United States
Environmental Protection FCAO C)w ^T^
A9encv January, 1986
&EPA Research and
Development
VERIFIED REFERENCE DOSES (RfDs)
OF THE U.S. EPA
Prepared for
THE RISK ASSESSMENT FORUM AND
THE RISK ADVISORY GROUP
Prepared by
THE ADI WORK GROUP OF THE RISK
ASSESSMENT FORUM
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DISCLAIMER
Mention of trade names or commercial products does not constitute
endorsement or recommendation for use.
AVAILABILITY NOTICE
For Information contact Dr. Peter Preuss, Acting Director, Office of
Health and Environmental Assessment, Office of Research and Development,
Washington, DC (202/382-7317).
11
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FOREWORD
As of May 1, 1985, the Age icy established a group of scientists familiar
with the development of reference doses (RfDs) under the direction of Dr.
Peter Preuss, Acting Director of the Office of Health and Environmental
Assessment of the Office of Research and Development. The purpose of this
group 1s to verify existing Agency RfDs and to resolve conflicting values
within the Agency.
The current procedure to accomplish these tasks 1s a biweekly meeting of
scientists from within the Agency. A file 1s created for each chemical that
Includes the critical reference, the supporting studies, the U.S. EPA docu-
ment that describes the calculation of the RfD, and a two page cover form
that summarizes the RfD, the chosen critical toxic effect, the chosen
uncertainty factors, and statements concerning the confidence in the data
base, the critical study, and the RfD.
The jgroup has discussed 144 RfDs. This package reflects the first 65 of
these values that were verified. Complete files are available on all RfDs
that have been discussed. The files consist of:
1. A cover form (one to several pages) that summarizes Information
pertinent to the development of an RfD, such as the chosen
effect levels and uncertainty factors, and statements of confi-
dence In the RfD, the chosen study and the associated data base
2. The U.S. EPA documentation that supports the RfD
3. The critical study from which the chosen effect level 1s taken
and
4. Supporting literature.
111
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OUTLINE
I. CAS NO. LISTING OF CHEMICALS FOR WHICH RfDs HAVE BEEN VERIFIED
II. ALPHABETICAL LISTING OF CHEMICALS FOR WHICH RfDs HAVE BEEN VERIFIED
III. COVER FORMS FOR CHEMICALS
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LIST OF ABBREVIATIONS
ACGIH American Conference of Governmental Industrial Hyg1en1sts
ADI Acceptable dally Intake
AEL Adverse-effect level
bw Body weight
CAS Chemical Abstract Services
CAG Carcinogen Assessment Group
cu. m Cubic meter
PEL Frank-effect level
g Gram
l.p. Intraperltoneal
kg Kilogram
L Liter
LOAEL Lowest-observed-adverse-effect level
LOEL Lowest-observed-effect level
MF Modifying factor
mg Milligram
MTD Maximum tolerated dose
NIOSH National Institute for Occupational Safety and Health
NOAEL No-observed-adverse-effect level
NOEL No-observed-effect level
NTP National Toxicology Program
RfD Reference dose
s.c. subcutaneous
TLV Threshold limit value
UF Uncertainty factor
ug Mlcrogram
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CAS No. Listing of Chemicals for Which RfDs Have Been Verified
Chemical CAS No.
Chemical CAS No.
Carbon TetrachloMde
CAS: 56-23-5
Cyanides
CAS: 57-12-5
Strychnine
CAS: 57-24-9
2,3,4,6-Tetrachlorop'henol
CAS: 58-90-6
Dlmethoate
CAS: 60-51-5
Phenyl Mercuric Acetate
CAS: 62-38-4
Carbaryl
CAS: 63-25-2
Formic Add
CAS: 64-18-6
Hydrogen Cyanide
CAS: 74-90-8
Methylene Chloride
CAS: 75-09-2
Carbon Dlsulflde
CAS: 75-15-0
Cacodyllc Acid
CAS: 75-60-5
TMchlorofluorome thane
CAS: 75-69-4
D1chlorod1fluoromethane
CAS: 75-71-8
l,l,2-Tr1chloro-l,2,2-tr1fluoroethane
CAS: 76-13-1
Tetraethyl Lead
CAS: 78-00-2
Methyl Ethyl Ketone
CAS: 78-93-3
Acrylic Acid
CAS: 79-10-9
Pentachloronltrobenzene (PCNB)
CAS: 82-68-8
Pentachlorophenol
CAS: 87-86-5
Dlnoseb
CAS: 88-85-7
MCPA
CAS: 94-74-6
2,4-DB
CAS: 94-82-6
1,2-D1chlorobenzene
CAS: 95-50-1
2,4,5-TMchlorophenol
CAS: 95-95-4
Nitrobenzene
CAS: 98-95-3
Ethylbenzene
CAS: 100-41-4
Toluene
CAS: 108-88-3
-1-
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Chemical CAS No.
Chemical CAS No.
Chlorobenzene
CAS: 108-90-7
Phenol
CAS: 108-95-2
Pyrldlne
CAS: 110-86-1
Malathlon
CAS: 121-75-7
Tetrachloroethylene
CAS: 127-18-4
Sodium Cyanide
CAS: 143-33-9
Potassium Cyanide
CAS: 151-50-8
Llnuron
CAS: 330-55-2
Cyanogen Cyanide
CAS: 460-19-5
Calcium Cyanide
CAS: 502-01-8
Potassium Silver Cyanide
CAS: 506-61-6
Silver Cyanide
CAS: 506-64-9
Chlorine Cyanide
CAS: 506-77-4
Barium Cyanide
CAS: 542-62-1
Copper Cyanide
CAS: 544-92-3
Nickel Cyanide
CAS: 557-19-7
Z1nc Cyanide
CAS: 557-21-1
Thallium Acetate
CAS: 563-68-8
Mercury Fulminate
CAS: 628-86-4
Selenourea
CAS: 630-10-4
Thalllc Oxide
CAS: 1314-32-5
Cresols
CAS: 1319-77-3
Methyl Ethyl Ketone Peroxide
CAS: 1338-23-4
Thallium Carbonate
CAS: 6533-73-9
Mercury (Inorganic)
CAS: 7439-97-6
Barium
CAS: 7440-39-2
Thallium Sulfate
CAS: 7446-18-16
Fluoride (fluorine)
CAS: 7782-41-4
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Chemical CAS No. Chemical CAS No.
Selenlous Add
CAS: 7783-00--8
Hydrogen Sulflde
CAS: 7783-06-4
Thallium Chloride
CAS: 7791-12-0
Phosphlne
CAS: 7803-51-2
Nitrogen Oxide
CAS: 10102-43-9
Nitrogen Dioxide
CAS: 10102-44-0
Thallium NHrate
CAS: 10102-45-1
Thallium Selenlte
CAS: 12039-52-0
Aluminum Phosphide
CAS: 20859-73-8
-3-
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Alphabetical Listing of Chemicals for Which RfDs Have Been Verified
Chemical
Chemical
Acrylic Acid
Aluminum Phosphide
Barium Cyanide
Barium
Cacodyllc Acid
Calcium Cyanide
Carbaryl
Carbon Dlsulflde
Carbon Tetrachlorlde
Chlorine Cyanide
Chlorobenzene
Copper Cyanide
Cresols
Cyanide (free)
Cyanogen
2,4-DB
l,2-D1chlorobenzene
Dlchlorodlfluoromethane
Dlmethoate
Dlnoseb
Ethylbenzene
Fluoride (Fluorine)
Formic Add
Hydrogen Cyanide
Hydrogen Sulflde
Unuron
Malathlon
MCPA
Mercury Fulminate
Mercury (Inorganic)
Methylene Chloride
Methyl Ethyl Ketone
Methyl Ethyl Ketone Peroxide
Nickel Cyanide
NUrlc Oxide
Nitrobenzene
Nitrogen Dioxide
Pentachloronltrobenzene (PCNB)
Pentachlorophenol
Phenol
Phenyl Mercuric Acetate
Phosphlne
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Chemical CAS No.
Chemical
Potassium Cyanide
Potassium Silver Cyanide
Pyr1d1ne
Selenlous Add
Selenourea
Silver Cyanide
Sodium Cyanide
Strychnine
Tetrachloroethylene
2,3,4,6-Tetrachlorophenol
Tetraethyl Lead
ThalUc Oxide
Thallium Acetate
Thallium Carbonate
Thallium Chloride
Thallium Nitrate
Thallium Selenate
Thallium Sulfate
Toluene
Trlchlorofluoromethane
2,4,5-TMchlorophenol
l,l,2-Trlchloro-l,2,2-tr1fluoroethane
Zinc Cyanide
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Acrylic Acid
Carclnogenlclty: None.
Systemic ToxIcHy: See below.
CAS #: 79-10-7
DePass
Endpolnt
et al.
(1983)
Experimental Doses
83 mg/kg/day
UF
1000
MF
RfD (ADI)
0.08 mg/kg/day
NOAEL
Rat oral subchronlc
study (drinking
water)
or
6 mg/day for a
70 kg man
Reduced body weights 250 mg/kg/day
altered organ weights (LOAEL)
Endpolnt and Experimental Doses:
DePass, L.R., M.D. Woodslde, R.H. Garman and C.S. Hell. 1983. Subchronlc and
reproductive toxicology studies on acrylic add 1n drinking water of the rat.
Drug Chem. Toxlcol. 6(1): 1-20.
In this subchronlc study acrylic add was Incorporated Into the drinking
water of rats (15/group/sex) for 3 months at doses of 750, 250, 83 and 0
mg/kg/day. At the high (750 mg/kg) and middle (250 mg/kg) dose levels reduc-
tion In body weight and changes In organ weights were observed. These effects
coincided with a dose-related reduction 1n food and water consumption. At the
83 mg/kg dose the only effect was a reduction In water consumption. No sig-
nificant treatment-related hlstologlcal effects were seen at any dose level.
A NOAEL of 83 mg/kg was established In this study.
In a short-term Inhalation study (Gage, 1970) no adverse effects were
observed 1n eight rats exposed to 80 ppm (about 240 mg/cu. m) acrylic acid, 6
hours/day, 5 days/week for 4 weeks. This exposure Is approximately equivalent
mg/kg/day (I.e., 240 mg/cu. m x 0.223 cu. m/day x 6
days x 0.5/1.0 / 0.35 = 14 mg/kg/day). Eight rats
51 mg/kg/day) experienced nose Irritation, lethargy
Hlstologlcal and hematologlcal examinations were
shorter periods of time resulted In liver, kidney
to an oral exposure of 14
hours/24 hours x 5 days/7
exposed at 300 ppm (about
and reduced weight gain.
normal. Higher doses for
and lung damage.
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Endpolnt and Experimental Doses (cont.):
The subchronlc oral study of DePass et al. (1983) appears to be the most
appropriate for deriving an ADI, 1n view of the limited data available.
Uncertainty Factors (UFs):
Using the NOAEL of 83 mg/kg/day and aplylng an uncertainty factor of 1000,
(10 to account for subchronlc to chronic conversion, 10 for Intraspedes
extrapolation and 10 to protect sensitive Individuals) an ADI of 0.08 mg/kg/
day or 6 mg/day was derived.
Modifying Factors (MFs):
None.
Additional Comments:
No oral chronic data are available.
Confidence In the RfD:
Study: Medium
Data Base: Low
RfD: Medium
The confidence In the study 1s medium because of the number of animals/
dose used, several parameters were studied, and a good dose-severity was
obtained. The confidence In the data base 1s low because of the general Jack
of supporting studies. The overall confidence In the RfD 1s rated medium to
low.
Documentation of RfD and Review:
ECAO-Clnclnnatl Internal Review, August 1985.
U.S. EPA. 1985. Acrylic Add: Review and Evaluation of ADI. Contract No.
68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH.
Agency RfD Review:
First Review: 08/19/85
Second Review:
Verification Date: 08/19-/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Aluminum Phosphide
CarclnogenlcHy: None.
Systemic Toxlclty: See below.
CAS #: 20859-73-8
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
Hackenburg (1972)
Rat chronic oral
study
Body weight and
clinical parameters
0.0004 mg/kg/day
or
0.03 mg/day for a
70 kg person
0.51 mg/kg of food 100
or 0.025 mg/kg/day
(phosphlne) con-
verted to 0.043 mg/
kg/day aluminum
phosphide (NOAEL)
Conversion Factors:
Food consumption: 5% bw;
molecular weight: A1P/PH3: x 57.95/34.0
thus, 0.51 mg/kg of food x 0.05 kg food/kg bw/day x
57.95/34.0 = 0.043 mg/kg/day
Endpolnt and Experimental Doses:
Hackenburg, U. 1972. Chronic 1ngest1on by rats of standard diet treated with
aluminum phosphide. Toxlcol. Appl. Pharmacol. 23(1): 147-158.
Aluminum phosphide pellets and tablets (Phastoxln) are used as fumlgants
for wheat and other grains (D1eter1ch e't al., 1967). Upon exposure to mois-
ture In the air, they Immediately decompose to phosphlne gas, with little
trace residue of phosphide remaining, which could be lost In handling of the
grain.
A chronic feeding study of aluminum phosphide-fumigated chow fed to 30
rats/sex was conducted by Hackenburg (1972). The average concentration was
0.51 mg phosph1ne/kg food for a 2-year period. At the end of the treatment
period, there were no differences between treated and control rats 1n blood or
urine chemistry, hlstologlcal parameters.
The phosphlne gas measured In the Hackenburg (1972) study was liberated by
decomposition of aluminum phosphide pellets. Acute toxlclty data generated
(Sax, 1984) suggest that the phosphide moiety contributes the most to the
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Endpolnt and Experimental Doses (cont.):
acute toxUHy of this compound as opposed to any deleterious effect due to
aluminum cation. The steep slope of the dose-response curve of phosphlne gas
(KHmmer, 1969) Implies that phosphlne 1s extremely hazardous at doses
slightly above a NOEL. Therefore, It 1s appropriate to derive an ADI for
aluminum phosphide based' upon the ADI for phosphlne.
Uncertainty Factors (UFs):
After correcting for the molecular weight of aluminum phosphide relative
to that of phosphlne (57.95/34.00). and by application of an uncertainty
factor of 100 (10 for Interspedes conversion and 10 for sensitive popula-
tion), an ADI for aluminum phosphide of 0.00043 (0.00025 mg/,kg/day phosphlne x
1.70) can be derived.
Modifying Factors (MFs):
None.
Additional Comments:
The ACGIH (1984) has recommended a TLV of 0.3 ppm (0.42 mg/cu. m) for
phosphlne, based principally upon an ep1dem1olog1cal study by Jones (1964)
where workers were exposed Intermittently to about 10 ppm phosphlne gas.
Based on this TLV an ADI of 0.0021 mg/kg/day (I.e., 0.42 mg/cu. m x 10 cu.
m/day x 5 day/7 day x 0.5/70 kg/10 = 0.0021 mg/kg/day) can be derived. How-
ever, an ADI for phosphlne of 0.00025 mg/kg/day based on the 2-year rat study
by Hackenburg (1972) (described above) has been derived for providing adequate
protection against adverse human health effects.
Confidence In the RfD:
Study: High Data Base: High RfD: High
The confidence 1n the study was rated high because of the moderate number
of animals/dose, the extensive methodology employed to assure proper admin-
istration of the test compound, and the extensive number of parameters mea-
sured. The data base was rated high because the effectiveness and safety of
this chemical has been long reported through supporting studies. The overall
rating for the RfD 1s, thus, high.
0420P -2- 01/11/86
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Documentation of RfD and Review:
ECAO-C1nc1nnat1 Internal Review, August 1985.
U.S. EPA. 1985. Aluminum Phosphide: Review and Evaluation of ADI. Contract
No. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH.
Agency RfD Review:
First Review: 08/19/85
Second Review:
Verification Date: 08/19/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534. or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0420P
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Barium Cyanide
Cardnogenlclty: None.
Systemic ToxUHy: See below.
CAS #: 542-62-1
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
Perry et al. (1983)
Rat oral chronic
study
Hypertension
10 ppm barium 1n 100
drinking water
(NOAEL)
0.07 mg/kg/day
or
5 mg/day for a
70 kg man
100 ppm (LOAEL)
estimated as
5.1 mg/kg/day
(U.S. EPA, 1985)
converted to 7 mg
Ba (CN)2
Conversion Factor: Exposure dose was based on U.S. EPA
(1985) estimate; molecular weight ratio of Ba(-CN)2/Ba 1s
189/137; thus, 5.1 mg/kg/day x (189/137) = 7 mg/kg/day
Endpolnt and Experimental Doses:
Perry, H.H., E.F. Perry, M.N. Erlanger
effects of chronic barium Ingestlon.
stances 1n Environmental Health, Vol.
Columbia, MO. p. 155-164.
and S.J. Kopp. 1983. Cardiovascular
In: Proc. 17th Ann. Conf. Trace Sub-
17. University of Missouri Press,
Perry et al. (1983) exposed 10 female rats/group to 0, 1, 10 or 100 ppm
barium. 1ji drinking water for up to 16 months. Barium exposure produced no
change In growth rate, and no evidence of toxldty was recognized. Limited
and preliminary physiologic and biochemical parameters, such as, myocardlal
pathophyslology and disturbances In myocardlal metabolism were significantly
depressed 1n rats exposed to 100 ppm barium (Perry et al., 1983; Kopp et al.,
1985). In addition, rats from this exposure group showed Increased average
systolic blood pressure (16 mm Hg average elevation).
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Endpolnt and Experimental Doses (cont.):
A moderate Increase (6 mm Hg) 1n systolic blood pressure was observed In
rats exposed to 10 ppm barium; however, the U.S. EPA (1985) determined that
the Increase seen after 16 months 1s not large enough to constitute an adverse
health effect.
Brennlman et al. (1979, 1981) reported a significant Increase In death
rate for cardiovascular diseases 1n communities whose water supply contained
an average of 7 mg Ba/L, compared with communities whose water supply con-
tained an average of 0.1 mg Ba/L. The exposure levels tested 1n these studies
did not evaluate a continuous range of exposure to barium and so, although a
NOEL may well have been Identified, It 1s Impossible to Identify the highest
NOAEL within the framework of their experimental designs.
Uncertainty Factors (UFs):
The U.S. EPA (1985) justified the use of an uncertainty factor of 100 (10
for Interspecles extrapolation and 10 for sensitive population) to the esti-
mated dose of 5.1 mg/kg/day barium on the grounds that the rats 1n Perry et
al. (1985) study were exposed to very low levels of all essential metals
(specifically calcium).
Modifying Factors (MFs):
None.
Additional Comments:
If an ADI for barium cyanide Is based on cyanide (0.02 mg/kg/day CN/6.28,
% CN) an ADI of 0.08 mg/kg/day for barium cyanide would result In a dally
Intake of 0.06 mg/kg/day of barium. An 'ADI of 0.07 mg/kg/day (0.051 mg/kg/day
Ba/0.72, % Ba) for barium cyanide Is somewhat lower than would be derived by
analogy to cyanide (0.08 mg/kg/day) and 1s, therefore, recommended to provide
adequate protection against adverse health effects.
Confidence In the RfD:
Study: Medium Data Base: Low RfD: Low
The confidence In the study 1s rated medium because three doses were used
and a sensitive Indicator (I.e., blood pressure changes) of the critical
effect of barium (I.e., cardiac toxlclty) was measured. The confidence 1n the
study 1s not rated any higher because of the use of only one sex, and the low
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Confidence In the RfD (cont.):
level of essential element exposure that may have predisposed the animals to
barium toxldty. The data base 1s rated low because It 1s limited to a few
studies. The overall confidence 1n the RfD 1s rated low.
Documentation of RfD and Review:
Limited peer review and ECAO-Clnclnnatl Internal review, August, 1985.
U.S. EPA. 1985. Drinking Water Criteria Document for Barium. Office of
Drinking Water, Washington, DC.
Agency RfD Review:
First Review: 08/05/85
Second Review:
Verification Date: 08/05/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Barium CAS #: 7440-39-2
CarclnogenlcHy:
Systemic Toxldty: See below.
Endpolnt Experimental Doses UF MF RfD (ADI)
Information to be provided by the Office of Drinking Water
Endpolnt and Experimental Doses:
Preparation Date:
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Uncertainty Factors (UFs):
Modifying Factors (MFs):
Additional Comments:
Confidence In the RfD:
Study:
Data Base;
RfD:
Documentation of RfD and Review:
Agency RfD Review:
First Review:
Second Review:
Verification Date:
U.S. EPA Contact:
Primary:
Secondary:
FTS/684-75
FTS/684-75
or 513/569-75
or 513/569-75
0420P
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Cacodyllc Add CAS #: 75-60-5
Carclnogenldty.: None.
Systemic ToxIcHy: See below.
Endpolnt Experimental Doses UF MF RfD (ADI)
Nees (1968) TOO ppm 1n diet as 1000 - 0.01 mg/kg/day
NOEL converted to or
Rat subchronlc 10 mg/kg/day 0.7 mg for a
feeding study 70 kg man
(30-90 days)
Conversion Factor: Young rat food
consumption = 10% bw/day
Endpolnt and Experimental Doses:
Nees, P.O. 1968. Report on cacodyllc add toxlclty to animals. Wisconsin
Alumni Res. Found. EPA Pesticide Petition No. OF0911.
In this study weanling rats were fed cacodyllc add as 3, 15, 30 or 100
ppm In the diet for 90 days (estimated 0.3, 1.5, 3 or 10 mg/kg/day). No
effects were seen on body weight, food consumption, hematology, organ weight
or histology which were attributed to treatment. Therefore, 10 mg/kg repre-
sents a free-standing NOEL from this study.
Nees et al. (1960) cited In the same pesticide petition (Report on
Cacodyllc Add Toxldty to Animals Wisconsin Alumni Res. Found.) reported that
feeding 280 mg/kg cacodyllc add to weanling rats for 20 days resulted In
testlcular hlstopathologlcal changes, while feeding 140 mg/kg represented a
NOEL. While these results provide additional support that the Nees et al.
(1968),. feeding levels were Indeed below effect levels and also suggest that
the highest NOEL from Nees (1968) may be considerably below the threshold
region this study was of Inadequate duration for use In ADI calculation. In
addition, doses of 130 mg/kg/day administered to pregnant rats by gastric
Intubation resulted 1n Irregular palatine rugae 1n the offspring. Higher
doses resulted 1n Increased prenatal death delayed sternal and cerndal ossifi-
cation, and depressed fetal weight. These data provide additional supports
for not employing the doses from the 20-day study as a basis for ADI
estimation.
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Uncertainty Factors (UFs):
The uncertainty factor of 1000 reflects 10 for both Intraspecles and
Interspedes variability to the toxlclty of this chemical In lieu of specific
data, and 10 for extrapolation of a subchronlc effect level to Us chronic
equivalent.
Modifying Factors (MFs):
None.
Additional Comments:
None.
Confidence 1n the RfO:
Study: Low
Data Base: Low
RfD: Low
The low confidence ratings for this study and data base reflect the
limited secondary descriptions available at the time of this writing. Low
confidence In the RfD follows.
Documentation of RfD and Review:
ECAO-CIn Internal Review, 1985.
U.S. EPA. 1985. Cacodyllc Acid: Review and Evaluation of ADI. Contract No.
68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH
Agency RfD Review:
First Review: 08/05/85
Second Review:
Verification Date: 08/05/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: H.L. Dourson
FTS/684-7544 or 513/569-7544
0420P
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Calcium Cyanide
Carclnogenldty: None. ,
Systemic Toxlclty: See below.
CAS #: 502-01-8
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
Howard and Hanzal
(1955)
Rat chronic oral
study
Phllbrlck
(1979)
et al
Rat subchronlc to
chronic oral bloassay
Weight loss, thyroid
effects and myelln
degeneration
10.8 mg/kg/day CN
(NOAEL) converted
19.1 mg/kg/day of
calcium cyanide
30.0 mg/kg/day CN
(LOAEL)
100
to
0.04 mg/kg/day
or
3 mg/day for a
70 kg man
Conversion Factor: Molecular weight ratio of Ca(CN)2/2
CN 1s 92/52; thus 10.8 mg/kg/day x 92/52 = 19.1
mg/kg/day
Endpolnt and Experimental Doses:
Howard, J.H. and R.F. Hanzal. 1955. Chronic toxldty for rats of food
treated with hydrogen cyanide. Agrlc. Food Chem. 3: 325-329.
Since calcium Is present 1n a very high level physiologically, ADIs for
CaCN2 can be calculated based on the maximum molar equivalents of cyanide
generated 1n adequeous or dilute acid solution.
In this 2 yr. dietary study, rats (10/sex/group) were administered food
fumigated with HCN. The average dally concentrations were 73 and 183 mg CN/kg
diet. From the data reported on food consumption and body weight, dally esti-
mated doses were 4.3 mg and 10.8 mg CN/kg bw. The average food CN concentra-
tions were estimated based on the author's data for concentration at the be-
Preparatlon Date: 01/06/86
0420P
-1-
01/11/86
-------
Endpolnt and Experimental Doses (cont.):
ginning and end of each food preparation period and by assuming a first order
rate of loss for the Intervening period. There were no treatment related
effects on growth rate, no gross signs of toxIcHy, and no hlstopathologkal
lesions.
Studies by PhllbMck et al. (1979) showed decreased weight gain and
thyroxln levels and myelln degeneration In rats at 30 mg/kg/day CM. Other
chronic studies either gave higher effect levels or used subcutaneous route
(Crampton et al., 1979; Lessen, 1971; Herthlng et al., 1960). Human data do
not provide adequate Information from which to derive an ADI because effective
dose levels of chronically Ingested CN are not documented. Therefore, the
study of Howard and Hanzel (1955) provides the highest NOAEL 10.8 mg/kg/day
for CN and 1s chosen for the derivation of an ADI for CN of 1.5 mg/day or 0.02
mg/kg/day.
Cyanide 1s metabolized extensively 1n the liver, Indicating that the only
relevant route of administration for quantitative risk assessment 1n the deri-
vation of an oral ADI 1s the oral route of administration.
Uncertainty Factors (UFs):
According to the U.S. EPA (1985) an uncertainty factor of 100 Is used to
derive the ADI (10 for species extrapolation, 10 for sensitive population).
Modifying Factors (MFs):
A modifying factor of 5 Is used for the apparent tolerance of cyanide when
H 1s Ingested with food rather than when administered by gavage or drinking
water.
Additional Comments:
Decreased protein efficiency ratio was produced by dietary cyanide treat-
ment of rats during gestation, lactation and postweanlng growth phase 1n the
Tewe and.Maner (1981a) experiment: the dose level of cyanide (10.6 mg/kg/day)
producing that effect Is slightly lower than the currently accepted NOAEL of
10.8 mg/kg/day (U.S. EPA, 1985). Furthermore, Tewe and Maner (1981b) tested
sows. Possible effects observed at about 9.45 mg/kg/day were proliferation of
glomerular cells of the kidneys and reduced activity of the thyroid glands In
the gilts. However, the number of animals In this experiment was very small.
A Japanese study (Amo. 1973) Indicated that 0.05 mg/kg/day of cyanide obtained
from drinking water decreased the fertility rate and survival rate 1n the Fl
generation and produced 100% mortality In the F2 generation 1n mice. However,
042°p -2- 01/11/86
-------
Additional Comments (cont.):
these data are not consistent with the body of available literature. Thus,
until additional chronic studies are available, an ADI of 3 mg/day for a 70 kg
man Is recommended.
Confidence 1n the RfD:
Study: Medium
Data Base: Medium
RfD: Medium
The confidence 1n the study 1s medium because adequate records of food
consumption and body weight were maintained and animals of both sexes were
tested at two doses for 2 years. The data base 1s rated medium because a
small but sufficient number of studies support the chosen study. The confi-
dence In the RfD follows. Additional chronic/reproductive studies are needed
to support a higher level of confidence 1n the RfD.
Documentation of RfD and Review:
ECAO-C1nc1nnat1 Internal Review, July 1985.
U.S. EPA. 1985. Cyanides: Review and Evaluation of ADI. Contract No.
68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH.
Agency RfD Review:
First Review: 08/05/85
Second Review:
Verification Date: 08/05/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0420P
-3-
01/11/86
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Carbaryl CAS #: 63-25-2
Carclnogenlclty: None.
Systemic Toxlcity: See below.
Endpolnt Experimental Doses UF MF RfD (ADI)
Carpenter et al. 200 ppm of diet 100 - 0.1 mg/kg/day
(1961) (9.6 mg/kg/day
(NOAEL)
Rat chronic feed- 400 ppm of diet
1ng study 15.6 mg/kg/day
(LOAEL)
Kidney and liver
toxlclty
Endpolnt and Experimental Doses:
Carpenter, C.P., C.W. Well, P.E. Polln, et al. 1961. Mammalian toxldty of
1-naphthayl-N-methylcarbamate (Sevln Insecticide). J. Agrlc. Food Chem. 9:
30-39.
Groups of 20 CF-N rats/sex were fed carbaryl at 0, 50, 100, 200 or 400 ppm
of diet for 2 years. Food consumption and body weight records were
maintained. Interim sacrifices (4-8 animals) from concurrent auxiliary groups
were performed at 6, 9 and 12 months for organ weight comparisons and
hlstopathologlcal analysis. Hematologlcal analyses were done at semi-regular
Intervals throughout the study. Surviving animals were sacrificed at 2 years
with gross and hlstopathologlcal examinations performed. The only noteworthy
effects .reported were slight hlstopathologlcal changes In the kidneys and
liver at the high-dose level. Diffuse cloudy swelling of renal tubules was
observed at 1 and 2 years. A statistically significant Increase 1n cloudy
swelling of the hepatic cords was also observed after 2 years. Based on body
weight and food consumption data, the LOAEL of 400 ppm was equivalent to a
dose of 15.6 mg/kg bw/day. The NOAEL established was 9.6 mg/kg bw/day.
Preparation Date: 01/09/86
0420P -1 01/11/86
-------
Uncertainty Factors (UFs):
UF = lOa x lOh. The UF of TOO Includes uncertainties In Interspecles and
Intrahuman variability.
Modifying Factors (MFs):
None.
Additional Comments:
Effect and no-effect levels (14 and 7 mg/kg/day, respectively) similar to
those found In the critical study were observed for rat body weight reduction
and chollnesterase Inhibition 1n a 1 year study. In subchronlc rat studies,
higher dose levels (85-200 mg/kg/day) caused kidney toxldty and biochemical
changes. Kidney lesions were observed In dogs fed carbaryl,at 5 mg/kg/day for
1 year; however, the effect was not clearly associated with treatment since
the lesions appeared In control animals but not In lower dose groups.
Carbaryl was teratogenlc for several species with widely varying NOELs.
The lowest effect levels of 5-6 mg/kg were observed for dogs, with NOELs of
2-3 mg/kg. Other LOELs were higher than the established chronic LOAEL of 15.6
mg/kg/day. Carbaryl was not teratogenlc for monkeys at 20 mg/kg. The dog
studies were judged Inappropriate for human health risk assessment because of
differences 1n the metabolism of carbaryl between dogs and humans.
Carbaryl has Induced numerical chromosome aberrations (aneuploldy and
polyploldy) 1n experimental animals. Carbaryl has not been found to be car-
cinogenic, but the data are equivocal.
Confidence 1n the RfD:
Study: High Data Base: Medium RfD: Medium
The critical study was well designed and clearly reported with unequivocal
effect levels established. The data base 1s moderately supportive of the
nature of the critical effect, 1f somewhat sparse. The principal problem 1s
the observation of teratogenlclty In dogs at lower doses. Because the sig-
nificance of these data cannot be discounted entirely, confidence In the RfD
should be considered medium to low.
0420P -2- 01/11/86
-------
Documentation of RfD and Review:
Limited Agency review of 1984 Health and Environmental Effects Profile with
the help of two external scientists.
U.S. EPA. 1984. Health and Environmental Effects Profile for Carbaryl.
Environmental Criteria a/id Assessment Office, Cincinnati, OH. ECAO-CIN-P039.
Agency RfO Review:
05/31/85
First Review:
Second Review:
Verification Date: 05/31/85
U.S. EPA Contact:
Primary: M.L. Dourson
FTS/684-7544 or 513/569-7544
Secondary: C.T. OeRosa
FTS/684-7534 or 513/569-7534
0420P
-3-
01/11/86
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Carbon D1sulf1de
Car dnogenl city: None.
Systemic Toxlclty: See below.
CAS #: 75-15-0
Endpolnt
Experimental Doses
UF
100
MF
RfD (ADI)
Hardln et al. (1981)
Rabbit Inhalation
teratogenic
Toxlclty/fetal mal-
formations
20 ppm (62.3 mg/
cu. m) (NOEL) con-
verted to 11.0
mg/kg/day
Price et al. (1984) 25 mg/kg/day (LOAEL)
Rabbit oral tera-
tology study
Fetal resorptlons
0.1 mg/kg/day
or
8 mg/day for a
70 kg man
Conversion Factors: 6 hour/24 hour, 1.6 cu. m/day
breathing rate; 1.13 kg bw and 0.5 absorption rate
(I.e., 62.3 mg/cu. m x 6 hour/24 hours x 1.6 cu.
m/day / 1.13 kg bw x 0.5 = 11.0 mg/kg/day)
Endpolnt and Experimental Doses:
Hardln, B.D., G.P. Bond,
Nlemelr. 1981. Testing
potential. Scand. J. Work
M.R. Slkor, F.D. Andrew, R.P. Bellies and R.H.
of selected work place chemicals for teratogenic
Environ. Health. 7(Suppl. 4): 66-75.
The data reported In this study were generated at Litton Blonetlcs, Mary-
land (under contract to NIOSH). Rats and rabbits were exposed to 20 ppm or
62.3 mg/cu. m (recommended occupational exposure limit) and 40 ppm or 124.6
mg/cu. m of CS2 during the entire length of the pregnancy period and also
3 weeks prior to breeding to simulate occupational exposure. This report con-
taining data on maternal/fetal toxldty and fetal malformations failed to show
any adverse effects of CS2 exposure, even at the high dose (124.6 mg/cu. m).
Preparation Date: 01/06/86
0420P
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01/11/86
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Endpolnt and Experimental Doses (cont.):
A NCTR/NTP study (Price et al., 1984) observed 25 mg/kg In rabbHs as an
AEL (fetal resorptlon). FetotoxUHy and fetal malformations 1n this study
were not observed 1n rats at the lowest level (100 mg/kg) of CS2 exposure.
Uncertainty Factors (UFs):
The 100-fold uncertainty factor reflects 10-fold adjustments for both the
expected 1ntra- and Interspedes variability to the toxldty of this compound
1n lieu of chemical-specific data. Note that the usual factor of 10$
(subchronlc to chronic extrapolation 1s not used here sTnce the exposure
duration covered the entire critical period for the el1dtat1on of the
critical effect.
Modifying Factors (MFs):
None.
Additional Comments:
A Bulgarian study (Tabatsova et al., 1983) reported significant fetal mal-
formations In rats exposed to a low CS2 dose of 0.03 mg/cu. m over three gen-
erations. Based on these data, an ADI would be drastically lower than the
ADIs that could be derived from existing guidelines, ep1dem1olog1cal data or
other experimental data. Moreover, the Bulgarian study did not present Infor-
mation on mode of control exposure, animal diet, selection of F1/F2 breeding
pairs and purity of CS2 (hydrogen sulflde, a potent teratogen. Is often found
as a contaminant). In a mult1generat1on study, toxic effects of a compound
can be confounded by the above factors. The data of Price et al. (1984)"also
suggest that the rabbit fetus 1s more sensitive than the rat fetus to
CS2-1nduced toxldty. Hardln et al. (1981) observed no effects on fetal
development In rats or rabbits following Inhalation exposure to 62.3 or 124.6
mg/cu. m which corresponds to estimated equivalent oral dosages of 5 and 10
mg/kg for rats, and 11 and 22 mg/kg 1n rabbits. The highest NOEL from this
study. 22 mg/kg 1n the rabbit, should not be used for an ADI estimate because
adverse effects were seen In rabbit fetuses following oral exposure of preg-
nant does to 25 mg/kg. Therefore, the highest NOEL which Is below an effect
level Is the estimated low dose from the Harden et al. (1981) Inhalation study
using rabbits. This dose level, >11 mg/kg, 1s proposed as the basis for ADI
derivation.
0420P -2- 01/11/86
-------
Confidence In the RfD:
Study: High
Data Base: Low
RfD: Low
The confidence In the chosen study 1s high because the exposure encom-
passed the critical period, and several species and doses were tested. Confi-
dence In the data base Is low because of the unavailability of supporting oral
chronic studies. Overall confidence 1n the RfD is low because of uncertainty
In the Inter-route conversion model. Until further oral chronic/reproductive
studies using U.S. EPA multlgeneratlon protocol are available, a low confi-
dence In the RfD 1s recommended.
Documentation of RfD and Review:
U.S. EPA. 1985. Carbon D1sulf1de: Review and Evaluation of ADI. Contract
No. 68-03-3228. Environmental Criteria and Assessment Office, U.S. EPA,
Cincinnati, OH.
This RfD received an ECAO-C1nc1nnat1 Internal Review during,Hay 1985.
Agency RfD Review:
First Review: 07/08/85
Second Review:
Verification Date: 07/08/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0420P
-3-
01/11/86
-------
REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Carbon TetrachloMde CAS #: 56-23-5
CardnogenlcHy:
Systemic Toxlclty: See below.
Endpolnt Experimental Doses UF MF RfD (ADI)
Information to be provided by the Office of DMnkfng Water
Endpolnt and Experimental Doses:
Preparation Date:
0420P -1- 01/11/86
-------
Uncertainty Factors (UFs):
Modifying Factors (MFs):~
Additional Comments:
Confidence In the RfD:
Study: Data Base: RfD:
Documentation of RfD and Review:
Agency RfD Review: U.S. EPA Contact:
First Review: Primary:
Second Review: FTS/684-75 or 513/569-75
Verification Date: Secondary:
FTS/684-75 or 513/569-75
0420P -2- 01/11/86
-------
REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Chlorine Cyanide (cyanogen chloride) CAS #: 506-77-4
Carclnogenldty: None.
Systemic Toxlclty: See below.
Endpolnt Experimental Doses
Howard and Hanzal 10.8 mq/kq/day CN
UF
100
MF
5
RfD (ADI)
0.05 mg/kg/day
(1955)
Rat chronic oral
study
PhUbMck et al.
(1979)
Rat subchronlc to
chronic oral bio-
assay
Height loss and
thyroid effects;
myelln degeneration
(NOAEL), converted
to 25.3 mg/kg/day of
chlorine cyanide
30 mg/kg/day (LOAEi;
or
4 mg/day for a
70 kg man
Conversion Factor: Molecular weight C1CN/CN Is 61/26;
thus, 10.8 mg/kg/day x 61/26 = 25.3 mg/kg/day
Endpolnt and Experimental Doses:
Howard, J.W. and R.F. Hanzal. 1955. Chronic toxldty for rats by food
treated with hydrogen cyanide. Agrlc. Food Chem. 3: 325-329.
Since chloride Is present In very high levels physiologically an ADI of
3.5 mg/day 1s recommended based on the maximum number of molar equivalents (1)
of cyanide released 1n aqueous solutions or dilute adds.
In this 2 yr. dietary study, rats (10/sex/group) were administered food
fumigated with HCN. The average dally concentrations were 73 and 183 mg CN/kg
diet. From the data reported on food consumption and body weight, dally
estimated doses were 4.3 mg and 10.8 mg CN/kg bw. The average food CN
Preparation Date: 01/09/86
0420P
-1-
01/11/86
-------
Endpolnt and Experimental Doses (cont.):
concentrations were estimated based on the author's data for concentration at
the beginning and end of each food preparation period and by assuming a first
order rate of loss for the Intervening period. There were no treatment
related effects on growth rate, no gross signs of toxlclty, and no histo-
pathologlcal lesions.
Studies by Philbrlck et al. (1979) showed decreased weight gain and thy-
roxln levels and myelln degeneration 1n rats at 30 mg/kg/day CN. Other
chronic studies either gave higher effect levels or used subcutaneous route
(Crampton et al., 1979; Lessen, 1971; Herthlng et al., 1960). Human data do
not provide adequate Information from which to derive an ADI.because effective
dose levels of chronically Ingested CN are not documented. Therefore, the
study of Howard and Hanzel (1955) provides the highest NOAEL 10.8 mg/kg/day
for CN and 1s chosen for the derivation of an ADI for CN of 1.5 mg/day or 0.02
mg/kg/day.
Cyanide 1s metabolized extensively 1n the liver, Indicating that the only
relevant route of administration for quantitative risk assessment In the deri-
vation of an oral ADI Is the oral route of administration. '
Uncertainty Factors (UFs):
According to the U.S. EPA (1985) an uncertainty factor of 100 is used to
derive the ADI (10 for species extrapolation, 10 for sensitive population).
Modifying Factors (MFs):
A modifying factor of 5 1s used for apparent tolerance of cyanide when It
Is Ingested with food rather than when administered by gavage or drloklng
water.
Additional Comments:
Decreased protein efficiency ratio was produced by dietary cyanide treat-
ment of .rats during gestation, lactation and postweanlng growth phase in the
Tewe and Haner (1981a) experiment: the dose level of cyanide (10.6 mg/kg/day)
producing that effect is slightly lower than the currently accepted NOAEL of
10.8 mg/kg/day (U.S. EPA, 1985). Furthermore, Tewe and Maner (1981b) tested
sows. Possible effects observed at about 9.45 mg/kg/day were proliferation of
glomerular cells of the kidneys and reduced activity of the thyroid glands 1n
the gilts. However, the number of animals In this experiment was very small.
A Japanese study (Amo, 1973) Indicated that 0.05 mg/kg/day of cyanide obtained
from drinking water decreased the fertility rate and survival rate in the Fl
generation and produced 100% mortality in the F2 generation In mice. However,
0420P -2- 01/11/86
-------
Additional Comments (cont.):
these
until
kg man 1s
data are not consistent with the body of available literature. Thus,
additional chronic studies are available, an ADI of 3.5 mg/day for a 70
recommended.
Confidence In the RfD:
Study: Medium
Data Base: Medium
RfD: Medium
The confidence 1n the study 1s medium because adequate records of food
consumption and body weight were maintained and animals of both sexes were
tested at two doses for 2 years. The data base Is rated medium because a
small but sufficient number .of studies support the chosen study. The .confi-
dence In the RfD follows. Additional chronic/reproductive studies are needed
to support a higher level of confidence 1n the RfD.
Documentation of RfD and Review:
U.S. EPA. 1985. Cyanides: Review and Evaluation of ADI. Contract No.
68-03-3228. Environmental Criteria and Assessment Office,. Cincinnati, OH.
ECAO-C1nc1nnat1 Internal Review, July 1985.
Agency RfD Review:
First Review: 08/05/85
Second Review:
Verification Date: 08/05/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0420P
-3-
01/11/86
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Chlorobenzene CAS #: 108-90-7
Cardnogenlclty:
Systemic Toxldty: See below.
Endpolnt Experimental Doses UF MF RfD (ADI
Last minute Information prevented the release of these values.
Endpolnt and Experimental Doses:
Preparation Date:
0420P -1- 01/11/86
-------
Uncertainty Factors (UFs):
Modifying Factors (MFs):
Additional Comments:
Confidence In the RfD:
Study: Data Base: RfD:
Documentation of RfD and Review:
Agency RfD Review: U.S. EPA Contact:
First Review: Primary:
Second Review: FTS/684-75 or 513/569-75
Verification Date: Secondary:
FTS/684-75 or 513/569-75
0420P -2- 01/11/86
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REFERENCE DOSES (RfOs) FOR ORAL EXPOSURE
Chemical: Copper Cyanide
Carclnogenlclty: None.
Systemic Toxlclty: See below.
CAS #: 544-92-3
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
Howard and Hanzal
(1955)
Rat chronic oral
study
PhUbrlck et al.
(1979)
Rat subchronlc to
chronic oral bio-
assay
Weight loss, thyroid
effects and myelln
degeneration
10.8 mg CN/kg/day
(NOAEL) converted to
37.2 mg C.u(CN)2/kg/
day
30 mg/kg/day CN
(LOAEL)
100
0.07 mg/kg/day
or
5 rog/day for a 70
kg man
Conversion Factors:
Molecular weight: Cu(CN)2/CN 1s 89.5/26;
thus, 10.8 mg CN kg x (89.5/26) = 37.2 mg/kg/day)
Endpolnt and Experimental Doses:
Howard,. J.W. and R.F Hanzal. 1955. Chronic toxlclty to rats of food treated
with hydrogen cyanide. Agrlc. Food Chem. 3: 325-329.
Copper cyanide has not been tested for toxlclty. Copper cyanide can exist
as cuprlc cyanide or cuprous cyanide. Cuprlc cyanide Is extremely unstable
and dissociates to form cyanide and a cuprous cyanide complex. An ADI can be
derived for cuprlc cyanide based on the molar equivalents of free cyanide only
since cuprous cyanide (CuCN) Is not soluble In water or dilute add. An ADI
calculated based on molar equivalents (1) of free CN would be 5.20 mg/day.
Preparation Date: 01/09/86
0420P
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01/11/86
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Endpolnt and Experimental Doses (cont.):
In this 2-year dietary study, rats (10/sex/group) were administered food
fumigated with HCN. The average dally concentrations were 73 and 183 mg CN/kg
diet. From the data reported on food consumption and body weight, dally esti-
mated doses were 4.3 mg and 10.8 mg CN/kg bw. The average food CN concentra-
tions were estimated based on the author's data for concentration at the
beginning and end of each food preparation period and by assuming a first
order rate of loss for the Intervening period. There were no treatment
related effects on growth rate, no gross signs of toxldty. and no hlsto-
pathologlcal -lesions.
Studies by PhllbMck et al. (1979) showed decreased weight gain and thy-
roxln levels and myelln degeneration 1n rats at 30 mg/kg/day CN. Other
chronic studies either gave higher effect levels or used subcutaneous route
(Crampton et al., 1979; Lessen. 1971; Herthlng et al., 1960). Human data do
not provide adequate Information from which to derive an ADI because effective
dose levels of chronically Ingested CN are not documented. Therefore, the
study of Howard and Hanzel (1955) provides the highest NOAEL. 10.8 mg/kg/day
for CN and Is chosen for the derivation of an ADI for CN of,1.5 mg/day or 0.02
mg/kg/day.
Cyanide Is metabolized extensively 1n the liver, Indicating that the only
relevant route of administration for quantitative risk assessment 1n the deri-
vation of an oral ADI Is the oral route of administration.
Uncertainty Factors (UFs):
According to the U.S. EPA (1985) an uncertainty factor of 100 Is used to
derive the ADI (10 for species extrapolation, 10 for sensitive population).
Modifying Factors (MFs):
A modifying factor of 5 Is used for' apparent tolerance of cyanide when It
1s Ingested with food than when administered by gavage or drinking water.
Additional Comments:
Decreased protein efficiency ratio was produced by dietary cyanide treat-
ment of rats during gestation, lactation and postweanlng growth phase In the
Tewe and Maner (1981a) experiment: the dose level of cyanide (10.6 mg/kg/day)
producing that effect is slightly lower than the currently accepted NOAEL of
10.8 mg/kg/day (U.S. EPA, 1985). Furthermore, Tewe and Maner (1981b) tested
sows. Possible effects observed at about 9.45 mg/kg/day were proliferation of
glomerular cells of the kidneys and reduced activity of the thyroid glands In
the gilts. However, the number of animals 1n this experiment was very small.
0420P -2- 01/11/86
-------
Additional Comments (cont.):
A Japanese study (Amo, 1973) Indicated that 0.05 mg/kg/day of cyanide obtained
from drinking water decreased the fertility rate and survival rate In the Fl
generation and produced 100% mortality In the F2 generation 1n mice. However,
these data are not consistent with the body of available literature. Thus,
until additional chronic studies are available, an ADI of 5.2 mg/day for a 70
kg man Is recommended.
Confidence In the RfD:
Study: Medium
Data Base: Low
RfD: Low
The confidence In the study Is medium because adequate records of food
consumption and body weight were maintained and animals of both sexes were
tested at two doses for 2 years. The data base Is rated low because this
chemical has not been tested. The confidence 1n the RfD 1s low because It Is
based on analogy. Chronic/reproductive studies are needed to support a higher
level of confidence In the RfD.
Documentation of RfD and Review:
U.S. EPA. 1985. Cyanides: Review and Evaluation of ADI. Contract No.
68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH.
ECAO-C1nc1nnat1 Internal Review, July 1985.
Agency RfD Review:
First Review: 08/05/85
Second Review:
Verification Date: 08/05/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0420P
-3-
01/11/86
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Cresols
Carclnogenldty: None.
Systemic Toxldty: See below.
CAS #: 1319-77-3
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
NIOSH (1978)
Occupational expo-
sure criterion
TLV = 10 mg/cu. m
10 mg/cu. m TLV con-
verted to 0.51 mg/
kg/day
Conversion Factors;
0.05 mg/kg
or
4 mg/day for a
70 kg man
10 mg/cu. m x 10 cu. m/day x 0.5 absorption factor x 5
days/7 days / 70 kg = 0.51 mg/kg/day
Endpolnt and Experimental Doses:
NIOSH (National Institute of Occupational Safety and Health)
for a Recommended Standard...Occupational Exposure to Cresol.
CDC, Cincinnati, OH. DHEW (NIOSH) Publ. No. 78-133.
1978. Criteria
U.S. DHEW, PHS,
NIOSH's recommendation Is based on a review and assessment of the avail-
able literature primarily the subchronlc Inhalation studies of Uzhdavlne et
al. (1972). Uzhdavlne et al. (1972) exposed rats and guinea pigs to 0-cresol
at a concentration of 9.0 (plus or minus 0.9) mg/cu. m. No effect was seen 1n
guinea pigs. In rats, the authors reported various hematopo1et1c effects,
respiratory tract Irritation and sclerosis of lungs. Uzhdavlne et al. (1972)
also reported humans exposed to 6 mg/cu. m (duration unspecified) cresol
experienced nasopharynegeal Irritation. No adequate chronic or subchronlc
data exist to base an ADI. Environ lists an ADI of 0.113 mg/kg/day based on
ACGIH (1980) TLV of 22 mg/cu. m. The NIOSH (1978) criterion based on a far
more complete, detailed and critical review of the available literature than
Is the ACGIH TLV. Other studies support the findings (effects) reported In
the Uzhdavlne et al. (1972) study cited by NIOSH. Consequently, the NIOSH
(1978) criterion 1s a more prudent basis for an ADI of 0.051 mg/kg/day to
protect against adverse health effects.
Preparation Date: 01/09/86
0420P
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Uncertainty Factors (UFs):
The 10-fold uncertainty factor represents the expected Intrahuman varl
ability to the toxldty of this chemical In lieu of chemical-specific data.
Modifying Factors (MFs):
None.
Additional Comments:
No chronic toxldty studies were conducted and the subchronlc data was
poorly characterized and documented. Until further oral chronic, subchronlc
or reproductive data Is available, a low confidence 1n the RfD 1s recom-
mended. An additional factor of 10 was not deemed necessary due to the fact
the various hematopoletlc effects observed In rats were considered slight and
reversible. No effects wre seen 1n guinea pigs and no hlstopathologlcal
effects were reported 1n either species.
Confidence 1n the RfD:
Study: Low
Data Base: Low
RfD: Low
The confidence 1n both the procedure to estimate an oral RfD by a TLV and
the resulting RfD 1s low since this method 1s only used when sufficient oral
and Inhalation toxldty data do not exist.
Documentation of RfD and Review:
U.S. EPA. 1985. Cresol: Review and Evaluation of ADI. Contract No.
68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH.
U.S. EPA. 1985. Health and Environmental Effects Profile for Cresols.
Environmental Criteria and Assessment Office, Cincinnati. OH. ECAO-CIN-P138.
The Health and Environmental Effects Profile has received an Agency-wide
review with the help of two external scientists.
Agency RfD Review:
F1rs.t Review: 07/08/85
Second Review:
Verification Date: 07/08/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0420P
-2-
01/11/86
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Cyanide (free)
Cardnogenldty: None.
Systemic Toxldty: See below.
CAS #: 57-12-15
Endpolnt
Experimental Doses
UF
MF
RfD (ADI;
Howard and Hanzal
(1955)
Rat oral chronic
study
Ph1lbr1ck et al.
(1979)
Rat oral subchronlc
to chronic study
Primary myelln
degeneration and
decreased thyroxln
levels
10.8 mg/kg/day CN
(NOAEL)
30 mg/kg/day CN
(LOAEL)
100
0.02 mg/kg/day
or
2 mg/day for a
70 kg man
Endpolnt and Experimental Doses:
Howard, J.W. and R.F. Hanzal. 1955. Chronic toxldty to rats of food treated
with hydrogen cyanide. AgMc. Food Chem. 3: 325-329.
Hydrogen cyanide Is soluble 1n water and dilute acid (which Includes the
gastric environment) and 1s readily hydrolysed to 1 molar equivalent of CN and
1 molar equivalent of hydrogen (Hartung, 1982).
In this 2-year dietary study, rats (10/sex/group) were administered food
fumigated with HCN. The average dally concentrations were 73 and 183 mg CN/kg
diet. From the data reported on food consumption and body weight, dally esti-
mated doses were 4.3 mg and 10.8 mg CN/kg bw. The average food CN concentra-
tions were estimated based on the author's data for concentration at the
beginning and end of each food preparation period and by assuming a first
Preparation Date: 01/09/86
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Endpolnt and Experimental Doses (cont.):
order rate of loss for the Intervening period. There were no treatment
related effects on growth rate, no gross signs of toxlclty, and no hlstopatho-
loglcal lesions.
Studies by Phllbrlck et al. (1979) showed decreased weight gain and
thyroxln levels and myelln degeneration 1n rats at 30 mg/kg/day CN. Other
chronic studies either gave higher effect levels or used subcutaneous route
(Crampton et al., 1979; Lessen, 1971; Herthlng et al., 1960). Human data do
not provide adequate Information from which to derive an ADI because effective
dose levels of chronically Ingested CN are not documented. Therefore, the
study of Howard and Hanzel (1955) provides the highest NOAEL 10.8 mg/kg/day
for CN and 1s chosen for the derivation of an ADI for CN of 1.5 mg/day or 0.02
mg/kg/day.
Cyanide Is metabolized extensively In the liver. Indicating that the only
relevant route of administration for quantitative risk assessment 1n the deri-
vation of an oral ADI 1s the oral route of administration.
Uncertainty Factors (UFs):
According to the U.S. EPA (1985) an uncertainty factor of 100 Is used to
derive the ADI (10 for species extrapolation, 10 for sensitive population).
Modifying Factors (MFs):
A modifying factor of 5 1s used for apparent tolerance of cyanide when It
1s Ingested with food than when administered by gavage or drinking water.
Additional Comments:
Decreased protein efficiency ratio was produced by dietary cyanide treat-
ment of rats during gestation, lactation and postweanlng growth phase In the
Tewe and Maner (1981a) experiment: the dose level of cyanide (10.6 mg/kg/day)
producing that effect Is slightly lower than the currently accepted NOAEL of
10.8 mg/Jcg/day (U.S. EPA, 1985). Furthermore, Tewe and Maner (1981b) tested
sows. Possible effects observ.ed at about 9.45 mg/kg/day were proliferation of
glomerular cells of the kidneys and reduced activity of the thyroid glands In
the gilts. However, the number of animals In this experiment was very small.
A Japanese study (Amo, 1973) Indicated that 0.05 mg/kg/day of cyanide obtained
from drinking water decreased the fertility rate and survival rate In the Fl
generation and produced 100% mortality 1n the F2 generation In mice. However,
these data are not consistent with the body of available literature. Thus,
until additional chronic studies are available, an ADI of 1.5 mg/day for a 70
kg man Is recommended.
0420P -2- 01/11/86
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Confidence in the RfD:
Study: Medium
Data Base: Medium
RfD: Medium
The confidence 1n the study 1s medium because adequate records of food
consumption and body weight were maintained and animals of both sexes were
tested at two doses for 2 years. The data base 1s rated medium because a
small but sufficient number of studies support the chosen study. The confi-
dence In the RfD follows. Additional chronic/reproductive studies are needed
to support a higher level of confidence 1n the RfD.
Documentation of RfD and Review:
U.S. EPA. 1984. Health Effects Assessment for Cyanides. Environmental Cri-
teria and Assessment Office, Cincinnati, OH. ECAO-CIN-H011.
U.S. EPA. 1985. Drinking Water Criteria Document for Cyanides. Office of
Drinking Water, Washington, DC.
The ODW criteria document and OERR health effects assessment have both had an
extensive Agency-wide and limited external review.
Agency RfD Review:
First Review: 08/05/85
Second Review:
Verification Date: 08/05/85
U.S. EPA Contact:
Primary: C.T. DeRosa
fTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0420P
-3-
01/11/86
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REFERENCE DOSES (RfDs) FOR'ORAL EXPOSURE
Chemical: Cyanogen
Cardnogenldty: None.
Systemic Toxlclty: See below.
CAS #: 460-19-5
Endpolnt
Experimental Doses
UF
MF
5
-RfO (ADI)
Howard and Hanzal
(1955)
Rat chronic oral
study
Phllbrlck et al.
(1979)
Rat subchronlc to
chronic oral bio-
assay
Weight loss and thy-
roid effects; myelln
degeneration
10.8 mg/kg day CN
(NOAEL) converted
to 21.6 mg/kg/day
of cyanogen
100
0.04 mg/kg/day
or
3 .mg/day for a
70 kg man
30 mg/kg/day
(LOAEL)
CN
Conversion Factors: Molecular weight of C2N2/CN 1s
52/26; thus 10.8 mg/kg/day x 52/26 = 21.6 mg/kg/day.
Endpolnt and Experimental Doses:
Howard, J.W. and R.F. Hanzal.
with hydrogen cyanide. Agrlc.
1955. Chronic toxIcHy to
Food Chem. 3: 325-329.
rats of food treated
Cyanogen does not completely dissociate Into free CN In water or dilute
acetic solution. However, without an evaluation of the toxlclty of the parent
compound, an ADI based on molecular equivalents (1) CN would be 3 mg/day.
In this 2-year dietary study, rats (10/sex/group) were administered food
fumigated with HCN. The average dally concentrations were 73 and 183 mg CN/kg
diet. From the data reported on food consumption and body weight, dally estl-
Preparatlon Date: 01/09/86
0420P
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Endpolnt and Experimental Doses (cont.):
mated doses were 4.3 mg and 10.8 mg CN/kg bw. The average food CN concentra-
tions were estimated based on the author's data for concentration at the
beginning and end of each food preparation period and by assuming a first
order rate of loss for the Intervening period. There were no treatment
related effects on growth rate, no gross signs of toxldty, and no hlstopatho-
loglcal lesions.
Studies by Phllbrlck et al. (1979) showed decreased weight gain and
thyroxln levels and myelln degeneration In rats at 30 mg/kg/day CN. Other
chronic studies either gave higher effect levels or used subcutaneous route
(Crampton et al., 1979; Lessell, 1971; Herthlng et al., I960.). Human data do
not provide adequate Information from which to derive an ADI because effective
dose levels of chronically Ingested CN are not documented. Therefore, the
study of Howard and Hanzel (1955) provides the highest NOAEL 10.8 mg/kg/day
for CN and 1s chosen for the derivation of an ADI for CN of 1.5 mg/day or 0.02
mg/kg/day.
Cyanide Is metabolized extensively In the liver, Indicating that the only
relevant route of administration for quantitative risk assessment In the deri-
vation of an oral ADI Is the oral route of administration.
Uncertainty Factors (UFs):
According to the U.S. EPA (1985) an uncertainty factor of 100 Is used to
derive the ADI (10 for species extrapolation, 10 for sensitive population).
Modifying Factors (MFs):
An additional 5 1s used for apparent tolerance of cyanide when It Is
Ingested with food than when administered by gavage or drinking water.
Additional Comments:
Decreased protein efficiency ratio was produced by dietary cyanide treat-
ment of rats during gestation, lactation and postweanlng growth phase 1n the
Tewe and Maner (1981a) experiment: the dose level of cyanide (10.6 mg/kg/day)
producing that effect 1s slightly lower than the currently accepted NOAEL of
10.8 mg/kg/day (U.S. EPA, 1985). Furthermore, Tewe and Maner (1981b) tested
sows. Possible effects observed at about 9.45 mg/kg/day were proliferation of
glomerular cells of the kidneys and reduced activity of the thyroid glands In
the gilts. However, the number of animals In this experiment was very small.
A Japanese study (Amo, 1973) Indicated that 0.05 mg/kg/day of cyanide obtained
from drinking water decreased the fertility rate and survival rate In the Fl
generation and produced 100% mortality in the F2 generation in mice. However,
0420P -2- 01/11/86
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Additional Comments (cont.):
these data are not consistent with the body of available literature. Thus,
until additional chronic studies are available, an ADI of 3.0 mg/day for a 70
kg man 1s recommended.
Confidence In the RfD:
Study: Medium
Data Base: Low
RfD: Low
The confidence In the study 1s medium because adequate records of food
consumption and body weight were maintained and animals of both sexes were
tested at two doses for 2 years. The data base 1s rated low because this
chemical has not been tested. The confidence 1n the RfD Is low because It 1s
based on analogy. Chronic/reproductive studies are needed to support a higher
level of confidence 1n the RfD.
Documentation of RfD and Review:
ECAO-C1nc1nnat1 Internal Review, July 1985.
U.S. EPA. 1985. Cyanides: Review and Evaluation of ADI. Contract No.
68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH.
Agency RfD Review:
First Review: 08/05/85
Second Review:
Verification Date: 08/05/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0420P
-3-
01/11/86
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: 2,4-DB CAS #: 94-82-6
CarclnogenlcHy: None.
Systemic Toxlclty: See below.
Endpolnt Experimental Doses UF HF RfD (ADI)
CBI 8 mg/kg/day (NOAEL) 1000 - 0.008 mg/kg/day
Dog subchronlc oral 25 mg/kg/day (LOAEL)
bloassay
Internal hemorrhage,
mortallty
Endpolnt and Experimental Doses:
CBI (Confidential Business Information)
Four beagle dogs/sex/group were fed 2,4-DB at dose levels of 0, 2.5, 8.0,
25 or 80 mg/kg bw/day for 90 days. The two higher doses produced frank
effects Including death, hemorrhage throughout the body and aspermatogenesls
within 3-9 weeks of treatment. Slightly Increased 11 ver-to-body weight ratios
were observed at both lower dose levels, but no gross or microscopic pathology
was evident.
Uncertainty Factors (UFs):
The uncertainty factor of 1000 reflects 10 for both Intraspecles and
Interspecles variability to the toxlclty of this chemical In lieu of specific
data, and 10 for extrapolation of a subchronlc effect level to Its chronic
equivalent.
Preparation Date: 01/09/86
°420P -1- 01/11/86
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Modifying Factors (MFs):
None.
Additional Comments:
A subchronlc rat study (CBI) showed somewhat higher effect and no-effect
levels than were observed 1n the dog study. Severe kidney and liver damage
was observed at 1000 ppm 2,4-DB In the diet (80-100 mg/kg bw/day). A NOEL of
about 25-30 mg/kg/day was established.
2,4-DB does not appear to be teratogenlc, but the data are very limited.
Structurally related compounds (2,4-D and 2,4,5-T) are teratogenlc. No data
on carclnogenldty are available. 2,4-DB has not been shown to be mutagenlc.
Confidence In the RfD:
Study: Medium
Data Base: Low
RfD: Low
Confidence In the critical study Is medium because of the moderate number
of animals and large number of dose groups employed, but not high, because
some data are lacking. Confidence In the data base 1s low, because of the.
general lack of data, but tends toward medium because one moderately sup-
portive study Is available. Confidence in the RfD 1s low because of the weak
data base.
Documentation of RfD and Review:
The ADI In the 1984 Health and Environmental Effects Profile has had a limited
Agency review with the help of two external scientists.
U.S. EPA. 1984. Health and Environmental Effects Profile for 2,4-DB. Envi-
ronmental Criteria and Assessment Office, Cincinnati, OH. ECAO-CIN-P060AP.
Agency .RfD Review:
First Review: 05/31/85
Second Review: 06/19/85
Verification Date: 06/19/85
U.S. EPA Contact:
Primary: M.L. Dourson
FTS/684-7544 or 513/569-7544
Secondary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
0420P
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01/11/86
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: 1,2-D1chlorobenzene CAS #: 95-50-1
Cardnogenlclty:
Systemic Toxlclty: See below.
Endpolnt Experimental Doses UF MF RfD (ADI)
Last minute Information prevented the release of these values.
Endpolnt and Experimental Doses:
Preparation Date:
0420P -]-
01/11/86
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Uncertainty Factors (UFs):
Modifying Factors (MFs):
Additional Comments:
Confidence In the RfD:
Study; Data Base: RfD:
Documentation of RfO and Review:
Agency RfO Review: U.S. EPA Contact:
First Review: Primary:
Second Review: FTS/684-75 or 513/569-75
Verification Date: Secondary:
FTS/684-75 or 513/569-75
0420P -2- 01/11/86
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REFERENCE DOSES (RfOs) FOR ORAL EXPOSURE
Chemical: Dlchlorofluoromethane CAS #: 75-71-8
Cardnogenldty: None.
Systemic ToxIcHy: See below.
e6eťoŤoŤeoo*BťŤoťŤ'"''eo6Doi>efto.BBeooŤeaooo6Ť<'Oo*ooce*o<'ť*'Ť>00ťŤťeťť*0"ť"*ťťť"Ťťo
Endpolnt Experimental Doses UF MF RfD (ADI)
Sherman (1974) 15 mg/kg/day (NOEL) 100 - 0.2 mg/kg/day
or
Rat chronic oral 10' mg/day for a
study 70 kg man
Reduced body weight 150 mg/kg/day (LOAEL)
Endpolnt and Experimental Doses:
Sherman, H. 1974. Long-term feeding studies In rats and dogs with dlchloro-
dlfluoromethane (Freon 12 Food Freezant). Haskell Laboratory for Toxicology
and Industrial Medicine Report No. 24-74.
The study reported by the Haskell Laboratory (Sherman et al., 1974)
Involved 2-year feeding studies In which dogs and rats received 300 ppm or
3000 ppm of d1chlorod1fluoromethane. This report contained data on clinical
biochemical, urine analytical, hematologlcal or hlstopathologlcal evalua-
tions. Additionally, carcinogenic and three-generation reproductive studies
were conducted In rats. Except for decreased weight gain in rats (about 20/4
In females) which received 3000 ppm (150 mg/kg/day) dlchlorodlfluoromethane In
the diet, no other adverse effects were attributable to this compound In
either rats or dogs.
The Haskell Laboratory study reported above Is sufficiently complete to
derive an ADI for adequate protection against adverse human health effects.
The high dose (3000 ppm or 150 mg/kg/day) caused decreased body weights In
rats and thus considered as a LOAEL; whereas the low dose (300 ppm or 15
mg/kg/day) 1n rats produced no adverse effects attributable to the oral
administration of dlchlorodlfluoromethane (Freon 12).
Preparation Date: 01/06/86
0420P -1- 01/11/86
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Uncertainty Factors (UFs):
The NOEL from the 2-year rat study (15 mg/kg/day) and an uncertainty
factor of 100 (10 for species extrapolation and 10 for sensitive Individuals)
were used to derive the ADI of 0.2 mg/kg/day or 10 mg/day for a 70 kg human
being.
Modifying Factors (MFs):
None.
Additional Comments:
None.
Confidence In the RfD:
Study: High
Data Base: Low
RfD: High
The Haskell Laboratory study Is a chronic oral study In two species which
Incorporated extensive clinical and toxlcologlcal parameters. Therefore, a
high level of confidence 1n study Is appropriate. Confidence 1n the data base
Is low because of the lack of other data. Confidence In the RfD follows at
high to medium.
Documentation of RfD and Review:
This document has undergone a limited Agency review.
U.S. EPA. 1982. Errata: Halomethanes' Ambient Water Quality Criteria Docu-
ment for the Protection of Human Health. Environmental Criteria and Assess-
ment Office. Cincinnati, OH. ECAO-CIN-D023.
Agency RfD Review:
First Review: 07/08/85
Second Review: 07/22/85
Verification Date: 07/22/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0420P
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01/11/86
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Dlmethoate CAS #: 60-51-5
Carclnogenldty: None.
Systemic Toxlclty: See below.
Endpolnt Experimental Doses UF MF RfD (ADI)
Edson et al. (1967) NOEL: 0.2 mg/kg/day 10 - 0.02 mg/kg/day
Short-term feeding LOAEL: 0.4 mg/kg/day
study In humans
Decreases 1.n chol-
Inesterase (ChE)
activity
Endpolnt and Experimental Doses:
Edson, E.F., K.H. Jones and W.A. Watson. 1967. Safety of dlmethoate Insecti-
cide. Br. J. Med. 4: 554-555.
Thr1ty-s1x male and female adult volunteers without occupational exposure
to organophosphate Insecticides were arranged In groups and given repeated
doses of dlmethoate. The dlmethoate was administered as a flavoured aqueous
solution. Venous blood samples were taken twice before and once or twice/week
after dlmethoate dosage started. ChE 1n whole blood was measured and Us
depression taken as the critical first response to dlmethoate. Activity In
red cells and plasma were also determined separately. The study was under
close medical supervision, and Inquiry was also made for any effects other
than ChE depression, though none was detected.
The results show that no significant change occurred with 0.068 or 0.202
mg/kg/day. ChE values at 0.434 mg/kg/day began to show a slow downward trend
by day 20, and this continued to the end of the test at 57 days. Higher doses
showed the same effects at an earlier stage, and a somewhat faster rate. The
rate and extent of red cell ChE depression closely paralleled those of whole-
blood ChE. No localized gastrointestinal or other clinical effects occurred
In any group.
Preparation Date: 01/09/86
0420P -1- 01/11/86
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Uncertainty Factors (UFs):
The uncertainty factor of 10 accounts for the expected Interhuman vari-
ability to the toxlclty of this chemical In Heu of specific data. An addi-
tional uncertainty factor of 10-fold to adjust the results found after short-
term to chronic exposures Is not considered necessary here because the criti-
cal toxic effect, chollriesterase Inhibition 1s Immediate and occurs regardless
of exposure duration.
Modifying Factors (MFs):
None.
Additional Comments:
None.
Confidence 1n the RfD:
Study: High
Data Base: High
RfD: High
The study Is given a confidence rating of high because 1t was conducted In
humans with a fair amount of subjects at each of five doses. Chollnesterase
Inhibition, the critical toxic effect was measured. The supporting animal
data base 1s given a confidence rating of high because It Is extensive and
yields similar RfD values. High confidence In the RfD follows.
Documentation of RfD and Review:
The ADI has been through the Registration Standard process of the OPP.
Gessert, R.A. 1982. Memorandum to P. Parsons. Dlmethoate Registration
Standard; Toxicology Assessment. Office of Pesticide Programs, U.S. EPA,
Washington, DC, August 31.
Agency RfD Review:
First Review: 07/08/85
Second Review: 07/22/85
Verification Date: 07/22/85
U.S. EPA Contact:
Primary: R. Engler
FTS/537-7490 or 202/557-7490
Secondary: M.I. Dourson
FTS/684-7544 or 513/569-7544
0420P
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01/11/86
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Dlnoseb CAS #: 88-85-7
Carclnogenlclty: Limited data are negative.
Systemic Toxldty: See below.
Endpolnt Experimental Doses UF MF RfD (ADI)
CBI NOEL: None 1000 - 0.001 mg/kg/day
Rat chronic oral LOAEL: 1 mg/kg/day
bloassay
Decreased body and
thyroid weights
Endpolnt and Experimental Doses:
CBI (Confidential Business Information)
Sixty rats/sex/group were fed diets containing dlnoseb at 0, 1, 3 or 10
mg/kg bw/day for up to 104 weeks. Ten animals/sex were sacrificed at 1 year
for Interim results. Clinical signs of toxldty attributed to dlnoseb were
evident 1n all treated groups (hunched posture and urine staining of coat). A
statistically significant and dose-related reduction In body weight gain was
observed at 3 and 10 mg/kg/day. This effect was evident within the first year
of treatment, and occurred despite Increased food consumption. Decreased mean
relative absolute thyroid weights In all treated males and decreased relative
thyroid weights 1n mid-dose males were observed at the 104-week terminal kill.
No consistent dose-related effects were observed for hematology, selected
blood chemistries or urlnalysls values.
IIl.vicky and Caslda (1969) suggested that the mechanism of toxldty for
dlnoseb Involved an elevated metabolic rate associated with uncoupling of
oxldatlve phosphorylatlon. The observation of decreased growth rate with
Increased food consumption, concurrent with decreased thyroid weight Is con-
sistent with this hypothesis.
Preparation Date: 01/06/86
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Uncertainty Factors (UFs):
The uncertainty factor of 1000 reflects 10 for both Intra- and Inter-
species variability to the toxlclty of this chemical In lieu of specific data,
and 10 for extrapolation from a LOAEL to It hypothesized NOAEL.
Modifying Factors (MFs):
None.
Additional Comments:
Body weight losses due to dlnoseb treatment have also been reported for
rats treated at 9.1 mg/kg/day for 11 weeks and at 10 mg/kg/day for 6 months.
A 90-day dog study showed reversible heart and liver effects at 5.3 mg/kg/day
with a NOEL of 3 rag/kg/day.
Dlnoseb was not carcinogenic 1n one rat study, and has not been found to
be rautagenlc. Dlnoseb was teratogenlc by l.p. and s.c. administration to
mice, but not by the oral route. Male reproductive toxlclty was observed for
rats fed dlnoseb at 15.6 mg/kg/day for 11 weeks.
Confidence 1n the RfD:
Study: High Data Base: Medium RfD: Medium
The confidence 1n the chosen study 1s high because of the large number of
animals/sex 1n three dose groups, the large number of parameters measured, and
because of the Interim kill. The data base Is rated medium because the sup-
porting studies are only subchronlc 1n duration. Confidence 1n the RfD Is not
higher than medium because a NOAEL was not established.
Documentation of RfD and Review:
The ADJ. In the 1984 Health and Environmental Effects Profile has received
limited Agency review with the help of two scientists.
U.S. EPA. 1984. Health and Environmental Effects Profile for Dlnoseb.
Environmental Criteria and Assessment Office, Cincinnati, OH.
ECAO-CIN-PO-87AP.
0420P -2- 01/11/86
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Agency RfD Review:
First Review: 07/08/85
Second Review: 07/22/85
Verification Date: 07/22/85
U.S. EPA Contact:
Primary: M.L. Dourson
FTS/684-7544 or 513/569-7544
Secondary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
0420P
-3-
01/11/86
-------
REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Ethylbenzene CAS #: 100-41-4
CarclnogenlcHy: None.
Systemic Toxlclty: See below.
Endpolnt Experimental Doses UF MF RfD (ADI)
Wolf et al. (1956) 136 mg/kg/day (NOEL); 1000 - 0.1 mg/kg/day
408 mg/kg/day (LOAEL)
Rat subchronlc to
chronic oral bio-
assay
Liver and kidney
toxlclty
Conversion Factor: 5 days/7 days; thus, 136 mg/kg/
day x 5 days/7 days =97.1 mg/kg/day
Endpolnt and Experimental Doses:
Wolf, H.A., V.K. Rowe, D.D. McColHster, R.L. HolUngsworth and F. Oyen.
1956. lexicological studies of certain alkylated benzenes and benzene. Arch.
Ind. Health. 14: 387-398.
The chosen study Is a rat 182-day oral bloassay where ethylbenzene was
given 5 days/week at doses of 13.6, 136, 408 or 680 mg/kg/day In olive oil
gavage. There were 10 albino female rats/dose group with 20 controls.
The criteria considered In Judging the toxic effects on the test animals
were growth, mortality, appearance and behavior, hematologlcal findings,
terminal-concentration of urea nitrogen 1n the blood, final average organ and
body weights, hlstopathologlcal findings, and bone marrow counts. The LOAEL
of 408 mg/kg/day 1s associated with hlstopathologlcal changes In liver and
kidney.
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Uncertainty Factors (UFs):
The uncertainty factor of 1000 reflects 10 for both Intraspecles and
Interspecles variability to the toxldty of this chemical In Heu of specific
data, and 10 for extrapolation of a subchronlc effect level to Us chronic
equivalent.
Modifying Factors (MFs):
None.
Additional Comments:
None.
Confidence In the RfD:
Study: Low Data Base: Low RfD: Low
Confidence In the chosen study 1s low because rats of only one sex were
tested and the experiment was not of chronic duration. Confidence 1n the
supporting data base Is low because other oral toxldty data are not found. A
low confidence In the RfD follows.
Documentation of RfD and Review:
A recent ORD document reaffirms the ADI from the ODW criteria document. -Both
documents have extensive Agency review with the help of selected outside
scientists review.
An Identical ADI was publicly reviewed during the 1980 Ambient Water Quality
Criteria series.
U.S. EPA. 1980. Ambient Water Quality Criteria for Ethylbenzene. Environ-
mental .Criteria and Assessment Office, Cincinnati, OH. EPA 440/5-80-048.
U.S. EPA. 1985. Drinking Water Criteria Document for Ethylbenzene. Office
of Drinking Water, Washington, DC. (Public review draft)
U.S. EPA. 1985. Health Effects Assessment for Ethylbenzene. Environmental
Criteria and Assessment Office, Cincinnati, OH. ECAO-CIN-H008.
0420P -2- 01/11/86
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Agency RfD Review:
First Review: 05/20/85
Second Review:
Verification Date: 05/20/85
U.S. EPA Contact:
Primary: M.L. Dourson
FTS/684-7544 or 513/569-7544
Secondary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
0420P
-3-
01/11/86
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Fluoride
Cardnogenlclty: None.
Systemic Toxlclty: See below.
CAS #: 7782-41-4
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
Hodge (1950)
Cited In: Underwood
(1977)
Children epidemic-
logical study
Dental mottling
1 ppm (NOAEL con-
verted to 0.05 mg/
kg/day
2 ppm (LOAEL)
Coverslon Factor: 1 mg/L
child = 0.05 mg/kg/day
0,05-0.2 mg/
kg/day
or
1 mg/day for a 20
kg child excess
fluoride Intake
over background
(NOAEL) x 1 L/day / 20 kg
Endpolnt and Experimental Doses:
Hodge, H.C. 1950. The concentration of fluorides In drinking water to give
the point of minimum carles with maximum safety. J. Am. Dent. Assoc. 40:
436. Cited In: Underwood, E.J. 1977. Trace Elements In Human and Animal
Nutrition. Academic Press, NY.
Fluoride related compounds are used In the prevention of dental carles.
Extensive human epldem1olog1cal studies with large populations have been
carried out over the last 40 years. The NOAEL (1 ppm) and LOAEL (2 ppm) In
drinking water are defined within a narrow dose range. Underwood (1977) Is
the secondary reference cited for RfD (ADI) basis. Hodge (1950) 1s the
primary reference dted 1n Underwood (1977).
Hodge (1950) studied children consuming fluoride In their drinking water.
Fluoride levels of 0-14 ppm were Investigated. Dental mottling was the
parameter of Interest. Fluoride levels of 2-10 ppm produced a linear dose
response curve (Increasing mottling with Increasing dose). Fluoride levels of
0.1-1.0 ppm produced no observable effect. An assumption of 20 kg bw for
children was used as the children studied were 12-14 years old.
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Uncertainty Factors (UFs):
Uncertainty factors were not deemed necessary since the NOAEL Is that of
the critical toxic effect (I.e., dental fluorosls) In a sensitive population
of humans (I.e., children for a length of exposure that encompasses both the
critical toxic effect and the sensitive population.
Modifying Factors (MFs):
None.
Additional Comments:
A range of RfD of 0.05-0.2 mg/kg/day Is given. The upper limit Is based
on the Surgeon General's statement that no adverse medical effects occur at
excess fluoride exposures of 4 ppm of drinking water or less (I.e., 4 mg/L x 1
L/day / 20 kg = 0.2 mg/kg/day).
Confidence, 1n the RfD:
Study: Medium
Data Base: High
RfD: High
Confidence 1n the study Is medium because the exposures represent excess
fluoride Intake and not total doses. Confidence In the data base Is high
because of the large number of _studies conducted 1n children all support the
chosen NOAEL. Confidence In the RfD Is high because little uncertainty
remains In the toxlclty data base.
Documentation of RfD and Review:
ECAO-C1nc1nnat1 Internal Review, July 1985.
U.S. EPA. 1985. FlouMne: Review and Evaluation of ADI. Contract No.
68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH.
Agency RfD Review:
First Review: 08/05/85
Second Review:
Verification Date: 08/05/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0420P
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01/11/86
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REFERENCE DOSES (RfOs) FOR ORAL EXPOSURE
Chemical: Formic Add
CarclnogenlcHy: None.
Systemic Toxldty: See below.
CAS #: 64-18-6
Endpolnt
Experimental Doses
UF
MF
RfD (ADI
Malorny (1969)
Rat oral chronic
study
200 mg/kg/day
(NOAEL)
0.2* drinking water
100
2 mg/kg/day
or
140 mg/day for a
70 kg man
Solmann (1921)
Rat oral subchronlc
bloassay
Body weight
0.5% drinking water
(LOAEL)
Endpolnt and Experimental Doses:
Malorny. G. 1969. Acute and chronic toxldty of formic add and formate. Z.
Ernachrungswlss. 9: 332-339.
Formic add Is a normal component of human tissues and foods and is
Important In Intermediary metabolism. Ingested formic add 1s rapidly
metabolized and excreted (Malorny, 1969). The best Information on which to
base an ADI Is the study of Malorny (1969) In which no adverse effects were
observed 1n several generations (5) of rats that consumed 150-200 mg/kg/day
(author's estimated range) of formic add. None of the other Information
available suggests that toxic effects would occur at lower levels. Solmann
(1921) reported a series of studies 1n which rats received 0.25X formic acid
In drinking water (mean dosage of 160 mg/kg) for 15 week without showing any
effects on growth or food and water consumption. Solmann (1921) also reported
a study 1n which men consumed sodium formate 1n doses of 10 g/day (150
mg/kg/day) for some time without any harmful effects. On the other hand,
formate doses of 2-3 g several times dally has been reported to cause nausea
and albumlnurla In men (von Oettlngen, 1969).
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Endpolnt and Experimental Doses (cont.):
The TLV for formic add vapor In the atmosphere Is 5 ppm (ACGIH, 1984),
the same as the OSHA standard (CFR, 1981). Formic add 1s "generally recog-
nized as safe" as a synthetic flavoring substance and an Indirect food sub-
stance (Guest et al., 1982).
Uncertainty Factors (UFs):
Based on the Information available, the NOEL of 200 mg/kg/day (Malorny,
1969) can be divided by an uncertainty factor of 100 (10. for Intraspedes
extrapolation and 10 for sensitive population) to derive an ADI of 2 mg/kg/day
for protection against adverse human health effects.
Modifying Factors (MFs):
None.
Additional Comments:
None.
Confidence In the RfD:
Study: Medium
Data Base: Medium
RfD: Medium
The study Is given a medium confidence because of the extensive length of
testing (I.e., 5 generations), several parameters were measured. The data
base 1s rated medium because several studies are available that support the
choice of NOAEL. A medium rating 1n the'RfD follows.
Documentation of RfD and Review:
ECAO-C1nc1nnat1 Internal Review, August 1985.
U.S. EPA. 1985. Formic Add: Review and Evaluation of ADI. Contract No.
68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH.
0420P
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Agency RfD Review:
First Review: 08/19/85
Second Review:
Verification Date: 08/19/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0420P
-3-
01/11/86
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Hydrogen Cyanide
Carctnogeniclty: None. -
Systemic Toxlclty: See below.
CAS #: 74-90-8
Endpolnt
Experimental Doses
UF
MF
5
RfD (ADI)
Howard and Hanzal
(1955)
Rat oral chronic
study
Phtlbrick et al.
(1979)
Rat subchronlc to
chronic oral bio-
assay
Decreased body and
thyroid weights and
rayelln degeneration
10,8 rag/kg/day CN
(NOAEL)
100
30 rag/kg/day
(LOAEL)
CN
0,02 mg/kg/day
or
2 mg/day for a
70 kg man
Conversion
27/26; thus
HCN
Factor: Molecular
10.8 mg/kg/day CN x
weight of HCN/CN is
27/26 =11.2 rag/kg/day
Endpolnt and Experimental Doses:
Howard, J.H. and R.F Hanzal. 1955, Chronic toxicity to rats of food treated
with hydrogen cyanide. Agric. Food Chen. 3: 325-329.
Since hydrogen is present in very high levels physiologically an ADI of
1.5 mg/day is recoonended based on cyanide content.
In this 2-year dietary study, rats (10/sex/group) were administered food
fumigated with HCN. The average daily concentrations were 73 and 183 mg CN/kg
diet. Froa ttie data reported on food consumption and body weight, daily esti-
mated doses were 4.3 mg and 10.8 mg CN/kg bw. The average food CN concentra-
tions were estimated based on the author's data for concentration at the
Preparation Date: 01/06/86
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Endpolnt and Experimental Doses (cont.):
beginning and end of each food preparation period and by assuming a first
order rate of loss for the Intervening period. There were no treatment
related effects on growth rate, no gross signs of toxldty, and no hlstopatho-
loglcal lesions.
Studies by PhUbrlck et al. (1979) showed decreased weight gain and
thyroxln levels and myelln degeneration In rats at 30 mg/kg/day CN. Other
chronic studies either gave higher effect levels or used subcutaneous route
(Crampton et al., 1979; Lessen, 1971; Herthlng et al., I960). Human data do
not provide adequate Information from which to derive an ADI because effective
dose levels of chronically Ingested CN are not documented. Therefore, the
study of Howard and Hanzel (1955) provides the highest NOAEL 10.8 mg/kg/day
for CN and 1s chosen for the derivation of an ADI for CN of 1.5 mg/day or 0.02
mg/kg/day.
Cyanide Is metabolized extensively In the liver. Indicating that the only
relevant route of administration for quantitative risk assessment In the deri-
vation of "an oral -ADI 1s the oral route of administration.
Uncertainty Factors (UFs):
According to the U.S. EPA (1985) an uncertainty factor of 100 1s used to
derive the ADI (10 for species extrapolation, 10 for sensitive population).
Modifying Factors (MFs):
A modifying factor of 5 1s used for apparent tolerance of cyanide when It
1s Ingested with food than when administered by gavage or drinking water.
Additional Comments:
Decreased protein efficiency ratio was produced by dietary cyanide treat-
ment of rats during gestation, lactation and postweanlng growth phase In the
Tewe and Haner (1981a) experiment: the dose level of cyanide (10.6 mg/kg/day)
producing that effect 1s slightly lower than the currently accepted NOAEL of
10.8 mg/kg/day (U.S. EPA, 1985). Furthermore, Tewe and Maner (1981b) tested
sows. Possible effects observed at about 9.45 mg/kg/day were proliferation of
glomerular cells of the kidneys and reduced activity of the thyroid glands In
the gilts. However, the number of animals 1n this experiment was very small.
A Japanese study (Amo, 1973) Indicated that 0.05 mg/kg/day of cyanide obtained
from drinking water decreased the fertility rate and survival rate 1n the Fl
generation and produced 100% mortality In the F2 generation In mice. However,
these data are not consistent with the body of available literature. Thus,
0420P -2- 01/11/86
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Additional Comments (cont.):
until additional chronic studies are available, an ADI of 2 mg/day for a 70 kg
man 1s recommended. Additional chronic/reproductive studies are needed to
support a higher level of confidence In the RfD.
Confidence 1n the RfD:
Study: Medium
Data Base: Medium
RfD: Medium
The confidence In the study 1s medium because adequate records of food
consumption and body weight were maintained and animals of both sexes were
tested at two doses for 2 years. The data base Is rated medium because a
small but sufficient number of studies support the chosen study. The confi-
dence In the RfD follows. Additional chronic/reproductive studies are needed
to support a higher level of confidence 1n the RfD.
Documentation of RfD and Review:
U.S. EPA. 1984. Health Effects Assessment for Cyanides. Environmental Cri-
teria and Assessment Office, Cincinnati, OH. ECAO-CIN-H01.1.
U.S. EPA. 1985. Drinking Water Criteria Document for Cyanides. Office of
Drinking Water, Washington, DC.
The Drinking Water Criteria document and the Health Effects Assessment
document have undergone an extensive Agency and limited external review.
Agency RfD Review:
First Review: 08/05/85
Second Review:
Verification Date: 08/05/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0420P
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01/11/86
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Hydrogen Sulflde CAS #: 7783-06-4
Cardnogenldty: None.
Systemic ToxIcHy: See below.
Endpolnt Experimental Doses UF MF RfD (ADI)
Watterau et al. 3.1 mg/kg/day (NOAEL) 1000 - 0.003 mg/kg/day
(1964-1965) or
0.2 mg/kg/day for
P1g oral toxicHy a 70 kg man
study (subchronlc)
GI disturbance 15 mg/kg/day (LOAEL)
Dose Conversion: 0.200 kg of diet/day x 1210 mg H2S/kg
of diet / 78 kg bw = 3.1 mg/kg bw/day
Endpolnt and Experimental Doses:
Watterau, H., H. Ockert and U.G. Knape. 1964-1965. In: ToxIcHy of Hydrogen
Sulflde 1n Animal Feeding. Survey of the literature. (Westermann et al.,
1975. Landwlrtsch. Forsch. 28: 70-80)
Data regarding chronlc/subchronlc toxldty of H2S was limited and H2S Is
not scheduled for cardnogenlcHy testing by the NTP (1985). The oral toxl-
clty data (Watterau et al., 1964-1965) may be used to calculate an ADI.
Although lacking 1n some detail, Watterau et al. (1964-1965) suggest that
adult pigs showed digestive disorders when their diet was replaced by a high
percentage of dried greens containing H2S at an approximate Intake of 15
mg/kg/day. This effect was not reproduced 1n a second experiment. This dose
may be .considered a LOAEL.
Watterau et al. (1964-1965) also tested pigs for 105 days at three lower
doses. An Intermediate dose of approximately 3.1 mg/kg/day (determined from
Information given 1n the critical study) was associated with no changes In
body weight gain when compared to control.
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Uncertainty Factors (UFs):
The uncertainty facotr of 1000 represents 10 for Interspedes extrapola-
tion, 10 for sensitive population and 10 for subchronlc exposure. An ADI of
0.003 mg/kg/day may be recommended for adequate protection against adverse
human health effects.
Modifying Factors (MFs):
None.
Additional Comments:
Based on ep1dem1olog1cal data (Poda, 1966) the ACGIH (1980) has recom-
mended a TLV-TWA of 10 ppm (13.9 mg/cu. m) for hydrogen sulflde. However,
citing evidence of eye Injury, headaches, nausea and Insomnia after exposure
to H2S at low concentrations for several hours, NIOSH (1977) adopted a celling
occupational exposure limit of 10 ppm with a I0-m1nute maximum exposure to
this concentration. More rigorous ep1dem1olog1cal evidence, however, Is
limited. Until further chronic/reproductive data available, a low confidence
In the RfD 1s recommended.
Confidence 1n the RfD:
Study: Low
Data Base: Low
RfD: Low
The confidence In the study 1s rated low because the number of animals/
dose group was unspecified and the study was designed to test for only minimal
toxic responses. The supporting oral toxldty data base Is rated low because
1t does not exist. Low confidence In the RfD follows.
Documentation of RfD and Review:
ECAO-C1nc1nnat1 Interanl Review, August 1985.
U.S. EPA. 1985. Hydrogen Sulflde: Review and Evaluation of ADI. Contract
No. 68-03-3228, Environmental Criteria and Assessment Office, Cincinnati, OH.
Agency RfD Review:
First Review: 08/19/85
Second Review:
Verification Date: 08/19/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0420P
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Llnuron CAS #: 330-55-2
CardnogenlcHy:
Systemic Toxlclty: See below.
Endpolnt Experimental Doses UF MF RfD (ADI)
Information to be provided by the Office of Pesticide Programs
Endpolnt and Experimental Doses:
Preparation Date:
°420P -1- 01/11/86
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Uncertainty Factors (UFs):
Modifying Factors (MFs)r
Additional Comments:
Confidence In the RfD:
Study: Data Base: RfD:
Documentation of RfD and Review:
Agency flfD Review: U.S. EPA Contact:
First Review: Primary:
Second Review: FTS/684-75 or 513/569-75
Verification Date: Secondary:
FTS/684-75 or 513/569-75
0420P -2- 01/11/86
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Malathlon CAS #: 121-75-7
Cardnogenlclty: None.
Systemic Toxlclty: See below.
oťaaoeŤ6Ťťťť*Ť6ť*ťi>ŤŤŤoťo"'>e*0ťBS*eoo>B8S'oe*'''"0*oe"ce"0"0''**e*'*''*Se""S''B**et**
Endpolnt Experimental Doses UF MF RfD (ADI)
*.ftťŤŤťŤeť*ťŤťť6"*"ťŤŤťŤťťŤtooIť"*eeoc'l80000C*eeeo''*"eOS**<'*ee****"*"****e****
Rider et al. (1959); 0.23 mg/kg/day 10 - 0.02 mg/kg/day
Moeller and Rider (NOEL);
(1962) -
Human subchronlc 0.34 mg/kg/day
oral bloassay (LOEL)
Chollnesterase
Inhibition
Endpolnt and Experimental Doses:
Rider, J.A., H.C. Hoeller, J. Swader and R.G. Devereaux. 1959. A study of
the antlchollnesterase properties of EPN and malathlon 1n human volunteers.
CUn. Res. 1: 81.
Moeller, H.C. and S.A. Rider. 1962. Plasma and red blood cell Chollnesterase
activity as Indications of the threshold of Incipient toxldty of ethyl-p-
nltrophenylthlonobenzenephosphonate (EPN) and malathlon In human being.
Toxlcol. Appl. Pharmacol. 4: 123-130.
Malathlon was administered by gelatin capsules to groups of five healthy
male volunteers ranging 1n age from 23-63 years at doses of either 8 mg/day
for 32 days, 16 mg/day for 47 days or 24 mg/day for 56 days. Chollnesterase
activity, was determined twice weekly before, during and after administration
of the chemical. The Intermediate dose was a NOEL. The high-dose was
associated with a depression In plasma and RCB Chollnesterase activity with no
clinically manifested side effects.
The choice of human study for derivation of the ADI 1s well supported by
animal studies. Although the clinical study appears to have been well
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Endpolnt and Experimental Doses (cont.):
conducted with five male volunteers In each of three dose groups, the duration
of the study Is rather short (32-56 days), Investigators only looked for one
type of effect and body weights were not given.
Uncertainty Factors (UFs):
The 10-fo.ld factor accounts for the expected Interhuman variability to the
toxldty of this chemical In lieu of specific data. Note that the usual
factor of 10S to estimate a chronic effect level from a .subchronlc effect
level 1s not considered necessary here because the critical toxic effect
(I.e., chollnesterase Inhibition) 1s thought to be Independent of exposure
duration.
Modifying Factors (HFs):
None.
Additional Comments:
None.
Confidence 1n the RfD:
Study: Medium Data Base: High RfD: Medium
Confidence 1n the chosen study Is rated medium because only one sex was
tested and the duration was rather short. Confidence 1n the supporting data
base Is rated high because several animal studies support the chosen effect
level. Confidence 1n the RfD Is rated medium to high.
Documentation of RfD and Review:
The ADI 1n this 1984 Health and Environmental Effects Profile has received a
limited Agency review with the help of two external scientists.
U.S. EPA. 1984. Health and Environmental Effects Profile for Malathlon.
Environmental Criteria and Assessment Office, Cincinnati, OH. ECAO-CIN-P101.
0421P -2- 01/11/86
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Agency RfD Review:
First Review: 07/22/85
Second Review:
Verification Date: 07/22/85
U.S. EPA Contact:
Primary: M.L. Dourson
FTS/684-7544 or 513/569-7544
Secondary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: MCPA
Carclnogenlclty: None.
Systemic Toxlcity: See below.
CAS #: 94-74-6
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
Reuzel et al. (1980) 1.0 mg/kg/day (NOEL)
1000
0.001 mg/kg/day
Dog subchc.onlc oral
bloassay
Kidney and liver
toxldty
3.0 mg/kg/day
(LOAEL)
Endpolnt and Experimental Doses:
Reuzel et al. 1980. CBI (Confidential Business Information)
Two 13-week studies were conducted In dogs by Reuzel et al. (1980). Col-
lectively five doses were given to groups of four dogs/sex. A clinical syn-
drome which Included Icterus, diarrhea, cornea! ulcers, severe dermatitis,
dehydration and severe weight loss led to the death or humane kill of 7/8
high-dose dogs. Elevated blood creatlnlne and urea nitrogen were observed In
a dose-related fashion at the three highest doses, suggesting Impaired kidney
function. (The lowest of these doses . was 3.0 mg/kg/day.) The two lowest
doses showed, no effects outside normal limits. (The highest of these doses
was 1.0 mg/kg/day.)
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Uncertainty Factors (UFs
The uncertainty factor of 1000 reflects
10 for both Intraspecies and
Interspecles variability to the toxlcity of this chemical In Heu of specific
data, and 10 for extrapolation of a subchronlc effect level to Us chronic
equivalent.
Modifying Factors (MFs):
None.
Additional Comments:
None.
Confidence 1n the RfD:
Study: Medium
Data Base: Medium
RfD: Medium
Confidence in the chosen study Is medium because the study appears to be
well conducted with four beagle dogs/sex in each of five dose groups. Con-
fidence In the data base is medium because the CBI study for the derivation of
the ADI is moderately well supported by studies 1n the open literature.
Medium confidence In the RfD follows.
Documentation of RfD and Review:
The ADI In the 1984 Health and Environmental Effects Profile has received a
limited Agency review with the help of two external scientists.
U.S. EPA. 1984. Health and Environmental Effects Profile for MCPA and MCPB.
Environmental Criteria and Assessment Office, Cincinnati, OH. ECAO-CIN-P082AP.
Agency RfD Review:
First Review: 07/22/85
Second Review:
Verification Date: 07/22/85
U.S. EPA Contact:
Primary: M.L. Dourson
FTS/684-7544 or 513/569-7544
Secondary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Mercury Fulminate
Cardnogenlclty: None.
Systemic Toxlclty: See below.
CAS #: 628-86-4
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
FHzhugh et al.
(1950)
Rat oral chronic
study
Renal and kidney
damage
NOEL: A well defined 1000
level was not avail-
able
0.003 mg/kg/day
or
0.2 mg/day for a
70 kg man
40 ppm Hg or 2 mg
Hg/kg/day (LOAEL)
converted to 2.83
mg/kg/day mercury
fulminate
Conversion Factors: 5% food consumptlon/g body weight;
molecular weight of mercury fulminate (C2HgN202) to
mercury (Hg) 1s 285/201; thus, 40 mg/kg of diet (I.e.,
40 ppm) x 0.05 kg of diet/kg bw/day x 285/201 = 2.83
mg/kg bw/day
Endpolnt and Experimental Doses:
FHzhugh, O.G., A.A. Nelson,
ties of mercuric phenyl and
433-441.
E.P. Lang and F.M. Kunze. 1950.
mercuric salts. Arch. Ind. Hyg.
Chronic toxld-
Occup. Med. 2:
Tht-s-ls the only chronic Ingestlon study designed to evaluate the. toxldty
of Inorganic mercury salts. In this study, rats of both sexes (20-24/group)
were given 0.5, 2.5, 10, 40 or 160 ppm mercury as mercury acetate for up to 2
years. Assuming food consumption was equal to 554 bw/day, the dally Intake of
Hg was 0.025, 0.125, 0.5, 2.0 or 8.0 mg/kg/day, respectively. Detailed micro-
scopic evaluation of various tissues Indicated that only the kidney was
affected to any degree with lesions 1n the proximal convoluted tubules and
cortex. Treatment related changes did not appear to be present at doses
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Endpolnt and Experimental Doses (cont.):
greater than 40 ppm. However, the description of effects occurring at the
lower doses was not well characterized. Therefore, 40 ppm (2.0 mg/kg) was
Identified as a LOAEL In the study.
There 1s no Information concerning the toxldty of mercury fulminate.
Assuming that the toxldty of this compound 1s due primarily to Us mercury
component, It Is appropriate to derive an ADI for mercury fulminate based on
analogy to mercury. This assumption 1s supported by the fact that cyanates do
not exhibit 'the high toxldty of cyanides and that mercury compounds are con-
siderably more toxic. Therefore, using the LOAEL 2 mg/kg/day provided by the
FHzhugh et al. (1950) study, an ADI of 0.003 mg/kg/day or 0.2 mg/day Is
derived.
Uncertainty Factors (UFs):
An uncertainty factor of 1000 was used to account for )nterspedes extrap-
olation, differences in sensitivity among humans and for the conversion of a
LOAEL to a NOAEL.
Modifying Factors (HFs):
None.
Additional Comments:
No data are available on the toxlclty of mercury fulminate.
Confidence 1n the RfD:
Study: Medium Data Base: Low RfD: Low
Confidence In the study Is rated medium as a medium amount of animals/sex
was used- In each of five dose groups and several parameters were measured.
The NOAEL, however, was not well defined. Confidence In the supporting data
base and RfD are both low; since the toxlclty of mercury fulminate has not
been tested, this RfD 1s based on analogy to Inorganic mercury.
-2- 01/11/86
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Documentation of RfD and Review:
ECAO-C1nc1nnat1 Internal Review, August 1985.
U.S. EPA. 1985. Mercury Fulminate: Review and Evaluation of ADI. Contract
No. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH,
Agency RfD Review:
First Review:' 08/19/85
Second Review:
Verification Date: 08/19/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 .or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0421P
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Mercury (Inorganic)
Cardnogenldty: None.
Systemic Toxlclty: See below.
CAS #: 7439-97-6
Endpolnt
Experimental Doses
UF
MF
RfD (ADI1
FHzhugh et al.
(1950)
Rat oral chronic
study
Renal and kidney
damage
NOAEL: None
1000
0.002 mg/kg/day
or
0.1 mg/day for a
70 kg man
40 ppm
verted
bw/day
Of diet con
to 2 mg/kg
(LOAEL)
Conversion Factor: Food consumption 5/4 body weight;
thus, 40 mg/kg of diet (I.e., 40 ppm) x 0.05 kg of
diet/kg bw/day = 2 mg/kg/day
Endpolnt and Experimental Doses:
FHzhugh, O.G., A.A. Nelson, E.P. Laug and P.M.
1c1t1es of mercuric phenyl and mercuric salts.
2: 433-441.
Kunze. 1950. Chronic'tox-
Arch. Ind. Hyg. Occup. Med.
This Is the only chronic Ingestlon study designed to evaluate the toxldty
of Inorganic mercury salts. In this study, rats of both sexes (20-24/ group)
were given 0.5, 2.5, 10, 40 or 160 ppm mercury as mercury acetate for up to 2
years. Assuming food consumption was equal to 5% bw/day, the dally Intake was
equal to- 0.025, 0.125, 0.5, 2.0 and 8.0 mg/kg bw, respectively. Detailed
microscopic evaluation of various tissues Indicated that only the kidney was
affected to any degree with lesions In the promlxal convoluted tubules and
cortex. Treatment-related changes did not appear to be present at doses less
than 40 ppm.
Also, 1t was noted
present to some degree '
that the damage occurring at these lower doses was
n older control animals. The 40 ppm feeding level was
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Endpolnt and Experimental Doses (cont.):
Identified as a LOAEL In this study. Although It appears that the 10 ppm
feeding level, as well as the two lower doses, may have been a NOAEL the
descriptive manner 1n which the data are presented makes 1t difficult to ade-
quately evaluate the hlstopathologlcal data for these doses. As a result of
this uncertainty and since the use of the 40 ppm LOAEL will result in a some-
what more protective estimate than a 10 ppm NOAEL, the 40 ppm LOAEL Is chosen
as the basis for an ADI calculation.
Short-term and subchronlc studies were conducted by Barlety et al. (1971),
Druet et al. (1978), Weening et al. (1978) and Makker and Alkawa (1979). A
NOAEL of 50 ug/kg for antibody formation could be derived from the study of
Druet et al. (1978). However, this study Is not chosen because the route of
exposure was subcutaneous Injection, the Immune response occurred only 1n a
genetically susceptible strain of rats and the duration of the study was only
8-12 weeks.
Uncertainty Factors (UFs):
Based upon these factors the Fltzhugh et al. (1950) study was considered
most appropriate for the development of an ADI. This study established a
LOAEL of 2 mg/kg bw/day. Applying scaling factors of 100 to account for
extrapolation from animals to humans and differences In sensitivity among
human population and an additional 10 for conversion of a LOAEL to a NOAEL an
ADI or 0.002 mg/kg/day or 0.1 mg/day for a 70 kg human was derived.
Modifying Factors (MFs):
None.
Additional Comments:
The data base for this chemical Is characterized by only one chronic
1ngest1on study with a small number of animals surviving past 18 months (20-24
animals/group). Short-term and subchronlc studies by 1.p. or s.c. exposures
and supporting ep1dem1olog1cal data are not well characterized.
Confidence In the RfD:
Study: Medium Data Base: Medium RfD: Medium
Confidence 1n the study 1s rated medium as a medium amount of animals/sex
was used in each of five dose groups and several parameters were measured.
0421P -2- 01/11/86
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Confidence In the RfD (cont.):
The NOAEL, however, was not well defined. Confidence In the data base U
medium because a small number of studies lends some support. Medium confi-
dence 1n the RfD follows.
Documentation of RfD and Review:
Limited peer review and Agency-wide Internal review, 1984.
U.S. EPA. 1984. Health Effects Assessment Document for Mercury. Environ-
mental Criteria and Assessment Office, Cincinnati, OH.
Agency RfD Review:
First Review: 08/05/85
Second Review:
Verification Date: 08/05/85
U.S. EPA Contact:
Primary: C.T. DeRosa'
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0421P
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Hethylene Chloride
Carc1nogen1c1ty: CAG, U.S. EPA - Category B2.
Systemic ToxIcHy: See below.
CAS #: 75-09-2
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
National Coffee
Association (1982)
2-year rat drinking
water bloassay
Liver toxldty
NOEL: 5.85 and 6.47
mg/kg/day for males
and females, respec-
tively
LOAEL: 52.58 and
58.32 mg/kg/day for
males and females,
respectively
100
0.06 mg/kg/day
Endpolnt and Experimental Doses:
National Coffee Association. 1982. 24-Month chronic toxldty and oncogenl-
dty study of methylene chloride 1n rats. Final Report. Prepared by Hazelton
Laboratories America, Inc., Vienna, VA, August 11.
The chosen study appears to have been very well conducted with 85 rats/
sex at each of four dose groups. A high-dose recovery group of 25 rats/sex,
as well as two control groups of 85 and 50 rats/sex, was also tested. Many
effects were monitored.
The supporting data base, In addition to this study, 1s limited with an
Inhalation NOEL of 87 mg/cu. m (Haun et al., 1972). [The equivalent oral dose
Is about 28 mg/kg bw/day (I.e., 87 mg/cu. m x 0.5 x 0.223 cu. m/day / 0.35 kg;
these exposure values are for rats).]
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Uncertainty Factors (UFs):
The 100-fold factor accounts for both the expected 1ntra- and Inter-
species variability to the toxldty of this chemical In lieu of specific data.
Modifying Factors (HFs):
None.
Additional Comments:
None.
Confidence In the RfD:
Study: High
Data Base: Medium
RfD: Medium
The study 1s given a high confidence rating because a large number of ani-
mals was tested of both sexes In four dose groups, with a large number of con-
trols. Many effects were monitored and a good dose-severity was obtained.
The data base Is rated medium to low because only a few studies support the
chosen NOAEL. Medium confidence In the RfD follows.
Documentation of RfD and Review.
The ADI has only been reviewed by the U.S. EPA's ADI Work Group during the
summer of 1985.
U.S. EPA. 1985. Drinking Water Criteria Document for Methylene Chloride.
Office of Drinking Hater, Washington, DC. (Draft)
Agency RfD Review:
First Review: 06/24/85
Second Review: 07/08/85
Verification Date: 07/08/85
U.S. EPA Contact:
Primary: K. Khanna
FTS/382-7588 or 202/382-7588
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Methyl Ethyl Ketone
Cardnogenldty: None.
Systemic Toxlclty: See below.
CAS #: 78-93-3
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
LaBelle and Brleger
(1955)
Rat 1nhalat1on/sub-
chronlc study
Schwetz et al.
(1974)
Teratology bloassay
Fetotoxldty tera-
togenlclty
235 ppm (693 mg/
cu. m) converted to
46 mg/kg/day (NOAEL)
130.5 mg/kg/day
(estimated LOAEL)
1000
0.05 mg/kg/day
or
3 mg/day for a
70 kg man
Conversion Factors: 7 hour/24 hour, 5 days/7 days,
0.223 cu. m/day/0.35 kg (rat breathing rate/rat body
weight) 0.5 absorption rate; thus, 693 mg/cu. m x 7
hour/24 hour x 5 days/7 days x 0.223 cu. m/day / 0.35
kg x 0.5 = 46 mg/kg/day
Endpolnt and Experimental Doses:
LaBelle, W. and H. Brleger. 1955. The vapor toxlclty of a composite solvent
and Its principal components. Am. Med. Assoc. Arch. Ind. Health. 12: 623-627.
Adequate chronic toxldty testing has not been performed with methyl ethyl
ketone. Although several more recent subchronlc studies have been conducted
(Freddl et al., 1982; Cavender et al., 1983; Takeuchl et al., 1983). only the
NOAEL of the LaBelle and Brleger (1955) provides the lowest and most protec-
tive dose for deriving an ADI. In this study, 25 rats were exposed to 235 ppm
of methyl ethyl ketone for 7 hour/day, 5 days/week for 12 weeks. No effects
were observed, but only a few parameters were measured. Methyl ethyl ketone
has also been tested for teratogenldty (Schwetz et al., 1974; Deacon et al..
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Endpoint and Experimental Doses (cont.):
1981) and the observed LOAELs for fetotoxIcHy are higher than the NOAELs of
LaBelle and Brieger (1955). The animal NOAEL of 693 mg/cu. m was converted to
a human NOAEL of 46 mg/kg/day to derive an ADI of 0.05 mg/kg/day.
The route extrapolation raises a level of uncertainty due to- differences
In pharmacoklnetlc parameters, notably, absorption and elimination.
Uncertainty Factors (UFs):
The uncertainty factor of 1000 reflects 10 for both Intraspecles and
Interspedes variability to the toxlclty of this chemical In lieu of specific
data, and 10 for extrapolation of a subchronlc effect level to Us chronic
equivalent.
Modifying Factors (MFs):
None.
Additional Comments:
No oral chronic studies are available at this time. Several subchronlc
Inhalation studies provided adequate data 1n support of a RfD with a medium
level of confidence.
Confidence 1n the RfD:
Study: Medium Data Base: Medium RfD: Medium
The study 1s given medium to low confidence because only 25 rats were
exposed to only one dose, and the sex, strain and amount of control animals
were unspecified. The data base Is given a medium rating because four differ-
ent studies lend some support to the chosen NOAEL. Medium to low confidence
In the -RfO follows.
Documentation of RfD and Review:
ECAO-C1ndnnat1 Internal Review, May 1985.
U.S. EPA. 1985. Methyl Ethyl Ketone: Review and Evaluation of ADI. Contract
NO. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH.
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Agency RfD Review:
First Review: 07/08/85
Second Review:
Verification Date: 07/08/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0421P
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Methyl Ethyl Ketone Peroxides CAS #: 1338-23-4
Carclnogenlclty: None.
Systemic Toxlclty: See below.
Endpolnt Experimental Doses UF MF RfD (ADI)
ACGIH (1984) 1.5 mg/cu. m (TLV) 10 - 0.008 mg/kg/day
converted to 0.077 or
mg/kg/day 0.5 nig/day for a
70 kg man
Conversion Factors:
x 5 days/7 days
x 10 cu. m/day (human breathing rate In 8 work hours)
0.5% absorption / 70 kg; thus, 1.5 mg/cu. m x 5 days/7
days x 10 cu. m/day x 0.5 / 70 kg = 0.077 mg/kg/day
Endpolnt and Experimental Doses:
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1984.
Methyl Ethyl Ketone Peroxides. Documentation of Threshold Limit Values, 4th
ed. Threshold Limit Values for Chemical Substances and Physical Agents In the
Workroom Environment with Intended Changes for 1984-1985. p. 279-280.
The ACGIH (1984) has set a celling limit TLV of 0.2 ppm for methyl ethyl
ketone peroxides, by analogy to hydrogen peroxide. Floyd and Stoklnger (1958)
conducted Inhalation and oral acute testing of this compound establishing Us
LD50 and LC50 In rats and mice. The results of this study Indicated that
methyl ethyl ketone peroxide was more toxic than benzozyl peroxide (TLV=5
mg/cu. .m) and similar In toxlclty to hydrogen peroxide (TLV=1.4 mg/cu. m).
Based on these findings the ACGIH (1984) recommended a TLV for methyl ethyl
ketone peroxide as 1.5 mg/cu. m (0.2 ppm).
As of April 1985, the NTP (1985) has been conducting skin painting tests
and hlstopathology assays on this chemical. The results are not yet available.
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Endpolnt and Experimental Doses (cont.):
Limited carcinogenic and mutagenlc data studies have been conducted, but
results are Inconclusive (Koten and Falk, 1963). Using the TLV of 0.2 ppm
(1.5 mg/cu. m) an ADI of 0.076 mg/kg/day can be derived. This ADI should be
used only until the results of the NTP (1985) testing becomes available, at
which time H should be revised.
Uncertainty Factors (UFs):
The 10-fold factor accounts for the expected Interhuman variability to the
toxldty of this chemical 1n Heu of specific data.
Modifying Factors (MFs):
None.
Additional Comments:
No adequate chronic or subchronlc data are available upon which to base an
ADI. No supporting ep1dem1olog1cal data are available.
Confidence 1n the RfD:
Study: Low Data Base: Low RfD: Low
The confidence in the chosen effect level, supporting data base, and
resulting RfD are all low. TLV-based RfDs are only estimated when sufficient
oral or inhalation toxicity data are not available.
Documentation of RfD and Review:
ECAO-Ctndnnat1 Internal Review, August 1985.
U.S. EPA. 1985. Methyl Ethyl Ketone Peroxide: Review and Evaluation of ADI.
Contract No. 68-03-3228, Environmental Criteria and Assessment Office, Cin-
cinnati. OH.
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Agency RfD Review:
First Review: 08/19/85
Second Review:
Verification Date: 08/19/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0421P
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Nickel Cyanide
Carclnogenlclty: None.
Systemic Toxlclty: See below.
CAS #: 557-19-7
Endpolnt
Experimental Doses
UF
MF
RfD (ADI
Ambrose et al.
(1976)
Rat oral chronic
study
Decreased body
weight
100 ppm of diet 100
(NOAEL) converted to
1.89 mg/kg/day
nickel cyanide
0.02 mg/kg/day
or
1 mg/day for a
70 kg man
1000 ppm of diet
(50 mg/kg bw/day)
nickel (LOAEL)
Conversion Factors: 554 food consumptlon/g body weight;
0.2% assumed difference In nickel absorption 1n water
vs. diet; molecular weight N1(CN)2/N1: x 110.74/58.69;
thus, 100 mg/kg of diet (ppm) x 0.05 mg/kg of diet/kg
bw/day x 0.2 x 110.74/58.69 = 1.89 mg/kg bw/day
Endpolnt and Experimental Doses:
Ambrose, A.M., P.S. Larson, J.R. Borselleca and G.R. Hennlgar, Jr. 1976.
Long-term toxlcologlc assessment of nickel In rats and dogs. J. Food Scl.
Techno!. 13: 181-187.
Nickel cyanide 1s 47% cyanide and 53X nickel. Therefore, 1f nickel
cyanide were to completely dissociate 1n water or dilute adds, approximately
equal amounts would be released on a weight basis.
Based on recommended ADI for nickel (0.7 mg/day, U.S. EPA, 1985), the
toxlclty of nickel Is approximately 2 times greater than the currently
reported toxlclty of Cyanide (ADI of 1.5 mg/day, U.S. EPA, 1985). It 1s
apparent, therefore that an ADI for nickel cyanide based on the toxlclty of
cyanide might not be protective for adverse effects caused by nickel.
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Endpolnt and Experimental Doses (cont.):
Ambrose et al., (1976) reported the results of a 2-year study 1n groups of
25 rats/sex given 0, 100, 1000 or 2500 ppm nickel (estimated as 0, 5, 50 and
125 mg N1/kg bw) 1n the diet. Consistently, body weights In both high dose
male and female rats were significantly decreased compared with controls.
Groups of females on the 1000 or 2500 ppm-nickel diets had significantly
higher heart-to-body weight ratios and lower 11ver-to-bbdy weight ratios than
controls. No significant effects were reported at 100 ppm nickel (5 mg/kg
bw). The dose of 1000 ppm (50 mg N1/kg bw) represents a LOAEL from this
study, while the 100 ppm (5 mg N1/kg bw) dose is a NOAEL. The fact that
nickel was administered In the diet rather than 1n water caused some problem.
Nickel 1n the diet 1s absorbed at a different rate than N1 1n water; there-
fore, Foulkes (1984) recommeded an absorption factor of 0.2 to be applied to
the dietary data to derive an ADI for nickel 1n water.
Uncertainty Factors (UFs):
The 100-fold factor accounts for both Intra- and Inter'specles variability
to the toxlclty of the chemical 1n Heu of specific data.
Modifying Factors (MFs):
None.
Additional Comments:
By applying an uncertainty factor of 100 (10 for Intraspedes extrapola-
tion and 10 for sensitive population) and an absorption factor of 0.2 to the
NOAEL of 5 mg/NI/kg bw an ADI of 0.7 mg/day for nickel was derived. Because
nickel cyanide Is not soluble In water and 1s slightly soluble 1n dilute
adds, 1ngest1on of nickel cyanide would expose an Individual to nickel
cyanide as well as small amounts of cyanide and nickel. Based on toxldty
data an ADI of 6 mg/day for nickel cyanide (ADI CN 1.5/0.47CN x 2 moles CN)
may not provide adequate protection when compared to an ADI of 1 mg/day for
nickel cyanide (ADI N1 0.7/0.53 N1). Therefore, an ADI of 1 mg/day for nickel
cyanide 1s recommended.
0421P -2- 01/11/86
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Confidence In the RfD:
Study: Medium
Data Base: Low
RfD: Low
Medium confidence In the study 1s chosen because three doses were admin-
istered to a moderate number of animals and several parameters were measured.
Dogs were also tested. Low confidence 1s chosen for both the supporting data
base and RfD since nickel cyanide has not been tested for toxlclty and thus,
the RfD 1s by analogy. Until additional chronic/reproductive toxlclty data
are Is available a low confidence In the RfD Is recommended.
Documentation of RfD and Review:
Extensive Agency-wide and Peer review, 1985.
U.S. EPA. 1985. Drinking Water Criteria Document for Nickel. Office of
Drinking Hater, Washington, DC.
Agency RfD Review:
First Review: 08/05/85
Second Review:
Verification Date: 08/05/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Nitric Oxide
Cardnogenldty: None.
Systemic Toxlclty: See below.
CAS #: 10102-43-9
Endpolnt
Walton (1951)
Infant chronic expo-
sure to drinking
water
Methemoglob1nem1a
Experimental Doses
UF
MF
RfD (ADI)
10 ppm of drinking
water or 10 mg/L
(NOEL) converted to
1.0 mg/kg/day
11-20 ppm (LOAEL)
10 0.1 mg/kg/day
or
1 mg/day for a
10 kg child
Conversion Factor
thus, 10 mg/L x 1
: 1 L drinking water/day 10 kg child;
L/day / 10 kg = 1.0 mg/kg/day
Endpolnt and Experimental Doses:
Walton, G. 1951. Survey of literature relating to Infant methemoglob1nem1a
due to nitrate-contaminated water. Am. J. Public Health. 41: 986-996.
This 1s an ep1dem1olog1cal study on the formation of methemogloblnemla In
Infants routinely fed milk prepared from nitrate contaminated water. This
study analyzed all known cases of Infant methemoglob1nem1a occurring In 37
U.S. states Irrespective of date or type of water supply. Nitrate (nitrogen)
content ranged from 10 ppm to over 100 ppm. No Incidences of methemoglobl-
nemla were found to occur in drinking water containing greater than 10 ppm (10
mg/L) nitrate (nitrogen). A NOEL of 10 mg/L was derived from these studies.
NHrlc oxide 1n water generates N02 (nitrite). Methemogloblnemla 1s
formed by the oxidation of hemoglobin to methemoglob1nem1a by nitrite.
Infants are particularly susceptible to the formation of methemoglobln.
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Endpolnt and Experimental Doses (cont.):
Several more recent studies support Walton's (1951) 10 mg/L NOAEL for
Infant methemogloblnemla formation (NAS, 1977; Wlnton, 1971; Calabrese, 1978).
Using the. NOAEL from the Walton study, the ADI for
lated (U.S. EPA, 1985) for a 10 kg child drinking 1 L
1fy1ng factor of 10. An ADI of 0.1 mg/kg/day or 1
derived for nitric oxide.
nitric oxide was calcu-
of water/day and a mod-
mg/day was, therefore,
Uncertainty Factors (UFs):
No uncertainty factor was used In the derivation of the RfD because the
NOEL was of the critical toxic effect (I.e., methemogloblnemla) In the
sensitive human population (I.e., Infants). The length of exposure
encompassed both the critical effect and the sensitive population.
Modifying Factors (MFs):
A modifying factor of 10 was applied because of the direct toxlclty of
nitrite.
Additional Comments:
An RfD of 0.2 mg/kg/day could be calculated using the body weight of 4 kg
and fluid consumption of 0.64 L/day from the Walton (1951) study. The lower
value of 0.1 mg/kg/day Is maintained, however, due to the uncertainties 1n the
changing fluid consumption and body weight as a neonate (4 kg) ages to a
2-year-old child (10 kg), and the varying lengths of weaning time among
families.
Confidence In the RfD:
Study: High
Data Base: High
RfD: High
Confidence In the study, data base and RfD are all considered high because
the NOEL 1s determined 1n the known sensitive human population. The data base
contains several recent supporting ep1dem!olog1cal studies.
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Documentation of RfD and Review:
ECAO-C1nc1nnat1 Internal Review, August 1985.
U.S. EPA. 1985. Nitric Oxide: Review and Evaluation of ADI. Contract No
68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH.
Agency RfD Review:
First Review: 08/19/85
Second Review:
Verification Date: 08/19/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0421P
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01/11/86
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Nitrobenzene
Carclnogenlclty: None.
Systemic ToxIcHy: See below.
CAS #: 98-95-3
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
CUT (1984)
Rat/m1ce subchronlc
Inhalation study
Hematologlc, adrenal,
renal and hepatic
lesions
NOAEL: None 10,000 - 0.0005 mg/kg/day
or
0.03 mg/day for a
70 kg man
25 mg/cu. m (mice)
converted to 4.6
mg/kg/day
LOAEL)
Conversion Factors: 6 hour/24 hour, 5 days/7 days,
0.039 cu. m/day/0.03 kg (mice breathing rate/body
weight) and 0.8 absorption factor; thus, 25 mg/cu. m x
6 hour/24 hour x 5 days/7 days x 0.039 cu. m/day / 0.03
kg x 0.8 = 4.6 mg/kg/day
Endpolnt and Experimental Doses:
CUT (Chemical Industry Institute of Toxicology). 1984.
tlon toxldty study of nitrobenzene in F344 rats and
Research Triangle Park, NC. FYI-OTS-0874-0333.
Ninety day inhala-
B6C3F1 mice. CUT,
The CUT study provides the most appropriate data currently available to
derive an ADI. Ten animals/sex/specles/dose group were administered nitroben-
zene at J of 3 doses In a 90-day Inhalation study. Other than Increased Inci-
dence of hemolytlc anemia In rats at 25 mg/cu. m and vacuollzatlon of adrenal
cortical cells In female mice at 25 mg/cu. m and higher, adverse effects of
nitrobenzene exposure In mice and rats were comparable to unexposed controls
at this dose. Mice and rats exposed to nitrobenzene at 81 mg/cu. m showed
Increased Incidence and severity of liver and kidney lesions.
Environ, Inc. (1984) recommended an ADI of 0.057 mg/kg/day or 4 mg/day
which 1s based on the TLV of 1 ppm, a predicted level to protect workers
Preparation Date: 01/09/86
0421P
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Endpolnt and Experimental Doses (cont.):
against cyanogenlc and hematologlc effects. Absorption coefficients of 0.8
and dermal to Inhalation absorption ratio of 7:18, based on pharmacoklnetlc
data of P1otrowsk1 (1967, 1977) and Salmowa et al. (1963) were employed to
derive the dally exposure level of nitrobenzene.
Data regarding the effects of nitrobenzene 1n humans are limited to
symptoms and observations 1n workers Including headaches, vertigo, methemo-
globlnemla (ACGIH, 1980). The ADI derived from the TLV appears adequate to
protect workers from above adverse effects; however, the effects of occupa-
tional exposure to nitrobenzene on the liver and/or kidneys have not been ade-
quately evaluated. The CUT (1984) study Indicates that the liver and kidney
may be target organs of chronlc/subchronlc nitrobenzene exposure, and the ADI
based on the TLV may not be protective for the toxic effects of nitrobenzene
on the liver and/or kidney. Therefore, until more definitive chronic data are
available, the ADI of 0.0005 mg/kg/day 1s recommended to protect against
adverse health effects of nitrobenzene.
Uncertainty Factors (UFs):
The uncertainty factor of 1000 represents two 10-fold factors for both
Intra- and Interspedes variability to the toxlclty of this chemical In Heu
of specific data, a 10-fold factor for estimating a chronic effect level from
Us subchronlc equivalent and a 10-fold factor for estimating a RfD from a
LOAEL rather than a NOAEL.
Modifying Factors (MFs):
None.
Additional Comments:
Subchronlc animal Inhalation study provided adequate data over the recom-
mended TLV (ACGIH, 1985) to derive an ADI. Further chronic studies are needed
to recommend an ADI at a higher level of confidence.
Confidence In the RfD:
Study: Medium Data Base: Medium RfD: Medium
Medium confidence In the study Is recommended because a limited number of
an1mals/sex/dose was tested and a NOEL for the critical toxic effect (I.e.,
adrenal toxldty) was not determined; however, two species were used and many
0421P -2- 01/11/86
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Confidence 1n the RfD (cont.):
parameters were measured. Medium confidence 1n the data base 1s recommended
because many unpublished studies support the chosen LOAEL. Medium confidence
In the RfD follows.
Documentation of RfD and Review:
ECAO-C1ndnnat1 Internal Review, May 1985.
U.S. EPA. 1985. Health and Environmental Effects Profile for Nitrobenzene.
Environmental Criteria and Assessment Office, Cincinnati, OH. ECAO-CIN-P145.
U.S. EPA. 1985. Nitrobenzene: Review and Evaluation of ADI. Contract No.
68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH.
Agency RfD Review:
First Review: 07/08/85
Second Review:
Verification Date: 07/08/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0421P
-3-
01/11/86
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Nitrogen Dioxide
Cardnogenlclty: None.
Systemic Toxlclty: See below.
CAS #: 10102-44-0
Endpolnt
Walton (1951)
Infant chronic expo-
sure drinking water
Methemoglob1nem1a
Experimental Doses
UF
MF
RfD (ADI
10 ppm of drinking
water or 10 mg/L
(NOEL) converted to
1.0 mg/kg/day
11-20 ppm (LOAEL)
1 mg/kg/day
or
10 mg/day for
10 kg child
Conversion Factor: 1 L water consumed/day 10 kg child;
thus, 10 mg/L x 1 L/day / 10 kg = 1.0 mg/kg/day
Endpolnt and Experimental Doses:
Walton, G. 1951. Survery of literature relating to Infant methemogloblnemla
due to nitrate - contaminated water. Am. J. Public Health. 41: 986-996.
This Is an epldemlologlc study on the formation of methemogloblnemla In
Infants who routinely consumed milk prepared from water containing various
levels of nitrate. The study analyzed all cases of Infant methemogloblnemla
occurlng In 37 U.S. states Irrespective of date of occurrence or type of water
supply. Nitrate (nitrogen) content ranged for 10 ppm to greater than 100 ppm.
No Incidences of methemogloblnemla were found to occur In drinking waters con-
taining -less than 10 ppm (10 mg/L) nitrate (nitrogen). Therefore, a NOEL of
10 ppm (10 mg/L) was derived.
Several more recent epldemlologlcal studies support
threshold for Infant methemogloblnemla (NAS, 1977; Wlnton,
1978).
Walton's (1951)
1971: Calabrese,
Nitrogen dioxide In water dissociates to form nitrates and nitrite.
Nitrate toxldty appears to be due to Its conversion to nitrites which results
Preparation Date: 01/07/86
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Endpolnt and Experimental Doses (cont.):
In the oxidation of hemoglobin to methemoglobln 1n humans. Animals are not a
good model for methemoglobln formation because many species lack nitrate
reducing bacteria. Infants are, however, particularly susceptible due to the
high nitrate reducing bacteria content, their lower enzymatic capacity to
reduce methemoglobln to hemoglobin and finally to the presence of hemoglobin F
which Is more susceptible to oxidation.
An ADI of 1.0 mg/kg/day (U.S. EPA, 1985) for nitrate/nitrogen was derived
based on the NOEL of 10 mg/L (Walton, 1951).
Uncertainty Factors (UFs):
No uncertainty factor was used In the derivation of the RfD because the
NOEL was of the critical toxic effect (I.e., methemogloblnemla) 1n the sensi-
tive human population (I.e., Infants). The length of exposure encompassed
both the critical effect and the sensitive population.
Modifying Factors (MFs):
None.
Additional Comments:
A RfD of 2 mg/kg/day could be calculated using the body weight of 4 kg and
fluid consumption of 0.64 L/day from the Walton (1951) study. The lower value
of 1 mg/kg/day Is maintained, however, due to the uncertainties In the chang-
ing fluid consumption and body weight as a neonate (4 kg) ages to a 2-year-old
child (10 kg), and the varying lengths of weaning time among families.
Confidence 1n the RfD:
Study: High Data Base: High RfD: High
Confidence 1n the study, data base and RfD are all considered high because
the NOEL Is determined In the known sensitive human population. The data base
contains several recent supporting ep1dem1olog1cal studies.
0421P -2- 01/11/86
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Documentation of RfD and Review:
ECAO-Clnc1nnat1 Internal Review, August 1985.
U.S. EPA. 1985. Nitrogen Dioxide: Review and Evaluation of ADI. Contract
No. 68-03-3228. Environmental Criteria and Assessment, Cincinnati, OH.
Agency RfD Review:
First Review: 08/19/85
Second Review:
Verification Date: 08/19/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0421P
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Pentachloronltrobenzene (PCNB)
Carclnogenlclty: None.
Systemic ToxIcHy: See below.
CAS #: 82-68-8
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
Borzelleca and
Larson (1968)
2-year feeding study
In dogs
Liver toxlclty
0.008 mg/kg/day
NOEL: 30 mg/kg of 100
diet converted to
0.75 mg/kg bw/day
LOAEL: 180 mg/kg
of diet
Conversion Factor: x 0.025 kg of diet/kg of bw/day (an
assumed factor); thus, 30 mg/kg of diet x 0.025 kg of
diet/kg bw/day = 0.75 mg/kg/day
Endpolnt and Experimental Doses:
Borzelleca, J.F. and P.S. Larson. 1968. Toxldty study of the effect of add-
ing Terraclor to the diet of Beagle dogs for a period of two years. Unpub-
lished report prepared by the Dept. of Pharmacology, Medical College of
Virginia. Submitted by OUn Corp. as Report No. 2490. EPA Ace. No. 248283,
June 10.
Groups of four male and four female beagle dogs (4.5 months of age) were
given diets containing 0, 5, 30, 180 or 1080 ppm of the test substance for 2
years. "Minimal" cholesteral hepatosls with secondary bile nephrosls was
observed-1n all dogs In the 180 ppm groups (LOAEL). The dose of 30 ppm was
the highest NOEL 1n this study.
Chronic feeding studies need to be done In another species (rats). The
small sample size of Borzelleca and Larson (1968) reduces the statistical
validity of the study. PCNB may act synerglstlcally with oncogenlc HCB.
Preparation Date: 01/09/86
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Uncertainty Factors (UFs):
The uncertainty factor of 100 accounts for both 1ntra- and Interspedes
variability to the toxlclty of this chemical 1n lieu of specific data.
Modifying Factors (MFs):
None.
eeťeťoceťŤťŤoťťŤŤťťťŤťťť°ťťťoot*9eo°°*ool'**eooeo"ct'<>00e*0ee**0******"***''**'**t
Additional Comments:
None.
Confidence 1n the RfD:
Study: Medium Data Base: Low RfD: Medium
The confidence In the chosen study 1s medium because only eight animals/
dose were used; however, four doses were tested, several effects were mon-
itored and a dose-severity was observed. The data base Is rated low because
of the general lack of supporting data. The RfD 1s rated medium to low.
Documentation of RfD and Review:
This ADI has been Internally reviewed by the Office of Pesticide Programs,
U.S. EPA.
Agency RfD Review:
First Review: 05/20/85
Second Review:
Verification Date: 05/20/85
U.S. EPA Contact:
Primary: T. Farber
FTS/557-3710 or 513/557-3710
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0421P
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01/11/86
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Pentachlorophenol CAS #: 87-86-5
Carclnogenldty: None.
Systemic Toxlclty: See below.
Endpolnt Experimental Doses UF MF RfD (ADI)
Schwetz et al. 3 mg/kg/day (NOEL) 100 - 0.03 mg/kg/day
(1978) or
2 mg/day for a
Rat oral chronic 70 kg man
study
Liver and kidney 10 mg/kg/day (LOEL)
pathology
Endpolnt and Experimental Doses:
Schwetz, B.A., J.F. Quast, P.A. Keelev, C.G. Humlston and R.J. Kodba. 1978.
Results of 2-year toxlclty and reproduction studies on pentachlorophenol In
rats. In: Pentachlorophenol: Chemistry, Pharmacology and Environmental
Toxicology, K.R. Rao, Ed. Plenum Press, NY. p. 301.
Only one chronic study regarding oral exposure (Schwetz et al., 1978) was
located 1n the available literature. Twenty-five rats/sex were administered 1
of 3 doses 1n the diet. At the 30 mg/kg/day level of treatment, a reduced
rate of body weight gain and Increased specific gravity of the urine were
observed In females. Pigmentation of the liver and kidneys was observed In
females exposed at 10 mg/kg/day or higher levels and 1n males exposed to 30
mg/kg/ day. The 3 mg/kg/day level of exposure was reported as a chronic NOEL.
A number of studies that have Investigated the teratogenldty of orally
administered pentachlorophenol In rodents are available In the literature.
Although these studies (Larsen et al., 1975; Schwetz and Gehrlng, 1973;
Schwetz et al., 1978; Hlnkle, 1973), did not reveal teratogenlc effects
feto-maternal toxlclty were seen at 30 mg/kg/day. Since pentachlorophenol
apparently does not cross the placenta! barrier, the observed fetotoxldty may
be a reflection of maternal toxlclty (Larsen et al., 1975). The NOEL 1n these
studies was 3.0 mg/kg, which 1s the same as for the chronic study reported
earlier.
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Uncertainty Factors (UFs):
The 100-fold factor accounts for the expected Intra- and interspedes
variability to the toxlcity of this chemical In lieu of specific data.
Modifying Factors (MFs):
None.
Additional Comments:
None.
Confidence In the RfD:
Study: High
Data Base: Medium
RfD: Medium
The confidence 1n the chosen study is rated high because a moderate number
of animals/sex were used In each of three doses, a comprehensive analysis of
parameters was conducted, and a reproductive study was also run. Confidence
In the supporting data base Is rated medium because only one chronic study Is
available. Other subchronlc studies provide adequate but weaker supporting
data. The confidence In the RfD 1s medium. More chronic/reproductive studies
are needed to provide a higher confidence in the RfD.
Documentation of RfD and Review:
Limited Peer Review and Agency-wide Internal Review, 1984.
U.S. EPA. 1984. Health Effects Assessment for Pentachlorophenol. Environ-
mental Criteria and Assessment Office, Cincinnati, OH. ECAO-CIN-H043.
U.S. EPA. 1985. Drinking Hater Criteria Document for Pentachlorophenol.
Office of Drinking Hater, Hashington, DC.
Agency RfD Review:
First Review: 05/20/85
Second Review:
Verification Date: 05/20/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0421P
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01/11/86
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Phenol CAS #: 108-95-2
Carclnogenldty: None.
Systemic Toxldty: See below.
Endpolnt Experimental Doses UF MF RfD (ADI)
Dow Chemical (1976) NOAEL: None 500 - 0.1 mg/kg/day
or
Rat oral s.ubchronlc 7 mg/day for a
study 70 kg man
Kidney and liver 50 mg/kg/day (135
pathology doses) (LOAEL)
Endpolnt and Experimental Doses:
Dow Chemical Co. 1976. References and literature review pertaining to
toxlcologlcal properties of phenol. Toxlcol. Res. Lab. Unpublished Report.
This study reported slight kidney damage 1n rats treated by gavage at 50
mg/kg/day of phenol for 6 months. Higher doses produced moderate kidney and
slight liver damage. However, no effects on liver, kidneys or any other
organs were observed 1n 90-day studies 1n rats (780 mg/kg/day of phenol)" and
mice (1700 mg/kg/day of phenol) which received various doses of phenol 1n the
drinking water (NCI, 1980). In this study, when extended for 2 more weeks,
rats and mice treated with 153 and 313 mg/kg/day phenol, respectively, showed
decreased weight gain and reduced water Intake. In addition, male and female
rats at 344 mg/kg/day dose had a significantly Increased Incidence of chronic
kidney Inflammation.
The difference 1n LOAELs of the NCI (1980) study (344 mg/kg) and the Dow
Chemical (1976) study (50 mg/kg) are plausibly attributed to differences 1n
mode of administration with the gavage study of Dow Chemical producing the
lowest LOAEL.
Dlechmann and Oespar (1940) noted no effects on water consumption and
weight gain at phenol concentrations as high as 1600 mg/L. Further, 1n
studies using rats and spanning 3-5 generations, Heller and Purcell (1938)
Preparation Date: 01/07/86
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Endpolnt and Experimental Doses (cont.):
observed normal growth and reproduction at phenol concentrations up to 5000
mg/l. Taking the drinking water consumption data provided by Delchmann and
Oesper (1940) for the 1600 mg/L group, this NOEL represents an average dose of
49 mg/kg/day which Is equivalent to that used In the derivation of the ADI.
Consideration of all these factors suggest that the previously estimated
ADI of 7 mg/day (U.S. EPA, 1980) based on the LOAEL of 50 mg/kg/day from the
Dow Chemical (1976) study should provide adequate protection.
Uncertainty Factors (UFs):
A 500-fold uncertainty factor was applied to the LOAEL of 50 mg/kg/day (10
for subchronlc data, 10 for species extrapolation and 5 for use of LOAEL). A
factor of 500 was used because H was judged that the existing data did not
Justify the use of a factor of 100, but were better than the requirements for
a factor of 1000.
Modifying Factors (MFs):
None.
Additional Comments:
None.
Confidence In the RfD:
Study: Low Data Base: Medium RfD: Medium
The chosen study Is given a confidence rating of low because few animals
were used, a NOEL was not established and the study was never published. The
data base Is given a medium confidence rating because several studies support
the chosen effect level. Until other chronic studies are available, a medium
confidence In the RfD 1s recommended.
Documentation of RfD and Review:
The Health and Environmental Effects Profile has had a limited peer review and
Agency-wide Internal review during 1985. The Ambient Hater Quality Criteria
document was extensively reviewed by the Agency and underwent public comments
during 1980.
0421P _2-
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Documentation of RfD and Review (cont.):
U.S. EPA. 1985. Health and Environmental Effects Profile for Phenol. Env1
ronmental Criteria and Assessment Office, Cincinnati, OH. ECAO-CIN-P125.
U.S. EPA. 1980. Ambient Water Quality Criteria Document for Phenol. Envi-
ronmental Criteria and Assessment Office, Cincinnati, OH. EPA 440/5-80-066.
Agency RfD Review:
First Review: 08/05/85
Second Review:
Verification Date: 08/05/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0421P
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Phenyl Mercuric Acetate
Carclnogenldty: None.
Systemic Toxlclty: See below.
CAS #: 62-38-4
Endpolnt
Experimental Doses
UF
MF
RfD (ADI!
FHzhugh et al.
(1950)
Rat oral chronic
study
Renal damage
0.1 ppm Hg diet or 100
0.0084 mg/kg/day
phenyl mercuric
acetate (NOAEL)
0.08 ug/kg/day
or
6 ug/day for a
70 kg man
0.5 ppm Hg or 0.042
mg/kg/day phenyl
mercuric acetate
(LOAEL)
Conversion Factor: Food consumption
molecular weight PHA/Hg Is 337/201; thus,
diet (ppm) x 0.05 kg of diet/kg bw/day
0.0084 mg/kg bw/day
5X bw/day,
0.1 mg/kg of
x 337/201 -
Endpolnt and Experimental Doses:
FHzhugh, O.G, A.A. Nelson, E.
tox1cH1es of mercuric phenyl
Hed. 2: 433-442.
P. Laug and
and mercuric
I.H. Kunze. 1950.
salts. Arch. Ind.
Chronic oral
Hyg. Occup.
Phenyl mercuric acetate was administered to rats (10-24/group/sex) at
levels of 0, 0.1, 0.5, 2.5. 10, 40 and 160 mercury In their diet for 2 years.
Detailed, microscopic examinations of the liver and kidney were performed at
Microscopic examination of the
As little as 0.5 ppm mercury
resulted In detectable kidney damage In females after 2 years. No differences
were seen between controls and females receiving 0.1 ppm mercury. At higher
doses (greater than 2.5 ppm) renal lesions were observed In both males
females. A NOEL of 0.1 ppm was determined from these results.
and 2 years of age.
at the 2-year mark.
were performed at 1
viscera was also performed
as phenyl mercuric acetate
and
FHzhugh et
IcHy of phenyl
al. (1950) 1s the
mercuric acetate.
only chronic study regarding the oral tox-
Therefore, assuming that the rat consumed
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Endpolnt and Experimental Doses (cont,):
the equivalent of 5X of Us body weight In food/day, the 0.1 ppm Hg NOEL Is
equivalent to 0,005 mg/kg/day Hg or 0,0084 mg/kg bw phenyl mercuric acetate.
Uncertainty Factors (UFs):
An ADI o,f 0.08 ug/kg/day or 6 ug/kg/day for a 70 kg human was derived by
dividing the NOEL by an uncertainty factor of 100 to account for species
extrapolation and differences In human sensitivity.
Modifying Factors (MFs):
None.
Additional Comments:
The data base contains very Tittle Information on the oral toxlclty of
phenyl mercuric acetate. Some subchronlc testing has been conducted. Limited
data are available on the mutagenlc and teratogenlc effects of this compound.
No relevant carcinogenic data Is available.
Confidence In the RfD:
Study: Medium
Data Base: Low
RfD: Medium
The chosen study Is given a medium confidence rating because a moderate
number of animals/sex were tested at each of six doses; several parameters
were measured. The data base Is given a low confidence rating because IHtle
or no supporting data exist. Medium confidence 1n the RfD follows.
Documentation of RfD and Review:
ECAO-C1nc1nnat1 Internal Review, August 1985.
U.S. EPA. 1985. Phenyl Mercuric Acetate: Review and
tract No. 68-03-3228. Environmental Criteria and
clnnatl, OH.
Evaluation
Assessment
of ADI.
Office,
Con-
Cln-
0421P
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Agency RfD Review:
First Review: 08/19/85
Second Review:
Verification Date: 08/19/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0421P
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01/11/86
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Phosphlne
Carclnogenlclty: None.
Systemic ToxIcHy: See below.
CAS #: 7803-51-2
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
Hackenburg (1972)
Rat chronic oral
study
Body weight and
clinical parameters
0.51 mg/kg food con- 100
verted to 0.026 mg/
kg/day (NOEL)
LOAEL: None
Conversion Factor: Food
thus, 0.51 mg/kg of diet >
0.026 mg/kg bw/day
0.0003 mg/kg/day
or
0.02 mg/day for a
70 kg man
consumption of 5X bw/day;
0.05 kg of diet/kg bw/day =
Endpolnt and Experimental Doses:
Hackenburg, U. 1972, Chronic Ingestlon by rats of standard diet treated with
aluminum phosphate. Toxlcol. Appl. Pharmacol. 23(1): 147-153.
This study reported a no effects dose level for rats fed diet fumigated
with phastoxln over a 2-year period. The mean phosphlne concentration during
that time period was 0.51 mg/kg of feed.' Based on an average 5X food consump-
tion and average rat body weight of 610.4 g (reported In the study), the phos-
phlne dose can be calculated as 0.026 mg/kg bw/day. Hackenburg (1972) found a
slight, yet statistically Insignificant, tendency for test females to gain
weight faster than their control counterparts. There were no other differ-
ences be.tween controls and treated rats In hemoglobin content, hematocrlt,
differential white blood cell count, glucose levels, SGPT, serum urea, pro-
thrombln time, organ weights or tissue hlstopathology. Survival rates and
tumor Incidences were similar between controls and experimental animals.
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Uncertainty Factors (UFs):
Application of an uncertainty factor
latlon and 10 for sensitive population)
an ADI of 0.02 mg/day.
of 100 (10 for
to the rat NOEL
Intraspecles extrapo-
of 0.026 mg/kg yields
Modifying Factors (MFs):
None.
Additional Comments:
The ACGIH (1984) has recommended a TLV of 0.3 ppm (0.42 mg/cu. m) for
phosphlne, based principally upon an ep1dem1olog1cal study by Jones (1964).
In this s.tudy, workers exposed Intermittently to about 10 ppm phosphlne gas
experienced GI, cardloresplratory and CNS symptomatology. > Based on the TLV,
an ADI of 0.021 mg/kg/day can be recommended. However, the Hackenburg (1972)
study was a 2-year study 1n rats which explored a number of functional and
morphological endpolnts. This study forms a better basis for an RfD.
Confidence 1n the RfD:
Study: High
Data Base: High
RfD: High
The confidence In the study was rated high because of the moderate number
of animals/dose, the extensive methodology employed to assure proper admin-
istration of the test compound, and the extensive number of parameters mea-
sured. The data base was rated high because of the effectiveness and safety
of this chemical has been long reported. The overall rating for the RfD Is,
thus, high.
Documentation of RfD and Review:
ECAO-C1nc1nnat1 Internal Review, August 1985.
U.S. EPA. 1985. Phosphlne: Review and Evaluation of ADI. Contract No.
68-03-3228, Environmental Criteria and Assessment Office, Cincinnati, OH.
Agency RfD Review:
First Review: 08/19/85
Second Review:
Verification Date: 08/19/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0421P
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01/11/86
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REFERENCE DOSES (RfOs) FOR ORAL EXPOSURE
Chemical: Potassium Cyanide
Cardnogenlclty: None.
Systemic Toxlclty: See below.
CAS #: 151-50-8
Endpolnt
Experimental Oases
UF
MF
RfD (ADI)
Howard and Hanzal
(1955)
Rat oral chronic
study
PhUbrlck et al.
(1979)
Rat chronic oral
bloassay
Decreased body and
thyroid weights,
myelln degeneration
10.8 mg/kg/day CN
'(NOAEL) converted to
27.0 mg/kg/day of
potassium cyanide
30 mg/kg/day CN
(LOAEL)
100
0.05 mg/kg/day
or
4 mg/day for a
70 kg man
Conversion Factors: Molecular weight of KCN/CN 1s
65/26; thus, 10.8 mg/kg/day x 65/26 = 27.0 mg/kg/day
Endpolnt and Experimental Doses:
Howard, J.W. and R.F. Hanzal. 1955. Chronic toxlclty to rats of food treated
with hydrogen cyanide. AgMc. Food Chem. 3: 325-329.
Potassium cyanide 1s soluble In water and dilute add (which Includes the
gastric environment) and Is readily hydrolyzed to 1 molar equivalent of
cyanide and 1 molar equivalent of potassium (Hartung, 1982).
Since potassium 1s present 1n very high levels In food and the environ-
ment, an ADI of 3.8 mg/day for potassium cyanide, based on cyanide content Is
recommended.
Preparation Date: 01/09/86
0421P
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Endpolnt and Experimental Doses (cont.):
In this 2-year dietary study, rats (10/sex/group) were administered food
fumigated with HCN. The average dally concentrations were 73 and 183 mg CN/kg
diet. From the data reported on food consumption and body weight, dally esti-
mated doses were 4.3 mg and 10.8 mg CN/kg bw. The average food CN concentra-
tions were estimated based on the authors' data for concentration at the
beginning and end of each food preparation period and by assuming a first
order rate of loss for the Intervening period., There were no treatment
related effects on growth rate, no gross signs of toxlclty, and no hlstopatho-
loglcal lesions.
Studies by Phllbrlck et al. (1979) showed decreased weight gain and
thyroxln levels and myelln degeneration In rats at 30 mg/kg/day CN. Other
chronic studies either gave higher effect levels or used subcutaneous route
(Crampton et al., 1979; Lessen, 1971; Herthlng et al., 1960). Human data do
not provide adequate Information from which to derive an ADI because effective
dose levels of chronically Ingested CN are not documented. Therefore, the
study of Howard and Hanzel (1955) provides the highest NOAEL 10.8 mg/kg/day
for CN and -1s chosen for the derivation of an ADI for CN of '1.5 mg/day or 0.02
mg/kg/day.
Cyanide 1s metabolized extensively In the liver, Indicating that the only
relevant route of administration for quantitative risk assessment In the deri-
vation of an oral ADI 1s the oral route of administration.
Uncertainty Factors (UFs):
According to the U.S. EPA (1985) an uncertainty factor of 100 1s used to
derive the ADI (10 for species extrapolation, 10 for sensitive population).
Modifying Factors (MFs):
A modifying factor of 5 1s used for apparent tolerance of cyanide when It
1s Ingested with food than when administered by gavage or drinking water.
Additional Comments:
Decreased protein efficiency ratio was produced by dietary cyanide treat-
ment of rats during gestation, lactation and postweanlng growth phase 1n the
Tewe and Haner (1981a) experiment; the dose level of cyanide (10.6 mg/kg/day)
producing that effect is slightly lower than the currently accepted NOAEL of
10.8 mg/kg/day (U.S. EPA, 1985). Furthermore, Tewe and Maner (1981b) tested
sows. Possible effects observed at about 9.45 mg/kg/day were proliferation of
glomerular cells of the kidneys and reduced activity of the thyroid glands In
the gilts. However, the number of animals 1n this experiment was very small.
0421P -2-
01/11/86
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Additional Comments (cont.):
A Japanese study (Amo, 1973) Indicated that 0.05 mg/kg/day of cyanide obtained
from drinking water decreased the fertility rate and survival rate 1n the Fl
generation and produced 100% mortality 1n the F2 generation In mice. However,
these data are not consistent with the body of available literature. Thus,
until additional chronic studies are available, an ADI of 3.8 mg/day for a 70
kg human 1s recommended.
Confidence 1n the RfD:
Study: Medium
Data Base: Medium
RfD:Med1um
The confidence 1n the study 1s medium because adequate records of food
consumption and body weight were maintained, and animals of both sexes were
tested at two doses for 2 years. The data base 1s rated medium because a
small but., sufficient number of studies support the chosen study. The confi-
dence In the RfD follows. Additional chronic/reproductive* studies are needed
to support a higher level of confidence 1n the RfD.
Documentation of RfD and Review:
ECAO-Clndnnatl Internal Review, 1985. Limited peer review and Agency-wide
review, 1985.
U.S. EPA. 1985. Cyanides: Review and Evaluation of ADI. Contract No.
68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH.
U.S. EPA. 1984. Health Effects Assessment for Cyanides. Environmental Cri-
teria and Assessment Office, Cincinnati, OH. ECAO-CIN-H011.
Agency RfD Review:
First Review: 08/05/85
Second Review:
Verification Date: 08/05/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0421P
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01/11/86
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Potassium Silver Cyanide
Carc1nogen1c1ty: None.
Systemic ToxIcHy: See below.
CAS #: 506-61-6
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
Howard and Hanzal
(1955)
Rat oral chronic
study
Phllbrlck et al.
(1979)
Rat chronic oral
bloassay
Decreased body and
thyroid weights,
myelln degeneration
10.8 mg/kg/day CN
(NOAEL) converted
to 82.7 mg/kg/day
potassium silver
cyanide
30.0 mg/kg/day CN
(LOAEL)
100
0.2 mg/kg/day
or
10 mg/day for a
70 kg man
Conversion Factor: Molecular weight KAg{CN)2/CN: x
199/26; thus, 10.8 mg/kg/day x 199/26 = 82.7 mg/kg/day
Endpolnt and Experimental Doses:
Howard, J.W. and R.F. Hanzal.
with hydrogen cyanide. Agrlc.
1955. Chronic toxlclty
Food Chem. 3: 325-329.
to rats of food treated
Because of potassium, silver cyanide dissociates to form potassium,
cyanide and silver cyanide, only 1 molar equivalent of cyanide Is generated
(Wlndholz, 1983). Based on free cyanide liberated by the dissociation of
potassium silver cyanide an ADI of 12 mg/day for 70 kg man 1s recommended.
In this 2-year dietary study, rats (10/sex/group) were administered food
fumigated with HCN. The average dally concentrations were 73 and 183 mg CN/kg
diet. From the data reported on food consumption and body weight, dally esti-
mated doses were 4.3 mg and 10.8 mg CN/kg bw. The average food CN concentra-
Preparatlon Date: 01/09/86
0421P
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Endpolnt and Experimental Doses (cont.):
tlons were estimated based on the author's data for concentration at the
beginning and end of each food preparation period and by assuming a first
order rate of loss for the Intervening period. There were no treatment
related effects on growth rate, no gross signs of toxldty, and no hlstopatho-
loglcal lesions.
Studies by PhUbrlck et al. (1979) showed decreased weight gain and
thyroxln levels and myelln degeneration 1n rats at 30 mg/kg/day CN. Other
chronic studl'es either gave higher effect levels or used subcutaneous route
(Crampton et al., 1979; Lessen, 1971; Herthlng et al., 1960). Human data do
not provide adequate Information from which to derive an ADI because effective
dose levels of chronically Ingested CN are not documented. Therefore, the
study of Howard and Hanzel (1955) provides the highest NOAEL 10.8 mg/kg/day
for CN and Is chosen for the derivation of an ADI for CN of 1.5 mg/day or- 0.02
mg/kg/day.
Cyanide Is metabolized extensively In the liver. Indicating that the only
relevant route of administration for quantitative risk assessment 1n the deri-
vation of an oral ADI Is the oral route of administration.
Uncertainty Factors (UFs):
According to the U.S. EPA (1985) an uncertainty factor of 100 Is used to
derive the ADI (10 for species extrapolation, 10 for sensitive population).
Modifying Factors (HFs):
A modifying factor of 5 was used for apparent tolerance of cyanide when It
Is Ingested with food than when administered by gavage or drinking water.
Additional Comments:
Decreased protein efficiency ratio was produced by dietary cyanide treat-
ment of rats during gestation, lactation and postweanlng growth phase In the
Tewe and-Maner (1981a) experiment: the dose level of cyanide (10.6 mg/kg/day)
producing that effect Is slightly lower than the currently accepted NOAEL of
10.8 mg/kg/day (U.S. EPA, 1985). Furthermore, Tewe and Maner (1981b) tested
sows. Possible effects observed at about 9.45 mg/kg/day were proliferation of
glomerular cells of the kidneys and reduced activity of the thyroid glands 1n
the gilts. However, the number of animals In this experiment was very small.
A Japanese study (Amo, 1973) Indicated that 0.05 mg/kg/day of cyanide obtained
from drinking water decreased the fertility rate and survival rate 1n the Fl
generation and produced 100% mortality In the F2 generation In mice. However,
0421P -2- 01/11/86
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Additional Comments (cont.):
these data are not consistent with the body of available literature. Thus,
until additional chronic studies are available, an ADI of 12 mg/day for a 70
kg man 1s recommended.
Confidence In the RfD:
Study: Medium
Data Base: Medium
RfD: Medium
The confidence 1n the study 1s medium because adequate records of food
consumption and body weight were maintained and animals of both sexes were
tested at two doses for 2 years. The data base 1s rated medium because a
small but sufficient number of studies support the chosen study. The confi-
dence In the RfD follows. Additional chronic/reproductive studies are needed
to support a higher level of confidence 1n the RfD.
Documentation of RfD and Review:
ECAO-C1nc1nnat1 Internal Review, July 1985.
U.S. EPA. 1985. Cyanides: Review and Evaluation of ADI. Contract No.
68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH.
Agency RfD Review:
First Review: 08/05/85
Second Review:
Verification Date: 08/05/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0421P
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01/11/86
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: PyMdlne
Cardnogenlclty: None.
Systemic Toxlclty: See below.
CAS #: 110-86-1
Endpolnt
Experimental Doses
UF
1000
MF
RfD (ADI)
Encyclopedia of
Occupational Safety
and Health. (1983)
Rats subchronlc to
chronic Inhalation
bloassay
Reduced liver weight
NOEL: None
0.002 mg/kg/day
or
0.2 mg/day for a
70 kg man
10 ppm (32.35 mg/
cu. m) converted
to 2.15 mg/kg/day
(LOEL)
Conversion Factors: 7 hour/24 hour, 5 days/7 days,
0.223 cu. m/day/0.35 kg (rat breathing rate/rat body
weight) 0.5 absorption rate; thus, 32.35 mg/cu. m x 7
hour/24 hour x 5 days/7 days x 0.223 cu. m/day / 0.35
kg x 0.5 = 2.15 mg/kg/day
Endpolnt and Experimental Doses:
Encyclopedia of Occupational Safety and Health.
national Labour Office, Geneva, p. 1810-1811.
1983. Vol. II: L-Z. Inter-
The -study reported In the above encyclopedia contains data taken from a
rat Inhalation study 1n which the exposure chamber contained 10-50 ppm pyrl-
dlne vapor over 7 hours/day. 5 days/week for a 6-month period. The lower
dose, 10 ppm pyrldlne (2.15 mg/kg/day) had no effect upon growth rate and
mortality, but an Increase 1n the relative Hver weights was observed. Fur-
ther details of the study were unavailable from the data base. The 2.15 mg
dose was considered a LOEL.
Preparation Date: 01/07/86
0421P
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Uncertainty Factors (UFs):
The 1000-fold represents 10 for both Intra- and Interspedes variability
to the toxldty of this chemical In lieu of specific data and an additional lo
because the RfD 1s based on a LOAEL and not a NOAEL.
Modifying Factors (MFs):
None.
Additional Comments:
Chronic oral studies for a RfD of high level of confidence are unavail-
able. Need data base on chronic/reproductive studies.
Confidence 1n the RfD:
Study: Low
Data Base: Low
RfD: Low
The confidence In the chosen study Is low because many details were
unavailable and a NOEL was not determined. Confidence In the data base 1s low
because of the general lack of Information. Low confidence In the RfD follows.
Documentation of RfD and Review:
ECAO-C1nc1nnat1 Internal Review, May and July 1985.
U.S. EPA. 1985. Pyr1d1ne: Review and Evaluation of ADI. Contract No.
68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH.
Agency RfD Review:
First Review: 07/08/85
Second Review:
Verification Date: 07/08/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0421P
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01/11/86
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Selenlous Add CAS #: 7783-00-8
CarclnogenlcHy: None.
Systemic Toxlclty: See below.
Endpolnt Experimental Doses UF MF RfD (ADI)
Yang et al. (1983) 0.750 mg/day (NOAEL) 10 1.5 0.003 mg/kg/day
or
Human epidemiology 0.2 mg/day for a
study 70 kg man
Selenosls 3.2 mg/day or 0.046
mg/kg/day (LOAEL)
Endpolnt and Experimental Doses:
Yang, G., S. Wang, R. Zhou and S. Sun. 1983. Endemic selenium Intoxication
of humans 1n China. Am. J. CUn. Nutr. 37: 872-881.
In solution selenium from selenlous acid and selenlte salts 1s present
predominantly as the blselenlte Ion (NAS, 1976). The toxldty of selenlte
salts and selenlous add would therefore be expected to be similar at sub-
lethal doses. It would thus be appropriate to derive a selenlous add ADI by
analogy to selenium.
The effects of oral selenium exposure have been relatively thoroughly
studied In experimental animals and man. The NAS (1980) has determined an
adequate and safe range for selenium Intake of 0.05-0.2 mg/day for an adult
man.
The. affects of selenium deficiency are potentially as serious as those of
selenium toxlclty. Selenosls has been reported In high selenium areas where
the average Intake was 5 mg/day (range 3.2-6.7), but no selenosls occurred
when the average Intake was 0.750 mg/day (range 0.240-1.51) (Yang et al.,
1983). Therefore, care must be exercised 1n deriving an ADI to Insure that
minimum dietary requirements are met.
Preparation Date: 01/09/86
0421P -1- 01/11/86
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Uncertainty Factors (UFs
An uncertainty factor of 10
applied to derive an ADI of 0.2
against adverse
population of
variability 1s
for the LOAEL for selenosls (3.2 mg/day) was
mg selenlous add/day for adequate protection
Since the LOAEL 1s from a large
humans the usual uncertainty factor of 10 for Interhuman
not thought to be necessary.
health effects In humans.
Modifying Factors (MFs):
A modifying factor of 1.5 Is used based on Information suggesting that
selenium 1n water Is absorbed more efficiently than selenium In food (U.S.
EPA, 1985).
Additional Comments:
None.
Confidence 1n the RfD:
Study: Medium
Data Base: High
RfD: High
Confidence 1n the chosen study Is medium because doses are given as
ranges. Confidence In the data base and RfD are both high because many
supportive animal studies (reviewed by NAS, 1977) and ep1dem1olog1cal studies
exist.
Documentation of RfD and Review:
Office of Drinking Water and ECAO-C1nc1nriat1 Internal Reveiw, 1985.
U.S. EPA. 1985. Health Effects Assessment for Selenium (and Compounds),
Environmental Criteria and Assessment Office, Cincinnati, OH. ECAO-CIN-H058.
Agency RfD Review:
First Review: 08/19/85
Second Review:
Verification Date: 08/19/85
U.S. EPA Contact:
Primary: C.T. DeRoa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0421P
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01/11/86
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Selenourea
Cardnogen1c1ty: None.
Systemic Tox1c1ty: See below.
CAS #: 630-10-4
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
Yang et al. (1983)
Human epidemiology
study
Selenosls
0.005 mg/kg/day
or
0.3 mg/day for a
70 kg man
0.750 mg/day (NOAEL) 10 1.5
3.2 mg/day Se or
0.046 mg/kg/day con-
verted to 0.072 mg/
kg/day equivalent
exposure of seleno-
urea by analogy to
selenium (LOAEL)
Conversion Factor: Molecular weight of Se(NH2)2/Se(-2]
Is 123.03/78.96; thus, 0.046 mg/kg/day x 123.03/78.96 =
0.072 mg/kg/day
Endpolnt and Experimental Doses:
Yang, G., S. Wang, R. Zhou and S. Sun. 1983. Endemic selenium Intoxication
of humans 1n China. Am. J. CUn. Nutr. 37: 872-881.
There 1s little Information regarding the toxldty of selenourea. Cummins
and Klmura (1971) reported a rat oral LD50 of 50 mg/kg, compared with 7 mg/kg
for sodium selenlte. It was postulated that the lower toxldty of selenourea
was probably due to Its lower water solubility and consequent poorer GI
absorption compared with sodium selenlte. Because of the lack of data regard-
Ing the-toxiclty of selenourea, the best approach In deriving an ADI for
selenourea Is by analogy to selenium.
The NAS (1980) has determined an adequate and safe range for selenium
Intake of 50-200 ug/day for an adult man. The effects of selenium deficiency
are potentially as serious as those of selenium toxldty. Selenosls has been
reported In high selenium areas where the average Intake was 5 mg/day (range
3.2-6.7), but no selenosis occurred when the average Intake was 0.75 mg/day
(range 0.24-1.51; Yang et al., 1983). U.S. EPA (1985) recommended an ADI of
Preparation Date: 01/09/86
042 IP
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Endpolnt and Experimental Doses (cont.):
0.21 mg/day for selenium by applying an uncertainty factor of 15 to the LOAEL
of 3.2 mg/day (Yang et a!., 1983). This ADI was derived on the Intake of
selenium 1n drinking water, and an uncertainty factor of 15 rather than 10 was
applied because of Information that selenium in water Is absorbed more effi-
ciently than selenium In' food.
This ADI should be adjusted for differences In molecular weight between
selenourea (123.03) and selenium (78.96) and, thus, an ADI of 0.005 mg/kg/day
(0.003 mg Se ,x 1.6) or 0.33 mg/day for selenourea 1s recommended to provide
adequate protection against adverse health effects.
Uncertainty Factors (UFs):
An uncertainty factor of 10 for the LOAEL for selenosls (3.2 mg/day) was
applied to derive an ADI of 0.2 mg selenlous add/day for adequate protection
against a'dverse health effects In humans. Since the LOAEL Is from a large
population of humans the usual uncertainty factor of '10 for Interhuman
variability Is not thought to be necessary.
Modifying Factors (MFs):
A modifying factor of 1.5 1s used based on Information suggesting that
selenium 1n water 1s absorbed more efficiently than selenium 1n food (U.S.
EPA, 1985).
Additional Comments:
None.
o6ctteoeoŤťBoať*ťBBBťtoBeťeťŤoŤťŤŤictŤec*Ťťeeťe*eťBŤeŤ.ťŤŤťť,,...,..ť,ť,,Ť,ť.ť*t
Confidence 1n the RfD:
Study: Medium Data Base: High RfD: High
Confidence In the chosen study Is medium because doses are given as
ranges. Confidence In the data base and RfD are both high because many
supportive animal studies (reviewed by NAS, 1977) and ep1dem1olog1cal studies
exist.
0421P -2-
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Documentation of RfD and Review:
ECAO-C1ndnnat1 Internal Review, August 1985.
U.S. EPA. 1985. Selenourea: Review and Evaluation of ADI. Contract No.
68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH.
U.S. EPA. 1985. Health Effects Assessment for Selenium (and Compounds).
Environmental Criteria and Assessment Office, Cincinnati, OH. ECAO-CIN-H058.
Agency RfD Review:
First Review: 08/19/85
Second Review:
Verification Date: 08/19/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Doursorr
FTS/684-7544 or 513/569-7544
0421P
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Silver Cyanide
Carclnogenldty: None.
Systemic Toxldty: See below.
CAS #: 506-64-9
Endpolnt
Experimental Doses
UF
MF
5
RfD (ADI)
Howard and Hanzal
(1955)
Rat oral chronic
bloassay
PhUbrlck et al.
(1979)
Rat chronic oral
bloassay
Decreased body and
thyroid weights,
myelln degeneration
10.8 mg/kg/day CN
(NOAEL) converted
to 55.66 mg/kg/day
silver cyanide
30.0 mg/kg/day
(LOAEL)
100
0.1 mg/kg/day
or
8 mg/day for a
70 kg man
Conversion Factor: Molecular weight of AgCN/CN Is
134/26; thus, 10.8 mg/kg/day x 134/26 = 55.66 mg/kg/day
Endpolnt and Experimental Doses:
Howard, J.W. and R.F. Hanzal. 1955. Chronic
treated with hydrogen cyanide. Agrlc. Food Chem.
toxlclty for
3: 325-329.
rats by food
Silver cyanide Is not soluble In water or dilute add (Wlndholz, 1983).
Currently the data base does not provide any toxlclty Information on silver
cyanide. It Is, therefore, recommended that an ADI of 8 mg/day for a 70 kg
human based on cyanide will provide adequate protection against an adverse
health effects. Note that this Is a conservative protective assumption In
light of silver cyanide's lack of solubility.
In this 2-year
fumigated with HCN.
dietary study, rats (10/sex/group) were administered food
The average dally concentrations were 73 and 183 mg CN/kg
Preparation Date: 01/09/86
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Endpolnt and Experimental Doses (cont.):
diet. From the data reported on food consumption and body weight, dally esti-
mated doses were 4.3 mg and 10.8 mg CN/kg bw. The average food CN concentra-
tions were estimated based on the authors' data for concentration at the
beginning and end of each food preparation period and by assuming a first
order rate of loss for the Intervening period. There were no treatment
related effects on growth rate, no gross signs of toxlclty, and no hlstopatho-
loglcal lesions.
Studies by Phllbrlck et al. (1979) showed decreased weight gain and
thyroxln levels and myelln degeneration In rats at 30 mg/kg/day CN. Other
chronic studies either gave higher effect levels or used s-ubcutaneous route
(Crampton et al., 1979; Lessell, 1971; Herthlng et al., 1960). Human data do
not provide adequate Information from which to derive an ADI because effective
dose levels of chronically Ingested CN are not documented. Therefore, the
study of Howard and Hanzel (1955) provides the highest NOAEL 10.8 mg/kg/day
for CN and Is chosen for the derivation of an ADI for CN of 1.5 mg/day or 0.02
mg/kg/day..
Cyanide Is metabolized extensively In the liver. Indicating that the only
relevant route of administration for quantitative risk assessment In the deri-
vation of an oral ADI Is the oral route of administration.
Uncertainty Factors (UFs):
According to the U.S. EPA (1985) an uncertainty factor of 100 Is used to
derive the ADI (10 for species extrapolation, 10 for sensitive population).
Modifying Factors (MFs):
A modifying factor of 5 Is used for apparent tolerance of cyanide when It
Is Ingested with food than when administered by gavage or drinking water.
Additional Comments:
Decreased protein efficiency ratio was produced by dietary cyanide treat-
ment of rats during gestation, lactation and postweanlng growth phase In the
Tewe and Maner (1981a) experiment; the dose level of cyanide (10.6 mg/kg/day)
producing that effect Is slightly lower than the currently accepted NOAEL of
10.8 mg/kg/day (U.S. EPA, 1985). Furthermore, Tewe and Maner (1981b) tested
sows. Possible effects observed at about 9.45 mg/kg/day were proliferation of
glomerular cells of the kidneys and reduced activity of the thyroid glands In
the gilts. However, the number of animals In this experiment was very small.
A Japanese study (Amo, 1973) Indicated that 0.05 mg/kg/day of cyanide obtained
from drinking water decreased the fertility rate and survival rate In the Fl
generation and produced 100% mortality In the F2 generation In mice. However,
0421P -2- 01/11/86
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Additional Comments (cont.):
these data are not consistent with the body of available literature. Thus,
until additional chronic studies are available, an ADI of 7.8 mg/day for a 70
kg man Is recommended.
Confidence In the RfD:
Study: Medium
Data Base: Low
RfD: Low
The confidence 1n the study 1s medium because adequate records of food
consumption and body weight were maintained and animals of both sexes were
tested at two doses for 2 years. The data base Is rated low because this
chemical has not been tested. The confidence In the RfD 1s low because It Is
based on analogy. Chronic/reproductive studies are needed to support a higher
level of confidence 1n the RfD.
Documentation of RfD and Review:
ECAO-C1nc1nnat1 Internal Review, July 1985.
U.S. EPA. 1985. Cyanides: Review and Evaluation of ADI. Contract No.
68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH.
Agency RfD Review:
First Review: 08/05/85
Second Review:
Verification Date: 08/05/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: H.L. Dourson
FTS/684-7544 or 513/569-7544
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Sodium Cyanide
Carclnogenlclty: None.
Systemic Toxlclty: See below.
CAS #: 143-33-9
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
Howard and Hanzal
(1955)
Chronic rat feeding
study as HCN
PhUbrlck et al.
(1979)
Rat chronic oral
bloassay
Body weight loss,
myelln degeneration,
thyroid effects
10.8 mg/kg/day CN
(NOAEL) converted
to 20.4 mg/kg/day
of sodium cyanide
30.0 mg/kg/day CN
(LOAEL)
100
0.04 mg/kg/day
or
3 mg/day for a
70 kg man
Conversion Factor: Molecular weight of NaCN/CN 1s
49/26; thus, 10.8 mg/kg/day x 49/26 = 20.4 mg/kg/day
Endpolnt and Experimental Doses:
Howard, J.W. and R.F. Hanzal.
treated with hydrogen cyanide.
1955. Chronic
Agrlc. Food Chem.
toxldty for
3: 325-329.
rats of food
Since sodium Is present In very high levels physiologically, an ADI for
sodium cyanide of 0.04 mg/kg/day or 3 rag/day can be calculated based on the
maximum molar equivalents (1) of cyanide generated In aqueous solution or
dilute acids.
In this 2-year dietary study, rats (10/sex/group) were administered food
fumigated with HCN. The average dally concentrations were 73 and 183 mg CN/kg
diet. From the data reported on food consumption and body weight, dally esti-
mated doses were 4.3 rag and 10.8 rag CN/kg bw. The average food CN concentra-
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Endpolnt and Experimental Doses (cont.):
tlons were estimated based on the authors' data for concentration at the
beginning and end of each food preparation period and by assuming a first
order rate of loss for the Intervening period. There were no treatment
related effects on growth rate, no gross signs of toxldty. and no hlstopatho-
loglcal lesions.
Studies by Phllbrlck et al. (1979) showed decreased weight gain and
thyroxln levels and myelln degeneration 1n rats at 30 mg/kg/day CN. Other
chronic studies either gave higher effect levels or used subcutaneous route
(Crampton et al.. 1979; Lessen, 1971; Herthlng et al., 1960). Human data do
not provide adequate Information from which to derive an ADI.because effective
dose levels of chronically Ingested CN are not documented. Therefore, the
study of Howard and Hanzel (1955) provides the highest NOAEL 10.8 mg/kg/day
for CN and 1s chosen for the derivation of an ADI for CN of 1.5 mg/day or 0.02
mg/kg/day.
Cyanide 1s metabolized extensively 1n the liver. Indicating that the only
relevant route of administration for quantitative risk assessment 1n the deri-
vation of an oral ADI 1s the oral route of administration. '
Uncertainty Factors (UFs):
According to the U.S. EPA (1985) an uncertainty factor of 100 Is used to
derive the ADI (10 for species extrapolation, 10 for sensitive population).
Modifying Factors (MFs):
A modifying factor of 5 1s used for apparent tolerance of cyanide when It
1s Ingested with food than when administered by gavage or drinking water.
Additional Comments:
Decreased protein efficiency ratio was produced by dietary cyanide treat-
ment of rats during gestation, lactation and postweanlng growth phase 1n the
Tewe and. Maner (1981a) experiment; the dose level of cyanide (10.6 mg/kg/day)
producing that effect 1s slightly lower than the currently accepted NOAEL of
10.8 mg/kg/day (U.S. EPA, 1985). Furthermore, Tewe and Maner (1981b) tested
sows. Possible effects observed at about 9.45 mg/kg/day were proliferation of
glomerular cells of the kidneys and reduced activity of the thyroid glands In
the gilts. However, the number of animals In this experiment was very small.
A Japanese study (Amo. 1973) Indicated that 0.05 mg/kg/day of cyanide obtained
from drinking water decreased the fertility rate and survival rate 1n the Fl
generation and produced 100% mortality 1n the F2 generation In mice. However,
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Additional Comments (cont.):
these data are not consistent with the body of available literature. Thus,
until additional chronic studies are available, an ADI of 2.8 mg/day for a 70
kg man Is recommended.
Confidence 1n the RfD:
Study: Medium
Data Base: Medium
RfD: Medium
The confidence In the study Is medium because adequate records of food
consumption and body weight were maintained and animals of both sexes were
tested at two doses for 2 years. The data base 1s rated medium because a
small but sufficient number of studies support the chosen study. The confi-
dence In the RfD follows. Additional chronic/reproductive studies are needed
to support a higher level of confidence 1n the RfD.
Documentation of RfD and Review:
ECAO-C1nc1nnat1 Internal Review, July 1985.
U.S. EPA. 1985. Cyanides: Review and Evaluation of ADI. Contract No.
68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH.
Agency RfD Review:
First Review: 08/05/85
Second Review:
Verification Date: 08/05/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Strychnine
Cardnogenldty: None.
Systemic Toxldty: See below.
CAS #: 57-24-9
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
Seldl and Zblnden
(1982)
Rat oral short-term
to subchronlc study
Tox1dty/h1sto-
pathology
NOAEL: None
10,000
2.5 mg/kg/day
LOAEL/FEL
0.0003 mg/kg/day
vOr
0.02 mg/day for a
70 kg man
Endpolnt and- Experimental Doses:
Seldl, I. and G. Zblnden. 1982. Subchronlc oral toxldty of strychnine In
rats. Arch. Toxlcol. 51(3): 267-271.
This Is the only oral subchronlc study reported, 1n which rats received
dally doses of 0 through 10 mg/kg of strychnine by gavage for 28 days. Data
recorded for the surviving animals Included blood cell count, electrocardio-
grams, eye examinations, urine chemistry, weight gain, tissue histology, organ
weights, behavioral tests, and food and water consumption. Mortality was
observed 1n 5/12 male rats receiving 10 mg/kg, 1/12 1n each of the 5 mg and
2.5 mg/kg groups. All deaths occurred 0.5-6 hours after oral doses. While
one rat that died 1n the 2.5 mg/kg/day group showed signs of poisoning, no
symptoms were exhibited by survivors, nor did any of the survivors differ from
controls hlstologlcally or 1n any of the parameters monitored. The systemic
level of. this rapidly degradable toxicant [based on pharmacoklnetlcs data,
Sgaragll and Mannalon (1973)] was probably much higher than In normal oral
Intake with food and water because H was administered all at once by gavage.
Thus, 2.5 mg/kg/day could be considered a subchronlc LOAEL for rats.
Additional studies (GrHzelmann et al., 1978) reported that a 6-month-old
human patient received strychnine doses of 0.3-1.1 mg/kg/day over an 18-month
period without any adverse effects. However, the patient may have had a
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Endpolnt and Experimental Doses (cont.):
higher strychnine tolerance as a result of nonketotlc hyperglydnemla. The
011 and Hazardous Materials-Technical Assistance Data Systems (1984) reported
that "adults may safely drink dally 0.078-0.25 gallons of water containing 10
mg/L of strychnine" (equivalent to 2.9-9.5 mg/day). This corresponds to
0.041-0.136 mg/kg.
Uncertainty Factors (UFs):
An ADI of 0.0003 mg/kg/day or 0.02 mg/day for a 70 kg man 1s derived from
the Seldl and Zblnden (1982) short-term to subchronlc study by applying an
uncertainty factor of 1000 to account for extrapolation from a subchronlc to a
chronic exposure study, extrapolation from animals to humans and differences
1n sensitivity among the human population. An additional 10 Is used because a
LOAEL/FEL (2.5 mg/kg/day) was utilized In the estimation of the RfD Instead of
a NOAEL. ..In view of this concern and the limitations In the data base, the
derived ADI should be viewed as an Interim estimate. Despite the limitations
of the data base the additional factor of 10 should result In a sufficiently
protective level.
Modifying Factors (MFs):
None.
Additional Comments:
The data base contained only one rat subchronlc study for ADI with suppor-
tive clinical data. Until further chronic/reproductive studies are available,
a low confidence 1n the RfD Is recommended.
Confidence 1n the RfD:
Study: Low Data Base: Low RfD: Low
Confidence 1n the chosen study Is low because a small number of animals
was tested, a NOEL was not established, and the study Is extremely short.
Confidence 1n the data base Is low because of the limited supporting studies.
Low confidence In the RfD follows.
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Documentation of RfD and Review:
ECAO-C1ndnnat1 Internal Review, July 1985.
U.S. EPA. 1985. Strychnine: Review and Evaluation of ADI. Contract No
68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH.
Agency RfD Review:
First Review: 08/05/85
Second Review:
Verification Date: 08/05/85
U.S. EPA Contact:
Primary: C.T. OeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Tetrachloroethylene
Carc1nogen1c1ty: CAG, U.S. EPA - Category B2.
Systemic Toxlclty: See below.
CAS #: 127-18-4
Endpolnt
Carpenter (1937)
Rat Inhalation, 7
months at 8 hour/
day, 5 days/week
Kidney and liver
changes
Experimental Doses
UF
MF
RfD (ADI)
NOAEL: 70 ppm Inha-
lation converted to
an oral dose of 19.4
mg/kg/day
LOAEL: 230 ppm
1000
0.02 mg/kg/day
Conversion Factors: 70 ppm = 475 mg/cu. m x 1 cu.
m/hour (assumed ventilation rate) x 8 hours/day x 5
days/7 days x 0.5 (assumed Inhalation retention
factor) / 70 kg (assumed human body weight) = 19.4
mg/kg/day
Endpolnt and Experimental Doses:
Carpenter, C.P- 1937. The chronic toxlclty of tetrachloroethylene. J. Ind.
Hyg. Toxlcol. 19: 323-336.
Carpenter (1937) exposed groups of 24 rats (12/sex) to 1 of 3 doses by
Inhalation for 8 hours/day. 5 days/week for 7 months. No significant changes
were observed at the low dose of 70 ppm. At 230 ppm, renal congestion and
swelling were noted. At 470 ppm, the liver aslo was congested and exhibited
cloudy swelling, which remained for 46 days after termination of exposure.
The kidney showed Increased secretion, cloudy swelling and desquamatlon; the
spleen was congested and showed an Increase In pigment content.
The study showed good dose-response, but the U.S. EPA was obligated to use
the Inhalation route of exposure since no good oral data are available.
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Uncertainty Factors (UFs
The uncertainty factor of 1000 reflects 10 for both Intraspedes and
to the toxldty of this chemical 1n Heu of specific
of a subchronlc effect level to Us chronic
Interspecles variability
data, and 10 for extrapolation
equivalent.
Modifying Factors (MFs):
None.
Additional Comments:
None.
Confidence In the RfD:
Study: Medium
Data Base: High
RfD: Medium
Confidence In the chosen study Is medium because while only a small number
of animals/sex were tested at each dose, the number of parameters measured was
large. Confidence 1n the supporting data base 1s high to medium because
several Inhalation studies support the chosen effect level. Medium to high
confidence In the RfD normally would follow, but medium 1s chosen because the
data are from Inhalation exposures.
Documentation of RfD and Review:
Extensive Internal (I.e., Red Border) and Steering Committee review. Public
comment period was June 12 to September 15, 1984.
U.S. EPA. 1985. Drinking Water Criteria Document for Tetrachloroethylene.
Office of Drinking Water, Washington, DC.
Agency RfD Review:
First Review: 05/20/85
Second Review:
Verification Date: 05/20/85
U.S. EPA Contact:
Primary: P. Fenner-Crlsp
FTS/382-7589 or 513/382-7589
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: 2,3,4,6-Tetrachlorophenol
Cardnogenldty: None.
Systemic Toxlclty: See below.
CAS #: 58-90-2
Endpolnt
Experimental Doses
UF
HF
RfD (ADI)
Hattula et al.
(1981)
Rat oral short-term
to subchronlc study
Liver necrosis
10 mg/kg/day (NOEL;
1000
50 mg/kg/day (LOAEL)
0.01 mg/kg/day
or
0.7 mg/day for a
70 kg man
Endpolnt and Experimental Doses:
Hattula, M.L., V.M. Wasenius, R. Krees, A.N. ArstHa and H. Klhlstrom. 1981.
Acute and short-term toxldty of 2,3,4,6-tetrachlorophenol In rats. Bull.
Environ. Contam. Toxlcol. 26: 795-800.
The reported study Is a short-term toxldty study 1n which body weight
changes and organ hlstopathology were observed. There Is concern about the
duration of exposure (55 days) which could be mitigated by rapid rate of
urinary elimination of the compound. Based on the data the 10 mg/kg/day 1s
considered as a NOEL and application of an uncertainty factor of 1000 (10 for
subchronlc study, 10 for Interspecles conversion and 10 for sensitive popula-
tion) was used to derive the ADI of 0.01 mg/kg/day. Additional data are pre-
sented to substantiate the above ADI.
Schwetz et al. (1974) Incorporated an acute range finding toxldty study
which resulted In the selection of an MTD of 30 mg/kg/day for the reproduction
study. The lower dose (10 mg/kg) was a NOAEL, although subcutaneous edema In
exposed fetuses was considered a chance alone Incidence. The subcutaneous
edema was not observed In the high-dose group. High dose exposure (30 mg/kg)
caused significant delayed ossification of the skull bones; however, this
anomaly normally occurs in all control populations. No other maternal or
fetal toxldty was reported 1n any of the doses tested 1n this study. Since
subcutaneous edema was a chance alone Incidence, It Is recommended that the 10
mg/kg dose may be used as a NOEL.
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Uncertainty Factors (UFs):
The uncertainty factor of 1000 reflects 10 for both
Interspecles variability to the toxlclty of this chemical 1n
data, and 10 for extrapolation of a subchronlc effect
equivalent.
Intraspedes and
Heu of specific
level to Us chronic
Modifying Factors (HFs):
None.
Additional Comments:
Chronic studies are not available. Subchronlc and reproductive studies
provided adequate data for a RfD of medium level confidence.
Confidence In the RfD:
Study: Medium
Data Base: Medium
RfD: Medium
Medium confidence In the critical study 1s selected because although only
a few animals were tested/dose and sex was unspecified, dosing was conducted 7
days/week, and several parameters were measured. Medium confidence 1n the
data base Is selected as two bloassays are available that support the chosen
NOEL. Medium confidence In the RfD follows.
Documentation of RfD and Review:
ECAO-C1nc1nnat1 Internal Review, May 1985.
U.S. EPA. 1985. 2.3,4.6-Tetrachlorophenol: Review and Evaluation of ADI.
Contract No. 68-03-3228. Environmental Criteria and Assessment Office,
Cincinnati, OH.
Agency RfD Review:
First Review: 07/08/85
Second Review:
Verification Date: 07/08/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Tetraethyl Lead
Cardnogenldty: None.
Systemic Toxlclty: See below.
CAS #: 78-00-2
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
Schepers (1964)
Rat subchronlc study/
gavage 5 days/7 days
Hlstopathology of
liver and thymus
NOAEL: None 10,000
0.0001 ug/kg/day
or
0.008 ug/day for
a 70 kg man
1.7 ug/kg/day (LOAEL)
converted to 1.2 ug/
kg/day
Conversion Factor: 5 days/7 days; thus. 1.7 ug/kg/
day x 5 days/7 days =1.2 ug/kg/day
Endpolnt and Experimental Doses:
Schepers, G.W. 1964. Tetraethyl
Health. 8: 277-295.
and tetramethyl lead. Arch. Environ.
In a 20-week study, Schepers (1964) administered tetraethyl lead In peanut
oil by gavage to groups of 12 CD rats (6/sex) at 1.7 and 170 ug/kg/bw 5 days/
week. Gross observations revealed swollen Hvers and fatty plaques In the
thymus at both dose groups. H1stolog1cal preparations revealed hepatocyte
vacuoHzatlon, cytoplasmlc degeneration and neuronal damage among low-dose
rats. Rats exposed to the higher dose developed similar, but more severe,
hlstopathologles. Based on these findings a LOAEL of 1.2 ug/kg/day (1.7
ug/kg/da.y x 5 days/7 days) was determined.
A subchronlc Inhalation study by Davis et al. (1963) In rats and dogs sup-
ports these findings. However, the equivalent oral doses derived from this
study are substantially higher than the LOAEL derived from the Schepers (1964)
study. Therefore, a human ADI of 0.0001 ug/kg/day was derived based on the
LOAEL of 1.2 ug/kg/day from Schepers (1964) and on a standard scaling factor
of 10,000.
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Uncertainty Factors (UFs):
The uncertainty factor of 10,000 represents 10 to extrapolate from animal
to human, 10 to convert subchronlc to chronic exposure and 10 to protect for
sensitive humans, and an additional factor of 10 to convert a LOAEL to a NOAEl.
Modifying Factors (MFs):
None.
Additional Comments:
The data base contained limited long-term oral studies, as well as limited
subchronlc Inhalation and oral data. Reproductive, carcinogenic and terato-
genlc data are available but Inconclusive. Limited ep1dem,1olog1cal data are
also available.
Confidence In the RfD:
Study: Medium
Data Base: Medium
RfD: Medium
The chosen study Is given medium confidence because although only a few
animals/sex/dose were tested, a good hlstopathology was conducted, and a
dose-severity was observed. The data base was considered to have medium to
low confidence because some supporting Information was available. Medium
(that tends to low) confidence 1n the RfD follows.
Documentation of RfD and Review:
ECAO-C1nc1nnat1 Internal Review, July 1985.
U.S. EPA. 1985. Tetraethyl Lead: Review and Evaluation of ADI. Contract No.
68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH.
Agency RfD Review:
First Review: 08/05/85
Second Review:
Verification Date: 08/05/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: ThaTMc Oxide
Cardnogenlclty: None.
Systemic Tox1c1ty: See below.
CAS #: 563-68-8
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
Downs et al. (I960)
Rat subchronlc feed-
Ing
Increased kidney
weight, alopecia
5 ppm In diet thai- 1000
llum^acetate (NOEL)
converted to 0.39
mg/kg/day as thal-
lium or 0.43 mg/kg/
day thalUc oxide
0.0004 mg/kg/day
thallium
or
0.0004 mg/kg/day
thalllc oxide
or
0.03 mg/day
thalUc oxide for
a 70 kg man
15 ppm In diet as
thallium acetate
(LOAEL) converted
to 1.16 mg/kg/day
thallium or 1.30
mg/kg/day thalUc
oxide
Conversion Factor: Young rat food consumption 10%
bw/day; molecular weight of T1/T1C2H30 Is 204/263;
molecular weight of T1203/2 Tl Is 456/408; thus, 5
mg/kg of diet (ppm) x 0.1 kg of diet/kg bw/day x
204/263 x 456/408 = 0.433 mg/kg/day
Endpolnt and Experimental Doses:
Downs, W.L., J.K Scott, L.T. Steadman and E.A.
subacute toxldty studies of thallium compounds.
399-406.
Maynard.
Am. Ind.
1960. Acute and
Hyg. Assoc. 21:
Groups of rats (5/sex/dose) were fed diets containing nominal concentra-
tions of thallium acetate of 0, 5, 15 or 50 ppm. An additional group (30 ppm)
was added partway through (time not specified). Animals were allowed ad lib
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Endpoint and Experimental Doses (cont.):
access to these diets for 15 weeks. The 50 ppm level resulted in 100% mortal-
ity by week 5. The 30 ppm level resulted in 100% mortality by week 9. Four
of 10 control animals died (2/sex) by week 15 making interpretation of sur-
vival 1n the remaining dose groups difficult (15 ppm 3/5 males died, 1/5
females; 5 ppm 2/6 males died, 0/4 females). At termination, the only gross
finding was alopecia in the 15 and 30 ppm groups. The authors state there was
a slight Increase in kidney weight (doses not specified, data not shown). The
authors reported that histopathologlcal evaluations did not Indicate treat-
ment-related pathology. In addition, other groups of rats (10/sex/dose) were
fed thai He oxide at dietary levels of 20, 35, 50, 100 and 500 ppm for 15
weeks. All animals fed greater than or equal to 50 ppm died. Increased mor-
tality was seen at 35 ppm. At 20 ppm males showed weight depression, both
sexes showed alopecia and both sexes showed increased kidney weight. These
data Indicate that the toxldty of thalHc oxide is substantially similar to
thallium acetate. Unfortunately, lower feeding levels corresponding to a
NOAEL were not utilized for this salt. It is proposed that the, NOEL for thal-
lium acetate, 5 ppm (0.39 mg/kg/day as thallium), be used Ło calculate an ADI
for thalllc oxide. A feeding level of 0.43 mg/kg/day thai lie oxide would pro-
vide an equivalent thallium intake.
Uncertainty Factors (UFs):
The uncertainty factor of 1000 reflects 10 for both intraspecies and
Interspedes variability to the toxldty of this chemical In lieu of specific
data, and 10 for extrapolation of a subchronic effect level to its chronic
equivalent.
Modifying Factors (HFs):
None.
Additional Comments:
Downs et al. (1960) is the only subchronic study available for the oral
route. .There appear to be no chronic data. An abstract of a Russian study
was located which reported administration of thallium sulfate or carbonate by
l.p. or s.c. Injection. However, 1n the absence of data for oral absorption
efficiency, H 1s difficult to compare these doses. Further chronic/reproduc-
tive toxldty data are needed for a higher level of confidence In the RfD.
0421P -2-
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Confidence in the RfD:
Study: Low
Data Base: Low
RfD: Low
Confidence In the
group sizes, mortality
chosen study 1s low. This study Is flawed by small
In the control group, failure to monitor food consump-
tion and lack of detail in the reported results. However, four doses were
tested and were preceded by a short-term bloassay that tested six doses.
Confidence In both the data base and the RfD is low because no supporting data
are available.
Documentation of RfD and Review:
ECAO-C1nc1nnat1 Internal Review, July 1985.
U.S. EPA. 1985. Thallium Compounds: Review and Evaluation of.ADI. Contract
No. 68-03^3228. Environmental Criteria and Assessment Office, Cincinnati, OH.
Agency RfD Review:
First Review:
Second Review:
Verification Date:
08/05/85
08/05/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Thai 1lum Acetate
CarclnogenlcHy: None.
Systemic Toxldty: See below.
CAS #: 563-68-8
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
Downs et al. (1960)
Rat subchr.onlc feed-
Ing study
Increased kidney
weight, alopecia
5 ppm 1n diet (NOEL) 1000
converted to 0.5
mg/kg/day
0.0005 mg/kg/day
or
0.04 mg/day for
a 70 kg human
15 ppm In diet
(LOAEL) converted
to 1.5 mg/kg/day
Conversion Factor: Young rat food consumption 10%
bw/day; thus, 5 mg/kg of diet (ppm) x 0.1 kg of diet/kg
bw/day = 0.5 mg/kg bw/day
Endpolnt and Experimental Doses:
Downs, W.L., J.K Scott, L.T. Steadman and E.A.
subacute toxldty studies of thallium compounds.
399-406.
Maynard.
Am. Ind.
1960. Acute and
Hyg. Assoc. 21:
Groups of rats (5/sex/dose) were fed diets containing nominal concentra-
tions of thallium acetate of 0, 5, 15 or 50 ppm. An additional group (30 ppm)
was added partway through (time not specified). Animals were allowed ad lib
access to these diets for 15 weeks. The 50 ppm level resulted In 100% mortal-
ity by week 5. The 30 ppm level resulted In 100% mortality by week 9. Four
of 10 control animals died (2/sex) by week 15 making Interpretation of
survival In the remaining dose groups difficult (15 ppm 3/5 males died, 1/5
females; 5 ppm 2/6 males died, 0/4 females). At termination, the only gross
finding was alopecia In the 15 and 30 ppm groups. The authors state there was
a slight Increase In kidney weight (doses not specified, data not shown). The
authors reported that hi stopathologlcal evaluations did not Indicate treat-
ment-related pathology
Preparation Date: 01/09/86
0421P
-1-
01/11/86
-------
Uncertainty Factors (UFs):
The uncertainty factor of 1000 reflects 10 for both Intraspecles and
Interspecles variability to the toxlclty of this chemical In Heu of specific
data, and 10 for extrapolation of a subchronlc effect level to Its chronic
equivalent.
Modifying Factors (HFs):
None.
Additional Comments:
Downs et al. (1960) Is the only subchronlc study available for the oral
route. There appear to be no chronic data. An abstract of a Russian study
was located which reported administration of thallium sulfate or carbonate by
l.p. or s.c. Injection. However, In the absence of data for oral absorption
efficiency, It 1s difficult to compare these doses. Further chronic/reproduc-
tive toxlclty data are needed for a higher level of confidence In the RfD.
Confidence In the RfD:
Study: Low
Data Base: Low
RfD: Low
Confidence In the chosen study 1s low. This study 1s flawed by small
group sizes, mortality In the control group, failure to monitor food consump-
tion and lack of detail 1n the reported results. However, four doses were
tested and were preceded by a short-term bloassay that tested six doses.
Confidence In both the data base and the RfD 1s low because no supporting data
are available.
Documentation of RfD and Review:
ECAO-Clnclnnatl Internal Review, July 1985.
U.S. EPA. 1985. Thallium Compounds: Review and Evaluation of ADI. Contract
No. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH.
Agency RfD Review:
First Review: 08/05/85
Second Review:
Verification Date: 08/05/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0421P
-2-
01/11/86
-------
REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Thallium Carbonate
Cardnogenlclty: None.
Systemic Toxlclty: See below.
CAS #: 6533-73-9
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
Downs et al. (1960)
Rat subchronlc feed-
Ing study
Increased kidney
weight, alopecia
5 ppm In diet as 1000
thallium acetate
(NOEL) converted to
0.39 mg/kg/day
thallium or 0.44
mg/kg/day thallium
carbonate
0.0004 mg/kg/day
thallium
or
0.0004 mg/kg/day
thallium
carbonate
or
0.03 mg/day thal-
lium carbonate
for a 70 kg man
15 ppm In diet
(LOAEL) converted to
1 .2 mg/kg/day as
thalllum or 1.3 mg/
kg/day thallium
carbonate
Conversion Factors: Young rat food consumption 10%
bw/day; molecular weight of T1/T1C2H302 1s 204/263;
molecular weight of T12C03/2 Tl is 467/408; thus, 5
mg/kg of diet (ppm) x 0.1 kg of diet/kg bw/day x
204/263 x 467/408 = 0.44 mg/kg/day
Endpolnt and Experimental Doses:
Downs, W.L., J.K Scott, L.T. Steadman and E.A. Maynard. 1960. Acute and
subacute toxldty studies of thallium compounds. Am. Ind. Hyg. Assoc. 21:
399-406.
Groups of rats (5/sex/dose) were fed diets containing nominal concentra-
tions of thallium acetate of 0, 5, 15 or 50 ppm. An additional group (30 ppm)
Preparation Date: 01/08/86
0421P
-1-
01/11/86
-------
Endpolnt and Experimental Doses (cant.):
was added partway through (time not specified). Animals were allowed ad lib
access to these diets for 15 weeks. The 50 ppra level resulted In 100% mortal-
ity by week 5. The 30 ppra level resulted In 10054 mortality by week 9, Four
of 10 control animals died (2/sex) by week 15 making Interpretation of sur-
vival In the remaining dose groups difficult (15 ppra 3/5 males died, 1/5
females; 5 ppra 2/6 males died, 0/4 females). At termination, the only gross
finding was alopecia In the 15 and 30 ppra groups. The authors state there was
a slight Increase In kidney weight {doses not specified, data not shown). The
authors reported that hlstopathologlcal evaluations did not Indicate treat-
ment-related pathology.
Data concerning the toxicity of thallium carbonate per se were not
located. The toxicity of thallium acetate and thallium carbonate should be
substantially similar. This assumes that gastrointestinal absorption of the
two compounds Is also substantially similar. An Interim ADI 1s proposed by
analogy to thallium acetate based upon the feeding level of 5 ppnt thallium
acetate which corresponds to a NOEL. This feeding level provided a thallium
equivalent of 0.39 rag/kg/day corresponding to a feeding level of 0.44 rog/kg/
day thallium carbonate.
Uncertainty Factors (UFs):
The uncertainty factor of 1000 reflects 10 for both intraspecles and
Interspecles- variability to the toxicity of this chemical in lieu of specific
data, and 10 for extrapolation of a subchronic effect level to Its chronic
equivalent.
Hodlfylng Factors (HFs):
None.
Additional Comments:
Downs et al. (I960) is the only subchronic study available for the oral
route, - There appear to be no chronic data. An abstract of a Russian study
was located wfoleh reported administration of thallium sulfate or carbonate by-
l.p. or s,c. Injection, However, in the absence of data for oral absorption
efficiency, it Is difficult to compare these doses. Further chronic/reproduc-
tive toxicity data are needed for a higher level of confidence In the RfD.
0421P .2- 01/11/86
-------
Confidence In the RfD:
Study: Low
Data Base: Low
RfD: Low
Confidence In the chosen study Is low. This study Is flawed by small
group sizes, mortality 1n the control group, failure to monitor food
consumption and lack of detail 1n the reported results. However, four doses
were tested and were preceded by a short-term bloassay that tested six doses.
Confidence In both the data base and the RfD are low because no supporting
data are available.
Documentation of RfD and Review:
ECAO-C1nc1nnat1 Internal Review, July 1985.
U.S. EPA. 1985. Thallium Compounds: Review and Evaluation of ADI. Contract
No. 68-03^3228. Environmental Criteria and Assessment Office, Cincinnati, OH.
Agency RfD Review:
First Review: 08/05/85
Second Review:
Verification Date: 08/05/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0421P
-3-
01/11/86
-------
REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Thallium Chloride
Carclnogenldty: None.
Systemic Toxldty: See below.
CAS #: 7791-12-0
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
Downs et al. (1960)
Rat subchronlc feed-
Ing study
Increased kidney
weight, alopecia
5 ppm 1n diet thai- 1000
Hum acetate (NOEL)
converted to 0.39
mg/kg/day thallium
or 0.45 mg/kg/day
thallium chloride
0.0004 mg/kg/day
thallium
or
' 0.0005 mg/kg/day
thallium chloride
or
0.03 mg/day thal-
lium chloride for
a 70 kg man
15 ppm In diet as
thallium acetate
(LOAEL) converted to
1.16 mg/kg/day thal-
lium or 1.36 mg/kg/
day thallium chloride
Conversion Factor: Young rat food consumption 10%
bw/day; molecular weight of T1/T1C2H303 Is 204/263;
molecular weight of T1C1/T1 1s 239/204; thus, 5 mg/kg
of diet (ppm) x 0.1 kg of diet/kg bw/day x 204/263 x
239/204 = 0.454 mg/kg/day
Endpolnt and Experimental Doses:
Downs, H.L., J.K Scott, L.T. Steadman and E.A. Haynard. 1960. Acute and
subacute toxlclty studies of thallium compounds. Am. Ind. Hyg. Assoc. 21:
399-406.
Groups of rats (5/sex/dose) were fed diets
tlons of thallium acetate of 0, 5, 15 or 50 ppm.
was added partway through (time not specified).
containing nominal concentra-
An additional group (30 ppm)
Animals were allowed ad Hb
Preparation Date: 01/09/86
0421P
-1-
01/11/86
-------
Endpolnt and Experimental Doses (cont.):
access to these diets for 15 weeks. The 50 ppm level resulted In 100% mortal-
ity by week 5. The 30 ppm level resulted In 100% mortality by week 9. Four
of 10 control animals died (2/sex) by week 15 making Interpretation of sur-
vival 1n the remaining dose groups difficult (15 ppm 3/5 males died, 1/5
females; 5 ppm 2/6 males died, 0/4 females). At termination, the only gross
finding was alopecia In the 15 and 30 ppm groups. The authors state there was
a slight Increase 1n kidney weight (doses not specified, data not shown). The
authors reported that hlstopathologlcal evaluations did not Indicate treat-
ment-related pathology.
No data were located concerning the toxicology of thallium chloride per
The toxlclty of thallium chloride should be substantially similar to that
thallium acetate. This presumes that absorption by the gastrointestinal
Is also substantially similar for the two compounds. Utilizing the
feeding level from the thallium acetate study an Interim
se
of
tract
no-observable effect
ADI may be calculated for thallium chloride by correcting for differences In
thallium .content. Thallium acetate (5 ppm) contributes 0.39 mg/kg/day thal-
lium which would be equivalent (In terms of thallium content) to 0.45 mg/kg/
day thallium chloride.
Uncertainty Factors (UFs):
The uncertainty factor of 1000 reflects 10 for both Intraspedes and
Interspedes variability to the toxlclty of this chemical In Heu of specific
data, and 10 for extrapolation of a subchronlc effect level to Us chronic
equivalent.
Modifying Factors (MFs):
None.
Additional Comments:
Downs et al. (1960) 1s the only subchronlc study available for the oral
route. -There appear to be no chronic data. An abstract of a Russian study
was located which reported administration of thallium sulfate or carbonate by
l.p. or s.c. Injection. However, In the absence of data for oral absorption
efficiency. It Is difficult to compare these doses. Further chronic/reproduc-
tive toxlclty data are needed for a higher level of confidence 1n the RfD.
0421P
-2-
01/11/86
-------
Confidence In the RfD:
Study: Low
Data Base: Low
RfD: Low
Confidence 1n the chosen study Is low. This study Is flawed by small
group sizes, mortality 1n the control group, failure to monitor food consump-
tion and lack of detail In the reported results. However, four doses were
tested and were preceded by a short-term bloassay that tested six doses.
Confidence In both the data base and the RfD Is low because no supporting data
are available*.
Documentation of RfD and Review:
ECAO-C1nc1nnat1 Internal Review, July 1985.
U.S. EPA. 1985. Thallium Compounds: Review and Evaluation of ADI. Contract
No. 68-03-.3228. Environmental Criteria and Assessment Office, Cincinnati, OH.
Agency RfD Review:
First Review:
Second Review:
Verification Date:
08/05/85
08/05/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0421P
-3-
01/11/86
-------
REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Thallium Nitrate
Cardnogenlclty: None.
Systemic ToxUity: See below.
CAS #: 10102-45-1
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
Down et al. (1960)
Rat subchr.onlc feed-
Ing study
Increased kidney
weight, alopecia
5 ppm 1n diet as
thallium acetate
(NOEL) converted
0.39 mg/kg/day
thallium or 0.51
kg/day thallium
nitrate
1000
to
mg/
0.0004 mg/kg/day
thallium
or
0.0005 mg/kg/day
thallium nitrate
or
0.04 mg/day thal-
lium nitrate for
a 70 kg man
15 ppm 1n diet
(LOAEL) converted to
1.16 mg/kg/day as
thallium or 1.52
mg/kg/day thallium
nitrate
Conversion Factor: Young rat food consumption 10%
bw/day; molecular weight of T1/T1C2H302 1s 204/263;
molecular weight of T1N03/T1 Is 266/204; thus, 5 mg/kg
of diet (ppm) x 0.1 kg of diet/kg bw/day x 204/263 x
266/204 = 0.506 mg/kg/day
Endpolnt and Experimental Doses:
Downs, W.L., J.K Scott, L.T.
subacute toxlclty studies of
399-406.
Steadman and E.A.
thallium compounds.
Maynard.
Am. Ind.
1960.
Hyg.
Acute and
Assoc. 21:
Groups of rats (5/sex/dose) were fed diets containing
tlons of thallium acetate of 0, 5, 15 or 50 ppm. An
was added partway through (time not specified).
nominal concentra-
addHlonal group (30 ppm)
Animals were allowed ad lib
Preparation Date: 01/08/86
0421P
-1-
01/11/86
-------
Endpolnt and Experimental Doses (cont.):
access to these diets for 15 weeks. The 50 ppm level resulted In 100% mortal-
ity by week 5. The 30 ppm level resulted In 10054 mortality by week 9. Four
of 10 control animals died (2/sex) by week 15 making Interpretation of sur-
vival In the remaining dose groups difficult (15 ppm 3/5 males died, 1/5
females; 5 ppm 2/6 males died, 0/4 females). At termination, the only gross
finding was alopecia In the 15 and 30 ppm groups. The authors state there was
a slight Increase In kidney weight (doses not specified, data not shown). The
authors reported that hlstopathologlcal evaluations did not Indicate treat-
ment-related pathology.
No data were located concerning the toxlclty of thallium nitrate per se.
The toxlclty of thallium nitrate and thallium acetate should be substantially
similar. This presumes that absorption of these compounds from the gastro-
intestinal tract 1s similar. By analogy an ADI for thallium nitrate may be
calculated from the NOEL for thallium acetate. The thallium nitrate feeding
level equivalent to the NOEL dose was 5 ppm. This corresponds to 0.39
mg/kg/day..thallium, which would be equivalent (In terms of- thallium content)
to 0.51 mg/kg/day thallium nitrate.
Uncertainty Factors (UFs):
The uncertainty factor of 1000 reflects 10 for both Intraspecles and
Interspedes variability to the toxlclty of this chemical In Heu of specific
data, and 10 for extrapolation of a subchronlc effect level to Us chronic
equivalent.
Modifying Factors (MFs):
None.
Additional Comments:
Downs et al. (1960) Is the only subchronlc study available for the oral
route. There appear to be no chronic data. An abstract of a Russian study
was located which reported administration of thallium sulfate or carbonate by
1.p. or s.c. Injection. However, In the absence of data for oral absorption
efficiency. It Is difficult to compare these doses. Further chronic/reproduc-
tive toxlclty data are needed for a higher level of confidence In the RfD.
0421P -2- 01/11/86
-------
Confidence In the RfD:
Study: Low
Data Base: Low
RfD: Low
Confidence 1n the chosen
group sizes, mortality Tn the
study Is low. This study Is flawed by small
control group, failure to monitor food consump-
tion and lack of detail In the reported results. However, four doses were
tested and were preceded by a short-term bloassay that tested six doses.
Confidence In both the data base and the RfD 1s low because no supporting data
are available.
Documentation of RfD and Review:
Limited In-house review by ECAO-C1nc1nnat1, July 1985.
U.S. EPA. 1985. Thallium Compounds: Review and Evaluation of,ADI. Contract
No. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH.
Agency RfD Review:
First Review: 08/05/85
Second Review:
Verification Date: 08/05/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: H.L. Dourson
FTS/684-7544 or 513/569-7544
0421P
-3-
01/11/86
-------
REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Thallium Selenlte
Carc1nogen1c1ty: None.
Systemic Toxldty: See below.
CAS #: 12039-52-0
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
Downs et al. (1960)
Rat subchr.onlc feed-
Ing study
Increased kidney
weight, alopecia
5 ppm 1n diet as 1000
thallium acetate
(NOEL) converted to
0.39 mg/kg/day thal-
lium or 0.54 mg/kg/
day thallium selenlte
0.0004 mg/kg/day
thallium
or
0.0005 mg/kg/day
thallium selenHe
or
0.04 mg/day thal-
lium selenlte for
a 70 kg man
15 ppm 1n diet
(LOAEL) converted to
1.16 mg/kg/day thal-
lium or 1.62 mg/kg/
day thallium selenlte
Conversion Factor: Young rat food consumption 10%
bw/day; molecular weight of T1/T1C2H302 1s 204/263;
molecular weight of TISe/Tl 1s 284/204; thus, 5 mg/kg
of diet (5 ppm) x 0.1 kg of diet/kg bw/day x 204/263 x
284/204 = 0.540 mg/kg/day
Endpolnt and Experimental Doses:
Downs, W.L., J.K Scott, L.T. Steadman and E.A.
subacute- tox1c1ty studies of thallium compounds.
399-406.
Maynard.
Am. Ind.
1960. Acute and
Hyg. Assoc. 21:
Groups of rats (5/sex/dose) were fed diets containing nominal concentra-
tions of thallium acetate of 0, 5, 15 or 50 ppm. An additional group (30 ppm)
was added partway through (time not specified). Animals were allowed ad lib
access to these diets for 15 weeks. The 50 ppm level resulted In 100% mortal-
ity by week 5. The 30 ppm level resulted In 100% mortality by week 9. Four
Preparation Date: 01/08/86
0421P
-1-
01/11/86
-------
Endpolnt and Experimental Doses (cont.):
of 10 control animals died (2/sex) by week 15 making Interpretation of sur-
vival In the remaining dose groups difficult (15 ppm 3/5 males died, 1/5
females; 5 ppm 2/6 males died, 0/4 females). At termination, the only gross
finding was alopecia 1n the 15 and 30 ppm groups. The authors state there was
a slight Increase In kidney weight (doses not specified, data not shown). The
authors reported that hlstopathologlcal evaluations did not Indicate treat-
ment-related pathology.
No toxlcologlcal data were located concerning thallium selenlte per se.
It 1s possible to develop an ADI based on equivalent thallium exposure from
data concerning thallium acetate. However, this extrapolation 1s considered
more uncertain than extrapolations among the simple thallium salts.
The no-effect feeding level for thallium acetate was 5 ppm which con-
tributed 0.39 mg/kg/day thallium. The dietary thallium selenlte Intake which
would provide an equivalent thallium Intake 1s 0.54 mg/kg/day thallium
selenlte... The exposure to selenium from this compound, based upon the pro-
posed Interim ADI of 38 yg/day, should be well below the toxic range for
selenium alone.
Uncertainty Factors (UFs):
The uncertainty factor of 1000 reflects 10 for both Intraspedes and
Interspecles variability to the toxldty of this chemical 1n Heu of specific
data, and 10 for extrapolation of a subchronlc effect level to Its chronic
equivalent.
Modifying Factors (MFs):
None.
Additional Comments:
Downs et al. (1960) Is the only subchronlc study available for the oral
route. -There appear to be no chronic data. An abstract of a Russian study
was located which reported administration of thallium sulfate or carbonate by
1.p. or s.c. Injection. However, 1n the absence of data for oral absorption
efficiency, It 1s difficult to compare these doses. Further chronic/reproduc-
tive toxldty data are needed for a higher level of confidence 1n the RfD.
0421P -2-
01/11/86
-------
Confidence 1n the RfD:
Study: Low
Data Base: Low
RfD: Low
Confidence In the chosen study 1s low. This study Is flawed by small
group sizes, mortality 1n the control group, failure to monitor food consump-
tion and lack of detail 1n the reported results. However, four doses were
tested and were preceded by a short-term bloassay that tested six doses.
Confidence 1n both the data base and the RfD Is low because no supporting data
are available.
Documentation of RfD and Review:
ECAO-Clndnnatl limited Internal Review, July 1985.
U.S. EPA. 1985. Thallium Compounds: Review and Evaluation of.ADI. Contract
No. 68-03r3228. Environmental Criteria and Assessment Office, Cincinnati, OH.
Agency RfD Review:
First Review: 08/05/85
Second Review:
Verification Date: 08/05/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0421P
-3-
01/11/86
-------
REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Thallium Sulfate
Cardnogenlclty: None.
Systemic Toxlclty: See below.
CAS #: 7446-18-6
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
Downs et al. (1960)
Rat subchronlc feed-
Ing study
Increased kidney
weight, alopecia
5 ppm In diet as 1000
thallium' acetate
(NOEL) converted to
0.39 mg/kg/day thal-
lium or 0.48 mg/kg/
day thallium sulfate
0.0004 mg/kg/day
thallium
or
0.0005 mg/kg/day
thallium sulfate
or
0.03 mg/day thal-
lium sulfate for
a 70 kg man
15 ppm 1n diet (LOEL)
converted to 1.16
mg/kg/day thallium
or 1.44 mg/kg/day
thallium sulfate
Conversion Factor: Young rat food consumption 10%
bw/day; molecular weight of T1/T1C2H302 1s 204/263;
molecular weight of T12S04/2 Tl 1s 504/408; thus, 5
mg/kg of diet (ppm) x 0.1 of diet/kg bw/day x 204/263 x
504/408 = 0.479 mg/kg/day
Endpolnt and Experimental Doses:
Downs, W.L., J.K Scott, L.T. Steadman and E.A.
subacute.. toxldty studies of thallium compounds.
399-406.
Maynard. 1960. Acute and
Am. Ind. Hyg. Assoc. 21:
Groups of rats (5/sex/dose) were fed diets containing nominal concentra-
tions of thallium acetate of 0, 5, 15 or 50 ppm. An additional group (30 ppm)
was added partway through (time not specified). Animals were allowed ad lib
access to these diets for 15 weeks. The 50 ppm level resulted In 100% mortal-
ity by week 5. The 30 ppm level resulted in 100% mortality by week 9. Four
Preparation Date: 01/08/86
0421P
-1-
01/11/86
-------
Endpolnt and Experimental Doses (cont.):
of 10 control animals died (2/sex) by week 15 making Interpretation of sur-
vival 1n the remaining dose groups difficult (15 ppm 3/5 males died, 1/5
females; 5 ppm 2/6 males died, 0/4 females). At termination, the only gross
finding was alopecia In-the 15 arxd 30 ppm groups. The authors state there was
a slight Increase 1n kidney weight (doses rrot specified, data not shown). The
authors reported that hlstopathologlcal evaluations did not Indicate treat-
ment-related pathology.
No data concerning the toxldty of thallium sulfate per se were located.
The toxldty of thallium sulfate and thallium acetate should be substantially
similar. This presumes that gastrointestinal absorption 1s substantially sim-
ilar. An ADI for thallium sulfate may be estimated by analogy to thallium
acetate. The no-effect feeding level for thallium acetate was 5 ppm which
provided 0.39 mg/kg/day thallium. A thallium sulfate Intake providing a cor-
responding thallium Intake would be 0.48 mg/kg/day.
Uncertainty Factors (UFs):
The uncertainty factor of 1000 reflects 10 for both Intraspecles and
Interspedes variability to the toxldty of this chemical 1n Heu of specific
data, and 10 for extrapolation of a subchronlc effect level to Us chronic
equivalent.
Modifying Factors (MFs):
None.
Additional Comments:
Downs et al. (1960) 1s the only subchronlc study available for the oral
route. There appear to be no chronic data. An abstract of a Russian study
was located which reported administration of thallium sulfate or carbonate by
l.p. or s.c. Injection. However, In the absence of data for oral absorption
efficiency, 1t 1s difficult to compare these doses. Further chronic/reproduc-
tive toxJclty data are needed for a higher level of confidence 1n the RfD.
0421P -2- 01/11/86
-------
Confidence In the RfD:
Study: Low
Data Base: Low
RfD: Low
Confidence 1n the chosen study 1s low. This study Is flawed by small
group sizes, mortality In the control group, failure to monitor food consump-
tion and lack of detail In the reported results. However, four doses were
tested and were preceded by a short-term bloassay that tested six doses.
Confidence in both the data base and the RfD is low because no supporting data
are available.
Documentation of RfD and Review:
Limited In-house review by ECAO-C1nc1nnat1, July 1985.
U.S. EPA. 1985. Thallium Compounds: Review and Evaluation of ADI. Contract
No. 68-03-3228. Environmental Criteria and Assessment Office. Cincinnati, OH.
Agency RfD Review:
First Review: 08/05/85
Second Review:
Verification Date: 08/05/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
0421P
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Toluene
Carclnogenldty: None.
Systemic Toxlcity: See below.
CAS #: 108-88-3
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
CITT (1980)
Rat chronic Inha-
lation study
Clinical chemistry
and hematologlcal
parameters
300 ppm (1130 mg/
cu. m) converted to
29 mg/kg/day (NOAEL)
LOAEL: None
100
0.3 mg/kg/day
or
20 mg/day for a
70 kg man
Conversion Factors: 5 days/7 days, 6 hour/24 hour; 0.5
absorption factor, 20 cu. m human breathing rate; 70
kg; thus, 1130 mg/cu. m x 5 day/7 days x 6 hours/24
hours x 0.5 x 20 cu. m/day / 70 kg = 28.8 mg/kg/day
Endpolnt and Experimental Doses:
CUT (Chemical Industry Institute of Toxicology). 1980. A twenty-four month
Inhalation toxicology study In F1scher-344 rats exposed to atmospheric
toluene. CUT, Research Triangle Park, NC.
Toluene Is most likely a potential source of respiratory hazard. The only
chronic toxlclty study on toluene was conducted for 24 months In male and
female F344 rats (CUT, 1980). Toluene was administered by Inhalation at 30,
100 or 300 ppm (113, 377 or 1130 mg/cu. m) to 120 male and female F344 rats
for 6 .hours/day. 5 days/week. The same number of animals (120 male and
female) was used as a control. Clinical chemistry, hematology and urlnalysls
testing was conducted at 18 and 24 months. All parameters measured at the
termination of the study were normal except for a dose-related reduction 1n
hematocrlt values In females exposed to 100 and 300 ppm toluene.
Based on these
An oral ADI of 20
findings, a NOAEL of 300 ppm or 1130 mg/cu. m was derived.
mg/day can be derived using route-to-route extrapolation.
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Endpolnt and Experimental Doses (cont.):
This was done by expanding the exposure from 6 hours/day, 5 days/week to con-
tinuous exposure and multiplying by 20 cu. m/day and 0.5 to reflect a 50%
absorption factor.
Uncertainty Factors (UFs):
An uncertainty factor of 100 (10 for sensitive Individuals and 10 for
Intraspecles extrapolation was also applied.
Modifying Factors (MFs):
None.
Additional Comments:
The only oral study found in the data base (Wolf et al., 1956) contains
subchronlc data 1n which no adverse effects of toluene were reported at the
highest dose tested (590 mg/kg/day).
Confidence 1n the RfD:
Study: High Data Base: Medium RfD: Medium
A high confidence 1s chosen for the critical study because a large number
of animals/sex were tested In each of three dose groups and many parameters
were studied. Interim kills were performed. The data base 1s rated medium
because several studies support the chosen effect level. The confidence of
the RfD Is not any higher than medium because the critical study was by the
Inhalation route.
Documentation of RfD and Review:
Limited Peer Review and Agency-wide Internal Review, 1984.
U.S. EPA. 1985. Drinking Water Criteria Document for Toluene. Office of
Drinking Hater, Washington, DC.
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Agency RfD Review:
First Review: 05/20/85
Second Review: 08/05/85
Verification Date: 08/05/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/6B4-7544 or 513/569-7544
0421P
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Trlchloromonof luoromethane
Carclnogenldty: None.
Systemic Toxlclty: See below.
CAS #: 75-69-4
Endpolnt
Experimental Doses
UF
MF
RfD (ADI;
NCI (1978)
Cancer blpassay
studies 1n rats and
mice
Survival and hlsto-
pathology
NOAEL: None
1000 - 0.3 mg/kg/day
or
20 mg/day for a
70 kg man
488 mg/kg/day (LOAEL)
converted to 349 mg/
kg/day
Conversion Factor: 5 days/7 days; thus, 488 mg/kg/
day x 5 days/7 days = 349 mg/kg/day
Endpolnt and Experimental Doses
NCI (National
for possible
78-1356.
Cancer Institute)
carclnogenlclty.
1978. Bloassay of trlchlorofluoromethane
Report. No. 106, PHS/NIH, DHEW Pub!.' No.
The NCI bloassay was performed on rats and mice exposed to various doses
of tr Ichloromonof luoromethane by gavage over a period of 78 weeks (50 animals/
specles/sex/dose for each of two doses with 20 an1mals/spedes/sex for each of
two control groups. A statistically significant positive association between
Increased dosage and accelerated mortality by the Tarone test In male and
female .rats and female mice was observed. In treated rats of both sexes there
were also elevated Incidences of pleurltls and pericarditis not seen 1n con-
trols. Inhalation studies which employed multlspedes exposures to higher
levels of the compound than used by NCI (Leuschner et al., 1983; Colman et
al., 1981; Hansen et al., 1984), reported no adverse clinical/pathological
signs of toxldty due to subchronlc or short-term exposures.
The LOAEL of 488 mg/kg/day (mortality
mg/kg/day on a 7-day exposure basis.
In rats) was converted to 349
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Uncertainty Factors (UFs):
An uncertainty factory of 1000 (10 for LOAEL, 10 for species conversion,
and 10 for sensitive human population), results In an ADI of 0.3 mg/kg/day.
Modifying Factors (MFs):
None.
Additional Comments:
None.
Confidence In the RfD:
Study: High
Data Base: High
RfD: High
The chosen study Is given a high to medium confidence because large
numbers of animals/sex were tested 1n two doses for chronic exposures. One
difficult was the study did not establish a NOEL. The data base 1s given a
high confidence because multi-species Inhalation studies provide supporting
data. High to medium confidence In the RfD follows.
Documentation of RfD and Review:
ECAO-Clnclnnatl Internal Review, May 1985.
U.S. EPA. 1985. Trlchloromonofluoromethane: Review and Evaluation of ADI.
Contract No. 68-03-3228. Environmental Criteria and Assessment Office, Cin-
cinnati, OH.
Agency RfD Review:
First Review: 07/08/85
Second Review:
Verification Date: 07/08/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: 2,4,5-Trlchlorophenol
Carc1nogen1c1ty: None.
Systemic Toxlcity: See below.
CAS #: 95-95-4
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
McColHster et al.
(1961)
Rat oral subchronlc
study
Liver and kidney
pathology
100 mg/kg/day (1000
ppm) (NOEL)
1000
0.1 mg/kg/day
or
7 mg/day for a
70 kg man
300 mg/kg/day
ppm) (LOAEL)
'3000
Conversion Factor: Food consumption 10X of body weight
young adult animals; thus, 1000 mg/kg of diet x 0.1 kg
of diet/kg bw/day = 100 mg/kg/day
Endpolnt and Experimental Doses:
McColllster, D.D., D.T. Lockwood and V.K. Rowe. 1961.
tion on 2,4,5-trlchlorophenol . Toxlcol. Appl. Pharmacol
Toxlcologlc
3: 63-70.
Informa-
This Is the only subchronlc (98 days) oral study In rodents available In
the literature. Ten rats of each sex were exposed to different levels (from
100 through 10,000 ppm) of 2,4,5-trlchlorophenol for 98 days. Mild diuresis
and slight degenerative changes In the liver and kidneys were observed In rats
of both sexes In the 3000 ppm and higher doses. In this study 1000 ppm (100
mg/kg/day based on food consumption as 10% of body weight In young adults) was
considered to be a NOEL, as Judged by behavior, mortality, food consumption,
growth, body and organ weights and hlstopathology . Until further chronic/
reproductive studies are available,. this ADI, 0.1 mg/kg/day. Is recommended.
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Uncertainty Factors (UFs):
The uncertainty factor of 1000 reflects 10 for both intraspecles
Interspedes variability to the toxldty of this chemical In lieu of specific
data, and 10 for extrapolation of a subchronlc effect level to Us chronic
equivalent.
Modifying Factors (MFs):
None.
Additional Comments:
None.
Confidence 1n the RfD:
Study: Medium
Data Base: Low
RfD: Medium
The confidence 1n the chosen study Is medium because five dose groups were
tested and several parameters were monitored. It Is not higher than medium
because only a few animals were tested/dose. Confidence In the data base Is
low because little, If any, supporting data exist. Confidence 1n the RfD 1s
medium to low. Additional chronic/reproductive toxlclty studies are needed to
support a higher confidence In the RfD.
Documentation of RfD and Review:
limited Peer Review and Agency-wide Internal Review, 1984.
U.S. EPA. 1984. Health Effects Assessment for 2,4,5-Trlchlorophenol. Envi-
ronmental Criteria and Assessment Office, Cincinnati, OH. ECAO-CIN-H034.
Agency RfD Review:
First Review: 05/20/85
Second Review:
Verification Date: 05/20/85
U.S. EPA Contact:
Primary: C.T. DeRos.a
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: 1,1,2-TMchloro-l ,2,2-trlfluoroethane CAS #: 76-13-1
Cardnogenlclty: None.
Systemic Toxlclty: See below.
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
Imbus and Adklns
(1972)
Ep1dem1olog1c study:
Human occupational
exposure
Psychomotor Impair-
ment
5358 mg/cu. m con-
verted to 273 mg/kg/
day {'NOAEL)
10
30 mg/kg/day
or
2000 mg/day for a
70 kg man
Conversion Factors: 10 cu. m (8-hour human breathing
volume), 5 days/7 days, 0.5 absorption factor, 70 kg
bw; thus, 5358 mg/cu. m x 10 cu. m x 5 days/7 days x
0.5/70 kg = 273 mg/kg/day
Endpolnt and Experimental Doses
Imbus, H.R. and C. Adklns
trlchlorotrlfluoroethane.
1972. Physical examination of workers exposed to
Arch. Environ. Health. 24(4): 257-261.
Several animal Inhalation studies reported negative results In dogs, rab-
bits, and rats chronically exposed to very high concentrations of trlchloro-
trlfluoroethane (U.S. EPA, 1983, Health Assessment Docuement). No apparent
adverse effects have been reported In humans occupatlonally exposed to tr1-
chlorotrifluoroethane at either 500 mg/cu. m levels for 11 years or 5358
mg/cu. m levels for 2.77 years (Imbus and Adklns, 1972).
Slight Impairment of psychomotor performance was reported 1n male volun-
teers exposed to tMchlorotrlfluoroethane concentrations of 19,161 mg/cu. m
for 2.75 hours (Stopps and Mclaughlin, 1967). This exposure period was too
brief to consider a NOAEL for chronic exposure. Therefore, the ADI of 30
mg/kg/day Is considered protective.
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Uncertainty Factors (UFs):
The uncertainty factor of 10 accounts for the expected Interhuman vaM
ability to the toxldty of this chemical In lieu of specific data.
Modifying Factors (MFs):
None.
Additional Comments:
None.
Confidence 1n the RfD:
Study: Low
Data Base: Low
RfD: Low
Confidence In the chosen study, data base and RfD are all considered low.
Although based on human data, and the fact that several chronic studies In
animals support the human NOEL, uncertainties In both the exposure levels and
route extrapolation preclude a higher confidence rating.
Documentation of RfD and Review:
ECAO-C1nc1nnat1 Internal Review, Hay 1985.
U.S. EPA. 1985. l,l,2-Tr1chloro-l,2,2-tr1fluoroethane: Review and Evaluation
of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment
Office, Cincinnati, OH.
Agency RfD Review:
First Review:
Second Review:
Verification Date:
07/08/85
07/08/85
U.S. EPA Contact:
Primary: C.T. DeRosa
FTS/684-7534 or 513/569-7534
Secondary: M.L. Dourson
FTS/684-7544 or 513/569-7544
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REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE
Chemical: Z1nc Cyanide
CarclnogenlcHy: None.
Systemic Toxlclty: See below.
CAS #: 557-21-1
Endpolnt
Experimental Doses
UF
MF
RfD (ADI)
Howard and Hanzal
(1955)
Chronic rat feeding
study as HCN
PhlbMck et al.
(1979)
Rat subchronlc to
chronic oral bloassay
Body weight loss,
thyroid effects,
myelln degeneration
10.8 mg/kg/day CN
(NOAEL) converted to
24.3 mg/kg/day zinc
cyanide
100
30.0 mg/kg/day
(LOAEL)
CN
0.05 mg/kg/day
or
3 mg/day for a
70 kg man
Conversion
1s 117/52;
kg/day
Factor: Molecular weight of Zn(CN)2/(CN)2
thus, 10.8 mg/kg/day x 117/52 = 24.3 mg/
Endpolnt and Experimental Doses:
Howard, J.W. and R.F. Hanzal. 1955. Chronic toxlclty for rats by food
treated with hydrogen cyanide. Agrlc. Food Chem. 3: 325-329.
Since zinc 1s present at high levels 1n foods and Is considerably less
toxic than cyanide, an ADI for zinc cyanide of 0.05 mg/kg/day or 3.4 mg/day
can be calculated based on the maximum molar equivalents (2) of cyanide gen-
erated 1n aqueous solution or dilute adds.
In this 2-year dietary study, rats (10/sex/group) were administered food
fumigated with HCN. The average dally concentrations were 73 and 183 mg CN/kg
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Endpolnt and Experimental Doses:
diet. From the data reported on food consumption and body weight, dally esti-
mated doses were 4.3 mg and "10.8 mg CN/kg bw. The average food CN concentra-
tions were estimated based on the authors' data for concentration at the
beginning and end of each food preparation period and by assuming a first
order rate of loss for the Intervening period. There were no treatment
related effects on growth rate, no gross signs of toxldty. and no hlstopatho-
loglcal lesions.
Studies by PhllbMck et al. (1979) showed decreased weight gain and
thyroxln levels and myelln degeneration In rats at 30 mg/kg/day CN. Other
chronic studies either gave higher effect levels or used subcutaneous route
(Crampton et al., 1979; Lessen, 1971; Herthlng et al., 1960). Human data do
not provide adequate Information from which to derive an ADI because effective
dose levels of chronically Ingested CN are not documented. Therefore, the
study of Howard and Hanzel (1955) provides the highest NOAEL 10.8 mg/kg/day
for CN and Is chosen for the derivation of an ADI for CN of 1.5 mg/day or 0.02
mg/kg/day.
Cyanide Is metabolized extensively In the liver, Indicating that the only
relevant route of administration for quantitative risk assessment In the deri-
vation of an oral ADI Is the oral route of administration.
Uncertainty Factors (UFs):
According to the U.S. EPA (1985) an uncertainty factor of 100 1s used to
derive the ADI (10 for species extrapolation, 10 for sensitive population).
Modifying Factors (HFs):
A modifying factor of 5 1s used for apparent tolerance of cyanide when It
1s Ingested with food than when administered by gavage or drinking water.
Additional Comments:
Decreased protein efficiency ratio was produced by dietary cyanide treat-
ment of rats during gestation, lactation and postweanlng growth phase 1n the
Tewe and Maner (1981a) experiment; the dose level of cyanide (10.6 mg/kg/day)
producing that effect 1s slightly lower than the currently accepted NOAEL of
10.8 mg/kg/day (U.S. EPA, 1985). Furthermore, Tewe and Maner (1981b) tested
sows. Possible effects observed at about 9.45 mg/kg/day were proliferation of
g.lomerular cells of the kidneys and reduced activity of the thyroid glands In
the gilts. However, the number of animals 1n this experiment was very small.
A Japanese study (Amo, 1973) Indicated that 0.05 mg/kg/day of cyanide obtained
from drinking water decreased the fertility rate and survival rate In the Fl
0421P -2- 01/11/86
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Additional Comments (cont.):
generation and produced 100% mortality in the F2 generation in mice. However,
these data are not consistent with the body of available literature. Thus,
until additional chronic studies are available, an ADI of 3.4 mg/day for a 70
kg man 1s recommended.
Confidence In the RfD:
Study: Medium
Data Base: Medium
RfD: Medium
The confidence 1n the study 1s medium because adequate records of food
consumption and body weight were maintained and animals of both sexes were
tested at two doses for 2 years. The data base 1s rated medium because a
small but sufficient number of studies support the chosen study. The confi-
dence In the RfD follows. Additional chronic/reproductive studies are needed
to support a higher level of confidence 1n the RfD.
Documentation of RfD and Review:
ECAO-Cincinnatl Internal Review, July 1985.
U.S. EPA. 1985. Cyanides: Review and Evaluation of ADI. Contract No.
68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH.
Agency RfD Review:
First Review: 08/05/85
Second Review:
Verification Date: 08/05/85
U.S. EPA Contact:
Primary:
Secondary:
C.T. DeRosa
FTS/684-7534 or 513/569-7534
M.L. Dourson
FTS/684-7544 or 513/569-7544
0421P
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01/11/86
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