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
                                      -2-

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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
                                      -4-

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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
                                       -5-

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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.
                                                    Preparation Date:  01/09/86
0420P
                                    -1-
01/11/86

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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
0420P
    -2-
     01/11/86

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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

                                                    Preparation Date:  01/06/86
0420P
            -1-
                                              01/11/86

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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
-3-
                                                                     01/11/86

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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).
                                                    Preparation  Date:   01/09/86
 0420P
             -1-
             01/11/86

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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
0420P                               -2-                              01/11/86

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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
0420P
                                    -3-
                                                                     01/11/86

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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:
0420P                               -1-                             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 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
    -2-
                                                                     01/11/86

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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.

                                                    Preparation Date:   01/06/86
0420P                               -1-                              01/11/86

-------
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
    -2-
                                                                      01/11/86

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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

-------
                    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

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 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
            -1-
                     01/11/86

-------
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

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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

-------
                    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

-------
                    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
             -1-
                      01/11/86

-------
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

-------
                    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
             -1-
                     01/11/86

-------
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

-------
                    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
0420P
             -1-
                      01/11/86

-------
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

-------
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

-------
                    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
             -1-
                                 01/11/86

-------
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

-------
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

-------
                    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

-------
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
    -2-
     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

-------
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

-------
                    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

-------
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
    -2-
     01/11/86

-------
                    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

-------
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
    -2-
     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
0420P                               -1-                               01/11/86

-------
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

-------
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

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                    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.
                                                    Preparation Date:  01/09/86
0420P                               -1-                              01/11/86

-------
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

-------
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

-------
                    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.
                                                     Preparation Date:   01/06/86
0420P
             -1-
              01/11/86

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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
    -2-
     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).
                                                    Preparation  Date:   01/09/86
0420P
             -1-
                                                                      01/11/86

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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
    -2-
     01/11/86

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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
 Q42QP
             -1-
                                 01/11/86

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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
    -3-
     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.
                                                    Preparation Date:  01/10/86
0420P                               -1-                               01/11/86

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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
    -2-
     01/11/86

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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

                                                     Preparation Date:   01/09/86
0421P                               -1.                               01/11/86

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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
 0421P
-3-
                                                                      01/11/86

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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.)
                                                    Preparation Date:  01/06/86
0421P
             -1-
                     01/11/86

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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
0421P
                                    -2-
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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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01/11/86

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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
                                    -3-
                                                                      01/11/86

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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
0421P
    -2-
                                                                      01/11/86

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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.
0421P-                              -2-
                                                                      01/11/86

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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
                                     -3-
                                 01/11/86

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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.
 0421P                                -2-                              01/11/86

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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
                                    -3-
                                                                     01/11/86

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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.
                                                    Preparation Date:  01/09/86
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                     01/11/86

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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
 0421P
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     01/11/86

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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.
                                                    Preparation Date:  01/09/86
0421P
             -1-
                                                                      01/11/86

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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.
0421P
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     01/11/86

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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
                                    -3-
                                                                     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
             -1-
                     01/11/86

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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
0421P
                                                                      01/11/86

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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
                                    -3-
                                                                     01/11/86

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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
0421P
            -1-
                                              01/11/86

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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
-2-
                                                                      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.

                                                    Preparation Date:   01/07/85
0421P                               -1-                              01/11/86

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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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                    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
0421P                                -1-                              01/11/86

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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.
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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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01/11/86

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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

                Preparation  Date:   01/09/86
0421P
                                    -1-
                                                                      01/11/86

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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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     01/11/86

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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.
                                                    Preparation Date:  01/09/86
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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.
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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-
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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
    -3-
     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-

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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
    -3-
                                                                      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
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             -1-
                      01/11/86

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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
    -2-
                                                                      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
                     -2-
                                                                      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
            -1-
                                              01/11/86

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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-
                                                                      01/11/86

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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
-3-
01/11/86

-------
                    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
0421P
                -1-
                                                                      01/11/86

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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
0421P
    -3-
                                                                      01/11/86

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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-

                                                    Preparatlon Date:   01/08/86
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             -1-
                      01/11/86

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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,
0421P                               -2-
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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.
 0421P                                -2-                              01/12/86

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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
0421P
                                    -2-
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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-
                                                                      01/11/86

-------
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
 0421P
                                     -3-
                                01/11/86

-------
                    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

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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

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 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

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                    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

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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
                                    -3-
                                                                     01/11/86

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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.

                                Preparation  Date:   01/08/86
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                 -1-
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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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                                                                      01/11/86

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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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01/11/86

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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
                                                    Preparation  Date:   01/09/86
 0421P
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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
 0421P
                                     -2-
                                     01/11/86

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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.
                                                    Preparation  Date:   01/09/86
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             -1-
                                                                      01/11/86

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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
 0421P
    -2-
                                     01/11/86

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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.

                                                    Preparation Date:  01/09/86
0421P
             -1-
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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
0421P
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                                                 01/11/86

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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
                                                    Preparation Date:   01/09/86
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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
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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
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