TOXICOLOGICAL PROFILE FOR
ORTHO-CRESOL
Criteria and Standards Division
Office of Drinking Water
U.S. Environmental Protection Agency
Washington, DC  20460
              August  1989

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                                             August  1989
       TOXICOLOGICAL PROFILE

                FOR

            ORTHO-CRESOL
   Criteria  and  Standards  Division
      Office of Drinking Water
U.S. Environmental Protection Agency
        Washington, DC   20460

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                                 ORTHO-CRESOL
A.  GENERAL
    1.  CAS Number:   95-48-7
    2.   RTECS  Number:   G06300000
    3.   General  Name/Synonyms;   2-Methyl phenol
                                o-Cresylic  acid
                                o-Hydroxytoluene
    4.  Molecular Formula:   C7H80
    5.  Molecular Weight;   108.14
    6.  Structure:
B.  PHYSICAL AND CHEMICAL PROPERTIES
    1.  State:   Colorless liquid; becomes dark
                with age and exposure to
                air/light


    2.  Vaoor Pressure:   1 mm Hg at 38.2°C.
Windholz et al. (1983)
Sax (1975)
    3.  Melting Point;  30°C
Windholz et al. (1983)
    4.  Boiling Point;  191-192°C
Windholz et al. (1983)
    5.  Specific Gravity;  1.047 at 20°C
Windholz et al. (1983)
                                      -1-

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    6.  Solubility;  Soluble in alcohol, ether,            Sax and Lewis (1987)
                    chloroform; and
                    2.5g/100 mL water                     Windholz (1976)
                    at 25°C

    7.  Log Ka...:   1.95                                     Leo et al.  (1971)

    8.  UV Absorption:  No  information was  found.


C.  PHYSICAL/CHEMICAL EQUILIBRIUM FACTORS

    1.  Bioconcentration  Factors  (BCF):   No information was found.

    2.  Kwa:   No information was found.

    3.  K,,.:   No  information was found.


D.  ENVIRONMENTAL  FATE

    1.  Photolysis;   Direct photolysis of o-cresol  in water at 254 nm gave the
       following  detectable products (Joschek and  Miller 1966):
                   OH
                o-er*so1
        However,  the analytical  method used in these experiments provided
        qualitative identification of only phenolic products (Smith et al.,
        1978).

    2.   Leaching;  Cresols are adsorbed weakly onto soils and organic matter
        (Smith  et al., 1978) and will readily leach into the aquatic
        compartment.
                                      -2-

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3.  Route of Water Contamination:  o-Cresol is likely to enter the aquatic
    compartment from a number of sources; the major release probably is
    industrial wastewater.

    Bartle et al. (1977) utilized injections into a Tenax precolumn followed
    by gas chromatography to analyze an industrial effluent before and after
    an unspecified waste treatment process.  The o-cresol concentrations
    were 12 ppm and <1 ppm, respectively.

    Baird et al. (1977) analyzed wastewater discharges from a petroleum
    refinery and reported a concentration of 5482 ppm o-cresol.  Sampling
    further downstream in the trunk sewer system revealed concentrations of
    118 and 21.8 ppm.  On another sampling occasion, the following
    concentrations were reported for o-cresol:  418 ppm from the same
    refinery discharge and 34.2 ppm in the sewer downstream.

4.  Hydrolysis:  No information was found.

5.  Plant Uptake:  No information was found.

6.  Microbial Degradation:  The biological degradation of o-cresol by
    adapted activated sludge was determined by measuring the decrease  in
    chemical oxygen demand (COD) (Pitter,  1976).  Following 120 hours  of
    incubation  at 20 ± 3°C, 95.0% of the  initial COD was removed.  The rate
    of biodegradation was calculated as 54.0 mg COD/g of dry matter of the
    activated sludge/hour.  o-Cresol was  considered to be biologically ready
    to decompose.

    In a study  designed to model anaerobic aquatic systems, such as heavily
    polluted waters or waste lagoons, o-cresol at concentrations of 1  and 50
    ppm was completely degraded  in about  7 and 15 days, respectively,  at
    ambient temperatures.  The rate of degradation decreased at lower
    temperatures  (Ettinger et al., 1951).
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    Semov  and  Andreeva (1972)  treated wastewater  discharged from a coke-
    chemical plant with increasing concentrations of phenol over a period of
    8 months.   A total of 309  strains were  isolated from the  activated
    sludge.  Five microbes  completely metabolized o-cresol at a
    concentration of 100 ppm in 2 to 4 days  at  a  dilution of  1:20 cresol to
    wastewater.  At increased  concentrations o-cresol (1:5),  21  strains were
    able to  completely oxidize cresol.  These studies indicate that microbes
    adapt  to various chemical  effluents by  a gradual change  in their
    metabolic  behavior and/or  by selection.

7.  Persistence in Soil/Water:  No information  was found.

8.  Byproducts;  A summary  of possible o-cresol biodegradation pathways,
    under  aerobic conditions,  based on whole cells or cell-free extracts
    from pure  cultures,  is  presented  in Figure 1.  This  scheme depicts  the
    pathways for Pseudomonas sp  and  Bacillus stearothermoohilus that are
    known  to degrade o-cresol.
           (1,2,3)
   o-crtsol
                        CM,
3-nathylMtKhol
2-hydrox/-6-
oxohepu-2,4-
dlenoic »e1d
                                                   CH.COOH
                                                   ""«
                                                     ""
                                                              .  , ..
                                                             a, 3, 4).
                                 CH,.C-COO'
                                    C pyrmatt
                                    and
                                 CHj-CHO
                                 actuldvhyd*
                                                    4-hydro»y-2-o»o-
                                                    vtltric tcid
     (1) Bayly et al. (1966) Pseudomonas sp
     (2) BusweII (1975) Bacillus stearothermophilus
     (3) Ribbons (1966) Pseudomonas aeruginosa
     (4) Feist and Hegeman (1969) Pseudomonas sp
                  Figure 1.   Degradation of o-cresol  by pure
                              cultures or cell-free extracts of  microorganisms.
                                     -4-

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   9.  Vaporization;  No information was found.
E. ACUTE TOXICITY IN MAMMALS
    Animal/strain/sex    Route
              LDSO (nig/kg)
                  Reference
Rat/-V-
Oral
1350
Diechmann and Witherup
(1944)
Rat/Wistar/M,F
Rabbi t/-/-
Rabbit/New Zealand
White/F
Oral
Dermal
Dermal
360
>2000
890
(460-1690)"
Bailey (1982a)
Bailey (1982b)
Vernot et al . (1977)
"Data not provided.
"95% confidence limits.
F.  SKIN AND EYE IRRITATION AND SENSITIZATION IN MAMMALS
     No information was found.
G.  SUBCHRONIC TOXICITY IN MAMMALS

     Groups of 30 male and 30 female Sprague-Dawley rats were administered, by
gavage, o-cresol  (99.5% pure) in corn oil at 0, 50, 175, or 600 mg/kg/day  for  13
consecutive weeks.  Animals were examined twice daily, and body weight and food
consumption were measured weekly.  Ophthalmologic examinations were conducted
before dosing and at  termination.  Batteries of hematological, clinical
chemistry, and urinalysis tests were administered prior to study  initiation, at
study week 7, and at  termination.  At termination, all rats underwent gross
necropsy, and the heart, liver, spleen, brain, kidneys, gonads, adrenals,  and
thyroid/parathyroid were weighed.  Histopathological examinations of tissues
                                      -5-

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from all control, mid-dose, and high-dose groups were conducted.   Rats at the
high-dose level (600 mg/kg/day) exhibited signs of central  nervous system (CMS)
depression that included lethargy, tremors, and coma; 9 males and 19 females
died during the study.  Approximately 1-hour postdosing, the surviving animals
"recovered" and appeared normal.  No other significant clinical signs were
observed in treated rats.  Statistically significant (p <0.05) reductions in
body weight gain were seen in males during study weeks 2 through 10; a similar
effect was not observed in females.  The mean food consumption values of males
at this level were significantly (p <0.05) lower than control values during
study weeks 1 through 6.  At the mid-dose level (175 mg/kg/day),  one female
exhibited lethargy and tremors on day 27 of the study; these signs were not
observed at any other time.  Male rats at this level exhibited significant (p
<0.05) reductions in body weight during week 2 only.  No treatment-related
effects were observed in rats given 50 mg/kg/day.  Clinical chemistry,
hematology, opthalmology, urinalyses, and organ weight measurements did not show
any treatment-related changes.  Histopathological examinations did not identify
o-cresol target organs.  Thus, the cause of death among the high-dose animals
was not established.  o-Cresol exerted central nervous system effects only at
the high dose.  (Dietz and Mulligan, 1988).

H.   REPRODUCTIVE EFFECTS AND TERATOGENICITY IN MAMMALS

      No information was found.
I.   MUTAGENICITY/GENOTOXICITY

      Data are presented in tabular form on page 8.
                                      -6-

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            I.  HUTAGENICITY/GENOTOXICITY
                Test
                                         Strain
                                                               Activation
                                          Dose/concentrati on
                                                                                                                Toxic effects
                                                                                                                                                Reference
Ames mutagenicity
assay





Salmonella +S9
tvnhimurium
TA98, TA100,
TA1535, TA1537,
TA1538


0. 0.01, 0.1, 1.0,
5.0. 10.0. 25.0.
and 50.0 /([./plate




No mutagenicity
detected with or
without metabolic
activation.
o-Cresol was toxic
to all strains at
>10 Ml/plate
Jagarmath (1981)






            Ames mutagenicity
            assay
             Forward mutation
             assay
S. typhlmurium
TA98, TA100,
TA1535. TA1537

Mouse lymphoma
cell LS178Y
TK+/-
                                                                »S9
                                                                +S9
0, 1.0, 3.3,  10.0,
33.0, and 100.0 /ig/
plate

0, 3.91, 7.81,
15.6, 31.3,  and 62.5
nL/ml
Non mutagenic
with or without
activation.

Nomutagenic
with or without
activation.
                                                                                                                                            Haworth  et  al.  (1983)
                                                                                                                                            Cifone (1981)
 I
-J
 I
             Sister chromatid
             exchange (SCE)
Chinese hamster
ovary cells
                                                                -S9
                                                                +S9
             Sister chromatid
             exchange
Hunan
fibroblasts
(in vitro)
                                                                -S9
                                                                None
0, 15.6, 31.3,  62.5,
125.0, and 250.0
nL/mL

0, 0.56, 3.13,
6.25, 12.5. and
15.0 nL/mL
0, 12.5, 25.0, 50.0.
75.0, and 100.0 nL/mL

0. 0.8, 4. 8. 10.
and 30 nM
Significant
(p <0.1) dose-
related increase
in SCE both with
and without
activation.
At 8.0 nM,
significant (p <0.05)
increase in SCE
frequency; doses of
10 or 30 nM were
toxic.
                                                                                                                                            Galloway (1981)
Cheng and Kligerman
(1984)

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           I.   MUTAGENICITr/GENOTOXICITY  (continued)
Co
I
Test
Sister chromatic!
exchange
Unscheduled DNA
synthesis
Strain Activation
Bone marrow. None
alveolar macro-
phages. and
regenerating
liver cells of
DBA/male mice

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J.  CHRONIC TOXICITY/CARCINOGENICITY
Animal
Strain   Sex   Route   Dose
                 Treatment
                 Effects
                                                                         Reference
Mouse
Sutter
Dermal  20X(IV/V)
Mice received
a single dermal
application of
25 1L of 0 3%
9.10-dimethyl -
1,2-benzanthracene
After 12 weeks
of treatment, skin
papillomas devel-
oped in 10 of 17
surviving mice,
no skin papillomas
                                      in acetone followed were seen in the
                                      by twice weekly
                                      applications of
                                      25 1L of 20X
                                      o-cresol in
                                      benzene for 12
                                      weeks
                                              vehicle (benzene)
                                              control.  Study
                                              was terminated at
                                              12 weeks
Boutwell and Bosch
(1959)
K.  PHARMACOKINETICS IN MAMMALS


      Bray et  al.  (1950) administered  the cresols  (250-500 mg)  in NaHC03
solutions to  rabbits (number,  strain,  and sex not specified)  by gavage  and
recovered 65-80% of the doses  as free and conjugated cresols  in the urine
within 24 hours  of dosing.   The results indicate  that at least 65-80% of the
dose  was absorbed from the  gastrointestinal tract.   In rabbits, of the  500 mg
of  o-cresol administered  by gavage,  15% was recovered in the  urine as ethereal
sulfate and 72%  as ether  glucuronide.   A minor metabolite detected after
administration of o-cresol  was conjugated dihydroxytoluene.   Approximately 80%
of  the o-cresol  administered was recovered in the urine within 24 hours

postdosing.


L.  HUMAN HEALTH  EFFECTS


      No information was found.
                                          -9-

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M.  EXISTING STANDARDS/CRITERIA
    Type      Standards/Criteria      Proponent           Reference
TLV-TWA'
PEL"
IDLHC
5 ppm (?22 mg/m3)
5 ppm (?22 mg/m3)
250 ppm
ACGIH
NIOSH/OSHA
NIOSH/OSHA
ACGIH (1988)
NIOSH/OSHA (1978)
NIOSH/OSHA (1978)
"Threshold Limit Value-Time Weighted Average.
"Permissible Exposure Level.
'Immediately Dangerous to Life or Health.
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N.  REFERENCES

ACGIH.  1988.  American Conference of Governmental Industrial Hygienists.
Threshold Limit Values and Biological Indices for 1986-1987.  Cincinnati, OH.

Bailey DE.  1982a.  Acute oral toxicity in rats.  Report No. 878210720.  Food
and Drug Research Laboratories, Inc.  Unpublished.  FYI-OTS-84003A.

Bailey DE.  1982b.  Acute dermal toxicity study in rabbits.  Report No.
878210721.  Food and Drug Research Laboratories,  Inc.  Unpublished.  FYI-OTS-
84003A.

Baird RB, Carmona LG, Jenkins RL.  1977.  The direct-injection GLC analysis of
xylenols in industrial wastewaers.  Bull. Env. Cont. and Toxicol.  17(6):764-
767.

Bartle KD, El stub J, Novotny M, Robinson RJ.  1977.  Use of a modified tenax
BC column packing for the direct gas chromatographic analysis of phenols in
water at the  ppm level.  J. of Chromatog.  135:351-358.

Bayly RC, Dagley S, Gibson DT.  1966.  The metabolism of cresols by species of
Pseudomonas.  Biochem. J. 101:293-301.

Bray HG, Thorpe WV, White K.  1950.  Metabolism of derivatives of toluene.  4.
Cresols.  Biochem. J. 46:275-278.

Boutwell RK,  Bosch DK.   1959.  The tumor-promoting action of phenol and
related compounds for mouse skin.  Cancer. Res. 19:413-424.

Buswell JA.   1975.  Metabolism of phenol and cresols by Bacillus
stearothermophilus.  J.  Bacteriol. 124(3):1077-1083.

Cheng M, Kligerman A.  1984.  Evaluation of the genotoxicity of cresols  using
sister-chromatid exchange (SCE).  Mutat. Res. 137:51-55.

Cifone M.  1981.  Mutagenicity evaluation of N50C-81-3 in the mouse lymphoma
forward mutation assay.  Litton Bionetics,  Inc.   Project No. 20989.  FYI-OTS-
0981-0126.

Deichmann WB, Witherup S.   1944.  Phenol Studies  IV.  The acute and
comparative  toxicity of  phenol and o-, m-,  and  p-cresols for experimental
animals.  J.  Pharmacol.  Exp.  Therap. 80:233-240.

Dietz D, Mulligan LT.  1988.  Subchronic toxicity of ortho-cresol  in Sprague-
Dawley rats.  Revised  final report.  Available  from NTIS, Springfield, VA.
PB 88-197496.

Ettinger MB,  Moore WA, Lishka RJ.   1951.  Anaerobic persistence of phenol  and
o-cresol.  Indust. Engineer.  Chem.  43(5):1132-1135.

Feist CF, Hegeman GD.  1969.   Phenol and benzoate megabolism by Pseudomonas
putida;  Regulation  of tangential pathways.  J. Bacteriol.  100(2):869-877.

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Galloway S.  1981.  Mutagenicity evaluation of N50C-81-3 in the sister
chromatid exchange assay with Chinese hamster ovary (CHO) cells.   Litton
Bionetics, Inc.  Project No. 20990.  FYI-OTS-0981-0126.

Haworth S, Lawlor T, Mortelmans K, Speck U, Zeiger E.   1983.  Salmonella
mutagenicity test results for 250 chemicals.  Environ. Mutagen. 1: 3-142.

Ishihara N, Kanaya A, Keda M.  1976.  m-Dinitrobenzene intoxication due to
skin absorption.  Int. Arch. Occup. Environ. Hlth.  36:161-168.

Jagannath D.  1981.  Mutagenicity evaluation of N50C-81-3 in the Ames
Salmonella/microsome plate test.  Litton Bionetics, Inc.  Project No. 20988.
FYI-OTS-0981-0126.

Joschek HI, Miller SI.  1966.  Photooxidation of phenol, cresols, and
dihydroxybenzene.  J. Am. Chem. Soc. 88(14):3273-3281.

Leo A, Hansch C, Elkins D.  1971.  Partition coefficients and their uses.
Chem. Rev. 71(6):525-616.

Myhr B.  1981.  Evaluation of N50C-81-3 in the primary rat hepatocyte
unscheduled DNA synthesis assay.  Litton Bionetics, Inc.  Project No. 20991.
FYI-OTS-0981-0126.

NIOSH/OSHA.  1978.  National Institute for Occupational Safety and
Health/Occupational Safety and Health Administration.   Pocket Guide to
Chemical Hazards.  Washington, DC:  U.S. Department of Health and Human
Services, Public Health Service, Centers for Disease Control/U.S. Department
of Labor.  September.

Pitter P.  1976.  Determination of biological degradability of organic
substances.  Water Res. 10:231-235.

Ribbons DW.  1966.  Metabolism of o-cresol  by Pseudomonas aeruainosa strain
TI.  J. Gen. Microbiol. 44: 221-231.

Rundell J.  1981.  Evaluation of N50C-81-3  in the jn vitro tranformation of
BALB/3T3 cells  assay.  Litton Bionetics, Inc.  Project No. 20992.  FYI-OTS-
0981-0126.

Sax, NI.   1975.  Dangerous properties of industrial materials.  4th Ed.  New
York: Van Nostrand Reinhold Company, p. 580.

Sax NI, Lewis RJ Sr.   1987.  Hawley's Condensed Chemical Dictionary, llth Ed.
New York:  Van  Nostrand Reinhold Company,  p. 307.

Semov V, Andreeva L.   1972.  Microbial degradation of  phenols  in  the
purification of phenolic waste waters with  activated sludge [translated  from
Bulgarian].  Jr. Nauchnoizsledovatel. Institut. Uodpsnabdyauane.  Kanaliz.
Sanit. Tech. 8:183-190.
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Smith JH, Mabey WR, Bohonos N, Holt BR, Lee SS,  Chou T,  Bomberger DC, Mill  T.
1978.  Environmental pathways of selected chemicals in freshwater systems.
Part II.  Laboratory studies.  SRI International, Menlo Park, CA, EPA-600/7-
78-074.

Vernot EH, MacEwen JD, Haun GC, Kinkead ER.  1977.  Acute toxicity and skin
corrosion data for some organic and inorganic compounds and aqueous solutions.
Toxicol. Appl. Pharmacol. 42:417-423.

Windholz N (ed.).  1976.  "The Merck Index." 9th ed.  Merck and Co., Inc.,
Rahway, NJ.  Merck and Company, Inc., p. 642.

Windholz M, Budavari S, Blumetti RF, Otterbein ES, eds.  1983.  The Merck
Index--An Encyclopedia of Chemicals, Drugs, and Biologicals, 10th Ed.  Rahway,
NJ:  Merck and Company, Inc., p. 568.
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