctiva and then
on the cornea was observed. These effects occurred earlier 1n colored
rabbits than 1n albinos, and 1n rabbits exposed to light opposed to those
kept 1n darkness.
In an early study, Vollmer (1932) demonstrated an Increased toxlclty In
mice with repeated subcutaneous Injections of p-hydroqulnone at doses below
the single lethal dose. In this experiment, 12 white mice (sex not speci-
fied) were Injected 6 times at 5-day Intervals with p-hydroquinone at 0.05
mg/g bw. Five control mice, which were handled 1n a manner similar to
treated mice, showed signs of restlessness throughout the study. After the
first Injection of p-hydroqulnone, the mice were restless. After the third
Injection, all treated mice displayed signs of trembling, and clonlc spasms
were noted 1n 9/12 mice after the fourth Injection. Four deaths occurred
after both the fifth and sixth Injections. This experiment was repeated
with a group of 29 mice, except p-hydroqulnone doses of 0.12 mg/g (0.12
vg/kg) bw were used. As In the first experiment, deaths were observed
after repeated doses of p-hydroquinone. The author Interpreted the results
0049d -34- 07/14/87
-------
to mean that small nonlethal doses of p-hydroqulnone stimulated metabolic
oxldatlve processes so that subsequent small doses were rapidly converted to
more toxic substances.
Vollmer (1932) also reported that the toxldty of p-hydroqulnone In mice
Increased following repeated subcutaneous Injections of ethyl alcohol. Six
days after seven alcohol Injections at 4.73 mg/g (4.73 vg/kg) given at
5- to 6-day Intervals, p-hydroqu1none Injected subcutaneously at 0.2 mg/g
was lethal to 21/32 mice. The surviving mice exhibited paralysis and clonlc
spasms. This 1n contrast to deaths of 6/32 mice receiving a single dose of
0.2 mg/g \Q.2 jig/fcg) without alcohol pro-treatment. Of the surviving mice,
19 suffered from clonlc spasms, 2 paralysis and 2 trembling.
In a cumulative toxlclty study, Carlson and Brewer (1953) found no
cumulative toxlclty when p-hydroqu1none was given to rats by stomach tube.
Groups of 20-48 rats were given nine doses of p-hydroqulnone at 500, 750,
1000, 1250, 1500 or 1750 mg/kg In 12 days. Deaths were observed 1n rats In
the 500-1750 mg/kg groups, with 71% of the mortality occurring within 24
hours after the first dose. During the remaining days of the study, mortal-
ity averaged <5% per day.
To determine an appropriate route of exposure for a chronic study, NTP
sponsored 14-day skin painting and gavage studies of p-hydroqulnone using
F344 rats and B6C3F1 mice (Davis, 1979). Treatment groups 1n both studies
consisted of five rats and mice of each sex. In the skin-painting study,
p-hydroqu1none In 95/4 ethanol was applied to the shaved scapular region of
the animals. No dose-related systemic or local effects were noted In rats
or mice that were given 12 applications of p-hydroqulnone. The rats were
treated at 0, 240, 480, 960, 1920 or 3840 mg/kg, while the mice were treated
at 0, 300, 600, 1200, 2400 or 4800 mg/kg.
0049d -35- 07/14/87
-------
In the gavage study, rats and mice were dosed 12 times with p-hydroqul-
none In corn oil. Rats were dosed at 0, 63, 125, 250, 500 or 1000 ing/kg and
mice were dosed at 0, 31, 63, 125, 250 or 500 mg/kg. All rats at 1000 mg/kg
died while 1/5 male and 4/5 females at 500 mg/kg died within 2 hours after
the first or second dose; death was preceded by body tremors and
convulsions. All rats at lower doses survived, and by the end of the
experiment exhibited a weight loss relative to controls. Gross pathology at
necropsy revealed no consistent dose-related changes. In mice, only one
male mouse survived at 500 mg/kg, while at 250 fflg/kg, 2/5 males and 5/5
females survived. Except for one malt at 31 mg/kg and one female In each of
the 63 and 31 mg/kg groups, the remaining mice survived. Signs before death
were similar to that described for rats. In mice, p-hydroqulnone treatment
did not significantly affect weight gain, and gross pathology did not reveal
a target organ.
Dlvlncetvzo et al. (1984) found no significant Increases In absolute or
relative liver weights, hepatic mlcrosomal protein, cytochrome b-5 concen-
trations or cytochrome c-reductase activity 1n male Sprague-Oawley rats
treated by gavage with four dally doses of p-hydroqu1none at 200 mg/kg. A
slight but significant decrease In cytochrome P-450 values was noted In
p-hydroqu1none treated rats compared with controls.
Acute LD,_ data for p-hydroqu1none are summarized In Table 6-1. As
Indicated 1n the table, p-hydroqu1none 1s more toxic to cats, a species In
which detoxification of p-hydroqulnone 1s limited to conjugation with
sulfate (Miller et al., 1976). The acute toxidty of p-hydroqu1none Is
restricted to a fairly narrow range. Woodard (1951) found that fasted rats
could tolerate an oral dose of 200 mg/kg with no mortality while the lowest
dose resulting In 100% mortality was 420 mg/kg.
0049d -36- 07/14/87
-------
TABLE 6-1
Acute 1050 Values for p-Hydroqu1none
Species/Strain
Rat/NS
Rat/Priestly
Rat/Sprague-
Dawley
Rat /Spr ague -
Dawley
Rat/Sprague-
Dawley
Rat/Sprague-
Oawley (fasted)
Rat./WUtar
Rat/W1star
(fasted)
Oog/NS
Cat/NS
Mouse/NS
Rat/NS
Guinea pig/NS
P1geon/NS
Solvent
NS
glycerin
glycerin
distilled
water
propylene
glycol
propylene
glycol
propylene
glycol
propylene
glycol
tablets
tablets
NS
NS
NS
NS
Route
oral
oral
oral
oral
oral
oral
oral
oral
oral
oral
oral
oral
oral
oral
(mg/kg)
781.3
1005-1295
1081
1182
1090
323
731
298
299
42-86
400
320
550
300
Reference
Anlkeeva, 1974
Carlson and
Brewer, 1953
Carlson and
Brewer, 1353
Carlson and
Brewer, 1953
Carlson and
Brewer, 1953
Carlson and
Brewer, 1953
Carlson and
Brewer, 1953
Carlson and
Brewer, 1953
Carlson and
Brewer, 1953
Carlson and
Brewer, 1953
Lehman et al . ,
1951
Lehman et al . ,
1951
Lehman et al . ,
1951
Lehman et al . ,
1951
0049d
-37-
06/02/87
-------
TABLE 6-1 (cont.)
Species/Strain Solvent Route
1059 Reference-
(mg/kg)
Dog/NS
Cat/NS
Rat/NS
NS
NS
NS
oral
oral
Intravenous
200
70
115
Lehman et al.,
1951
Lehman et al.,
19S1
Lehman et al.,
1951
NS = Not stated
0049d
-38-
06/02/87
-------
An abstract of a Russian study (Dzhokhadza and Papel1shv1li, 1973)
stated that when p-hydroqulnone was Incubated with Isolated rat liver nucle'1
at 10-50 yg/ms, the activity of nuclear RNA polymerase was Inhibited.
In an |n_ vitro study, Usaml et al. (1980) found that p-hydroqu1none
reduced the activity of tyroslnase Isolated from tissue cultures of human
melanoma cells when both dopa and tyroslne were used as substrates. The
reduction was dose-related and reached significance (p<0,001) at a concen-
tration of 0.1 H.
In a study by Galdo and Wlerda (1984), exposure of mouse bone marrow
stromal cells to p-hydroqulmme resulted 1n a significant dose-related
decrease 1n adherent colony formation. At a concentration of 1.5x10~4M,
a 29-37% decrease In colony formation was observed, while at 50xlO~6 and
IQOxlO"6 M complete Inhibition was noted. In a second study described by
Galdo and Wlerda (1984), p-hydroqulnone exposure of mouse bone marrow cells
also resulted 1n a significant decrease In the number of granulocyte/mono-
cyte colonies formed.
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the cardnogenldty of
p-hydroqulnone following Inhalation exposure could not be located 1n the
available literature as cited 1n Appendix A. p-Hydroqulnone, however, has
been shown to be a metabolite of benzene (Galdo and Wlerda, 1984), a human
carcinogen; the role of p-hydroqu1none In benzene carclnogenlclty is not
known.
6.2.2. Oral. The 103-week oral toxldty study of p-hydroqu1none using
rats (Carlson and Brewer, 1953) (see Section 6.1.2.2.) did not discuss tumor
Incidences.
0049d -39- 07/14/87
-------
The NTP has sponsored a 2-year gavage study of p-hydroqu1none using rats
and mice, but the report Is not yet available, as tfte quality assurance
phase 1s In progress (NTP, 1987).
6.2.3. Other Relevant Information. In a study by Boyland et al. (1964),
mice 1n which cholesterol pellets containing p-hydroqu1none were Implanted
1n the bladder developed significantly (p=0.03) more bladder tumors than
mice Implanted with just cholesterol. The results are from 19 treated mice
and 77 control mice that survived 25 weeks. Although not stated 1n Boyland
et al. (1964), IARC (1977) stated that 10 mg cholesterol pellets containing
20% p-hydrt>qulTK>ne were used.
In a study by Roe and Salaman (1955), an Increased skin tumor Incidence
was not observed In mice treated with weekly skin applications of 0.3 ma
of a 6.7% p-hydroqu1none solution 1n acetone. These mice were also treated
with 18 skin applications of croton oil starting 3 weeks after the p-hydro-
qulnone treatment began. Mice treated with croton oil served as controls.
The mice were observed for 18 weeks.
Boutwell and Bosch (1959) found that p-hydroqulnone was Inactive as a
promoter 1n mouse skin following a single application of DHBA. Details of
this study were not provided.
In a tumor promotion study, Holmberg et al. (1986) found that after an
Intraperltoneal dose of DENA, p-hydroqulnone, administered orally to rats at
100 mg/kg, caused a significant elevation of y-glutamyl-transpeptldase
positive foci 1n the liver. p-Hydroqulnone at 20 mg/kg did not cause this
effect when administered to male Sprague-Dawley rats that were treated with
DENA at 30 mg/kg 24 hours after a partial hepatectomy. p-Hydroqu1none
treatment began 7 days after the hepatectomy and was given 5 days/week for 7
weeks. The rats were sacrificed 10 days after the last p-hydroqulnone
treatment.
0049d -40- 07/14/87
-------
Parmentler and Oustln (1948) found that single doses of p-hydroqu1none
at 0.15 or 0.175 mg/g Injected 1ntraper1toneally or subcutaneous!y Into mice
resulted in arrested metaphase in cells of intestinal tissues. The Intes-
tinal tissue was examined during the first 2 hours after the p-hydroquinone
injection. In cells that were in arrested metaphase, small groups of
chromosomes were found near the poles in addition to those collected in the
equatorial plate (three-group metaphase). Signs of chromosomal stickiness,
as evidenced by clumping of the central mass of chromosomes and bridges
between central and polar chromosomes, were also observed from 1 hour after
p-hydroquinone injection. Similar mltotic effects have been noted following
p-hydroquinone exposure in the bone marrow of golden hamsters (Parmentler,
1953) and in the bone marrow, liver cells and cornea of rats (Rosin and
Doljanske, 1953).
Chavin et al. (1980) found that p-hydroquinone Injected subcutaneously
into mice with melanoma at 80 mg/kg/day-increased survival over a 140-day
observation period. The mice were treated on days 1-9 after they had
received melanoma transplants. The Incidence of successful transplantation
was 91.7% in untreated mice, and 55.6 and 23.7% in mice treated with
p-hydroquinone at 16 and 80 mg/kg, respectively.
6.3. MUTAGENICITY
p-Hydroquinone mutagenlcity data are summarized in Table 6-2. Gocke et
al. (1981) found that p-hydroquinone was positive for reverse mutation in j>.
typhimurium on ZLM medium without S-9 metabolic activation but negative on
VB medium. Other reverse mutation assays of p-hydroquinone using £. typhi-
murium have been negative (Goodyear Tire and Rubber Co., 1982; Sakai et al.,
1985).
0049d -41- 07/14/87
-------
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p-Hydroqu1none tested positive for DNA damage In the Pol1", Pol A" E_.
col 1 assay (Goodyear T1re and Rubber Co., 1982). The study was conducted
without metabolic activation.
In two studies of sex-linked recessive lethal mutations In Drosophlla
melanoqaster. p-hydroqulnone tested negative (Gocke et al., 1981; Goodyear
Tire and Rubber Co., 1S82).
p-Hydroqulnone did not Increase the percent of single strand DNA In
mouse lymphoma cells (Pellack-Walker and Blumer, 1986). In a study of cell
transformation, p-hydroqu1none was negative in 8alb/3T3 mouse cells
tGoodyear T1re and Rubber Co., 1982).
In_ vitro studies have shown that p-hydroqu1none Inhibits DNA and RNA
synthesis. Post et al. (1984) found that p-hydroqu1none at a concentration
of 6xlO~6 M Inhibited mRNA synthesis In rabbit bone marrow nuclei. Penney
et al. (1984) studied the effect of p-hydroqulnone on DNA and RNA synthesis
In two melanotlc and three nonmelanotlc cell lines. They found that
p-hydroqulnone has a dose-dependent Inhibitory effect on both RNA and DNA
synthesis. This effect was much greater 1n the melanotlc cell lines;
Inhibition to 50% of control values occurred at 1 yg/ma, 1n melanotlc
cells but at 100-500 yg/mi In nonmelanotlc cells. p-Hydroqulnone has
also been shown to Inhibit DNA synthesis In Hela cells (Painter and Howard,
1982).
Three In vitro studies Indicate that p-hydroqu1none Increases the rate
of SCE 1n human lymphocytes (Morlmoto and Wolff, 1980; Knadle, 1985; Erexson
et al., 1985).
Gocke et al. (1981) found positive results In a mlcronucleus test when
mice were Injected 1ntraper1toneally with 110 mg/kg p-hydroqu1none at 0 and
24 hours. The test was negative at lower doses. In a spot test, negative
0049d -44- 07/14/87
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results were observed when mice were given an 1ntraper1toneal Injection of
p-hydroqu1none at 110 mg/kg on gestation day 10 (Goclce et a!.. 1983).
Jowa et al. (1986) found that two adducts were formed when
[14C]p-hydroquinone was Incubated with [3H]deoxyguanos1ne. Similar
adducts were found when p-hydroqu1none was Incubated with DNA Isolated from
Clostrldlum perfrinqens. Hlcrococcus lysodeiktlcus. human placenta and calf
thymus. Based on NHR and mass spectral results, the authors suggested that
one adduct was (3'OH)benzepheno(l,fl-2)deoxyguanosine. The other adduct was
not Identified.
6.4. TEKATOSEflltm
Telford et al. (1962) found that p-hydroqu1none fed to a group of 10
pregnant Walter Reed-Carworth rats 1n the diet throughout gestation resulted
in an Increase in the resorptlon rate compared with controls. The rats were
fed a total of 0.5 g of the compound and were sacrificed on gestation day
22. Additional daia, Including maternal effects, were not reported.
In a study by Krasavage (1985), groups of 30 pregnant Crl:COBS*CD*(SD)BR
rats were dosed by gavage with p-hydroqulnone in distilled water at 0, 30,
100 or 300 mg/kg on gestation days 6-15. The dose levels were determined
using body weights of dams measured on gestation day 0. Maternal body
weight and food consumption were measured throughout the study. On gesta-
tion day 20, the dams were sacrificed and the number of live and resorbed
fetuses was determined. All fetuses were examined for gross anomalies, while
half were examined for visceral anomalies and the remaining fetuses were
examined for skeletal defects.
A slight but significant reduction in maternal body weight gain and food
consumption was observed in dams treated at 300 mg/kg. Results of histo-
pathologic examinations of the liver and kidneys of the high dose dams were
0049d -45- 06/02/87
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normal. Tissues of other groups were not examined. Pregnancy rate, the
number of litters with resorptlons, the number of Implantation sites, viable
fetuses and resorpt1ons/dam, mean gravid uterus weights and fetal sex ratio
did not differ among treated and control groups. Combined male and female
mean fetal body weight was significantly (p<0.05) reduced 1n the 300 mg/kg
group compared with controls. When body weights were analyzed separately,
however, only fewale fetal body weights were significantly lower than
controls. There were no treatment-related effects on the Incidence of
gross, visceral or skeletal malformations.
6.5. OTHER REPRODUCTIVE EFFECTS
The number of offspring produced In two successive Utters by male and
female rats treated with p-hydroqu1none In the diet for 6 months at levels
up to 1% was similar to controls (Carlson and Brewer, 1953). Normal growth
rate was observed In these offspring, reared on diets containing p-hydro-
qulnone 1n lard at 0, 0.1, 0.25 or 0.5%. This study was part of the chronic
oral study described In Section 6.1.2.2.
Groups of 10 female rats were fed p-hydroqu1none 1n the diet at 0, 0.003
or 0.3% for 10 days before ir.at1ng and throughout gestation (Ames et a!.,
1956). Fertility Index, Utter efficiency, mortality Index, mean length of
gestation, mean Utter size, viability Index and lactation Index were
similar 1n the treated and control rats.
In a study by Racz et al. (1959), 10 mature female rats were orally
dosed with p-hydroqulnone in saline solution at 200 mg/kg/day for 2 weeks.
Ten rats treated with saline solution served as controls. During the
experiment, three treated rats died and were replaced with an unspecified
number of rats dosed with p-hydroqulnone at 50 or 100 mg/kg/day. Dally
0049d -46- 08/26/87
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cytologlcal examinations of vaginal smears revealed prolonged estrus In all
rats dosed at 200 mg/kg/day and some rats at the lower doses. In the dead
rats, the fallopian tubes contained an excess amount of blood.
In a study of the effects of p-hydroqulnone on the fertility of male
rats, 16 males were Injected subcutaneously with p-hydroqulnone at 100
rag/kg/day for 51 days (Skalka^ 1964). Seventeen male rats served as
controls. At the end of the dosing period, seven treated and seven control
rats were sacrificed and the weights of the testes, ep1d1dym1des, seminal
vesicles and suprarenal glands were determined. H1stolog1cal examinations
of these tissues were also performed. The remaining rats were each mated
for 5 days to two female rats at some unspecified time during the study, as
soon as the Injections stopped or at 17 days after the Injections. The
females were sacrificed 7 days later and their uteri were examined for
fetuses.
The average weights of the testes, epldldymldes, seminal vesicles and
suprarenal glands were decreased In the treated group by 26.1, 21.4, 41.2
and 21.2%, respectively. H1stolog1cal examination of testes from the
treated group revealed that spermlogenesls had been disrupted. Untreated
females mated with treated males had an average of 10.4 fetuses/2 females;
39% were not pregnant. Untreated females mated with control males had an
average of 15.4 fetuses/2 females; 20% were not pregnant. Compared with
controls, male fertility was decreased by 32.5% and the pregnancies In mated
females were reduced by nearly 24% 1n the experimental group. At the end of
the Injection period, females mated with treated males had an average of 7.3
fetuses/2 females; 58% were not pregnant. Mating of 6 treated males 17 days
after the Injections resulted In an average of 6.3 fetuses/2 females; 58%
were not pregnant.
0049d -47- 08/26/87
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6.6. SUMMARY
Eye lesions have been reported 1n workers exposed to p-hydroqu1none dust
and qulnone vapor (Sterner et al., 1947; Anderson, 1947-, Miller, 1954). The
severity of eye lesions Increased with the length of exposure, and the
lesions can progress even after exposure has ended. Concentrations found In
a plant where eye Injuries were observed were 0.044-14.1 mg/m3 qulnone and
20-36 mg/ffl3 p-hydroqu1none (Oglesby et al., 1947). At these levels, no
signs of systemic Intoxication were noted In workers with or without eye
lesions (Sterner et al., 1947).
In a sufechrotrtc toxltlty study, Carlson and Brewer (1953) found that
rats fed a diet containing 5/4 p-hydroqu1none for 9 weeks ate less, lost
weight and developed aplastlc anemia. Atrophy of the bone marrow and other
tissues, and superficial ulceratlon and hemorrhage of the stomach were
noted. No changes were observed In dogs fed p-hydroqu1none at up to a TWA
dose of 25.1 mg/kg/day for 80 weeks or 100 mg/kg/day for 26 weeks (Carlson
and Brewer, 1953). Blood analyses and uMnalyses revealed no effects In
humans fed p-hydroqu1none at 300-500 mg/day for 3-5 months (Carlson and
Brewer, 1953). No effects were noted In Syrian hamsters fed p-hydroqulnone
1n the diet at 0.5% for 20 weeks (Hlrose et al., 1986).
Mozhayev et al. (1966) found that rats treated with p-hydroqu1none In
the drinking water at 100 mg/kg/day gained weight slower than controls.
Rats treated at 50 mg/kg/day or more exhibited a decrease In the number of
erythrocytes, and an Increase In the number of leukocytes and dystrophic
changes In the small Intestines, liver, kidneys and myocardium. Nakamura
(1982) found lowered hematocrlt and a decrease In the number of bone marrow
cells In mice provided with p-hydroqu1none 1n the drinking water at 4 g/2.
(4000 ppm) for 4 weeks.
0049d -48- 07/14/87
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Delcambre et al. (1962) observed blood effects In rats treated by gavage
with p-hydroqu1none at 15 mg/ktj, 6 days/week for 40 days. These effects
were not observed In rats treated at 7.5 mgAg/day for 40 days, or In rats
treated at 5 and 10 mg/kg, 6 days/week for 4 months. Mortality was high In
10 mg/kg group. Rats treated orally at 156 mg/kg for 30 days showed
Increased liver weights, decreased hepatic glycogen and vitamin C content
and decreased blood serum protein levels {Anlkeeva, 1974).
In an 8-week study (Christian et al., 1980), a depression 1n body weight
was observed 1n rats treated with p-hydroqu1none 1n the drinking water at
>470 mg/kg/day. Changes in relative organ weights were observed In rats
treated at >390 mg/kg/day. There were no effects at <270 mg/kg/day. In a
15-week study (Christian et al., 1980), the only significant change was an
Increase in relative liver and kidney weights In rats provided with p-hydro-
qulnone 1n the drinking water at >110 mg/kg/day.
The NTP sponsored a 13-week gavage study (Keller, 1982; Bloassay Systems
Corp., 1981a) In which rats died at >200 mg/kg/day. Survivors were lethar-
gic, and toxic nephropathy and squamous hyperplasla and acanthosls of the
stomach were observed. There were no effects at <100 mg/kg/day. The NTP
13-week gavage mice study (Keller, 1982; Bloassay Systems Corp., 1981b)
resulted 1n death at >200 mg/kg/day. Males treated dally at >25 mg/kg and
females at >100 mg/kg were lethargic, and hunched posture was observed at
>200 mg/kg. The only significant hlstopathologlc effects were forestomach
lesions at >200 mg/kg/day.
In a oral toxiclty study (Woodard, 1951), no changes In body weight gain
or blood counts were observed In dogs treated with p-hydroqu1- none in TWA
doses of 21.5 and 42.9 mg/kg/day for 810 days. Hyperplasla of the bone
marrow and excessive pigment deposits 1n the spleens were observed
0049d -49- 07/14/87
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In all dogs. No changes In hematologlcal parameters or hlstopathology were
noted in rats fed p-hydroqu1none 1n the diet at concentrations up to 1% for
103 weeks (Carlson and Brewer, 1953).
Gastrointestinal disease attributed to p-hydroqu1none was reported In
crewmen aboard a navy vessel (Hooper et al.,1978). Other symptoms noted In
humans Ingesting p-hydroqulnone at relatively large doses Include acldosls,
anemia, erosion of the gastric mucosa, edema of Internal organs, convul-
sions, coma and death (NIOSH, 1978).
A review of all the p-hydroqu1none toxldty data by the Cosmetic
Toiletry and fragrance Assoc. (1986) concluded that p-hydn>qu1nowe Is "safe
for cosmetic use at concentrations of <1.0/4 In formulations designed for
discontinuous, brief use followed by rinsing from the skin and hair."
In a 14-day gavage study sponsored by NTP (Davis, 1979), doses of 1000
and 500 mg/kg were lethal to rats, while 500 and 250 mg/kg doses were lethal
to mice. Rats at all doses (>63 mg/kg/day) lost weight. Gross pathology
revealed no consistent changes In either rats or mice.
The acute oral LD5Q ranged from -200-1200 mg/kg In rats, dogs, mice
and guinea pigs depending on the solvent of p-hydroqulnone (Anlkeeva, 1974;
Carlson and Brewer, 1953; Lehman et a!., 1951). The compound Is more toxic
to cats, with an oral LD5Q of 42-86 mg/kg (Carlson and Brewer, 1953).
No studies concerning the cardnogenldty of p-hydroqu1none by either
the Inhalation or oral routes of exposure were located. A gavage study of
the cardnogenldty of p-hydroqu1none has been completed but the data are
not yet available (NTP, 1987).
An Increased tumor Incidence was observed In mice In which cholesterol
pellets containing 20% p-hydroqu1none were Implanted in the bladder (Boyland
et al., 1964). In an 18-week study, Increased skin tumor Incidences were
0049d -50- 07/14/87
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not observed In mice treated weekly with p-hydroqu1none and croton oil (Roe
and Salaraan, 1955). Boutwell and Bosch (1959) concluded that p-hydfoqutnone
was Inactive as a promoter 1n mouse skin following a single application of
DMBA.
Holmberg et al. (1986) found that after an Intraperltoneal dose of DENA,
p~hydrot|u1none administered orally to rats at 100 mg/kg resulted 1n a
significant elevation of f-glutamyl-transpeptldase positive foci 1n the
Hver. p-Hydroqulnone Injected Into laboratory animals results In arrested
raetaphase (Parroentler and Oustln, 1948; Parroentler, 1953; Rosin and
Doljanske, 1953).
p-Hydroqulnone Injected subcutaneously Into mice with melanoma Increased
survival (Chavln et al., 1980).
p-Hydroqu1none tested positive for reverse mutation In £. typhlmuMum on
ZLM medium but was negative on VB medium (Gocke et al., 1981). The remain-
Ing Ames type assays have been negative {Goodyear T1re and Rubber Co., 1982;
Sakal et al., 1985). DNA damage was observed when p-hydroqu1none was tested
E_. coll {Goodyear T1re and Rubber Co., 1982).
Negative results have been found In studies of sex-1Inked recessive
lethal mutations In 0. melanogaster (Gocke et al., 1981; Goodyear Tire and
Rubber Co., 1982) and In a test for DNA damage 1n mouse lymphoma cells
(Pellack-Walker and Blumer, 1986). p-Hydroqu1none did not transform
Balb/3T3 mouse cells (Goodyear T1re and Rubber Co., 1982). Post et al.
(1984), Penney et al. (1984) and Painter and Howard (1982) have shown that
p-hydroqu1none Inhibits ONA and RNA synthesis. p-Hydroqulnone has been
shown to Increase the rate of SCE 1n human lymphocytes (MoMmoto and Wolff,
1980; Knadle, 1985; Erexson et al., 1985).
0049d -51- 07/14/87
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p-Hydroqu1none tested positive 1n a mouse mlcronucleus test (Gocke et
al., 1981). A spot test using mice was negative (Gocke et al., 1983). Jowa
et al. (1986) found that jn. vitro, p-hydroqulnone reacts with deoxyguanoslne
and DNA to form two adducts.
An Increase In the resorptlon rate was observed 1n rats fed a total of
0.5 g of p-hydroqu1none throughout gestation (Telford et al., 1962). The
only effects noted In rats dosed by gavage with p-hydroqu1none on gestation
days 6-15 at doses of 300 mg/kg were decreased maternal weight gain and
decreased female fetal weights (Krasavage, 1985). No effects were observed
at <1DO tag/kg.
The number of young produced In two successive Utters by male and
female rats treated with p-hydroqu1none 1n the diet for 6 months at levels
up to 1% were similar to controls (Carlson and Brewer, 1953). Female rats
fed p-hydroqu1none 1n the diet at concentrations up to 0.3/4 for 10 days
before mating and throughout gestation showed no changes In reproductive
parameters (Ames et al., 1956).
Racz et al. (1959) found that oral administration of p-hydroqu1none at
200 mg/kg/day and possibly at 50 and 100 mg/kg/day for 2 weeks prolonged
dlestrus In female rats. In a study by Skalka (1964), reduced fertility was
observed 1n male rats subcutaneously Injected with p-hydroqu1none at 100
mg/kg/day for 51 days before mating. Other effects noted were decreased
testes, ep1d1dym1des, seminal vesicle and suprarenal gland weights.
0049d -52- 07/14/87
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
The OSHA (1985) PEL and the ACGIH (1986a,b) TLV-TWA for p-hydroquinone
are 2 mg/m3. NIOSH' (1978) has also recommended 2 mg/m3 as a !5-m1nute
celling. The level of 2 mg/m3 1s based on human exposure which Indicated
that at 2 mg/m3 eye lesions do not occur or that 1f they do occur, they
are mild and reversible (ACGIH, 1986a; NIOSH, 1978).
Additional guidelines and standards for p-hydroqu1none could not be
located in the available literature as cited in Appendix A.
7.2. AQUATIC
Guidelines and standards for the protection of aquatic organisms from
the effects of p-hydroquinone could not be located in the available litera-
ture as cited In Appendix A.
0049d -53- 06/02/87
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8. RISK ASSESSMENT
8.1. CARCINQGENICITY
8.1.1. Inhalation, Pertinent data regarding the carc1nogen1c1ty of
p-hydroqu1none following Inhalation exposure could not be located 1n the
available literature as cited 1n Appendix A. p-Hydroqulnone has been shown
to be a metabolite of benzene, a human carcinogen. Whether p-hydroqu1none
plays a role in benzene care1nogen1city Is not clear.
8.1.2. Oral, Pertinent data regarding the cardnogenldty of p-hydro-
qulnone following oral exposure could not be located In the available
literature as cited 1n Appendix A. The 103-week toxlclty study usltvtj rats
(Carlson and Brewer, 1953) did not discuss tumor Incidences. The NTP has
sponsored a 2-year gavage study of p-hydroqulnone, but the data are not yet
available (NTP, 1987).
8.1.3. Other Routes. Cholesterol pellets containing p-hydroqulnone
'Implanted In the bladder of mice Induced significantly (p=0.03) more bladder
tumors than In mice Implanted with just cholesterol (Boyland et a!., 1964).
p-Hydroqu1none did not Increase tumor Incidences 1n the skin of mice
when It was applied with croton oil (Roe and Salaman, 1955) and when
p-hydroqulnone was applied following DMBA treatment (Boutwell and Bosch,
1959). p-Hydroqulnone treatment did, however, result In a significant
elevation of y-glutamyl-transpept1dase positive foci In the Hvers of rats
following a single DENA treatment.
p-Hydroqu1none treatment of rats (Parmentler and Dustln, 1948; Rosin and
Doljanskl, 1953) and hamsters (Parmentler, 1953) has been shown to affect
mitosis. A mitosis state called three-group metaphase has been observed In
bone marrow, liver and cornea! cells of treated animals.
0049d -54- 07/14/87
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Chavln et al. (1980) found that p-hydroqu1none Improved the survival of
mice receiving melanoma transplants.
8.1.4. Weight of Evidence. Although p-hydroqu1none Is a metabolite of
the human carcinogen, benzene, and p-hydroqu1none has been shown to cause
mltotlc effects, there are no laboratory animal studies of p-hydroqu1none by
relevant routes of exposure that Indicate that p-hydroqu1none Is a carcino-
gen. In addition, no human data are available. This lack of data Indicates
that p-hydroqu1none can be placed 1n U.S. EPA Group D (U.S. EPA, 1986c), not
classifiable as to human carclnogenldiy.
IARC 0977) reviewed all the available data concerning the carclnogenlc-
1ty of p-hydroqu1none and concluded that "the available data do not allow an
evaluation of carclnogenldty."
8.1.5. Quantitative Risk Estimates. There are no data Indicating that
p-hydroqu1none Is a carcinogen by either the Inhalation or oral routes of
exposure; therefore, q * values cannot be derived.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) -- No subchronlc
Inhalation toxldty studies of p-hydroqu1none are available. Therefore, an
Inhalation RfD for subchronlc exposure cannot be derived.
8.2.1.2. CHRONIC EXPOSURES Studies 1n which laboratory animals
were chronically exposed to p-hydroqu1none by Inhalation are not available.
Occupational exposure to p-hydroqu1none dust and qulnone vapor has been
shown to result 1n eye lesions. The eye lesions described varied from mild
Irritation and staining of the conjunctiva and cornea to changes 1n the
thickness and curvature of the cornea, loss of cornea! luster and Impaired
vision. The severe eye Injuries tended to occur only after exposures of >5
years (Anderson, 1947; Miller, 1954).
0049d -55- 07/14/87
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Concentrations that resulted In eye Injuries were reported by Oglesby et
al. (1947) as 0.044-14.1 mq/m* qulnone vapor and 20-36 mg/m3
p-hydroqu1none dust. At these concentrations. Sterner et al. (1947) found
no evidence of systemic effects In Individuals with eye Injuries as measured
by physical examinations and laboratory tests.
The Inhalation toxlclty of p-hydroqulnone has not been studied 1n
laboratory animals. p-Hydroqulnone In the air oxidizes to qu1non«^ NIQSH
(1978) stated tnat to Improve the basis for their recommendation, the
equilibrium between p-hydroqu1none and qulnone 1n air should be Investigated
further. Further, the role of p-hydroqulnone In the careInogenlcity of
benzene should be Investigated, so that H can be stated with some certainty
that p-hydroqulnone 1s not a carcinogen by Inhalation. A chronic Inhalation
RfO for p-hydroqulnone cannot be derived from the available data.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURE The subchronlc oral toxldty
of p-hydroqulnone has been studied 1n a number of species. In a 9-week
study using rats, Carlson and Brewer (1953) found that rats fed 5/4
p-hydroqulnone In the diet ate less, experienced a 46% loss 1n weight and
developed anemia. Microscopic examinations revealed atrophy of the bone
marrow, liver cord cells, lymphold tissue of the spleen, adipose tissue and
striated muscle. Superficial ulceratlon and hemorrhage of the stomach
mucosa were also noted. These effects were attributed In part to Inadequate
nutrition.
Dogs fed p-hydroqu1none at doses of 16 mg/kg/day, TWA of 23.5, or 100
mg/kg/day for up to 80 weeks showed no significant changes In urlnalysls,
hematologlcal analysis or hlstopathologlcal examinations as compared with
controls (Carlson and Brewer, 1953). No changes In blood analysis and urine
0049d -56- 07/14/87
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parameters were noted In humans fed three doses of p-hydroqu1none per day
for a total dose of 300 or 500 rag/day for 3-5 months {Carlson and Brewer,
1953).
Christian et al. (1980) treated rats with p-hydroqu1none In the drinking
water for 8 weeks at 230, 390 and 700 mg/kg/day for males, and 270, 470 and
810 mg/1cg/day for females. Decreased water Intake, decreased body weight
and Increased relative liver and kidney weights were noted In males at 700
mg/kg/day and females at 470 and 810 mg/kg/day. Relative liver and kidney
weights were also Increased In males at 390 mg/kg/day. Increased relative
Hver and kidney weights were also noted In rats treated with p-hydroq«1none
1n drinking water at 110, 200 and 360 mg/kg/day for males, and 140, 240 and
430 mg/kg/day for females.
Delcambre et al. (1962) found blood effects (polychromatophlUa and
erythroblastosls) 1n rats treated by gavage with p-hydroqulnone at 15
mg/kg/day, G days/week for 40 days. These effects were not observed at 7.5
mg/kg/day for 40 days, nor were they observed when rats were treated by
gavage with p-hydroqu1none at 5 or 10 mg/kg/day, 6 days/week for 4 months.
There was a high rate of mortality, however, at 10 mg/kg/day. The cause of
death was not reported, but three of the seven high-dose rats died during a
scabies epidemic. However, no rats or mice treated by gavage with <100
mg/kg/day for 13 weeks in a NTP study died (Keller, 1982).
Rats treated with p-hydroqu1none 1n the drinking water for 6 months at a
dose of >50 mg/kg/day showed a decrease 1n hemoglobin, a decrease in the
number of erythrocytes, an Increase In the number of leukocytes, and
dystrophlc changes In the small intestine, Hver, kidneys and myocardium
(Hozhayev et al., 1966). Anlkeeva (1974) reported that oral administration
0049d -57- 07/14/87
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of p-hydroqu1none to rats at 156 mg/kg/day for 30 days resulted 1n Increased
liver weights, decreased hepatic glycogen and vitamin C content, decreased
blood serum protein levels and an Inhibition of pseudochollnesterase.
In mice, p-hydroqu1none 1n the drinking water at 4000 ppm for 4 weeks
markedly lowered the hematocrH and slightly decreased the number of bone
marrow cells (Nakamura, 1982). p-Hydroqulnone In the diet of hamsters at
0.5X for 20 weeks did not result 1n significant changes 1n body weight,
Hver weight or hlstopathologlc changes (Hlrose et a!., 1986).
In the 13-week study sponsored by NTP (Keller, 1982), mice and rats
treated by gavage with p-hytiroqnlnone at 400 mg/Vg/ttay died. Signs of
toxlclty that occurred after dosing were tremors and convulsions. At 200
mg/kg, three female rats and two male mice died. No deaths occurred at <100
mg/kg/day. Toxic nephropathy was observed In rats and forestomach lesions
were observed In mice at 200 mg/kg/day. H1stopatholog1cal examinations of
animals at lower doses were not completed.
No significant changes 1n weight gain or blood counts were observed in
four dogs treated with p-hydroqu1none In gelatin capsules at TWA doses up to
42.9 mg/kg for 810 days (Woodard, 1951). Microscopic examination revealed
hyperplasla of the bone marrow and excessive deposits In the spleens of all
dogs. It was not clear 1f these lesions also occurred In control animals.
Because of the small number of dogs studied, and the lack of study details,
this study 1s not sufficient for risk assessment.
The LOAEL for the subchronlc effects was reported 1n the Oelcambre et
al. (1962) study 1n which blood effects were observed In rats treated by
gavage at 15 mg/kg/day, 6 days/week for 40 days. A dose of 12.9 mg/kg/day
for the LOAEL was derived by multiplying by 6 days/7 days. The most
appropriate NOAEL below the LOAEL 1s the NOAEL 1n humans found by Carlson
0049d -58- 07/14/87
-------
and Brewer (1953). In this study, a group of 17 men and women fed
p-hydroqulnone, 3 limes/day (with meals) for a total dose of 300 rag/day for
3-5 months, did not develop abnormalities 1n blood and urlnalyses. A dose
of 500 mg/day was also a NOAEL, but this was administered to only two
subjects. Because the body weights of the subjects In this study were not
provided, a human body weight of 70 kg (U.S. EPA, 1985) will be assumed to
estimate a NOAEL of 4.29 mg/kg/day for the 300 mg/day dosage. Dividing the
NOAEL of 300 mg/day by 10 to protect sensitive Individuals, a subchronlc
oral HfD of 30 mg/day for a 70 kg human or 0,4 mg/kg/day 1s derived.
Confidence In the subchronlc RfO 1s medium. The human study (Carlson
and Brewer, 1953) Is adequate 1n that blood analyses and urlnalyses of the
subjects were done 1 month before the start of the study so that the
subjects served as their own controls. Confidence In the RfD 1s not higher
because p-hydroqulnone, a metabolite of benzene, has not been adequately
studied for cardnogenldty. -When the results of the NTP cardnogenlclty
study are available, this RfD should be reviewed.
8.2.2.2. CHRONIC EXPOSURES Carlson and Brewer (1953) found no
hematologlc effects or hlstopathologlc changes In organs of rats provided
with p-hydroqulnone 1n the diet at levels up to 1% for 103 weeks. Tumor
Incidences were not discussed.
The highest NOAEL 1n the chronic rat study (Carlson and Brewer, 1953) Is
derived by multiplying the 10,000 ppm dose level by the 0.05 rat food factor
(U.S. EPA, 1985) to obtain a dose of 500 mg/kg/day. Because this dose Is
much higher than the subchronlc rat LOAEL, 12.9 mg/kg/day, found by
Delcambre et al. (1962), It cannot be used for risk assessment. The most
appropriate basis for the chronic RfD 1s the subchronlc human study by
Carlson and Brewer (1953). The chronic RfD will be derived from the
0049d -59- 07/14/87
-------
subchronlc NOAEL of 4.29 mg/kg/day. The subchronic NOAEL Is divided by an
additional uncertainty factor of 10 to extrapolate from subchronlc data, to
derive a chronic oral RfD of 3 mg/day for a 70 kg human, or 0.04 mg/kg/day.
Confidence In the chronic RfD 1s medium to low. The study used for the
derivation of the RfD examined blood and urine parameters In humans, but was
subchronlc. Furthermore, p-hydroquinone has not been adequately studied for
cardnogenlcity. When the results from the NTP cardnogenldty study are
available, this fifO should be reviewed.
0049d -60- 07/14/87
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
The toxlclty of p-hydroqu1none was discussed 1n Chapter 6. The data
suitable for deriving RQs are summarized in Table 9-1. The dog study by
Woodard (1951) is not Included because only two dogs/dose group were studied
and U Is not clear If bone marrow hyperplasla and pigment deposits 1n the
spleen were also observed In control dogs.
The derivation of RQs 1s summarized In Table 9-2. The most severe
effect was found In the 13-week study sponsored by the NTP (Keller, 1982;
Bloassay Systems Corporation, 1981a,t>). In this study, several deaths,
lethargy and some hlstopathologlc effects were noted 1n rats and mice
treated by gavage with p-hydroqu1none at 200 mg/kg, 5 days/week for 13
weeks. The RV for both rats and mice corresponds to 10. The human MED
values of 75.6 mg/day from the mouse study and 150.5 mg/day from the rat
study were calculated by multiplying the equivalent human dose by 70 and
dividing by 10 to approximate chronic exposure. The MED from the mouse
study corresponds to an RV. of 2.7, while the MED from the rat study
corresponds to an RV. of 2.2. Multiplying the RV s by the RV.s, CSs
of 27 and 22 are obtained. These CSs correspond to RQs of 100.
In two other studies, effects occurred at a lower human MED than ob-
served 1n the 13-week gavage study. In the study by Mozhayev et al. (1966),
rats treated with p-hydroqu1none 1n the drinking water at 50 mg/kg/day for 6
months showed decreased numbers of erythrocytes, Increased numbers of
leukocytes and dystrophlc changes In the small Intestines, liver, kidney and
myocardium. The MED, 59.5 mg/day, calculated by multiplying the human dose
by 70 kg and by dividing by an uncertainty factor of 10 to approximate
chronic exposure, corresponds to an RV. of 2.8. The effect corresponds to
0049d -61- 07/14/87
-------
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an RVg of 6. Multiplying the RVrf by the RVg results 1n a CS of 17,
corresponding to an RQ of 1000. In the study by Delcambre et al. (1962),
blood effects were observed 1n rats dosed by gavage with p~hydroqu1none at
15 mg/kg, 6 days/week for 40 days. The MED, 15.4 rag/day, calculated as
described above, corresponds to an RV. of 3.7. The effect corresponds to
an RVg of 5. Multiplying the RVrf by the RVg results In a CS of 19,
corresponding to an ftQ of 1000.
The remaining studies available for RQ derivation (Telford et al., 1962;
Krasavage, 1985; Carlson and Brewer, 1953; Nakaraura, 1982; Christian et al.,
1980) show effects less severe at doses higher than observed In the 13-week
gavage study; therefore, CSs need not be calculated.
The highest CS, 27, calculated from the 13-week gavage mice study
(Keller et al., 1981; Bloassay Systems Corporation, 1981b) Is recommended as
the basis for the RQ (Table 9-3).
9.2. BASED ON CARCINOGENICITY
The data on the cardnogenlcity of p-hydroqu1none were Inadequate to
calculate a q^* (see Section 8.1.). Therefore, an F factor cannot be
calculated and an RQ based on cardnogenldty cannot be derived.
0049d -65- 07/14/87
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TABLE 9-3
p-Hydroqu1none
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 74.9 mg/day
Effect: deaths of 2 males, lethargy, hunched position and
decreased weight gain 1n males, forestomach lesions
Reference: Keller, 1982
RVd: 2.7
RVe: 10
Composite Score: 27
RQ: 100
*Equ1valent human dose
0049d -66- 07/14/87
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0049d -69- 07/14/87
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Dore, M., N. Brunei and B. Legube. 1975. Participation of various organic
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0049d -86- 07/14/87
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APPENDIX A
LITERATURE SEARCHED
This HEED Is 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 In January, 1987. Tn addition, hand searches
were made of Chemical Abstracts (Collective Indices 5-9), and the following
secondary sources should be reviewed:
AC6IH (American Conference of Governmental Industrial Hyglenlsts).
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
1986-1987. Cincinnati, OH. Ill p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John Wiley and
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 28. John Wiley and
Sons, NY. p. 2879-3816.
Clayton, G.O. and F.E. Clayton, Ed. 1982. Patty's Industrial _
Hygiene and Toxicology, 3rd rev. ed., Vol. 2C. John WHey and
Sons, NY. p. 3817-5112.
0049d
-87-
07/14/87
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Grayson, M. and 0. 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.fi. Mabey, A.T. Lieu, 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. Chenlcals 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 Relnhold 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 Call in
Programs. Registration Standards and the Data Call in Programs.
Office of Pesticide Programs, Washington, DC.
U.S. EPA. 1985. CS8 Existing Chemical Assessment Tracking System.
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.
1422, Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
Worthing, C.R. and S.8. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
0049d -88- 07/14/87
U.S. Environmental Protection Agency,
Region V, Library
230 South Dearborn Street
Chicago, Illinois 60604
-------
In addition, approximately 30 compendia of aquatic toxldty 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. T980. 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. Dept. Interior, F1sh and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee. J.£. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for tt» 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.
0049d -89- 07/14/87
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