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0219d
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08/04/89
-------
The LQ50 values reported for oral exposure 1n rats are 207 mg/kg (Sax,
1984} and 1800 mg/kg (Delchmann and WHherup, 1944). Mortality was not
observed until 600 mg/kg/day In the subchronlc studies described previously
(Dletz and Mulligan, 1988; U.S. EPA, 1986b). The oral LD . for mice 1s
344 mg/kg (Sax, 1984} and the LD.- for rabbits Is 620 mg/kg (Delchmann and
WHherup. 1944}. The dermal LD5Q for rabbits Is 300 mg/kg (Vernot et al.,
1977); therefore, 4-methylphenol appears to be more toxic through the dermal
route for rabbits. The apparently rapid dermal absorption and resulting
mortality (see Section 5.1.) reported by Green (1975) corroborate these
acute data. Subcutaneous exposures resulted In LD s that were similar
for rats, mice, rabbits and guinea pigs (Sax, 1984; Gordon and McCandless,
1959).
Subchronlc dermal (Shelley, 1974) and Intravenous (Yehuda et al.t 1977)
studies with 4-methylphenol were also performed on mice and rats, respec-
tively. An unoccluded dose of 0.5X 4-methylphenol 1n acetone (total amount
not reported) was sprayed on the clipped or epllated caudal half of the
backs of CBA/J agouti and black mice 3 times/week for 6 weeks (Shelley,
1974). By 6 months following exposure, deplgmentatlon of the hair and skin
was observed. Intravenous administration of 4-methylphenol to rats as a
dally 0.1 mg/kg Injection for 7 weeks at room temperatures of 4, 20 and 37°C
resulted In convulsions, with minimum seizures at 20°C (Yehuda et al., 1977).
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the cardnogenHHy of
4-methylphenol following Inhalation exposure were not located 1n the
available literature cited in Appendix A.
6.2.2. Oral. Pertinent data regarding the cardnogenldty of 4-methyl-
phenol following oral exposure were not located In the available literature
cited In Appendix A.
0219d
-36-
03/21/90
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6.2.3. Other Relevant Information. The only relevant cancer data on
4-methylphenol In the literature was an experiment promoting skin tumors 1n
young adult albino mice of several strains (Boutwell and Bosch, 1959). A
single Initiating dose of 75 vq DMBA as a 0.3% solution In acetone was
applied to shaved back skin of groups of 28 animals. One week later,
4-methylphenol, as a 20% solution 1n benzene, was applied twice each week
for 12 weeks. A control group of 12 animals was exposed only to benzene
following DMBA Initiation. Clinical observations Included eight mortalities
In the 4-methylphenol group. Examination of the test group revealed 0.55
paplllomas per survivor and 35% of the survivors bearing paplllomas, but no
carcinomas were observed. No paplllomas or carcinomas were observed In the
control group. A 20-week experiment with DMBA Initiation (Identical to the
12-week experiment) and 4-methylphenol promotion as a 5.7% solution In
benzene revealed mortality 1n 2/20 control animals and In 6/20 treated
animals. Evaluation revealed 0.36 paplllomas per treated survivor and 29%
of the survivors had paplllomas; no paplllomas or carcinomas were observed
1n control animals. Further experimental protocol was not reported. The
Investigators concluded that 4-methylphenol was a tumor promoter In this
test.
6.3. GENOTOXICITY
Available data regarding the mutagenlclty and genotox1c1ty of 4-methyl-
phenol are summarized 1n Table 6-2. 4-Methylphenol has not been found to be
mutagenlc when tested up to levels of toxUlty In reverse mutation assays
with Salmonella typhlmurlum strains TA1535, TA1537, TA1538. TA98 or TA100
(Florin et a!., 1980; Douglas et al., 1980; Haworth et al., 1983; Crowley
and Margard, 1978; Case Western Reserve, 1980; Pool and Lin, 1982).
0219d
-37-
03/21/90
-------
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-------
ID. vivo and itt vUro SCE assays with human dlplold flbroblasts and DBA/2
mice (CUT, 1983; Cheng and KUngerman, 1984) revealed no significant
Increases 1n SCE. A cell transformation assay with C3H10T1/2 mouse flbro-
blasts was negative (Crowley and Hargard, 1978).
Crowley and Margard (1978), however, found 4-methylphenol to be positive
In an unscheduled DNA synthesis assay using human lung flbroblasts (HI-28)
and biological activation (further protocol not provided).
6.4. DEVELOPMENTAL TOXICITY
A range finding developmental toxlclty study with groups of eight mated
female New Zealand White rabbits administered 4-methylphenol 1n corn oil by
gavage at levels of 50, 150, 300 and 500 mg/kg/day for days 6-18 of gesta-
tion was performed for CMA (1987). Dose-related maternal mortality was
observed In the three highest dose levels (2/8, 4/8 and 7/8, respectively).
There were no mortalities 1n controls. Gasping and labored respiration were
observed at all dose levels, but only In a few rabbits at 50 mg/kg/day.
More Intense CNS and cardlopulmonary effects (hypoactlvlty, ataxla, twitch-
Ing and breathing problems) were observed In the dams at the two highest
levels. Significant maternal weight loss was observed at the 150 and 300
mg/kg levels; excessive (7/8) mortality at the highest level precluded
statistical analysis. External malformations possibly attributed to the
test chemical were restricted to forellmb and pectoral girdle variations at
300 mg/kg/day. There was no mention of examination for Internal malfor-
mations.
In the final study, groups of 14 mated New Zealand white rabbits were
treated by gavage with 4-methylphenol 1n corn oil at doses of 5.0, 50.0 or
100.0 mg/kg/day on gestation days 6-16 (CMA, 1988a). The day on which
mating was observed was designated gestation day 0. A negative control
group of 28 rabbits was treated on the same schedule with corn oil alone.
0219d
-39-
03/13/91
-------
The dams were observed for clinical signs, and body weights and food con-
sumption were measured until sacrifice on gestation day 29. Upon necropsy,
the dams were evaluated for body, liver and gravid uterine weight and the
number and condition of Implantation sites. Live fetus were weighed and
examined for external. Internal and skeletal variations. Approximately
one-half of the fetuses from each Utter were examined for soft tissue and
cranlofaclal malformations. Maternal mortality claimed 5/14 (p<0.01) and
2/14 (p>0.10) rabbits treated with 100.0 and 50.0 mg/kg/day, respectively,
(Fisher exact test performed at SRC). The Investigators attributed these
deaths to 4-methylphenol. Respiratory distress, cyanosis, ocular discharge
and hypoactlvlty were observed In dams treated with >50.0 mg/kg/day. There
were no effects on food consumption or body weight at any dose level and no
maternal effects of any kind at 5.0 mg/kg/day. There were no effects on
gestatlonal parameters, fetal body weight/litter or the frequency of
Internal, external or skeletal variation.
CMA (1988b) used a similar protocol to evaluate the developmental
toxldty of 4-methylphenol In rats. Groups of 25 mated Sprague-Dawley rats
were treated with 30.0, 175.0 or 450.0 mg/kg/day on days 6-15 of gestation.
Fifty rats were maintained as negative (vehicle) controls. The dams were
sacrificed on gestation day 21. Approximately one-half the fetuses 1n each
litter were examined for visceral and cranlofaclal malformations and
one-half were examined for skeletal variations. Maternal effects, limited
to the high dose group. Included clinical signs (CNS signs, labored respira-
tion), reduced food consumption, body weight and body weight gain during the
treatment period, and reduced body weight at termination. There were no
effects on gestatlonal parameters or on the Incidence of external, soft
tissue or skeletal variations. Fetal body weight/Utter was significantly
decreased at 450.0 mg/kg/day.
0219d -40- 03/13/91
-------
6.5. OTHER REPRODUCTIVE EFFECTS
Pertinent data regarding other reproductive effects of 4-methylphenol
were not located In the available literature cited 1n Appendix A.
6.6. SUMMARY
Data are lacking on the chronic toxlclty and carcinogenic potential of
4-methylphenol following oral or Inhalation exposure. 4-Hethylphenol
appeared to be a tumor promoter In the two-stage skin tumor assay In mice
following Initiation by DMBA (Boutwell and Bosch, 1959). Mutagenlclty and
genotoxlcty studies resulted In negative responses In reverse mutation
assays, In vitro and in vivo SCE tests and cell transformation assays (see
Table 6-2); however, Crowley and Margard (1978) reported positive results In
an unscheduled DNA synthesis assay. Subchronlc and acute Inhalation data
are lacking. Oral, IntraperHoneal, Intravenous, dermal or subcutaneous
acute, subchronlc and developmental toxldty studies resulted In common
toxlcologlcal effects. Mortality, CNS effects and decreases In body weights
were observed In each of these types of studies {Dletz and Mulligan, 1988;
U.S. EPA, 1987a; Yehuda et al., 1977; CMA, 1987, 1988a,b). Labored respira-
tion was also observed following subchronlc oral (U.S. EPA, 1987a) and
developmental toxldty (CMA, 1987) studies using rats and rabbits treated by
gavage at 50 mg/kg/day, the lowest dose tested. Subchronlc dermal exposure
1n mice resulted In deplgmentatlon of the skin and hair (Shelley, 1974).
0219d
-41-
03/15/91
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
ACGIH (1988) and OSHA (1989) adopted a TLV-TWA of 22 mg/m3 (5 ppm) for
cresols (all Isomers). NIOSH (1978), however, recommended a TLV-THA of 10
mg/m3 for cresol. The cresol TLV recommended by ACGIH 1s based on analogy
to the toxlclty of phenol (ACGIH, 1986).
U.S. EPA (1987b) reported a verified oral RfD of 5E-2 mg/kg/day for
4-methylphenol. The derivation of this RfD 1s explained In Chapter 8.
7.2. AQUATIC
Cresol (p-) 1s listed as a hazardous substance (U.S. EPA, 1982) and 1s a
substance designated for ground-water monitoring (U.S. EPA, 1988).
0219d -42- 03/13/91
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8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the Inhalation cardnogen-
Iclty of 4-methylphenol were not located 1n the available literature dted
1n Appendix A.
8.1.2. Oral. Pertinent data regarding the oral carclnogenlclty of
4-methylphenol were not located In the available literature dted In
Appendix A.
8.1.3. Other Routes. 4-methylphenol appeared to be a promoter 1n the
two-stage mouse skin assay In mice Initiated with DMBA (Boutwell and Bosch,
1959).
8.1.4. Height of Evidence. There Is Insufficient evidence regarding the
carclnogenlclty of 4-methylphenol 1n animals. There are no data regarding
the carclnogenlclty In humans; therefore, 4-methylphenol 1s most appro-
priately placed In Group 0, not classifiable as to human carclnogenlclty,
according to U.S. EPA (1986b) classification schene.
8.1.5. Quantitative Risk Assessment.
8.1.5.1. INHALATION No pertinent Inhalation carclnogenlclty
studies with 4-methylphenol are available, precluding the derivation of
v-
8.1.5.2. ORAL No pertinent oral carclnogenlclty studies with
4-methylphenol are available, precluding the derivation of a q *.
8.2. SYSTEMIC TOXICITY
In this section, "Rec. #" refers to the data records for the dose/
duration-response graphs In Appendix C.
0219d
-43-
03/15/91
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8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME EXPOSURE (SUBCHRONIC) Pertinent data
regarding the Inhalation toxldty of 4-methylphenol were not located In the
available literature cited 1n Appendix A.
8.2.1.2. CHRONIC EXPOSURE Pertinent data regarding the Inhalation
toxldty of 4-methylphenol were not located In the available literature
cited In Appendix A.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURE ~ The subchronH oral toxlclty
of 4-methylphenol 1s discussed In Section 6.1.2.1. Results from both D1etz
and Mulligan (1988) and U.S. EPA (1987a) Indicate that the NOAEL for
decreased body weights, hepatic and kidney effects and CNS Impairment 1n
rats Is 50 mg/kg/day (Recs. #7, 10) for a 90-day exposure to 4-methylphenol.
The LOAEL In each study was 175 mg/kg/day (Recs. 18, 11). Clinical signs of
CNS stimulation were observed at the 50 mg/kg/day level (Rec. #7) 1n the
U.S. EPA (1987a) study; however, these effects were observed principally In
the first hour after dosing during the first week of exposure, suggesting
that they occurred 1n response to the rapid bolus administration of the test
chemical and that some degree of tolerance may have developed.
This also suggests that the 50 mg/kg/day dose Is near the threshold for
adverse CNS effects In rats.
Recent development toxlclty gavage studies Identify the rabbit as more
sensitive than the rat to the maternal toxlclty of 4-methylphenol. A range-
finding study using groups of eight rabbits reported gasping and labored
respiration 1n "a few rabbits" treated with 50 mg/kg/day (Rec. #3); maternal
mortality occurred 1n rabbits treated with 150 (Rec. #3), 300 and 500
mg/kg/day (2/8, 4/8 and 7/8, respectively) (CMA, 1987). In the final study,
0219d -44- 03/15/91
-------
groups of 14 rabbits were treated with 5, 50 or 100 mg/kg/day during 13 days
of gestation (CHA, 1988a). There were no signs of maternal toxlclty In
rabbits treated with 5 mg/kg/day (Rec. #1), which 1s a NOEL 1n this study.
Respiratory distress, cyanosis, ocular discharge and hypoactlvlty were
observed In rabbits treated with 50 (Rec. #2) or 100 mg/kg/day. In
addition, deaths of two dams treated with 50 mg/kg/day and five dams treated
with 100 mg/kg/day were attributed to 4-methylphenol. The 50 mg/kg/day
dose, therefore, 1s a PEL (Rec. #2) associated with maternal mortality.
U.S. EPA (1978b) derived a chronic oral RfD from the NOAEL of 50 mg/kg/
day (Rec. #7, 10) 1n the two subchronlc studies 1n rats described above.
The Identification of 50 mg/kg/day as a FEL (Rec. #2) associated with
maternal mortality In rabbits 1n a more recent study (CMA, 1988a), however,
compels a reevaluatlon of the data.
The most defensible basis for a subchronlc oral RfD for 4-methylphenol
Is the NOEL of 5 mg/kg/day (Rec. #1) In the developmental toxlclty study In
rabbits (CHA, 1988a). Although the developmental toxlclty study was not of
sufficient duration to be considered subchronlc, the rabbit NOEL of 5
mg/kg/day 1s less than the NOAEL of 50 mg/kg/day (Rec. #7, 10) 1n the two
rat subchronlc studies. Furthermore, the rat data (U.S. EPA, 1987a) suggest
that tolerance may develop with continued exposure. The application of an
uncertainty factor of 100 (10 for Interspedes sensitivity and 10 for
Intraspecles sensitivity) to the NOEL of 5 mg/kg/day (Rec. #1) results 1n a
subchronlc oral RfD of 0.05 mg/kg/day. Confidence 1n the key study 1s high,
because an appropriate protocol applied to a suitable animal model Identi-
fied a NOEL and FEL for maternal toxlclty. Confidence 1n the data base Is
low; the subchronlc toxlclty of 4-methylphenol In rabbits, the more
sensitive species, has not been adequately Investigated. Confidence 1n the
subchronlc oral RfD 1s medium.
0219d -45- 03/15/91
-------
8.2.2.2. CHRONIC EXPOSURE Chronic oral exposure data were not
located In the available literature cited In Appendix A. A chronic oral
RfD, however, can be derived from the data chosen as the basis of the
subchronlc RfO. As discussed In Section 8.2.2.1., the most defensible basis
for the subchronlc oral RfD 1s the NOEL of 5 mg/kg/day (Rec. #1) for
maternal toxlclty 1n rabbits. Application of an uncertainty factor of 1000
(10 for Interspedes variability, 10 for Intraspedes variability and 10 to
extrapolate from subchronlc to chronic exposure) results 1n a chronic oral
RfD of 0.005 mg/kg/day. Confidence In the key study 1s high, confidence In
the data base 1s low, and confidence In the RfD Is medium.
0219d
-46-
03/15/91
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
A previous RQ of 100 was derived for cresols based on an Inhalation
study by Uzhdav1n1 et al. (1972) with rats exposed to ortho-cresol (U.S.
EPA, 1983a, 1985).
Data pertaining specifically to 4-methylphenol Inhalation exposure are
not available. The most severe effects occurring at each dosage In the
subchronlc oral exposure studies are summarized 1n Table 9-1. These studies
are described more fully 1n Section 6.1.2. Mortality occurring within the
first 3 days In female rats at 600 mg/kg/day 1n the D1etz and Mulligan
(1988) study was not Included 1n Table 9-1 because 1t was an acute effect.
For this reason, maternal mortality In rabbits 1n the developmental toxlclty
study by CMA (1988a) Is not Included In Table 9-1. The forellmb and
pectoral girdle malformations reported 1n rabbits at 300 mg/kg/day (CMA,
1987) were not Included In Table 9-1 because of maternal mortality at that
dosage. Oral exposure 1n rats resulted In mortality and CNS Impairment
(D1etz and Mulligan, 1988; U.S. EPA, 1987a). M1ld anemia, organ weight
changes (D1etz and Mulligan, 1988) and labored respiration (U.S. EPA, 1987a)
were also observed. The CSs and corresponding RQs for these effects are
summarized 1n Table 9-2. All of the resulting RQs were 1000. The labored
respiration observed In male and female rats at 175 mg/kg/day (U.S. EPA,
1987a) resulted 1n the highest CS, which Is selected as most stringently
representative of the chronic (noncancer) toxlclty of 4-methylphenol
(Table 9-3).
0219d
-47-
03/15/91
-------
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03/15/91
-------
TABLE 9-3
4-METHYLPHENOL
(CAS No. 106-44-5)
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Species/sex: rats/male and female
Dose*: 209.47 mg/day
Duration: 13 weeks
Effect: labored breathing
RVd: 2.0
RVe: B
CS: 16.2
RQ: 1000
Reference: U.S. EPA. 1987a
^Equivalent human dose
0219d -50- 03/13/91
-------
9.2. BASED ON CARCINOGENICITY
Pertinent data regarding the carclnogenldty 1n humans or animals of
4-methylphenol were not located In the available literature and the compound
was assigned to EPA Group D: not classifiable as to carclnogenldty to
humans. Hazard ranking 1s not performed for EPA Group D compounds; there-
fore an RQ based on carclnogenldty cannot be assigned to 4-methylphenol.
0219d
-51-
03/15/91
-------
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(Cited 1n Oelchmann and KepHnger, 1981)
KolUg, H.P.. J.J. Ellington, K.J. Hamrlck et al. 1987. Hydrolysis rate
constants, partition coefficients and water solubilities for 129 chemicals:
A summary of fate constants provided for the concentration-based listing
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Lebsack, M.E., A.O. Anderson, G.H. DeGraeve and H.L. Bergman. 1981. Com-
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Toxlcol. Hazard Assess. 737: 348-356.
Leuenberger, C., H.P. L1gock1 and J.F. Pankow. 1985. Trace organic
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0219d
-64-
03/15/91
-------
L1bert1, A., G. Gorettl and M.V. Russo. 1983. PCDD and PCDF formation In
the combustion of vegetable wastes. Chemosphere. 12: 661-663.
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Lund, F.A. and O.S. Rodriguez. 1984. Acclimation of activated sludge to
mono-substituted derivatives of phenol and benzole acids. J. Gen. Appl.
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Mackay, D., S. Paterson, B. Cheung and W.B. Neely. 1985. Evaluating the
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Marcus, C. and P. L1chtenste1n. 1979. Biologically active components of
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0219d
-65-
03/15/91
-------
Hattson, V.R., J.W. Arthur and C.T. Walbrldge. 1976. Acute toxldty of
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McCreary, J.J., J.G. Jackson and J. Zoltek. 1983. Toxic chemicals In an
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McKnlght, P.M., W.E. Perelra, M.L. Ceazan and R.C. Wlssmar. 1982. Charac-
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U.S. EPA, Athens, GA.
Mlzutanl, T., I Ishlda, K. Yamamoto and K. Taj 1ma. 1982. Pulmonary
toxldty of butylated hydroxytoluene and related alkylphenols: Structural
requirements for toxic potency 1n mice. Toxlcol. Appl. Pharmacol. 62:
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0219d
-66-
03/15/91
-------
NIOSH (National Institute for Occupational Safety and Health). 1984.
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0219d -67- 03/15/91
-------
Rogers, 3.E., S.W. l\ and L,J. Felice. 1984. Microbiological transforma-
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Sawhney, B.L. and R.P. Kozloskl. 1984. Organic pollutants In leachates
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0219d
-68-
03/15/91
-------
Schafer, E.W., Jr., H.A. Bowles, Jr. and J. Hurlbut. 1983. The acute oral
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0219d -69- 03/15/91
-------
Spain, J.C. and P.A. Van Veld. 1983. Adaptation of natural mlcroblal com-
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Stuermer, O.H., O.J. Ng and C.J. Morris. 1982. Organic contaminants 1n
groundwater near an underground coal gasification site In northeastern
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0219d
-70-
03/15/91
-------
U.S. EPA. 1980. Guidelines and Methodology Used In the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 79347-79357.
U.S. EPA. 1982. Designation of hazardous substances. List of Hazardous
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Office of Health and Environmental Assessment, Environmental Criteria and
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Response, Washington, DC.
U.S. EPA. 1984. Methodology and Guidelines for Ranking Chemicals Based on
Chronic Toxlclty Data. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1985. Health and Environmental Effects Profile for Cresols.
Prepared by the Office of Health and Environmental Assessment, Environmental
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and Emergency Response, Washington, DC.
U.S. EPA. 1986a. Methodology for Evaluating Reportable Quantity Adjust-
ments Pursuant to CERCLA Section 102. Prepared by Carcinogen Assessment
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Emergency and Remedial Response, Washington, DC.
0219d -71- 03/15/91
-------
U.S. EPA. 1986t>. Guidelines for Carcinogen Risk Assessment. Federal
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U.S. EPA. 1987a. Subchronlc neurotoxlclty study In rats of o- , m- and
p-Cresol. Office of Solid Waste, Washington, DC.
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and Environmental Assessment, Environmental Criteria and Assessment Office,
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f
U.S. EPA/OWRS. 1986. Guidelines for Deriving Numerical National Water
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Profzabol. 7: 115-119. (Cited In U.S. EPA, 1983, 1985)
0219d
-72-
03/15/91
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Van Veld, P.A. and J.C. Spain. 1983. Degradation of selected xenoblotlc
compounds 1n three types of aquatic test systems. Chemosphere. 12:
1291-1305.
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Wandel, 0. 1907. Zur pathologle der lysol-und kresolver-glftung. Arch.
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dose and (b) o-, m- and p-substHutlon on the sulfate detoxlcatlon of phenol
In the rabbit. Blochem. J. 32: 878-887.
Wlndholz, M., S. Budavarl, R.F. Blumettl and E.S. Otterbeln. 1983. The
Merck Index. Merck and Co., Inc., Rahway, NY.
Yalkowsky, S.H., S.C. Valvanl, W.Y. Kuu and R. Dannenfelser. 1987. Arizona
database of aqueous solubility.
Yasuhara, A. 1987. Identification of volatile compounds 1n poultry manure
by gas chromatography mass spectrometry. J. Chromatogr. 387: 371-378.
0219d -73- 03/15/91
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Yasuhara, A., H. Sh1ra1sh1, H. Tsujl and T. Okuno. 1981. Analysis of
organic substances 1n highly polluted river water by mass spectrometry.
Environ. Sc1. Technol. 15: 570-573.
Yehuda, S., R.L. Carasso and O.I. Mostofsky. 1977. The effects of
d-amphetamlne and temperature on p-cresol and pentylenetetrazol Induced
convulsion. Int. J. Neurosd. 7: 223-226.
Yoshloka, Y., Y. Ose and T. Sato. 1985. Testing for the toxldty of chemi-
cals with Tetrahymena pyrlformls. Scl. Total Environ. 43(1-2): 149-157.
Young, L.Y. and M.D. Rivera. 1985. Nethanogenlc degradation of four
phenolic compounds. Hater Res. 19: 1325-1332.
0219 d
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APPENDIX A
LITERATURE SEARCHED
This HEED Is based on data Identified by computerized literature
searches of the following:
CHEHLINE
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXLIT
TOXLIT 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HSDB
SCISEARCK
Federal Research In Progress
These searches were conducted 1n May, 1988, and the following secondary
sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyg1en1sts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyg1en1sts).
1987. TLVs: Threshold Limit Values for Chemical Substances 1n the
Work Environment adopted by ACGIH with Intended Changes for
1987-1988. Cincinnati, OH. 114 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.O. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2B. John Wiley and
Sons, NY. p. 2879-3816.
0219d -75- 03/15/91
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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.
Grayson, M. and D. Eckroth, Ed. 1978-1984. K1rk-0thmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. IARC, WHO, Lyons, France.
Jaber, H.M., W.R. 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.
EPA 600/6-84-010. NTIS PB84-243906. SRI International, Menlo
Park, CA.
NTP (National Toxicology Program). 1987. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1987. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1966. Report on Status Report In 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.
USITC (U.S. International Trade Commission). 1986. Synthetic
Organic Chemicals. U.S. Production and Sales, 1985, USITC Publ.
1892, 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.
0219d
-76-
03/15/91
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In addition, approximately 30 compendia of aquatic toxklty data were
reviewed, Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute Toxlclty
of Chemicals to F1sh and Aquatic Invertebrates. Summaries of
Toxlclty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee. J.E. and H.W. Wolf. 1963. Water Quality Criteria. 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmental, 0. 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.
0219d -77- 03/15/91
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0219d
-78-
03/15/91
-------
APPENDIX C
DOSE/DURATION RESPONSE GRAPHS FOR EXPOSURE TO 4-METHYLPHENOL
C.I. DISCUSSION
Dose/duration-response graphs for oral exposure to 4-methylphenol
generated by the method of Crockett et al. (1985) using the computer soft-
ware by Durkln and Meylan (1989) developed under contract to ECAO-C1nc1nnat1
are presented In Figures C-1 and C-2. Data used to generate these graphs
are presented In Section C.2. In the generation of these figures, all
responses are classified as adverse (PEL, AEL or LOAEL) or nonadverse (NOEL
or NOAEL) for plotting. For oral exposure, the ordlnate expresses dose as
human equivalent dose. The animal dose In mg/kg/day 1s multiplied by the
cube root of the ratio of the animal:human body weight to adjust for species
differences In basal metabolic rate (Mantel and Schnelderman, 1975). The
result 1s then multiplied by 70 kg, the reference human body weight, to
express the human equivalent dose as mg/day for a 70 kg human.
The boundary for adverse effects (solid line) 1s drawn by Identifying
the lowest adverse effect dose or concentration at the shortest duration of
exposure at which an adverse effect occurred. From this point, an Infinite
line 1s extended upward, parallel to the dose axis. The starting point Is
then connected to the lowest adverse effect dose or concentration at the
next longer duration of exposure that has an adverse effect dose or concen-
tration equal to or lower than the previous one. This process Is continued
to the lowest adverse effect dose or concentration. From this point, a line
1s extended to the right, parallel to the duration axis. The region of
adverse effects lies above the adverse effects boundary.
0219d -79- 03/15/91
-------
T
/
0
fi
a
9
v
9
X
10000 -r
1000 -r
100
0.0001
rn
LIB
Hi
4-
0.001 0.01 0.1
HUMAN EQUIU DURATION (fraction lifespan)
METHOC
KEY:
F - PEL
L » LOAEL
n - NOAEL
Solid Line » Adverse Effects Boundary
Dotted Line - No Adverse Effects Boundary
FIGURE C-1
Dose/Duration-Response Graph for Oral Exposure to 4-Methy1phenol,
Envelope Method
0219d
-80-
03/15/91
-------
100000 p
fr
73
-=- ioooo-t-
UJ
d
o
o
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1000--
100-
0.0001
4 methylphenol
F14
J I
I I I I
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N5
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L81
i i 1
0.001 0.01 0.1
HUMAN EQUIVALENT DURATION (fraction lifespan)
CENSORED MTfl fOHOD - (Oral Exposure)
KEY: F - FEL
L - LOAEL
N - NOEL
n * NOAEL
Solid Line « Adverse Effects Boundary
Dotted Line - No Adverse Effects Boundary
FIGURE C-2
Dose/Duration-Response Graph for Oral Exposure to 4-Methy!phenol,
Censored Data Method
02194
-81-
03/15/91
-------
Using the envelope method, the boundary for no adverse effects (dashed
line) 1s drawn by Identifying the highest no adverse effects dose or concen-
tration. From this point, a line parallel to the duration axis Is extended
to the dose or concentration axis. The starting point Is then connected to
the next lower or equal no adverse effect dose or concentration at a longer
duration of exposure. When this process can no longer be continued, a line
Is dropped parallel to the dose or concentration axis to the duration axis.
The no adverse effects region lies below the no adverse effects boundary.
At either ends of the graph between the adverse effects and no adverse
effects boundaries are regions of ambiguity. The area (If any} resulting
from Intersection of the adverse effects and no adverse effects boundaries
Is defined as the region of contradiction.
In the censored data method, all no adverse effect points located In the
region of contradiction are dropped from consideration and the no adverse
effect boundary Is redrawn so that 1t does not Intersect the adverse effects
boundary and no region of contradiction Is generated. This method results
In the most conservative definition of the no adverse effects region.
In Figures C-l and C-2, the adverse effects boundary 1s defined by a
dose associated with mortality In rabbits (Rec. #13), an L0cn 1n mice
t»u
(Rec. #16) and, 1t Us lowest Inflection, a dose of 50 mg/kg/day In develop-
mental studies 1n rabbits (Recs. #2 and 4), which was a LOAEL In one study
(CMA, 1987} and a PEL 1n the other (CMA, 1988a). These points are super-
Imposed and difficult to read. In Figure C-l, the no adverse effects
boundary Is defined by a NOEL for maternal and developmental effects In rats
(Rec. #5) and a NOAEL of 50 mg/kg/day 1n two, 13-week studies 1n rats (Recs.
#7 and 10, superimposed and difficult to read). Record #1, the NOEL of 5
mg/kg/day 1n the developmental study 1n rabbits chosen as the basis of the
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RfD (CMA, 1988a) 1s well below the adverse effects boundary, which
strengthens confidence 1n the choice of these data as the basis for the RfD.
In Figure C-2, generated by the censored data method, the no adverse
effects boundary Is defined only by the NOEL of 50 mg/kg/day 1n the two,
13-week studies 1n rats (Recs. #7 and 10, superimposed).
C.2. DATA USED TO GENERATE DOSE/DURATION-RESPONSE GRAPHS
C.2.1. Oral Exposure.
Chemical Name: 4-methylphenol
CAS Number: 06-44-5
Document Title: Health and Environmental Effects Document on 4-Methylphenol
Document Number: pending
Document Date: pending
Document Type: HEED
RECORD #1:
Species
Sex:
Effect:
Route:
Number
Number
: Rabbits
F ema 1 e
NOEL
Gavage
Exposed:
Responses:
Body weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
14
0
3.825 kg
5 mg/kg/day
5 mg/kg/day
13 days
24 days
Type of Effect:
SHe of Effect:
Severity Effect: 4
Comment: Doses of 5, 50 or 100 mg/kg/day were given on days 6-18 of
gestation In a developmental toxlclty study (see next record).
Citation: CMA, 1988a
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RECORD #2:
Comment:
Citation:
Comment:
Citation:
Comment:
Citation:
Species;
Sex:
Effect:
Route:
Rabbits
Female
PEL
Gavage
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Body Weight
Reported Dose:
Converted Dose:
Exposure Period;
Duration Observation:
14
2
DEATH
BODY
10
3.825 kg
50 mg/kg/day
50 mg/kg/day
13 days
24 days
See previous record; distressed respiration, cyanosis, ocular
dlschage, hypoactlvlty were also observed at this dose.
Mortality claimed 5/14 at 100 mg/gk/day.
CMA, 1988a
RECORD #3:
Species:
Sex:
Effect:
Route:
Rabbits
Female
FEL
Gavage
Body Weight
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
3.8 kg
150 mg/kg/day
150 mg/kg/day
13 days
24 days
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
8
2
DEATH
BODY
10
Doses used were 50, 150, 300 and 500 mg/kg/day; dose-related
maternal mortality occurred. Forellmb and pectoral girdle
malformations were observed at 300 mg/kg/day.
CHA, 1987
RECORD #4:
Species:
Sex:
Effect:
Route:
Rabbits
Female
LOAEL
Gavage
Body Weight
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
3.8 kg
50 mg/kg/day
50 mg/kg/day
13 days
24 days
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
8
NR
FUND
LUNG
8
See previous record for other doses.
respiration were observed at all doses,
CHA, 1987
Gasping and labored
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RECORD #5:
Comment:
Citation:
Comment:
Species:
Sex:
Effect:
Route:
Rats
Female
NOEL
Gavage
Body Weight
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
25
0
0.29 kg
175 mg/kg/day
175 mg/kg/day
10 days
16 days
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
Doses of 30, 175 and 450 mg/kg/day were given on days 6-15 of
gestation (see next record).
CMA, 1988b
RECORD #6:
Comment:
Citation:
RECORD #7:
Species: Rats
Sex: Female
Effect: LOAEL
Route: Gavage
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
See previous record.
CMA. 1988b
Species: Rats
Sex: Both
Effect: NOAEL
Route: Gavage
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
25 25
NR NR
FUND WGTDC
CNS FETUS
8 8
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
20
NR
FUNS
CNS
7
0.29 kg
450 mg/kg/day
450 mg/kg/day
10 days
16 days
0.35 kg
50 mg/kg/day
13 weeks
13 weeks
Citation:
Doses administered were 50, 175 or 600 mg/kg/day. Some CNS
signs were observed for 1 hour after dosing during first week
of study, probably as result of bolus administration of the
compound, (see next record).
U.S. EPA, 1987a
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RECORD #8:
Comment:
Citation:
Comment:
Citation:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Both
LOAEL
Gavage
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
20
NR
FUNDH
LUNG
8
0.35 kg
175 mg/kg/day
13 weeks
13 weeks
Labored respiration, tremors, hypoactWHy, rapid respiration,
myoclonus and low body posture were observed In both sexes at
this level (see previous record for further protocol).
U.S. EPA, 1987a
RECORD #9:
Species:
Sex:
Effect:
Route:
Rats
Both
PEL
Gavage
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
0.35 kg
600 mg/kg/day
13 weeks
13 weeks
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
20
8
DEATH
BODY
10
Nyotonus, labored respiration and decreased locomotor
activity were also observed (see previous records for further
protocol).
U.S. EPA, 1987a
RECORD #10:
Species:
Sex:
Effect:
Route:
Rats
Both
LOAEL
Gavage
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period
Duration Observation:
0.35 kg
50 mg/kg/day
13 weeks
13 weeks
Number Exposed: 60
Number Responses: 0
Type of Effect:
SHe of Effect:
Severity Effect: 2
Doses administered were 50, 175 and 600 mg/kg/day (see next
record)
D1etz and Mulligan, 1988
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RECORD
Comment:
Citation:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Both
LOAEL
Gavage
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
Body Weight
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
30
NR
WGTDC
BODY
4
0.35 kg
175 mg/kg/day
13 weeks
13 weeks
Females had anemia, males had Increased relative weight of
liver and kidneys (and other organs at higher doses);
Increased total serum protein. Also see previous record.
D1etz and Mulligan, 1988
RECORD #12:
Species:
Sex:
Effect:
Route:
Rats
Both
PEL
Gavage
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
0.35 kg
600 mg/kg/day
13 weeks
13 weeks
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
30
3
DEATH
BODY
10
30
NR
WGTDC
BODY
4
Comment :
Citation:
RECORD #13:
See previous records; other effects Included liver and kidney
lesions, organ weight changes, tracheal epithelial metaplasia.
D1etz and
Species:
Sex:
Effect:
Route:
Mulligan, 1988
Rabbits
NR
PEL
Oral (NOS)
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
3.8 kg
620 mg/kg/day
1 day
1 day
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
1
1
DEATH
BODY
10
Doses administered were 180, 280, 420,
2100 mg/kg as a 20% emulsion In water.
Dlechmann and WHherup, 1944
620, 940, 1400 and
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RECORD #14:
Comment:
Citation:
RECORD #15:
Comment:
Citation:
RECORD |16:
Comment :
Citation:
Species: Rats
Sex: NR
Effect: PEL
Route: Oral (NOS)
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
1800 mg/kg was the LOso
Dlechmann and Wltherup,
Species: Rats
Sex: NR
Effect: PEL
Route: Oral (NOS)
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
The LDgQ was 207 mg/kg;
Sax, 1984
Species: Rats
Sex: NR
Effect: PEL
Route: Oral (NOS)
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
The LDso was 344 mg/kg;
Sax, 1984
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation
10
5
DEATH
BODY
10
0.35 kg
1800 mg/kg/day
1 day
: 1 day
; other doses not specified
1944; Sax, 1984
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation
NR
NR
DEATH
BODY
10
other doses not sped
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation
NR
NR
DEATH
BODY
10
0.35 kg
207 mg/kg/day
1 day
: 1 day
fled
0.03 kg
344 mg/kg/day
1 day
: 1 day
other doses not specified
NR = Not reported
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