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                                  DISCLAIMER

    This report  Is  an external  draft  for review purposes .only  and  does not
constitute  Agency policy.   Mention of  trade  names  or  commercial  products
does not constitute endorsement or recommendation for use.
                                     11

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                               EXECUTIVE SUMMARY

    4-Am1nopyr1d1ne  Is  an  odorless,  white  crystalline   compound  that  1s
stable   to  light.   It  1s  moderately  soluble  In  water  (Farm  Chemicals
Handbook,  1987).  The  compound  Is  manufactured  by Rellly  Tar &  Chemical
Corporation  (Indianapolis, IN)  by a  synthetic  process (SRI,  1987);  recent
production figures are not available.
    4-Am1nopyr1d1ne,  sold  under  the  trade  name   Avltrol,   Is  used  as  a
registered  bird  repellent (Farm  Chemicals  Handbook,  1987;   Hadler,  1982).
Ingestlon  of   4-am1nopyr1d1ne-laden   bait   by  birds  results  In   aberrant
behavior  that  frightens  away  other  flock  members  (Hadler,   1982;  Carlson,
1984).   4-Amlnopyrldlne can also  be  used  as  a  chemical  Intermediate (Hawley,
1981).
    When  released to  the  atmosphere, 4-am1nopyr1d1ne can  be expected  to
exist partly  1n the  gas-phase where  1t will be  degraded  rapidly by reaction
              /
with  photochemlcally-produced   hydroxyl   radicals.   Using  the method  of
Atkinson  (1987),  the  half-life for this reaction in  a  typical ambient atmo-
sphere can be  estimated to be  8 hours.   Because  4-am1nopyr1d1ne has very low
volatility from soil  (Sims and Sommers, 1985,1986)  or  water,  however, 1t Is
not  expected   to  partition significantly  to  air  when  released  to soil  or
water.   By analogy to aromatic  amines  as  a chemical class (Mill and  Mabey,
1985), 4-am1nopyr1d1ne may  undergo significant degradation  In  sunlit natural
water by reaction with  photochemically-generated  free radicals.   Although
4-am1nopyr1d1ne  1s soluble  1n  water,  significant  partitioning  from  the water
column  to suspended  solids and  sediment may occur because  of a  covalent
binding  reaction  that  has  been observed  1n other  aromatic amines  (Parrls,
1980).   Hydrolysis,   direct  photolysis  and  bVoconcentratlon  may  not  be
                                      1v

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Important.  The  degradation  of 4-am1nopyr1d1ne 1n  soil  has  been studied by
several  Investigators  (Na1k  et al.,  1972;  Betts  et  al.,  1976;  Starr and
Cunningham, 1975; Sims and Sommers,  1985,  1986)..  Although  the  blodegradatlon
1n  soil  can  vary  greatly,  their  results  Indicate  that 4-am1nopyr1d1ne 1s
generally resistant  to blodegradatlon  1n soil.  Soil half-lives  ranging  from
3  months to  >22 months  have  been  observed  (Starr and Cunningham,  1975).
Soil column leaching studies have  shown that 4-am1no-pyr1d1ne  Is not  leached
significantly  In either  alkaline  or  addle   soils,  although  mobility 1n
alkaline soils 1s slightly greater  (Starr and Cunningham, 1975).
    4-Am1nopyr1d1ne  1s released directly to  the environment  (primarily  soil)
through  Us   use  as  a  bird  repellent. Environmental   releases  from  waste
streams or fugitive  emissions  from the manufacture  of 4-am1nopyr1d1ne  or Us
use as a chemical Intermediate  may be  minor  In relation  to  Us  use as  a  bird
repellent.  From a  NIOSH  survey (NOES) conducted  between  1981 and 1983, It
has  been estimated  that  annually  about   898  U.S. workers  are potentially
                       i
exposed  to  4-am1no-pyr1d1ne   (NIOSH,  1985).   Pertinent  water,  food,  air or
dermal monitoring data were not located In the available literature cited 1n
Appendix A.
    Studies  assessing the acute toxldty of  4-am1nopyr1d1ne  to  fish revealed
that  toxldty was  not dependent  on  water  temperature or  hardness.  The
96-hour  LC5Qs  for  channel catfish and  blueglll  sunflsh  exposed to 4-am1no-
pyrldlne  ranged  from 2.43-7.56   mg/l  (Schafer  and  Harking,  1975).   The
toxldty of 4-am1nopyr1d1ne to  aquatic  Invertebrates was assessed by  Marking
and Chandler  (1981).  Juvenile  glass  shrimp  were  the most sensitive  spedes
tested   (96-hour   LC5Q=0.37   mg/l),    followed   by  mayfly   nymphs    (0.58
mg/l),  crayfish  (2.2 mg/l),   frog  larvae  (2.4  mg/l),  water fleas   (3.2

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mg/l),  caddlsfly  larvae  (15  mg/l),  Asiatic  clams  (45  mg/l)  and  snails
(62  mg/l).   The  NOEC  for  larval  frogs  appears  to  be <1  mg/l  (Harking and
Chandler, 1981).
    The  tox1c1ty of 4-amlnopyrldlne  to  birds  was  studied extensively  by  a
series  of  Investigators.   Oral  L05Q  values  ranged  from  2.4-35 mg/kg  for
periods  of  exposure  and  observation  of  varying   lengths.  There  was  no
evidence  that  reproduction  among  the  progeny  of  4-am1nopyr1d1ne-treated
birds  was  affected  by  treatment  of  the  parents   (Schafer  et   al.,  1975).
There  was  no  evidence  of  secondary hazard potential among  predatory  birds
from  the consumption  of 4-am1nopyr1d1ne-k1lled  birds (Holler and  Schafer,
1982).
    Pharmacoklnetlc  data  1n humans Indicate that  4-am1nopyr1d1ne  1s  absorbed
readily  and  nearly  completely from the  gastrointestinal  tract (Uges  et  al.,
1982).   4-Am1nopyr1d1ne  appears to distribute  widely  throughout  the  tissues
(Rupp  et al.,  1983),  but  excretion data   (Uges  et  al.,  1982) suggest  that
              /
bloaccumulatlon  does not occur  1n  humans.   Metabolites  have not  been  found
In  the urine  of  humans  treated with  4-am1nopyr1d1ne, and  blotransformatlon
appears  unlikely  (Uges  et al., 1982).    In  a  study  using  volunteers  (Uges  et
al., 1982),  ~85X of  an oral  dose  and  90%  of  an Intravenous dose  of  4-am1no-
pyrldlne was  recovered  1n  the urine,  with an elimination half-life of  3.6
hours.
    4-Am1nopyr1d1ne  acts  on  the  nervous system  to  Increase  the  release  of
acetylchollne.   The  compound  has  been  used  In  humans  for the  reversal  of
residual neuromuscular  blockade from  some  neuromuscular  blocking  agents  and
antibiotics.   Experimental  uses  Include  treatment of patients  with Botullnus
Intoxication,  myoneural  disorders  and  Alzheimer's disease.  The clinical  use
of 4-am1nopyr1d1ne  Is  limited by  Us  narrow therapeutic  Index;  following  a
clinical dose  of 0.15-0.3 mg/kg  (route not  specified), the  only  side  effects

                                      v1

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noted  were a  slight  Increase  1n  systolic  blood  pressure  and  heart  rate,
while  doses  >0.5  mg/kg were  Hkely  to result  1n  restlessness,  confusion,
nausea, weakness  and ton1c-clon1c seizures  (Agoston et  al., 1985).  A case
report of  an accidental  oral  exposure  (Spyker et al.,  1980}  Indicated  that a
single dose of -0.6 mg/kg results In frank  effects  1n humans.
    The only data  concerning  the  subchronlc  oral toxlclty  of 4-am1nopyr1d1ne
are two 90-day  studies 1n the OPP CBI  files summarized by U.S.  EPA (1980b).
Kohn  (1968)  observed hyper1rr1tab1l1ty 1n  rats  at dietary concentrations of
30  and  300 ppm  4-am1nopyr1d1ne,  with  no  effects  noted at  3 ppm.  In dogs
(Cervenka  and  Vega,  1968),   salivation,  muscular  weakness  and  decreased
bralnwelght were observed at a doses of >1.0  mg/kg/day.
    4-Am1nopyr1d1ne  has  tested  negative for  reverse mutation  1n  Salmonella
typh1mur1um (Ogawa  et  al,,  1986;  Wakabayshl  et  al., 1982).   Data  concerning
the  carclnogenlcUy,  reproductive  effects  and  toxlclty  of  4-am1nopyr1d1ne
following  Inhalation  or  chronic  oral  exposure  were  not  available  1n  the
             /
literature  cited  1n  Appendix  A.   No effects  on  reproduction  or   fetal
development were  reported 1n rats  treated with  1-5 mg/kg/day by  Intraperl-
toneal Injection for 1 or 6 months (MHsov  and Uzunov,  1972).
    The only available  guideline  or standard for 4-am1nopyr1d1ne  Is an  RQ of
1000 pounds (U.S. EPA, 1985).                            •
    Because of  the  lack  of  data concerning cardnogen1c1ty  In  humans and
animals, 4-am1nopyr1d1ne  can  be  classified as a  CAG  Group  D  chemical.  The
derivation of  carcinogenic potency  factors  and a  cancer-based  RQ U pre-
cluded by  the  lack  of  carclnogenldty  data.  Based  on the  90-day  rat  study
by  Kohn  (1968),  subchronlc and chronic  oral  RfDs  of 0.0002  mg/kg/day  (0.01
mg/day) and  0.0002  mg/kg/day  (0.001  mg/day)  were calculated.   These RfDs
should be  considered  tentative because only limited  Information  concerning
the  CBI  studies  (Cervenka  and  Vega,  1968; Kohn,  1968)  were  available.

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Based on  low  confidence In the study  and  the  data base,  confidence In these
RfDs 1s  low.   Data were  Insufficient  for  the development  of freshwater and
saltwater criteria  for 4-am1nopyr1d1ne.  A chronic  toxic 1-ty. RQ for 4-amlno-
pyrldlne of 100 pounds was calculated from the Kohn (1968) 90-day rat study.

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                              TABLE  OF  CONTENTS
                                                                       Page
1.  INTRODUCTION. .	     1

    1.1.   STRUCTURE AND CAS NUMBER	     1
    1.2.   PHYSICAL AND CHEMICAL PROPERTIES 	     1
    1.3.   PRODUCTION DATA.	     2
    1.4.   USE DATA	     2
    1.5.   SUMMARY. .	     3

2.  ENVIRONMENTAL FATE AND TRANSPORT.	     4

    2.1.   AIR.	     4

           2.1.1.   Reaction with Hydroxyl  Radicals  	     4
           2.1.2.   Physical Removal .Processes	     4

    2.2.   WATER	     4

           2.2.1.   Hydrolysis	     4
           2.2.2.   Oxidation 	     4
           2.2.3.   Photolysis.	     5
           2.2.4.   M1crob1al Degradation ...  	     5
           2.2.5.   Volatilization	     5
           2.2.6.   Adsorption.  ...  	  ....     5
           2.2.7. .  Bloconcentratlon.  .	     6

    2.3.   SOIL	'.  .     6
           ./'•.•
          ,2.3.1.   Adsorption	     6
          12.3.2.   M1crob1al Degradation/Persistence 	     7
          1 2.3.3.   Volatilization	     8

    2.4.   SUMMARY	,	     8

3.  EXPOSURE	    10

    3.1.   HATER	    10
    3.2.   FOOD	    10
    3.3.   AIR.	    10
    3.4.   DERMAL	    10
    3.5.   SUMMARY	    10

4.  ENVIRONMENTAL TOXICOLOGY	    12

    4.1.   AQUATIC TOXICOLOGY	    12

           4.1.1.   Acute Toxic  Effects  on  Fauna	    12
           4.1.2.   Chronic Effects  on Fauna	    13
           4.1.3.   Effects on Flora	    14
           4.1.4.   Effects on Bacteria	    14
                                     1x

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                          TABLE OF CONTENTS (cont.)

                                                                       Page

     4.2.   TERRESTRIAL TOXICOLOGY  .  .  . .  .	   14

           4.2.1.   Effects on Fauna.  ...'.•	 .'	   14
           U4.2.2.   Effects on Flora	   22

     4.3.   FIELD STUDIES	   22
     4.4.   SUMMARY	   22

5.   PHARMACOKINETCS	   23

     5.1.   ABSORPTION	 .   23
     5.2.   DISTRIBUTION	   23
     5.3.   METABOLISM	   24
     5.4.   EXCRETION	   24
     5.5.   SUMMARY	   25

6.   EFFECTS	   27

     6.1.   SYSTEMIC TOXICITY	 .  . .   27

           6.1.1.   Inhalation Exposure 	 	   27
           6.1.2.   Oral Exposure  .	   27
           6.1.3.   Other Relevant Information.  .  	   28

     6.2.   CARCINOGENICITY	   31
     6.3.   MUTAGENICITY	   31
     6.4.   TERATOGENICITY	   31
     6.5.   OTHER REPRODUCTIVE EFFECTS 	   31
     6.6.   SUMMARY	,	   31

7.   EXISTING GUIDELINES AND STANDARDS	',•	   34

     7.1.   HUMAN.	   34
     7.2.,   AQUATIC	   34

8.   RISK ASSESSMENT	   35

    8.1.   CARCINOGENICITY.	   35

           8.1.1.   Weight of Evidence	,	   35
           8.1.2.   Quantitative Risk Estimates  .  . .	   35

    8.2.   SYSTEMIC TOXICITY	    35

           8.2.1.   Inhalation Exposure ...  	    35
           8.2.2.   Oral  Exposure . .  .	    35

    8.3.   AQUATIC	    38

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                           TABLE  OF  CONTENTS  (cont.)

                                                                        Page
 9.  REPORTABLE QUANTITIES .....	   40

     9.1.   BASED ON SYSTEMIC TOXICITY	   40
     9.2.   BASED ON CARCINOGENICITY	   40

10.  REFERENCES	   45

APPENDIX A: LITERATURE SEARCHED	   55
APPENDIX B: SUMMARY TABLE FOR 4-AMINOPYRIDINE	   58
                                      x1

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                               LIST OF TABLES
No.                               Title                               Page
4-1     Acute Toxldty of 4-AmlnopyMdlne to 36 Species of  Birds.  .  .   15
6-1     Acute Toxldty of 4-Am1nopyr1d1ne to Mammals.  . . '".:.	   30
6-2     Hutagenlc Testing of 4-Am1nopyr1d1ne	."  .   32
9-1     Oral Toxldty Data for 4-Am1nopyr1d1ne	   41
9-2     Composite Scores for 4-Am1nopyr1d1ne Based  on  Oral  Toxldty  .   42
9-3     Minimum Effective Dose (MED)  and Reportable Quantity  (RQ)  .  .   43

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                             LIST OF ABBREVIATIONS
ADI
BCF
CAS
CNS
CS
GMAV
HC1
LD50
LOAEL
MED
NOAEL
NOEC
NOEL
NOES
pKa
ppm
RBC
RfO
RQ
RVd
RVe
TLC
WBC
Acceptable dally Intake
Bloconcentratlon factor             ;
Chemical Abstract Service
Central nervous system
Composite score
Frank effect level
Genus mean acute value
Hydrochlorlde salt
Octanol/water partition coefficient
Concentration lethal to 50% of recipients
(and all other subscripted dose levels)
Dose lethal to SOX of recipients
Lowest-observed-adverse-effect level
Minimum effect dose
No-observed-adverse-effect level
No-observed-effect concentration
No-observed-effect level
National Occupational Exposure Survey
Negative log-|g of dissociation constant
Parts per million
Red blood cell
Reference dose
Reportable quantity
Dose-rating value
Effect-rating value
Thin layer chromatography
White blood cell

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                               1.  INTRODUCTION
1.1.   STRUCTURE AND CAS NUMBER
    4-AmlnopyMdlne  1s a  common chemical  name for  the compound  currently
referenced  'by  CAS  as 4-pyr1d1nam1ne  (SANSS,  1988).   Other  synonyms  for
4-am1nopyr1d1ne  Include   4-AP,   p-am1nopyr1d1ne,   am1no-4-pyr1d1ne,   gamma-
pyrldylamlne  and  4-pyr1dy1am1ne  (SANSS,  1988).   It 1s  also  known  by  the
tradename Avltrol  (Farm Chemicals Handbook,  1987).   The  structure,  molecular
weight, empirical  formula  and CAS Registry number for 4-am1nopyr1d1ne  are  as
follows:
Molecular weight:  94.12
Empirical formula:  CrH,N?
CAS Registry number:  504-24-5
1.2.   PHYSICAL AND CHEMICAL PROPERTIES
    4-Am1nopyr1d1ne  1s  an  odorless,  white  crystalline  compound  that  1s
stable  to  light and  moderately  soluble  1n water  (Farm Chemicals  Handbook,
1987).  It Is  soluble  In  alcohol, ether and benzene  (Weast,  1985).   Selected
physical properties are as follows:

Melting point:  <              158-9°C                    Weast,  1985
Boiling point:                273.5°C                    Hawley,  1981
Vapor pressure:
  at 180°C                    13 mm Hg                   Weast,  1985
  at  25°C (estimated)        0.00122 mm  Hg              U.S.  EPA,  1987
Water solubility:
  at 25°C                     76,600-83,000 ppm          U.S.  EPA/NIH. 1988

0124d                               -1-                              09/19/88

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 Log Kow:                       0.26                       Hansch and Leo, 1985
 pKa at  25°C                    9.11                       Weast, 1985
 A1r conversion                 mg/m3 =  3.9 ppm
 factors  (25*C):                ppm   =  0.26 mg/m3            .

 In  general,  the aminopyMdines react  with alkylatlng  agents  at  the aromatic
 nitrogen  to  give derivatives  (Goe,  1982).  With a pKa of 9.11 at 25°C (Weast,
 1985),  4-am1nopyr1d1ne Is a  strong  base 1n aqueous  solution  (U.S. EPA/NIH,
 1988).
 1.3.   PRODUCTION DATA
     4-Am1nopyr1d1ne  Is  manufactured   by  Rellly Tar  & Chemical  Corporation
 (Indianapolis,  IN),  which  produces  a  wide  range  of  pyrldlne compounds  by
 synthetic  processes  (SRI,  1987).   4-Am1nopyr1d1ne can be  produced by  the
 hydrogenatlon of 4-n1tro pyr1d1ne-N-ox1de 1n  the presence of  a  Raney-nlckel
 or  palladium-carbon catalyst  (Goe, 1982).
     Recent production  figures for 4-am1nopyr1d1ne  were not  located.   Rellly
 Tar  & Chemical  Corporation  sells  4-am1nopyr1d1ne  (97%  minimum purity)  1n
 packages  ranging from 1  kg cans to 55 gallon  drums (Kuney,  1986).   The U.S.
 EPA  TSCA  Production   File  for  1977   (U.S.  EPA, ,1977)  cites Rellly  Tar  &
 Chemical  Corp.   as  the only  U.S.  manufacturer of  4-am1nopyr1d1ne;  however,
        *                               •          (
 their 1977 production  volume  1s listed as confidential.
 1.4.   USE DATA
    4-Am1nopyr1d1ne,  sold  under the  trade  name AvHrol,  Is  used as a  bird
 repellent  (Farm  Chemicals Handbook, 1987; Hadler, 1982).  When Ingested from
 bait, 4-am1nopyr1d1ne  acts  as a soporific,  causing birds  to  utter  distress
 calls and  fly In uncoordinated and spiral patterns.   This aberrant  behavior
 frightens other   feeding flock  members  away from the crop area  (Hadler,  1982;
Carlson,  1984).   Some or all applications  of  Avltrol may be classified  by
0124d                               _2-                              09/19/88

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the  U.S.  EPA as  a  registered pesticide.   It  Is  used  to control  crows,
pigeons,  grackles,  starlings,  sparrows,  cowblrds, gulls  and blackbirds  In
and  around  structures  and agricultures  (sunflowers,  field  corn,  sweet corn).
It Is  applied  1n  grain baits  that  contain 0.5-3.0% 4-am1nopyr1d1ne or 25-50%
powder  concentrate  (Farm Chemicals  Handbook,  1987).   4-Am1nopyr1d1ne  can
also be used as an Intermediate (Hawley, 1981).
1.5.   SUMMARY
    4-Am1nopyr1d1ne  Is  an  odorless,   white   crystalline  compound  that  1s
stable  to light.   It  Is moderately soluble  1n water (Farm  Chemicals  Hand-
book,  1987).  The compound 1s  manufactured  by  Rellly  Tar  & Chemical  Corpora-
tion  (Indianapolis,  IN) by a  synthetic  process (SRI, 1987); recent  produc-
tion figures are not available.
    4-Am1nopyr1d1ne,  sold  under   the   trade   name  Avltrol,  1s  used  as  a
registered  bird   repellent  (Farm  Chemicals  Handbook, 1987;  Hadler,  1982).
Ingestlon  of  4-am1nopyr1d1ne-laden  bait  by  birds  results   1n  aberrant
behavior  that  frlghtenfs  away  other  flock members  (Hadler, 1982;  Carlson,
1984).  4-Am1nopyr1d1ne can also be used as an Intermediate (Hawley,  1981).
0124d                               -3-                              09/19/88

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                     2.   ENVIRONMENTAL FATE AND TRANSPORT
 2.1.   AIR
    Organic  compounds  having vapor  pressures  >0.0001  mm Hg are  expected to
 exist  almost   entirely   In  the  vapor   phase  In  the  ambient  atmosphere
 (E1senre1ch  et  al.,  1981).  Based on an  estimated vapor  pressure of 0.00122
 mm  Hg  at 25°C (U.S. EPA,  1987),  4-am1nopyr1d1ne  can  be expected  to exist 1n
 the vapor phase 1n ambient  air.
 2.1.1.   Reaction  with  Hydroxyl Radicals.   Using the method  of  Atkinson
 (1987),  the  rate constant  for   the  vapor phase reaction  of  4-am1nopyr1d1ne
 with  photochemlcally  produced   hydroxyl  radicals  can  be estimated  to  be
 47.9xlO~12   cm3/molecule-sec   at   25°C.    Assuming   a   typical   ambient
 atmospheric   hydroxyl   radical   concentration   of    5xlOf    molecules/cm3
 (Atkinson, 1985),  the  half-life for this reaction  can  be  estimated to be -8
 hours.   Thus,  reaction  with hydroxyl radicals  Is expected  to  cause  rapid
 loss of 4-am1nopyr1d1ne  1n  the atmosphere.
 2.1.2.   Physical  Removal  Processes.  4-Am1nopyr1d1ne  Is  soluble  1n water
 (Weast,  1985);  therefore,  removal  of the  free base  or  Its  salts  from  the
 atmosphere by wet deposition  processes (rainfall,  etc.) may be  possible.   If
 the salts of this compound  exist In  participate form  In the atmosphere,  they
 may be partly removed by dry deposition.
 2.2.   HATER
 2.2.1.   Hydrolysis.   Aromatic   amines  are  generally   resistant  to  aqueous
 environmental hydrolysis  (Harris,  1982).   Therefore,  4-am1nopyr1d1ne  1s  not
 expected to hydrolyze significantly 1n water.
      t
 2.2.2.   Oxidation.   As  a  chemical  class,   aromatic  amines  can   react
 relatively rapidly 1n sunlit  natural water  by  reaction  with photochemical1y-
 geqerated free  radicals  such as hydroxyl  radicals  and  peroxy radicals  (Mill

0124d                               -4-                              10/21/88

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and  Mabey,  1985).   Typical  half-lives for  the  reaction of  aromatic  amines
with  hydroxyl  and  peroxy  radicals on the  surface  of natural water are  -30
and  19.2 hours, respectively, (Mill and  Habey,  1985).   Although photooxlda-
tlon  rate constants specifically  for  4-am1nopyr1d1ne are  not available,  the
data  cited  above  suggest  that photooxldatlon of 4-am1nopyr1d1ne  In  natural
water may be an Important loss process.
2.2.3.   Photolysis.   4-Am1nopyr1d1ne  Is  reported  to   be  stable  to   light
(Farm  Chemicals   Handbook,   1987);   therefore,   direct   photolysis   Is  not
expected  to be  significant  1n  the  environment.  As  noted  above,  however,
4-am1nopyr1d1ne  may   react   relatively   rapidly with   oxldants  formed   by
sunlight In natural water.
2.2.4.   M1crob1al  Degradation.   Pertinent  data,  regarding  the  mlcroblal
degradation  of  4-am1nopyr1d1ne   In  water  could  not   be  located  In  the
available literature as  dted  1n Appendix A.  Based  on  the soil degradation
data presented  In  Section 2.3.,  however,  4-am1nopyr1d1ne may  be  resistant or
only slowly biodegradable by microbes 1n  water.
2.2.5.   Volatilization.  Using  the  chemical  bond estimation method of H1ne
and Mookerjee  (1975),  the Henry's Law constant  for  4-am1nopyr1d1ne can  be
estimated  to  be  2.81x10"'  atm-mVmol  at 258C.  This value  of  Henry's  Law
constant  Indicates  that  volatilization   from water  Is  not  environmentally
Important (Thomas, 1982).
2.2.6.   Adsorption.    Experimental   data   regarding   the   adsorption   of
4-am1nopyr1d1ne  to  suspended  solids  and sediment  1n   water could  not   be
located  1n  the available  literature  as  dted 1n  Appendix  A.   Although
4-am1nopyr1d1ne 1s  soluble  1n water,  the adsorption/leaching  data  presented
In  Section  2.3.  suggest that  some partitioning  from   the  water  column  to
humlc materials  present  1n  suspended  solids and  sediment may  occur  as  a
result of covalent binding.

0124d                               -5-                              09/19/88

-------
2.2.7.   B1oconcentrat1on.   The  BCF  of an organic  chemical  may be estimated
from  the equations  (Bysshe,  1982),

    log BCF » 0.76  log Kow - 0.23 and                       ;            (2-1)
    log BCF = 2.791 - 0.564  log water solubility
    (In ppm)                                                            (2-2)

Based  on  a log  K   of  0.26 (Hansch and  Leo,  1985) and a  water  solubility
of -80,000 ppm at 25°C  (U.S. EPA/NIH,  1988),  the BCF for 4-am1nopyr1d1ne can
be estimated  from both  equations  to be ~1.  This  Indicates  that  bloconcen-
tratlon 1n aquatic organisms may not be significant.
2.3.   SOIL
2.3.1.   Adsorption.  Starr  and  Cunningham (1975)  measured  the leaching  of
14C alpha-labeled 4-am1nopyr1d1ne In  three  alkaline soils (pH  7.6-7.8)  and
four  acidic soils (pH  4.1-5.8).   The leaching  tests  were  conducted  using 15
cm  long  soil columns  that  received an  Initial  surface application  of  the
4-am1nopyr1d1ne.   Over   a  20-day period,  1-7  Inches  of simulated  rainfall
                      t
were applied to  each column.  Sufficient  water  was  applied  every 2-3 days to
produce an  effluent  from the  bottom  of  each  column.   At  the  end  of  the
20-day  period,   only  0.02-0.18%  of  the  applied  radioactivity   had  been
recovered  In  the  effluents from   the  alkaline   soils,  while  <0.01%  was
recovered In  the effluents  from  the addle  soils.  Examination of  the soil
columns after the 20-day period  Indicated  that 95-99% of  the  radioactivity
applied to the alkaline  soils had remained  1n  the upper  1-Inch  layer of soil
and that essentially all of  radioactivity applied  to the acidic soils was In
the upper 1-Inch layer.   These  tests clearly demonstrated  that 4-am1nopyr1-
dlne may remain  adsorbed strongly onto  soil  colloids;  therefore,  significant
leaching 1s  not  expected to occur In most soils.
0124d                               -6-                              10/21/88

-------
    Aromatic  amines  have  been observed  to  undergo  rapid  and  reversible
covalent  binding with  humlc materials  In  aqueous solution  (Parrls,  1980).
The Initial  fast  reaction of the amlne group with carbonyl of humate to form
1m1ne  Unkoyd  1s  followed  by  a  slower and  much less  reversible  reaction
believed  to  represent  the addition  of the  amlne to  qulnoldal  structures,
followed  by oxidation of  the product to give an  amlno-substUuted  qulnone.
These processes  represent  pathways  by which  aromatic  amines may be converted
to latent  forms In the biosphere  (Parrls, 1980).   This covalent binding may
account for  the strong  adsorption  observed by Starr and Cunningham (1975) in
their soil column leaching studies.
2.3.2.   Mlcroblal  Degradation/Persistence.    The  degradation  of  4-amlno-
pyrldlne  1n  soil  has been  studied by  several  Investigators  (Na1k et  al.,
1972;  Betts  et  al., 1976;  Starr  and Cunningham, 1975;  S1ms  and  Sommers,
1985,  1986).    Their  results Indicate that   4-am1nopyr1d1ne  1s not  rapidly
destroyed 1n  soil, and may be relatively persistent.
    Na1k  et  al.  (1972)   examined  the degradation  of  4-am1nopyr1d1ne  1n
enrichment cultures using  a  1 mM solution of the chemical and a 0.5% aqueous
solution  of  fertile garden  soil  as  the   Inocula.    The  disappearance  of
applied 4-am1nopyr1d1ne  required >170 days  under  both  aerobic  and anaerobic
        *
conditions.   The  authors  concluded  that   am1nopyr1d1ne  Is   resistant  to
mlcroblal attack.
    Betts  et  al.  (1976)  examined  the degradation of  14C-labelled  4-am1no-
                i
pyrldlne  In  three  different soils  and 1n  pure cultures of five  soil  micro-
organisms.   In  aerobic   soil  degradation experiments,  a  lag  period of  -20
days   was  required   before  a   significant   rate   of   14CO_   evolution   was
observed In any  of  the  soils.   At  the end of 60 days,  6-24% of  the applied
radioactivity   had   been   recovered  as  14CO_.     In   60-day   flooded   soil


0124d                               -7-                              09/19/88

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 tests,  21-24% of applied radioactivity was  lost;  however,  the loss may have
 been  due  to  binding to  the soil  In an  unextractable  form  rather  than  to
 actual  degradation.   Pure cultures  of five microorganisms Isolated from soil
 were  unable to metabolize 4-am1nopyr1d1ne  In 5-6 days of Incubation.
    Starr  and  Cunningham  (1975)  studied  the degradation   of  14C-labeled
 4-am1nopyr1d1ne   In   various  alkaline   and  addle  soils   under  varying
 conditions.    Under   anaerobic   conditions,  metabollzatlon   to   14CO_  was
 negligible.   Under  aerobic conditions, a  lag  period of at least  1  week  was
 required  before  significant  conversion  to "CO-  was observed.   Metaboll-
 zatlon  rates  varied  significantly  with  soil type,  temperature and moisture
 content.   A  3-month C(L  evolution  rate  at  30°C  varied  from  0.4%  1n  an
 addle  (pH 4.1}  loam soil  to >50%  In a lighter textured,  alkaline (pH 7.8)
 loamy  sand.   The metabollzatlon  half-life  of  4-am1nopyr1d1ne In  the  soils
 tested ranged from -3 months to >22 months.
    Sims  and  Sommers  (1985,1986)   found   4-amlnopyrldlne  to  be  generally
              /
 resistant  to  degradation  1n  soil  decomposition  studies  using  a  silt  loam
 soil.   Only  -6%  degradation  at  an Initial concentration  of  2 mmol/kg  was
 observed   In  64  days.    The  authors  suggested  that  this   resistance   to
 blodegradatlon may  have been due to  toxlclty  of  the  4-am1nopyr1d1ne  to  the
 microorganisms.  'In  the  Belts  et  al.  (1976)   pure  culture study  mentioned
 above, 4-am1nopyr1d1ne was not toxic  to the  microorganisms, but also was  not
metabolized by the microorganisms.
 2.3.3.   Volatilization.   Sims   and  Sommers   (1985,  1986)   reported  that
4-am1nopyr1d1ne has  very low volatility from soil.
2.4.   SUMMARY
    When  released  to  the  atmosphere,  4-am1nopyr1d1ne  can be  expected  to
exist partly  1n  the  gas-phase where 1t will be degraded  rapidly  by reaction


0124d                               -8-                              09/19/88

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with  photochemically-produced  hydroxyl   radicals.   Using   the   method   of
Atkinson  (1987),   the  half-life  for  this  reaction  In  a  typical  ambient
atmosphere can be estimated  to  be 8  hours.   Because  4-am1nopyr1d1ne has  very
low volatility from soil  (S1ms  and Sommers,  1985,1986)  or  water,  however,  It
Is not  expected  to partition significantly  to  air when released  to  soil  or
water.  By  analogy  to  aromatic amines  as  a chemical class  (Mill  and  Mabey,
1985), 4-am1nopyr1d1ne may undergo significant  degradation  In  sunlit  natural
water by  reaction  with   photochemically-generated  free radicals.   Although
4-am1nopyr1d1ne Is soluble 1n water,  significant  partitioning  from .the water
                                                •
column  to  suspended solids  and  sediment  may  occur  because  of  a  covalent
binding reaction  that  has been observed  In  other  aromatic amines  (Parrls,
1980).   Hydrolysis,  direct   photolysis  and  bloconcentratlon may  not   be
Important.   The degradation  of  4-am1nopyr1d1ne 1n soil  has been  studied  by
several  Investigators  (Na1k  et al.,  1972; Betts et al.,  1976;   Starr  and
Cunningham,  1975;  S1ms and Sommers,  1985,  1986).  Although  the  blodegradatlon
                       »
In soil  can  vary  greatly,   their  results   Indicate  that  4-am1nopyr1d1ne  Is
generally  resistant to blodegradatlon In soil.  Soil  half-lives ranging  from
3  months  to  >22  months  have  been  observed (Starr  and  Cunningham,  1975).
Soil  column leaching studies  have  shown that 4-amlnopyrldlne  1s not  leached
significantly  1n  either  alkaline  or  addle  soils,  although  mobility  In
alkaline soils 1s  slightly greater  (Starr and Cunningham,  1975).
0124d                               -9-                              10/21/88

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                                 3.  EXPOSURE

    4-Am1nopyr1d1ne  1s  released  directly to the environment (primarily soil)
through  Us  use as a bird  repellent.   It  Is  applied  to  crop  fields  1n grain
baits  containing 0.5-3.0% 4-am1nopyr1d1ne or as a  25-50%  powder  concentrate
(Farm  Chemicals Handbook, 1987).  Environmental releases  from  waste  streams
or  fugitive  emissions  from the manufacture of  4-am1nopyr1d1ne  or  Us  use as
a  chemical  Intermediate  may  be minor  In relation  to Us  use  as  a  bird
repellent.
    From  the  preliminary  results   of   the   NIOSH  survey  (NOES)  conducted
between  1981  and 1983,  1t has been  estimated that  898  U.S. workers per  year
are potentially exposed to 4-am1nopyr1d1ne (NIOSH,  1985).
3.1.   WATER
    Pertinent  data  regarding the  monitoring  of   4-am1nopyr1d1ne  In  water
could not be located 1n the available literature as  dted 1n Appendix  A.
3.2.   FOOD
    Pertinent data regarding  the monitoring of  4-amlnopyrldlne  1n  food could
not be located  1n the available literature as  cited  1n Appendix  A.
3.3.   AIR
    Pertinent data regarding  the monitoring of  4-am1nopyr1d1ne In air  could
not be located  In the available literature as  cited  1n Appendix  A.
3.4.   DERMAL   /
    Pertinent data regarding  dermal  monitoring  of  4-am1nopyr1d1ne could  not
be located In the available literature as cited  In Appendix A.
3.5.   SUMMARY
    4-Am1nopyr1d1ne Is  released directly  to the environment (primarily  soil)
through  Us  use  as  a  bird  repellent.   Environmental  releases  from waste

0124d                               -10-                            10/21/88

-------
streams  or  fugitive  emissions  from  the manufacture  of  4-am1nopyr1d1ne or
Ususe as a  chemical  Intermediate may be minor  1n  relation  to Us use as a
bird repellent.  From a NIOSH survey  (NOES) conducted  between  1981 and  1983,
It  has  been  estimated that annually  about  398 U.S. workers are  potentially
exposed  to  4-am1nopyr1d1ne  (NIOSH,  1985).   Pertinent water,   food,  air or
dermal monitoring  data  could  not be  located  1n the available  literature as
cited In Appendix A.
0124d                               -11-                             10/21/88

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                         4.  ENVIRONMENTAL TOXICOLOGY
 4.1.    AQUATIC  TOXICOLOGY
 4.1.1.   Acute  Toxic  Effects on Fauna.  Schafer  and  Harking (1975) assessed
                                                   *         "i
 the  acute  toxlclty  of 4-am1nopyr1d1ne  to  channel catfish,  Ictalurus  punc-
 tatus.  and  blueglll  sunflsh,  LepomVs  macrochlrus.  at  various  temperatures
 and  water  hardnesses.  Water  hardness  concentrations  ranged  from  10-13,
 40-48,  160-180  and  280-320 mg/l  as  CaCO,  for  very  soft,  soft,  hard  and
 very  hard  water, respectively.  Toxdty of  4-am1nopyr1d1ne to catfish varied
 by  <2-fo1d  based on  variations  1n water  hardness  and  temperature.   The
 static  acute 3-, 6-,  24- and  96-hour  LC5Qs  (and  95X  confidence  limits)  for
 channel  catfish exposed to  4-am1nopyr1d1ne  at  22°C  1n  soft  water  were 13.8
 (12.3-15.5),< 13.8  (12.3-15.5),  9.35   (8.3-10.6) and  5.B  mg/l  (5.2-6.4),
 respectively.   Values  for   the  6-,  24- and  96-hour   exposure  periods  for
 catfish  1n  soft water  at 17°C  were 16.4 (13.8-19.4),  9.8 (8.6-11.2) and 4.36
 mg/l  (3.9-4.8),  respectively.  Toxldty of 4-am1nopyr1d1ne  to  catfish  at
 12°C  ranged  from  4.36  mg/l   (LCCQ)   ^n  verv  nard  water  to   8.74  mg/l
 (LC5Q)  In   soft  water  after 24  hours.   The  96-hour  LC5Qs ranged  from 2.43
 mg/l 1n very hard water to 4.00 mg/l 1n hard, soft and very soft water.
    The  ;3-,  6-, 24-  and  96-hour  LC5Qs  (and  95%  confidence  limits)  for
 blueglll sunflsh  exposed to 4-am1nopyr1d1ne at  22'C 1n  soft  water  were 18.1
 (15.3-21.4),  15.0 (13.0-17.3).  12.3  (10.7-14.1)  and  7.56 mg/l  (6.3-9.1),
 respectively.   Values  1n  soft  water  at 17°C  were  18.1  (15.3-21.4),  16.2
 (14.1-18.6),  11.8 (9.7-14.3)  and  5.60  mg/l  (4.8-6.5), respectively.   The
 3-hour  LC.Q for sunflsh at  12°C was Identical  1n very soft and soft  water
 (38.1   mg/l).   The  6-hour   LC5Qs  1n  very  soft,   soft  and  hard  water  were
 26, 23.2  and 38.1  mg/l,  respectively.   The 24-hour  LC5Q  ranged from  8.60
0124d                               -12-                             09/19/88

-------
mg/l  1n  very hard  water to  12.3 mg/l  1n  hard  water.   The 96-hour  LC5Q
ranged  from  2.82  mg/l 1n hard  water  to  4.41 mg/l  1n soft  water  (Schafer
and Marking,  1975).     :
    Marking  and  Chandler  (1981)  assessed the  acute  toxldty  of  4-am1nopyr1-
dlne  to a  variety of  aquatic  Invertebrates  1n  static tests.  All  studies
were  conducted  In  reconstituted  water  with  a  hardness  of <40  mg/l  as
CaCO-.   Tests with  mayfly  nymphs, Isonychla  sp., were  conducted at  12°C.
Tests with  water  fleas,  Daphnla  magna. were  conducted at 21°C.  All  other
tests  were  conducted  at 16°C.    The  6-,  24- and  96-hour  LC5Qs  (and  95%
confidence  Intervals)  for  D_. magna  were  24  (19-30),  17  (14-20)  and  3.2
mg/l  (2.3-4.5),   respectively.    Values   for  glass   shrimp,  Palaemonetes
kadlakensls.  were  47  (32-70),  3.3  (2.3-4..6)  and  0.37  mg/l  (0.25-0.56),
respectively.  Values  for crayfish,  Procambrus  acutus  acutus. were >60,  14
(11-18)   and  2.2  mg/l  (1.7-2.8),  respectively.  Values  for mayflys  were  24
(20-28),  5.3  (3.9-7.2)  and  0.58  mg/l  (0.45-0.74),  respectively.    Values
for caddlsfly larvae,  'Hydropsvche  sp., were  99  (78-130),   30  (21-41)  and  15
mg/l  (9.8-22),  respectively.   Values  for frog  larvae, Rana  sphenocephala.
were >30,  7.2 (6.6-7.8)  and  2.4 mg/l (2.0-2.9), respectively.  The  24- and
96-hour   .lCcQs  (and  95%  confidence  Intervals)  for  adult  Asiatic  clams,
Corblcula  manllensls.  were 78  (69-88)  and  45  mg/l (40-50),  respectively.
Values  for  adult  river  horn  snail,  Oxytrema  catenarla.   were  >100 and  62
mg/l (53-73), respectively.
4.1.2.   Chronic  Effects on  Fauna.
    4.1.2.1.   TOXICITY -- Marking   and   Chandler   (1981)   assessed  hatching
success   and  larval survival   of  the  leopard  frog,  Rana sphenocephala.  upon
exposure to 4-am1nopyr1d1ne.   Eggs were exposed  to 4-am1nopyr1d1ne within  16
hours after  deposition at a  temperature  of  16°C  under static  conditions.
0124d                               -13-                             09/19/88

-------
 The  exposures  were  continued  until   eggs  hatched  or  development  ceased.
 Hatching  of control eggs  required  9-11 days.  The  Investigators  reported a
 hatching  success of  <5X  among  eggs exposed  to  <10 mg/l.   Larval  survival
 was >95X  at  1 mg/i  but <5X at  2 mg/l.
    4.1.2.2.   BIOACCUMULATION/BIOCONCENTRATION — No  measured  steady-state
 BCF  value  for  4-am1nopyr1d1ne was  found 1n  the literature.  Based  on the
 regression  equation,  log  BCF  •  0.76   log  K   -  0.23  (Lyman et  al.,  1982)
 and  a  log  K   value  of  0.26  (see Section  1.2.),  a  BCF  value of  0.93 1s
 estimated  for  this  compound.  This  value  suggests  that 4-am1nopyr1d1ne will
 not bloaccumulate significantly 1n aquatic organisms.
 4.1.3.    Effects on Flora.
    4.1.3.1.   TOXICITY — Pertinent data regarding  the  effects  of  chronic
 exposure  of aquatic  flora to  4-am1nopyr1d1ne could not  be located  In the
 available literature as cited  In Appendix A.
    4.1.3.2.   BIOCONCENTRATION — Pertinent  data regarding  the  bloconcen-
 tratlon  of  4-am1nopyr1d1ne  by aquatic flora  could  not be  located  In  the
 available literature as cited  1n Appendix A.
 4.1.4.    Effects  on  Bacteria.   Pertinent  data  regarding  the  effects  of
 exposure  of  aquatic bacteria  to 4-am1nopyr1dlne could  not  be located 1n the
 available literature as cited In Appendix A.
 4.2.   TERRESTRIAL TOXICOLOGY
 4.2.1.    Effects on Fauna.   Schafer  et  al.  (1973a)  summarized  the existing
 Information  regarding  the  toxlclty  of   4-am1nopyr1d1ne  to birds  (Table 4-1).
 Oral LDgQ  values  ranged from  2.4 mg/kg for  several  species  to 35 mg/kg for
 the domestic chicken. Gall us gall us.  Only one study  reported an  Intramuscu-
 lar  LD5Q:  2.4  mg/kg  for  the  red-winged  blackbird,  Aqelalus  phoenlceus.
 Dermal  LD5Qs  reported for  red-billed   quelea,  Quelea  quelea. and  sparrows,
Passer  domestlcus.  were both >100 mg/kg.

0124d                               -14-                             09/19/88

-------
                                                     TABLE 4-1

                             Acute Toxlclty of 4-Amlnopyrldlne to 36 Species of Birds*
1
tn
1
CD
Species
(mixed or unknown sex
unless noted) — -
Scaled dove
.Scardafella squammata
Ruddy-breasted seedeater
Sporophlla rolnuta
Brown-throated parakeet
Aratlnga pertlnax
Blue-black grassqult
Volatina jacarlna
Olckclssel
Splza amerlcana
Orange-fronted parakeet
Aratlnga canlcularls
Ruddy ground dove
Columblgalllna talpacotl
Shiny cowblrd
Nolothrus bonarlensls
Black-billed magpie
Pica pica
Route
per os
per os
per os
per os
per os
per os
per os
per os
pef os
•--.. Carrier LDso
grain >4
grain <7.2
grain -10
grain 10
grain -10
grain -12
grain <25
propylene glycol , <1.0
propylene glycol 2.4
95X
Confidence Limits
(rag/kg)
NR
NR
NR
5.6-18
NR
NR
NR
NR
NR
GO
00

-------
                                                 TABLE 4-1  (cont.)
o.
1
1
o
VO
Species
(mixed or unknown sex
unless noted)
Common crow
Corvus brachyrhynchos
Yellow-billed magpie
Pica nuttalll
Common grackle
Qulscalus qulscula
Bronzed cowblrd
Tangavlus aeneus
Mallard
Anas platyrhynchos
Robin
Turdus migrator lus
Brown-headed cowblrd
Molothrus ater
Trlcolored blackbird
Agelalus tricolor
Sparrow hawk
Falco sparverlus
Budgerigar
Route
per os
per os
per os
per os
per os
per os
per os
per os
per os
per os
Carrier
propylene glycol
"propylene glycol
propylene glycol
propylene glycol
propylene glycol
propylene glycol
propylene glycol
propylene glycol
propylene glycol
propylene glycol
LD50
2.4
2.4
2.4
3.2
4.2
4.2
4.2
4.2
5.6
5.6
95%
Confidence Limits
(rag/kg)
NR
NR
NR
1.8-5.6
NR
2.4-7.5
NR
NR .
4.2-7.5
NR
     Melopslttacus  undulatus
CD
CO

-------
                                                 TABLE 4-1 (cont.)
0
no
Q.
1
_i
~J
O
tO
V.

Species
(mixed or unknown sex
unless noted)
House finch
Carpodacus mexlcanus
Golden -crowned sparrow
Zonotrlchla atrlcapllla
White-crowned sparrow
Zonotrlchla leucophrys
Ring-necked pheasant
Phaslanus colchlcus
(4 weeks) (female)
Coturnlx quail
Coturnlx coturnlx
(male, and female)
Hour n Ing dove
Zenaldura macroura
Green jay
Cyanocorax yncas
White-winged dove
Zenatda aslatlca
Ring-billed gull
Larus delawarensls
Bobwhlte


Route
per
per
per
per
per
per
per
per
per
per
per
per
OS
OS
OS
OS
OS
OS
OS
OS
OS
OS
OS
OS


Carrier
propylene
propylene
propylene
propylene
propylene
propylene
propylene
propylene
propylene
propylene
water
water
glycol
glycol
glycol
glycol
glycol
glycol
glycol
glycol
glycol
glycol '


LD50
5
5
5
7
5
7
8
8
13
8
15
.6
.6
.6
.5
.6
.65
.05
.1
(HC1)
(HC1)


95X
Confidence Limits
(rag/kg)
NR
3.2-10
3.2-10
5.7-9.8
3.2-10
6.59-8.89
7.01-9.24
7.5-10
NR
NR
NR
NR
00    Collnus vlrglnlanus

-------
                                                TABLE 4-1 (cont.)
to
o.
CO
            Species
     (mixed or unknown sex
         unless noted)
Route
Carrier
       95%
Confidence Limits
     (rag/kg)
Starling
Sturnus vulgar Is
Domestic chicken
Gallus gallus
(2-3 weeks)
per os
per os
per os
per os
per os
water
pellet
propylene glycol
water
water
14 (HC1)
<6
4.9
35 (HC1)
15 (HC1)
NR
NR
3.6-6.6
NR
NR
Red-winged blackbird
Agelalus phoenlceus
L (male)
CO
1
Common pigeon
Columbia llvla
House sparrow
Passer domes tlcus

Red-billed quelea
Quelea quelea
Boat-tailed grackle
o Cassldlx mexlcanus
to
per os
per os
per os
Intramuscular
per os
per os
per os
per os
per os
per os
dermal
per os
dermal
per os
per os
water ,
water
propylene glycol
propylene glycol
water
propylene glycol
propylene glycol
water
water
water
acetone
propylene glycol
acetone
propylene glycol
water
8.5
3.2 (HC1)
2.4
2.4
20 (HC1)
7.5
7.5
4.0
3.8
3.6
>100
5.6
>100
3.2
1.7-7.1
NR
NR
1.5-3.8
NR
NR
NR
NR
NR
NR
NR
NR
3.2-10
NR
1.8-5.6
NR
m *Source: Schafer et al., 1973a
   NR = Not reported

-------
    Schafer et al.  (19735)  reported  the  oral  and  dermal  toxldty of 4-am1no-
pyrldlne  to quelea.  Quelea quelea.  house  sparrows.  Passer domestlcus.  and
red-winged  blackbirds,  Agelalus  phoenlceus.   Oral  toxldty  was  determined by
per  os administration  of  propylene  glycol  solutions  from a  mlcrosyrlnge.
Dermal  toxldty  was determined by  applying  acetone solutions  to a  sparsely
feathered  skin  area.   The  acute oral  LD~Qs were  5.6,  7.5 and 2.4  mg/kg,
respectively.   The  dermal  LD..S  for quelea  and  sparrows were  both  >100
mg/kg.  LD5Qs  were  based on  a 4-day  observation period following a  single
dose of 4-am1nopyr1d1ne.
    Schafer and Harking  (1975) assessed  the  effects of long-term exposure of
bobwhHe  quail,   Collnus   v1rg1n1anus.   mourning  dove,  Zenalda   macroura.
ring-necked  pheasant,  Phaslanus  colchlcus.  quail, Coturnlx  coturnlx.  and
starling,   Sturnus  vulqarls.   to  4-am1nopyr1d1ne.    Acute   oral  LD5Qs  for
quail, dove and  female  pheasant  offered  3% 4-am1nopyr1d1ne-contam1nated bait
(cracked  corn)  for  7-35  days were  15.0, 8.1  and  7.5 mg/kg,  respectively.
The  acute  oral  LD5Qs'for  quail  offered 4-am1nopyr1d1ne-contam1nated  feed
(<1,000 ppm)  for 28-40  days  were 7.65  mg/kg for  males  and 8.05 mg/kg  for
females.  An  L05Q  for  doves  offered contaminated  feed  could  not be  calcu-
lated because of an  Insufficient  level of mortality.  Treatment  of  starlings
by gavage  dally  for  25  days  with a  propylene  glycol  solution  containing  a
dose  of  1.78 mg/kg  4-am1nopyr1d1ne resulted In  an acute  oral  LD5Q of  4.9
mg/kg.         >
    Schafer et al.  (1975) assessed  the effects  of  4-am1nopyr1d1ne on  repro-
duction and survival  In quail, Coturnlx  coturnlx. 1n three  separate  studies.
In the  Initial  study,  male and  female  birds were  gavaged  with a  propylene
glycol  solution  containing  either   0 or  5.62  mg/kg  4-am1nopyr1d1ne,  then
paired  with  untreated  mates.   All  birds  treated  with 4-am1nopyr1d1ne
0124d                               -19-                             09/19/88

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 exhibited hyperactlvlty, tremors and minor  motor  seizures  within 4 hours of
 treatment,  while two males  died within 24  hours  of treatment.  Egg produc-
 tion by treated females was reduced significantly during the 3rd week of  the
 study.   Hatchab111ty of eggs was not  affected.   In a second study, breeding
 pairs  were  fed  a   diet  that  contained  0-1,000  ppm 4-am1nopyr1d1ne  for 4
 weeks.   No  effects  were observed among  birds  fed  <31.6 ppm 4-amlnopyrldlne.
 There  were  no  significant  reproductive  effects among birds  fed 100 and  316
 ppm  4-am1nopyr1d1ne, although growth among males during the 4-week study  was
 depressed and  food  consumption was  reduced  for  the first  2 weeks In the  316
 ppm  dose group.  All birds  dosed with  1,000 ppm 4-amlnopyrldlne died within
 3  weeks.  The  28-day  LC5Qs  for male  and  female  quail  1n this  study  were
 447  and  562  ppm,  respectively.   In the  third study,  the F,  progeny  from
 the  second  study were mated when they reached sexual maturity; no effects on
 reproduction were observed among these birds.
     Garrison  et  al.  (1982)  assessed  the  lethal   and  sublethal effects  of
 4-am1nopyr1d1ne  to  three species of mannlklns, Lonchura punctulata. Lonchura
 leucogaster  and  Lonchura  malacca.  and  one  species  of  sparrow,  Passer
 montanus.   Birds were  dosed  with  various  concentrations  of  4-am1nopyr1d1ne
 1n  propylene  glycol. using  a  50 ml  syringe with  4 cm polyethylene  tubing
 attached  to the  needle.   Four to six birds per treatment {species dependent)
 received  a  dose  volume  of  10 yl/10  g   bw.   The  Investigators  reported
 L05Q   values   (and   95%  confidence  limits)   of   7.94   (5.47-11.52),   3.11
 (2.62-3.69), 4.45  (3.33-5.97) and  3.54 mg/kg  (1.84-6.80)  for  L. punctulata.
 L_. leucogaster.  L_.  malacca and  P.  montanus. respectively.  Garrison  et al.
 (1982)  reported that the  average  times  from  dosing with  5.0  mg/kg  to the
                                                            »
 first  distress  call  emitted  by dosed birds were  33.8,  21.3,   52.8  and  23.0
minutes,  respectively.    The  Investigators also   assessed  the  effects  of


0124d                               -20-                             09/19/88

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4-am1nopyr1d1ne-treated  grain  on  sparrows.   Six  birds  were force-fed  one
kernel  of  Mce  treated  with either  0.5   (4.4  rag/kg)  or  l.OX  (9.8  mg/kg)
4-am1nopyr1d1ne.   All  birds demonstrated effects  from  the  treatments  within
30  minutes.   The  average  times   to  mortality   were  90  and  26  minutes,
respectively.
    Holler  and  Schafer  (1982)  assessed the hazards to  sharp-shinned  hawks,
Acdpter  strlatus.  and  American   kestrels,   Falco  sparvelrus.  from  the
consumption  of  blackbirds killed with  4-am1nopyr1d1ne.  The  food source  for
Isolated  hawks  and kestrels  was obtained  by  feeding  caged  blackbirds a  1%
4-am1nopyr1d1ne bait diluted  1:1 or  1:9 or  a  3% 4-am1nopyr1d1ne  bait diluted
1:99.   Dead  blackbirds   were frozen  at  -20°C until  needed.   Hawks  were
offered two  dead  blackbirds/day for 7  days, while kestrels  were offered  one
dead blackbird/day  for  7 days. The  Investigators  reported  that  there  was  no
Indication of secondary  hazard potential to either  of  these  predatory birds
from the consumption of 4-am1nopyr1d1ne-contam1nated blackbirds.
    Hudson  et al.' (1984)  reported  acute oral  LD5Qs for male mallard  ducks,
Anas platyrhynchos.  offered  products  containing  95 and 99.9%  4-am1nopyr1-
dlne.   The   oral  LD5Qs  (and  95% confidence  limits)  for  3-  to  4-month-old
ducks were 4.36 (3.36-5.66) and 5.19 mg/kg (4.00-6.73),  respectively.
    Sultana  et   al.  (1986)  determined the  acute  oral  LD5Q  of  4-am1no-
pyrldlne  for rock  dove,  Columba  11v1a.  rose-ringed  parakeets,  PsUtacula
kramerl.  house   sparrows,  Passer   domestlcus.   and   white-backed   munlas,
Lonchura  strlata.   Birds  were  gavaged with  propylene  glycol  solutions  of
4-am1nopyr1d1ne by  mlcrosyrlnge or  ball-tipped gavage  needle,   then  segre-
gated  one  to a cage and monitored   for  mortality  for  48 hours  after  treat-
ment.   The   Investigators  reported  L05Q values  (and 95% confidence  limits)
of  2.50  (3.73-1.68),  3.02  (3.02-3.02),  4.20  (7.14-4.28)   and  2.97  mg/kg
(4.26-2.08), respectively.

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4.2.2.   Effects  on   Flora.    Pertinent  data  regarding  the   effects   of
exposure of  terrestrial  flora  to  4-am1nopyr1d1ne could  not  be located  In  the
available literature as dted In Appendix A.             '•;,.
4.3.   FIELD STUDIES
    Pertinent  data  regarding  the  effects  of 4-am1nopyr1d1ne  on flora  and
fauna  1n the  field  could  not  be located In the available literature  as  cited
In Appendix A.
4.4.   SUMMARY
    Studies assessing  the  acute  toxldty of  4-am1nopyr1d1ne  to  fish  revealed
that  toxldty  was  not  dependent  on  water  temperature or  hardness.    The
96-hour LC5Qs  for  channel catfish  and  blueglll  sunflsh exposed  to  4-amlno-
pyrldlne  ranged  from  2.43-7.56  mg/i   (Schafer  and  Marking,   1975).    The
toxldty of  4-am1nopyr1d1ne to  aquatic  Invertebrates was  assessed by Marking
and Chandler  (1981).   Juvenile  glass  shrimp were the most  sensitive spedes
tested  . (96-hour   LC5Q=0.37   mg/SL),    followed   by  mayfly   nymphs   (0.58
mg/l),  crayfish  (2.2  mg/i),   frog larvae  (2.4  mg/l),  water  fleas  (3.2
mg/i),  caddis fly larvae   (15  mg/i),   Asiatic  clams  (45  mg/l)  and snails
(62 mg/i).   The NOEC  for  larval  frogs  appears  to be  <1  mg/l  (Marking  and
Chandler, 1981).
                 ;
    The toxldty  of 4-am1nopyr1d1ne to  birds  was  studied  extensively  by a
series  of  Investigators.   Oral  LD5Q  values  ranged  from  2.4-35 mg/kg  for
periods  of  exposure   and   observation   of  varying  lengths. There  was   no
                i
evidence  that  reproduction  among the  progeny  of  4-am1nopyr1d1ne-treated
birds  was  affected  by  treatment   of  the parents  (Schafer  et  al., 1975).
There  was  no evidence  of  secondary hazard  potential  among  predatory  birds
from  the  consumption   of  4-am1nopyr1d1ne-k1lled  birds  (Holler  and  Schafer,
1982).


0124d                               -22-                             10/21/88

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                             5.  PHARHACOKINETICS
5.1.   ABSORPTION
    In a  study  by  Uges  et al.  (1982),  six volunteers (60-81 kg) were treated
                                                            <           t
orally  with  20  mg  4-amlnopyMdlne  (two  10  mg  enteric-coated  tablets).
Concentrations  of  4-am1nopyr1d1ne In  the serum and  urine were  measured  at
varying  Intervals  for up  to 9 and 36 hours,  respectively.   4-Am1nopyr1d1ne
was  detected  1n   the  serum 128±38  minutes  after  Ingestlon  of the  coated
tablets,  and a  maximum  serum concentration of  62±15 yg/l  was reached  at
193i51 minutes after  treatment.   Based on urinary excretion  data, the Inves-
tigators .estimated that 98±8% of  the  dose  was absorbed.  The  same subjects
and three  additional volunteers  (one  male,  two  females)  were  also  treated
with  an  Intravenous  Injection of 20  mg 4-aro1nopyr1d1ne  (at least  14  days '
between  treatments).   By  comparing  serum  4-am1nopyr1d1ne  concentrations
following  oral  and  Intravenous  dosing,  the  Investigators   calculated  that
b1oavanab111ty was 95^29%.
    Coated  capsules  were  required  for oral  treatment with  4-am1nopyr1d1ne
because of  the occurrence  of gastric cramps  1n  three  of  four persons treated
with  uncoated  tablets  (two  10  mg  tablets).   Following  treatment  with
uncoated  tablets,  urine  and  saliva  concentrations  of 4-am1nopyr1d1ne  were
measured.   4-Am1nopyr1d1ne  was  found   1n   the  saliva   -6  minutes  after
Ingestlon,  with salivary  concentrations higher  than  those  In serum,  and
peaking at  25±30  minutes.  The  Investigators  stated  that the  rapid  absorp-
tion of 4-am1nopyr1d1ne  (beginning within 15  minutes  of  Ingestlon)  Indicates
that the compound  1s absorbed from the  stomach.
5.2.   DISTRIBUTION
    Following oral  and  Intravenous  treatment  of human volunteers  (60-81  kg)
with a  20 mg dose of 4-am1nopyr1d1ne, no  difference was found  In 4-am1no-
pyrldlne  concentrations  1n the  serum   before  and  after  ultraflltratlon,

0124d                                -23-                              09/19/88

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 Indicating negligible binding  to  serum proteins  (Uges  et  al., 1982).  In a
 review of the pharmacoklnetlcs and side-effects of 4-am1nopyr1d1ne, Sohn and
 Uges   (1981)   stated   that   the compound   readily crosses   the   blood-brain
 barrier.   Supporting  data were  not  provided.
    Rupp  et al.  (1983)  treated seven fasted anesthetized  mongrel dogs with
 an  Intravenous   Injection  of  4-am1nopyr1d1ne  (1 mg/kg).    The   volume  of
 distribution  was  calculated  to  be  8.6   times   the  volume  of   the   serum,
 suggesting extensive  distribution to  the tissues.
 5.3.   METABOLISM
    In  the study by  Uges  et al.  (1982),  urine collected for  24  hours from
 persons  treated  with 4-am1nopyr1d1ne  as  described  above  (six  oral, nine
 Intravenous)  contained  >85%  of  the  administered  dose.    When   urine  was
 Incubated  with  beta-glucuronldase  or  hydrochloric  add  there was no Increase
 1n  the amount  of  detectable free  4-am1nopyr1d1ne In the  urine,   suggesting
 that  4-am1nopyr1d1ne  did not  undergo glucuronldatlon or sulfonatlon.   Using
 a TLC technique, N-ace'tyl-4-am1nopyr1d1ne  hydrochlprlde  was  not  detected In
 the  urine  from  volunteers  treated  with  4-am1nopyr1d1ne,   Indicating that
 N-acetylat1on   of   4-am1nopyr1d1ne   had  not  occurred.    The  Investigators
 concluded  that blotransformatlon of 4-am1nopyr1d1ne 1s unlikely.
 5.4.   EXCRETION
    In a  study  by Evenhuls  et  al.  (1981),  six  volunteers anesthetized for 1
 hour  with a  ketamlne-dlazepam anesthetic  were  treated  with  an  Intravenous
 Injection  of  4-am1nopyr1d1ne  (a ketamlne-dlazepam antagonist) at  a dose of
 0.3 mg/kg.   Blood and  urine were  sampled  and  analyzed  for  4~am1nopyr1d1ne
 for varying  periods  up to 8 or  48  hours,  respectively.   In  five  of  the  six
 volunteers, a  secondary  Increase In  plasma  concentration was  observed after
 the  Initial  decrease.   The  time   of onset of  the  secondary Increase  was

0124d                               -24-                             09/19/88

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highly  variable  between  Individuals,   occurring   20-90  minutes  after  the
Injection.  4-Am1nopyr1d1ne excreted  1n  the  urine  accounted  for  84.7% of the
dose 12-14 hours after the Injection and 87.3X of the dose at 48 hours.
    In  volunteers  given  an  Intravenous  Injection of 4-am1nopyr1d1ne (20 mg),
Uges et al.  (1982) reported that the elimination  half-life  In  the serum was
3.6±0.9  hours.  About  30  hours  after  six  human  volunteers  were given  an
Intravenous  Injection  of  4-am1nopyr1d1ne,  90.6±7.8X  of the  compound  was
excreted  In  the urine.   About  30 hours  following  an oral  dose  of 4-am1no-
pyrldlne  (20  mg)   1n enteric-coated  tablets,  88.5+4.8% of  the  unchanged
compound  was   excreted   1n  the   urine.   Treatment  of  four  volunteers  wHh
uncoated  tablets of 4-am1nopyr1d1ne resulted In  the recovery of  86.3^6.7% of
the  dose  1n   the  urine  1n -30  hours.   The   Investigators concluded  that
excretion was almost exclusively through the kidney.
    During  10 hours  after  dosing,  Rupp  et  al.  (1983)  recovered from the
urine of  seven fasted anesthetized dogs  60±9X of  a  dose  of 4-am1nopyr1d1ne
              /
at  1  mg/kg.   During  the same  period,  only 0.QUO.01% of  the  administered
compound was recovered In the bile.   An  elimination half-life  of 125  minutes
was calculated.   The  Investigators  estimated  renal  clearance rate  -4-fold
greater  than  glomerular  filtration rate  and concluded that renal  excretion
Involved tubular secretion.
5.5.   SUMMARY
    Pharmacok1net1c data  1n humans  Indicate  that 4-amlnopyrldlne  1s absorbed
readily and nearly  completely from  the gastrointestinal tract (Uges  et al.,
1982).   4-Am1nopyr1d1ne  appears  to  distribute widely  throughout  the  tissues
(Rupp et  al., 1983),  but excretion  data  (Uges  et  al.,  1982) suggest  that
bloaccumulatlon does  not occur  1n humans.   Metabolites  have not  been  found
In  the  urine  of humans  treated  with 4-am1nopyr1d1ne, and blotransformatlon


0124d                               -25-                             09/19/88

-------
appears  unlikely (Uges  et  al.,  1982).   In a  study using  human  volunteers
(Uges et  al.,  1982),  -85% of an oral dose and  90%  of  an Intravenous  dose of
4-am1nopyr1d1ne was recovered 1n  the  urine,  with  an elimination half-life of
3.6 hours.
0124d                               -26-                             10/21/88

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                                  6.   EFFECTS
6.1.   SYSTEMIC TOXICITY                           :
6.1.1.   Inhalation  Exposures.    Pertinent  data  regarding  the  toxlclty  of
4-am1nopyr1d1ne  following subchronlc  or  chronic  Inhalation  exposure  could
not be located In the available literature as  cited 1n Appendix  A.
6.1.2.   Oral Exposure.
    6.1.2.1.   SUBCHRONIC — The  only  data  regarding  the  subchronlc   oral
toxldty of  4-am1nopyr1d1ne  are two studies  In the OPP  CBI  files  summarized
by  U.S.   EPA  (19805).   Kohn   (1968)   fed   rats   (number  not   provided)
4-am1nopyr1d1ne hydrochlorlde In  the  diet at  concentrations of  3,  30 or 300
ppm for  90 days.  Information  regarding  controls was not provided.  At 300
ppm,  all   surviving  rats  (specific  survival  data   not   provided)   were
hyperlrrKable to  noise and touch.   Brain weights  of female rats  and  liver
weights  of  male  rats  treated  at  300  ppm  were   significantly  (p<0.05)
elevated..   No  changes  1n  blood  and  urlnalyses  were  noted.   Gross  and
              /•
hlstopathologlc  examinations  also  did  not  reveal  any  significant  changes.
Additional .data   In  the  CBI version  of the  study  Indicate  that  sporadic
hyper1rr1tab1l1ty also  occurred at 30  ppm,  and  that the 3  ppm dose  was  a
NOEL (U.S. EPA, 1986a).
    In a study by Cervenka and  Vega  (1968), beagle dogs  (number unspecified)
were  fed  diets  containing  4-am1nopyr1d1ne hydrochlorlde at concentrations
that provided doses  of  0.1,  1.0 or  2.0-3.25 mg  4-am1nopyr1d1ne/kg/day  for 90
days.   Information regarding controls was riot provided.  At  >2.0  mg/kg/day,
dogs  exhibited   salivation  and   muscular  weakness;  no  hlstopathologlcal
lesions were  observed.   According to  the summary, no  dose-related  trends In
mean organ weights  were  observed,  although  at  the  two highest doses  brain
weights  were slightly  decreased.  The  review .from  which these  data  were
taken  (U.S.  EPA,  1980b)  stated that  "examination of the brain revealed no

0124d                               -27-                             10/21/88

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 abnormalities,*  but  the  extent and  protocol of  that examination  were  not
 described.   No changes  1n blood and uMnalyses were noted.
     6.1.2.2.   CHRONIC  — Pertinent   data    regarding   the   toxldty   of
 4-am1nopyr1d1ne  following  chronic  oral  exposure could not  be  located 1n  the
 available literature  as dted  In Appendix A.
 6.1.3.   Other  Relevant  Information.   4-Am1nopyr1d1ne  acts  at  the  motor
 nerve  terminal  to  decrease membrane potassium conductance,  which  prolongs
 the  action  potential,  causing an  Influx of  calcium  and an Increase  In  the
 release  of  acetylchollne  (Agoston  et al., 1985).   Because  of  this activity,
 4-am1nopyr1d1ne  has  been  used 1n humans  to reverse  residual neuromuscular
 blockade  resulting from  nondepolarlzlng neuromuscular  blocking  agents  and
 certain  antibiotics.   Experimental uses  of  4-am1nopyr1d1ne  Include treatment
 of   patients , with   Botullnus  Intoxication,  myoneural   disorders   (e.g.,
 myasthenla  gravls, Eaton-Lambert  syndrome)  and  Alzheimer's  disease.   The
 clinical use  of  4-am1nopyr1d1ne Is  limited by  Its  narrow  therapeutic Index.
                       t
 Agoston  et  al.  (1985)  reported that following  a  clinical  dose  of  0.15-0.3
 mg/kg  (route not   specified),  the  only  side  effects  noted  were a  slight
 Increase 1n  systolic  blood pressure  and  heart  rate,  while doses  >0.5  mg/kg
 were  likely  to  result  1n  restlessness,  confusion,  nausea, weakness  and
 ton1c-don1c seizures.
    Lundh  et  al.  (1979)  treated   six  myasthenla   gravls   patients  with
 Intravenous Injections of 4-am1nopyr1d1ne at  a  dose of 10 mg  Injected over  a
 10-m1nute period (body  weights of patients  were not  provided).   The  treat-
ment alleviated  muscular  weakness.    Side  effects  reported  Included  paraes-
 thesla perlorally,  a  sensation of unsteadiness  during walking,  restlessness
and  pain  In  the  arm  of  the Injection.   Wessellng  et  al.  (1984)  found some
 Improvement 1n the  mental  capacity of 14  Alzheimer's  patients  treated with
4-am1nopyr1d1ne  (10 mg twice a day) compared  with treatment  with  placebos.

0124d                              -28-                              09/19/88

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    Spyker  et  al.  (1980)  reported  that  two men  (100 kg) who  accidentally
Ingested  a  pinch (estimated to  be  -60 mg) of  4-am1nopyr1d1ne were admitted
to  the  hospital  and survived the poisoning.  The  symptoms  observed 1n these
men  Included  nausea,  weakness,  dizziness,  profuse  perspiration,  altered
mental  status and hypertension.   One man  also  experienced three  tonlc-clonlc
seizures.
    Schafer  et  al.  (1973a) summarized the acute  toxldty of  4-am1nopyr1d1ne
1n  birds  and mammals;  LD~Q values  for mammals  are presented 1n  Table  6-1.
Dogs  were  the  most  sensitive  mammal  studied,  with an oral  LD5Q of  3.7
                                                                             t
mg/kg.
    Houston  and  Pleuvry  (1984)  reported  gross   ataxla  1n  >40%  of  mice
(Manchester  strain) given  an  Intraperltoneal  Injection of 4-am1nopyr1d1ne at
1.6 mg/kg.  Convulsions were also noted 1n an unspecified number  of mice.
    In  a  study  by  HUsov  and  Uzunov (1972), white rats  of both  sexes  were
treated with 4-am1nopyr1d1ne by  Intraperltoneal  Injection  for  1  or 6 months.
In  the  1-month  study, 'groups  of 10 rats/sex were  treated  with  4-am1nopyr1-
dlne  at  doses  of  1  or 5 mg/kg/day, while  1n  the  6-month  study,  similar
groups  of rats  were  treated at  doses of 1  or  4 mg/kg/day.   Control  groups
for  both, studies  were  Injected with  physiologic  saline.   H1stopatholog1c
examination was limited  to  heart, liver,  brain,  lung,  kidney  and spleen.  No
effects on  body  weight,  hemoglobin  concentration and  RBC or  WBC counts  were
noted  1n either  study.   The  only  hlstopathologlc   changes  noted  In  the
1-month  study  were a  dose-related  "plethora  of  the capillaries"  1n  the
myocardlal  1nterst1t1um.  and  cerebral  edema.   In addition  to  the  effects
observed  In  the  1-month study,  dose-related parenchymatous degeneration and
fatty degeneration of the liver were observed In the 6-month study.
0124d                               -29-                             01/11/89

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                                   TABLE  6-1
                 Acute ToxIcHy of 4-Am1nopyr1d1ne to Mammals
Species
Rat
Rat
Mouse
Mouse
Mouse
Mouse
Mouse
Dog
Dog
Rabbit
Route
oral
Intraperltoneal
Intraperltoneal
Intraperltoneal
Intraperltoneal
subcutaneous
Intravenous
oral
oral
dermal
Vehicle
water
water
water
water
water
water
water
capsule
water
water
LD50
(rag/kg)
20
6.5
14.7
10
9
5
7 ;
i
4 :
3.7
327 \
Reference
Schafer et al., 1973a
Schafer et al., 1973a
' Humphreys, 1962
Vohra et al., 1965
Pastier and Me Do wall,
1958
Lemelgnan and Lechat,
1967
Pastier and McDowall,
1958
Delchman and Gerarde,
1969
Schafer et al., 1973a
Delchman and Gerarde,
1969
0124d
-30-
10/21/88

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6.2.   CARCINOGENICITY
    Pertinent  data regarding  the cardnogenldty  of  4-am1nopyr1d1ne could
not be located 1n the available literature as dted 1n  Appendix  A.
6.3.   MUTAGENICITY
    4-Am1nopyr1d1ne has  tested negative  for  reverse mutation  In  Salmonella
typhlmuMum  (Ogawa et al., 1986;  Wakabayshl  et al.,  1982).   Details of these
studies  are  summarized  1n  Table  6-2.    Additional  data   concerning  the
mutagenldty of 4-am1nopyr1d1ne were not located.
6.4.   TERATOGENICITY
    HUsov and Uzunov  (1972)  did  not observe any malformations 1n offspring
born  to  rats  during  1- and 6-month  Intraperltoneal  Injection  studies (see
Section  6.1.3.).   This  study  was limited;  only  12 offspring  from  treated
rats and 7  offspring  from control rats were born  from an unspecified number
of  pregnancies  that   "evolved normally."   Additional  data  regarding  the
teratogenldty of 4-am1nopyr1d1ne  were not located.
6.5.   OTHER REPRODUCTIVE EFFECTS
    Pertinent  data  regarding  reproductive  effects  of  4-am1nopyr1d1ne could
not be located 1n the  available literature as cited In  Appendix  A.
6.6.   SUMMARY
    4-Am1nopyr1d1ne acts  on  the  nervous  system  to  Increase  the  release  of
acetylchollne.  The  compound  has  been used  1n  humans for  the reversal  of
residual  neuromuscular blockade from some neuromuscular  blocking agents  and
antibiotics.  Experimental uses Include treatment of patients with Botullnus
Intoxication, myoneural disorders  and Alzheimer's disease.  The clinical  use
of 4-am1nopyr1d1ne 1s  limited  by  Us  narrow therapeutic  Index; following  a
clinical  dose of 0.15-0.3 mg/kg (route not  specified),  the only side effects
noted were  a  slight  Increase  In systolic  blood  pressure  and  heart rate,


0124d                               -31-                            09/19/88

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rs)
                                                                              TABLE 6-2
                                                                         (

                                                               Hutagenlclty Testing of 4-Anlnopyrldlne
             Assay
              Indicator/
               Organ Is*
                   Purity     Application
                         Concentration
                            or Dote
Activating
  System
Response
CoMwnt
Reference
Reverse
•utatlon
04
Reverse
•utatlon
Salmonella
typhlmurlum
TA1537. TA2637,
TA98. TA100
S. typhlmurlua
TA98. TA100
NR       prelncubatlon
         plate Incor-
         poration
                                           >98X     prelncubatlon
                                                                       NR
                                                                                        none
                           up to 2
                           mg/plate
                          Also - when tested with       Ogawa
                          cobalt (II) chloride.         et al..  1986
                          which enhanced the muta-
                          genlclty of other hetero-
                          atomtc compounds (9-amlno-
                          acrtdlne. 4-amlnoqulnollne
                          and barman)

                          Also - when tested with       Uakabayashl
                          norbarman, caused 3-amlno-    et al..  1982
                          pyrldlne and 2-amlno-3-
                          methylpyrldlne to become
                          mutagentc In the presence
                          of S-9
            NR - Not reported
 S
 CO
 oo

-------
while  doses  >0.5  mg/kg  were  likely  to  result  In restlessness,  confusion,



nausea, weakness  and tonlc-clonlc seizures  (Agoston  et  al.,  1985).  A  case



report of an accidental oral  exposure  (Spyker  et  al.,  1980)  Indicated  that  a



single dose of -0.6 mg/kg results 1n frank effects In  humans.



    The only data  concerning  the  subchronlc  oral  toxlclty  of  4-am1nopyr1d1ne



are two 90-day  studies  In the OPP CBI  files summarized  by U.S.  EPA (1980b).



In  a   rat  study  (Kohn,   1968),  hyper1rr1tab111ty  was  observed  at dietary



concentrations of  30 and  300  ppm  4-am1nopyr1d1ne,  with no  effects  noted  at  3



ppm.   In  dogs  (Cervenka  and  Vega,  1968), salivation, muscular weakness  and



decreased brain weight were observed at doses of >1.0  mg/kg/day.

                                                                *i

    4-Am1nopyr1d1ne  has  tested negative  for  reverse  mutation In  Salmonella



typhlmurlum (Ogawa et al.,  1986;  Wakabayshl  et al.,  1982).   Data  concerning



the cardnogenldty,  reproductive  effects  and  toxlclty of  4-am1nopyr1d1ne



following  Inhalation or  chronic  oral  exposure were  not  available  In  the



literature  dted  In Appendix A.   No   effects  on  reproduction  or   fetal
             i
                      t      .

development were  reported 1n rats treated with 1-5 mg/kg/day by  Intraperl-



toneal Injection for 1 or 6 months (Mltsov and  Uzunov, 1972).
0124d                               -33-                             10/21/88

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                     7.  EXISTING GUIDELINES AND STANDARDS
 7.1.   HUMAN
    The  RQ for 4-am1nopyr1d1ne 1s 1000 pounds  (U.S.  EPA, 1985).   Additional
 guidelines  and  standards.  Including  EPA  ambient  water  and  air  quality
 criteria,  drinking  water  standards,  FAO/WHO ADIs, EPA or  FDA  tolerances  for
 raw agricultural commodities  or  foods,  and ACGIH,  NIOSH  or OSHA occupational
 exposure  limits could  not  be  located  1n the available literature  as dted 1n
 Appendix  A.
 7.2.   AQUATIC
    Guidelines  and  standards  for  the  protection  of   aquatic   life  from
 exposure  to 4-am1nopyr1d1ne could  not  be  located 1n  the  available literature
 as cited  1n Appendix A.
0124d                               -34-                             02/08/89

-------
                              8.  RISK ASSESSMENT
 8.1.    CARCINOGENICITY
    Pertinent  data  regarding  the  carclnogenldty  of 4-aro1nopyr1d1ne  could
 not be  located  1n the available literature as cited In Appendix A.   4-Amlno-
 pyrldlne  has  tested negative for reverse  mutation  In  Salmonella  typhlmurlum
 (Ogawa  et al.t 1986; Wakabayshl et al., 1982).
 8.1.1.   Weight  of  Evidence.   As  a  result  of  a  lack  of  data  concerning
 carclnogenldty  In humans and animals, 4-am1nopyr1d1ne can be  classified  as
 an  EPA  Group  D   chemical  (U.S.  EPA,  1986b),  not  classifiable  as  to  human
 carclnogenldty.
 8.1.2.   Quantitative  Risk   Estimates.    The  derivation  of   carcinogenic
 potency  factors   for  4-am1nopyr1d1ne  1s precluded  by the  lack of  carclno-
 genldty data.
 8.2.   SYSTEMIC TOXICITY
 8.2.1.   Inhalation  Exposure.   The  derivation  of Inhalation  risk assessment
                       t
 values for 4-am1nopyr1d1ne 1s precluded by the lack  of Inhalation  data.
 8.2.2.   Oral Exposures.
    8.2.2.1.   LESS  THAN  LIFETIME  EXPOSURES  (SUBCHRONIC) --  4-Am1nopyr1d1ne
 has been  used  1n humans  to  reverse  neurornuscular  blockade  resulting  from
 nondepolarlzlng  neuromuscular  blocking agents and  certain antibiotics, and
as an experimental  treatment  for  Botullnus Intoxication,  myoneural  disorders
and Alzheimer's1  disease  (Agoston  et al.,  1985).   Human experience  Indicates
 that the compound  has  a very  narrow therapeutic  Index, with a dose  of  0.15-3
mg/kg resulting  1n a  slight  Increase 1n  systolic  blood  pressure and  heart
 rate,  and  a dose  >0.5 mg/kg resulting  1n restlessness,  confusion, nausea,
weakness and  ton1c-clon1c seizures  {Agoston  et  al.,  1985).  The report  by
Spyker et al.  (1980),  In  which two 100 kg men who  accidentally Ingested -60


0124d                               -35-                            09/19/88

-------
mg  of 4-am1nopyr1d1ne developed  nausea,  weakness,  dizziness,  altered mental
status,  and  In one case  tonlc-clonlc seizures,  Indicates that  a dose of -0.6
rag/kg 1s a  PEL 1n humans.  The available acute human data are not sufficient
for  risk assessment,  but Indicate that a  subchronlc  RfD for 4-am1nopyr1d1ne
should be <0.15 mg/kg/day.
     In a study by  Cervenka  and Vega (1968), dogs were  fed  diets containing
4-am1nopyr1d1ne   at  concentrations  that  provided  doses  of   0.1,   1.0  or
2.0-3.25 mg/kg/day for 90 days.   At >2.0 mg/kg/day, dogs exhibited  saliva-
tion  and muscular weakness;  no compound-related hlstopathologlc lesions were
observed.   No  dose-related   trends  1n  mean  organ  weights  were  observed,
although brain weights  were  decreased  at  the two  highest dosages.   This
study  Indicates that >2.0 mg/kg/day  1s  an adverse  effect level, but  from the
Information  available,  1t   1s  not  clear  whether  the   slight  and  nondose-
related  decrease  1n brain weight at 1.0  mg/kg/day should be  considered  an
adverse  effect.
     In a 90-day  study  (Kohn, 1968), rats  fed 4-am1nopyr1d1ne  1n  the  diet  at
300  ppm  were  hyperlrrltable  to noise and  touch;  males had Increased  liver
weights  and  females had  Increased brain  weights.  Additional  Information  In
the  CBI  files  Indicates  that sporadic hyper1rr1tab1lHy also occurred  at  30
ppm.  No effects  were  observed 1n rats fed  4-am1nopyr1d1ne  In  the diet at 3
ppm.  Assuming rats consume  food  equivalent to 5% of  their body weight/day
(U.S.  EPA,  1986c), the  dietary concentrations  of  4-am1nopyr1d1ne  of  3,  30
and   300 ppm   correspond  to  dosages   of  0.15,  1.5   and   15   mg/kg/day,
respectively.
    Although the  Information concerning the Kohn  (1968)  study 1s also very
limited,   1t  1s the only  data available from which a subchronlc  RfD can  be
estimated.  Application of an uncertainty  factor of 1000  [10 for  species-to-
species  extrapolation,  10 to  protect sensitive  Individuals and  10 to  reflect

0124d                               -36-                            02/08/89

-------
deficiencies  1n the  data  base (U.S.  EPA,  1988)] to  the rat NOAEL  of  0.15
mg/kg/day  yields a  subchronlc  oral  RfD  of  0.0002 mg/kg/day or  0.01  mg/day
for  a  70  kg human.   This subchronlc  RfD 1s well below the acute human effect
level  of 0.5 mg/kg/day.
     Confidence  1n  the RfD  1s  low,  based on low confidence  In  the  study and
data   base.   Few  details   were  available  concerning  the  CBI  study.   The
validity  of the study  (Kohn,  1968)  completed at  Industrial  BloTest  Labora-
tories  1s  unknown.   The  supporting data are  limited  to a subchronlc study In
dogs  (Cervenka  and  Vega, 1968), for which few  details were available.  This
RfD  should be  considered preliminary and should  be  reviewed when additional
data  are  available.  The RfD  Is  currently under  review  by  the  Agency's RfD
Work Group  (U.S. EPA, 1989).
    8.2.2.2.   CHRONIC  EXPOSURE  ~ Chronic  oral  studies  of  4-am1nopyr1d1ne
were  not   available.   As  mentioned  1n Section  8.2.2.1.,  an  oral RfD  for
4-am1nopyr1d1ne  Is  under  review by  the Reference  Dose  Work  Group (U.S.  EPA,
1989).
    A  tentative  RfD of 0.00002 mg/kg/day  or  0.001 mg/day for a  70 kg human
can  be derived  by  dividing the subchronlc oral  RfD [derived from the  Kohn
(1968)  rat study]  by an additional  uncertainty factor  of  10  to extrapolate
from  chronic  to subchronlc  data.   Confidence 1n  this  RfD 1s low,  based  on
low confidence  In the study and  data base.   Because  the basis of this RfD 1s
not  defensible,,  verification  of  an   RfD  for  4-am1nopyr1d1ne  should  be
deferred until  the  details  of  the  Cervenka  and Vega  (1968) and  Kohn (1968)
studies are available or until additional studies are completed.
8.3.   AQUATIC
    Insufficient  data  prevented  the  development  of  a  criterion for  the
protection  of  freshwater  life exposed  to 4-am1nopyr1d1ne  (Figure 8-1).   The
data  base  lacked   an  acute  LCgQ  with  a  representative  species  from  the

0124d                               -37-                             02/08/89

-------
Farni ly
«tl
Chords! c < £a 1 rnc-n id-fish)
*rl
Chordate (wferrnwster fish)
«i
Chordate (fish or amphibian)
«t4
Crustacean (planktonic)
lib
Crustacean (benthic)
*L
Insect an
¥.7
non-Art hropod /-Chordat e
*fc
New Insect an or phylum
represent at i ve
«'3
algae
«ilO
Vascular plant
TEST TYPE
Acute* •»
N(H
3. 972«
4. £30*
0.37-
£.£'
«
0.56*
AS. 0"
15.0«
Nfl
NP
Chronic*
NP
NA
NA
NA
NA
NA
NA
NA
NA
NA
ECF«
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
    aNA « Not'available
    bAll values represent 96-hour
    cChannel catfish, Ictalurus punctatus
    dBlueg111 sunflsh, Lepotnls
—^macrochlrus
    eGlass shrimp, Palaemonetes
     kadlakensls
    ^Crayfish, Procambrus acutus acutus
    QMayfly, Isonychla sp.
    ^Asiatic clam, Corblcula manllensls
    kaddlsfly, Hydropsyche sp.
                                      FIGURE  8-1
       Organization chart for listing GHAVs required to derive numerical water
       quality criteria by the method of EPA/OWRS (1986) for the protection of
                  freshwater  aquatic life  exposed to 4-am1nopyr1d1ne
    0124d
-38-
02/08/89

-------
Salmon1d  family  and  the  results  of  chronic  tests  either with  freshwater
algae  or  vascular  plants.   The data  base  also  lacked  acceptable  chronic
tests  with  fish  or  Invertebrates  and  results from  studies  assessing  the
bloaccumulatlon or bloconcentration of 4-am1nopyr1d1ne In aquatic organisms.
    No data  were  available regarding  the effects of exposure of marine fauna
and  flora  to 4-am1nopyr1d1ne,  preventing  the development  of a  saltwater
criterion.
0124d                               -39-                             02/08/89

-------
                           9.   REPORTABLE  QUANTITIES
9.1.   BASED ON SYSTEMIC TOXICITY
    The  toxlclty  of 4-am1nopyr1d1ne  was  discussed In  Chapter  6.  The  only
data  suitable  for   the  derivation  of  an  RQ  are  the 90-day  dog  studies
(Cervenka  and Vega,  1968) rat  study  (Kohn,  1968).    Table  9-1  summarizes
these studies  and  Table  9-2 presents the  derivation of CSs and  RQs.   In  the
study  by  Cervenka  and  Vega   (1968),  muscular  weakness,  salivation  and  a
decrease  In  brain  weight was  observed In  dogs treated  at >2.0 mg/kg/day  and
a  slight decrease  1n  brain weight  was  observed at 1  mg/kg/day.  From  the
limited  Information available, H  1s  not  clear If  the  1.0 mg/kg/day dose  was
a  NOAEL  or  LOAEL;  therefore,  only the >2.0  mg/kg/day  dose, corresponding to
an  RV.  of 4.2, will be  considered for CS derivation.   Kohn  (1968) reported
sporadic  hyper1rr1tabH1ty to noise  and  touch  In rats  treated   orally  with
4-am1nopyr1d1ne  1n   the  diet   at  a  dose   of  -1.5  mg/kg/day,  or  an  RV.  of
5.1.   Effects   In   both  dogs  and   rats  correspond  to   an   RV    of   7.
Multiplying  the  larger  RVd of 5.1 from  the rat study by  the  RVg of 7,  a
CS of 35.7 Is calculated.
    The CS of  35.7  calculated  from the  rat study (Kohn, 1968), corresponding
to  an  RQ of 100 pounds, Is selected to  represent  the toxldty   of 4-amlno-
pyrldlne and 1s presented 1n Table 9-3.
9.2.   BASED ON CARCINOGENICITY
    No data  were available  concerning the  carclnogenlclty  of  4-am1nopyr1-
dlne.    4-Am1nopyr1d1ne   has   tested  negative   for   reverse  mutation   In
Salmonella typhlmurlum  (Ogawa  et al.,  1986; Wakabayshl et al.,  1982)  (see
Section 6.3.).  The  lack of  data concerning the carclnogenlcHy  of 4-am1no-
pyrldlne  In  either  humans  or   animals  Indicates  that  the  compound  should  be
0124d                               -40-                            10/21/88

-------
o
IV*
o
00
00
vD
                                                                          -  TABLE 9-1
                                                              Oral Toxlclty Data for 4-Amlnopyrldlne4
Species/
Strain* Sex
Dog/NR NR
Rit/NR Ntf
Average
Body Weight*
(kg)
12
0.35
Vehicle/
Physical
State
diet
diet
Exposure
2 mg/kg/day
In the diet
for 90 days
300 ppm In
the diet For
90 days
., Animal Dosage
(mg/kg/day)
2*
1.5'
Equivalent
Hunan Dosage0*
(•g/kg/day)
0.1
0.026
Effect
Salivation.
muscular weak-
ness
Sporadic hyper-
Irritability to
noise and touch
Reference
Cervenka and
Vega, 1968
Kohn. 1968
          3Pur1ty not reported
          DNumber of animals/group not  reported
          (Reference dog body weight (12 kg),  reference  rat body weight  (0.35 kg) (U.S. EPA. 1986c)
          dAnlmal dose Multiplied  by the cube root  of  the ratio  of the antMl  to reference human body weight (70 kg) and by 70 kg  to  express  human MED
           In mg/day. and divided by an uncertainty  factor of  10 to expand from subchronlc to chronic exposure
          'Estimated by Investigators
          'Reference food factor for rats -  0.05  (U.S. EPA. 1980b)
          NR • Not reported

-------
10
O.
.. 	 TABLE 9-2
Composite Scores for 4-Amlnopyrldlne Based on Oral Toxlclty
Chronic
Species Animal Dose Human MEDa RVd Effect RVe CSb RQ
(mg/kg/day) (mg/day) :
5 Dog 2 7.0 4.2 CMS effect 7 29.4 100
Rat 1.5 1.8 5.1 CNS effect 7 35.7 100




Reference
Cervenka and
Vega. 1968
Kohn. 1968
   Equivalent human dosage (mg/kg/day) multiplied by 70 kg

   bRVd multiplied by RVe
GO
03

-------
                                   TABLE  9-3

                                4-Amlnopyrldtne
           Minimum Effective  Dose  (MED) and Reportable Quantity  (RQ)
Route:
Dose*:
Effect:
Reference:
RVd:
RVe:
CS:
RQ:
oral
1.8
CNS
Kohn
5.1
7
' 35.7
100

mg/kg
effects
, 1968



pounds
*Equ1valent human dose
0124d
-43-
09/19/88

-------
 classified as  an  EPA  Group  D  chemical  (U.S. EPA, 1986b). not classifiable as
 to  human cardnogenldty.  Hazard  ranking  based on carclnogenlclty  1s  not
 possible  for EPA Group D compounds.
0124d                              -44-                            09/19/88

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                                10.  REFERENCES


Agoston,  S.,  D.  Langreher  and D.E. Newton.   1985.   Pharmacology and possible

clinical  applications of 4-amlnopyrldlne.  Semln. Anesth.  4(1): 81-86.


Atkinson,  R.   1985.   Kinetics and mechanisms  of the gas-phase  reactions  of

the  hydroxyl  radical  with organic  compounds  under  atmospheric  conditions.

Chem. Rev.  85: 69-201.


Atkinson,  R.  1987.   A  structure-activity  relationship  for  the estimation  of

the  rate  constants  for the  gas-phase  reactions  of OH  radicals  with organic

compounds.  Int. J. Chem. K1net.   19: 799-828.


Betts,  P.M.,  C.W.  Glddlngs,  and  J.R.  Fleeker.   1976.    Degradation  of
4-am1no-pyr1d1ne In soil.  J. Agrlc. Food Chem.  24: 571-574.
                       i

Bysshe,  S.E."  1982.    B1oconcentrat1on  factor  1n aquatic  organisms.   l£:

Handbook  of Chemical  Property  Estimation Methods,  W.J.  Lyman,  W.F.  Reehl and

D.H. Rosenbatt, Ed.  McGraw-Hill Book Co.,  NY.   p.  5-4,  5-10.


Carlson,  D.A.   1984.   Repellents.   In,: K1rk-0thmer Encyclopedia  of Chemical
Technology, 3rd  ed.,  M. Grayson  and D. Eckroth,  Ed.   John Wiley  and Sons,

Inc., NY.  Vol.'Supplement,  p. 798.
0124d                               -45-                             09/19/88

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Cervenka,  H. and  S.M.  Vega.   1968.   Ninety-day  subacute  oral  toxIcUy  of


compound  1861  (4-am1nopyr1d1ne) — Beagle dogs.   Project Number  777  (unpub-


lished  study).   Prepared  by  Llfestream  Laboratories,  Inc.  under IF  1013.


Submitted   by   Phillips   Petroleum  Co.,   Bartelsvllle,   OK.    CDU091756-G.


(Cited In U.S. EPA, 1980b)





Oelchman, W.B.  and H.W.  Gerarde.  1969.  Toxicology of  Drugs  and Chemicals.


Academic Press, New York.  p. 93.  (Cited In Schafer et al., 1973a)


                                                9

                *

E1senre1ch,  S.J.,  B.B.  Looney and D.J.  Thornton.  1981.  Airborne  organic


contaminants  In the  Great  Lakes ecosystem.   Environ.  Sd.. Technol.   15:


30-38.





EPA/OWRS.   (Environmental  Protection  Agency/Office of Water  Regulations  and


Standards).  1986.  Guidelines  for Deriving  Numerical  National  Water  Quality
                       r

Criteria  for  the  Protection of  Aquatic  Organisms  and their  uses.  EPA/OWRS


Washington, DC.  106 p.





Evenhuls,  J.,  S.  Agoston,  P.J.  Salt, A.R.  DeLange,  W. Wouthuyzen  and  W.


Erdmann.   1981.    Pharmacok1net1cs of 4-am1nopyr1d1ne  In human  volunteers.


Br. 0. Anaest.  53: 567-570.





Farm  Chemicals  Handbook.    1987.   Farm  Chemicals  Handbook  87.   Helster


Publishing Co., Wlllougby,  OH.   p. C26.





Fastler, F.N. and  M.A. McDowall.  1958.  A comparison  of  the  pharmacological


properties of three 1somer1c am1nopyr1d1nes.   Aust. J. Exp. B1o1. Med. Sc1.


36: 365-372.  (Cited 1n Schafer et al., 1973a)




0124d                              -46-                            10/21/88

-------
Garrison,  H.V.,  A. Ammayao  and J.L.  Llbay.   1982.   Evaluation  of  4-am1no-

pyrldlne  as  a  bird   control  agent  1n  the   Philippines.   Ph1l1pp.  Agrlc.

65(1): 53-58.




Goe,  G.L.   1982.   Pyr1d1ne  and  pyrldlne  derivatives.   In.:  K1rk-0thmer

Encyclopedia of  Chemical  Technology,  3rd  ed.,  H.  Grayson  and D. Eckroth,  Ed.

John Wiley and Sons, Inc., NY.  19: 454-483.




Hadler,  M.R.  1982.   Poisons,  economic.   In.:  Klrk-Othmer  Encyclopedia  of
                                                                         •
Chemical  Technology,  3rd. ed.,  H.  Grayson and  D.  Eckroth,  Ed.   John  Wiley

and Sons, Inc., New York.  18:317-318.




Hansch,  C.  and  A.J.  Leo.   1985.   Hedchem Project.   Issue  No.  26.   Pomona

College, Claremont, CA.




Harris, J.C. /1982.   Rate of hydrolysis.   I.n: Handbook of Chemical  Property

Estimation ; Methods,  W.J.,  Lyman,  W.F.   Reehl   and  D.H.   Rosenblatt,  Ed.

McGraw-Hill Book Co.,  NY.  p. 7-4.



        »
Hawley, G.G.  1981.  The  Condensed  Chemical Dictionary, 10 ed.   Van  Nostrand

Relnhold Co., New York.  p. 55.
                i

               I
               i
H1ne, J.  and P.K.  Mookerjee.  1975.  The Intrinsic  hydrophlUc  character  of

organic compounds.  Correlations 1n  terms  of structural contributions.   J.

Org. Chem.  40: 292-298.
0124d                               -47-                             09/19/88

-------
Holler,  N.R.  and E.H.  Schafer,  Jr.  1982.   Potential  secondary hazards  of



AvUrol  baits  to  sharp-shinned  hawks  and  American  kestrels.   3.  Vllldl.



Manage.  46(2): 457-4462.







Houston,  T.  and  B.J.  Pleuvry.   1984.   Comparison  of  some  pharmacological



properties  of  4-am1nopyr1d1ne  and  3,4-d1am1nopyr1d1ne  in  vivo.    Br.   J.



Anaes.  56(10): 1139-1142.







Hudson, R.H.,  R.K.  Tucher  and M.A.  Haegele.  1984. 'Handbook of toxldty  of



pesticides  to wildlife.   U.S.  Oept. of  the  Interior,  Fish  and  Wildlife



Service.  Resource Publ. No. 153.  Washington, DC.   p. 12.

                                                   t





Humphreys, S.R..  1962.  Toxldty and antlleukemlc  effectiveness of pyrldlne



derivatives and 1,2,4-thladlazol derivatives  1n mice — Relation to nlcotln-



amlde  antagonism.   Cancer  Res. Suppl.  22(2):483-550.   (CHed In Schafer  et



al., 1973a)







Kohn,  F.E. '  1968.    Four-week  subacute  oral   toxldty  of  compound  1861



Hydrochlorlde  —  Albino rats.  (Unpublished study),.  Prepared by Industrial
        t                                          •


Blotest  Laboratories,  Inc. under  224-12.   Submitted by  Phillips  Petroleum



Co., Bartlesvllle, OK.  CDL: 229844-E.  (Cited In U.S. EPA,  1980b)



               /



Kuney, J.H.,  Ed.  1986.  Chemcyclopedla  1987.  Volume  5.   American Chemical



Society, Washington, DC.  p. 51.







Lemelgnan, M  and P.  Lechat.   1967.   Antlcurare  action  of  am1nopyr1d1nes.



C.R. Acad. Sc1. Ser. D.   264:  169-172.  (CHed 1n Schafer et al., 1973a)









0124d                               -48-                             10/21/88

-------
Lundh,  H.,  0  Nllsson  and  I.  Rosen.  1979.   Effects  of 4-am1nopyr1d1ne  In
myasthenla gravls.  J. Neurol. Neurosurg. Psychlat.   42(2):  171-175.

Lyman,  W.J.,  M.F. Reehl  and  D.H. Rosenblatt.   1982.   Handbook of  Chemical
Property  Estimation  Methods.   Environmental  Behavior  of Organic  Compounds.
McGraw-Hill Book Co., New York, NY.  5-5.

Marking,  L.L.  and   J.H.  Chandler.   1981.    Toxlclty  of  six  bird   control
chemicals  to  aquatic  organisms.  Bull.  Environ. Contam.  Toxlcol.    26(6):
705-716.

Mill, T.  and W. Mabey.  1985.   Photochemical  transformations.'  In:  Environ-
mental Exposure From Chemicals,  Volume I, W.B. Neely and  G.E.  Blau,  Ed.   CRC
Press, Inc., Boca Raton, FL.  p.  206-210.
MHzov, V.  and P.  Uzunov.   1972.  ToxIcUy  of  the compound VMI-10-3.   EK.
sp. Med. No. .ful.   11(3): 162-165.  (Bulgarian with  English  translation)
Na1k,  M.N.,   R.B.  Jackson,  0.  Stokes  and  R.J.  Swaby.   1972.   Mlcroblal
degradation and  phytotoxldty  of plcloram  and  other substituted  pyrldlnes.
Soil B1ol. Blochem.  4: 313-323.
                I
                /
NIOSH  (National  Institute  for   Occupational   Safety   and   Health).    1985.
National  Occupational  Exposure Survey  (NOES).   Computer  printout of  survey
as of 9/20/85.
0124d                               -49-                             10/21/88

-------
 Ogawa,  H.I., K. Sakata,  T.  Inouye, et al.   1986.   Combined mutagenlcUy of
 cobalt(II)   salt  and  heteroaromatlc  compounds  In  Salmonella  typhlmurlum.
 Mutat.  Res.   172(2): 97-104.

 Parrls,  G.E.   1980.   Covalent binding  of aromatic amines  to  humates.   1.
 Reactions   with  carbonyls  and   qulnones.    Environ.   Scl.  Techno!.    14:
 1099-1106.        X

 Rupp,  S.M.,  Y. Shlnohara,  O.M.   Fisher,  R.D. Miller  and  N.J.  Castagnoll.
 1983.   Pharmacok1net1cs  and pharmacodynamlcs  of  4-am1nopyr1d1ne  In anesthe-
 tized dogs.   J. Pharmacol. Exp. Ther.  225(2): 351-354.

 SANSS.  (Structure and  Nomenclature Search System).   1988.   Chemical Informa-
 tion System  (CIS) computer data base.

 Schafer,  E.W.,  Jr.  and L.L.  Marking.   1975.   Long-term, effects of 4-amlno-
 pyrldlne exposure to birds and fish.  J. Wild!. Manage.  39(4): 807-811.

 Schafer, E.W.,  Jr.,  R.B.  Brunton  and D.J. Cunningham.   1973a.   A  summary of
 the acute  toxlclty  of  4-am1nopyr1d1ne  to birds and mammals.   Toxlcol.  Appl.
 Pharmacol.  26(4): 532-538.
                /
 Schafer,  E.W.,  Jr., R.B.  Bunton,  N.H.  Lockyer  and  J.F.  DeGrazlo.   19735.
 Comparative  toxlclty  of  seventeen pesticides to  the  quelea, house  sparrow
 and red-winged blackbird.   Toxlcol. Appl.  Pharmacol.   26(1):  154-157.
0124d                               -50-                             09/19/88

-------
Schafer,  E.W.,  Jr., R.B.  Brunton  and N.F.  Lockyer.   1975.   The effects  of

subacute  and  chronic exposure  to 4-am1nopyr1d1ne  on  reproduction  1n  coturnlx

quail.  Bull. Environ. Contain. Toxlcol.  13(6):  758-764.



S1ms, G.K.  and  I.E. Sommers.   1985.  Degradation of pyrldlne derivatives  In

soil.  J. Environ. Qual.  14:  580-584.



S1ms, G.K.  and  I.E. Sommers.   1986.  B1odegradat1on of  pyrldlne  derivatives

In soil suspensions.  Environ. Toxlcol. Chem.  5:  503-509.



Sohn,  Y.J.  and  D.R.A.   Uges.   1981.  Pharmacok1net1cs  and  side-effects  of

4-am1nopyr1d1ne.  Int. Congr.  Ser.  - Excerpta Med.  538:  224-228.



Spyker, D.A., C.  Lynch,  J.  ShabanowHz and  J.A. S1nn.  1980.  Poisoning  with

4-am1nopyr1d1ne: Report of three cases.  Cl1n. Toxlcol.   16(4):  487-497.
              /
                      i


SRI  (Stanford Research   Institute  International).   1987.  1987  Directory  of

Chemical  Producers.  United  States  of  America.    SRI   International, Menlo

Park, CA.  p. 325, 459.



Starr,  R.I.  and  D.J.   Cunningham.   1975.   Leaching   and   degradation  of

carbon-14 labeled  4-am1nopyr1d1ne  1n  several  soil  systems.   Arch.  Environ.
               I
Contam. Toxlcol1  3: 72-83.



Sultana,  P.,  J.E.  Brooke and  R.L.  Bruggers.  1986.  Repellency and  toxldty

of bird control  chemicals  to  pest  birds In  Bangladesh.  Trop.  Pest.  Manage.

32(3): 246-248.




0124d                               -51-                             10/21/88

-------
 Thomas,  R.G.  1982.   Volatilization from  water.   in:  Handbook of  Chemical
 Property  Estimation  Methods,  W.J.  Lyman,  W.F.  Reehl  and  O.H.  Rosenblatt,  Ed.
 McGraw-Hill  Book Co., NY.  p. 15-15, 15-16.

 Uges,  D.R.A.,  Y.J. Sohn, B.  Greljdanus,  A.H.J.  Scaf and S.  Agoston.   1982.
 4-Am1nopyr1d1ne kinetics.  CUn. Pharmacol.  31:  587-593.

 U.S.  EPA.   1977.   Computer  print-out  of  non-confidential  .production  data
 from the TSCA Production File for 1977.   U.S. EPA,  Washington, DC.

 U.S.  EPA.    1980a.   Guidelines  and  Methodology  used 1n  the Preparation  of
 Health  Effects Assessment  Chapters  of  the  Consent Decree  'Water  Criteria
 Documents.   Federal Register.  45(231):  79347-79357.

 U.S.   EPA.    1980b.    4-Am1nopyr1d1ne.   .AvHrol   Pesticide   Registration
 Standard. OPTS, U.S. EPA, Washington, DC.   NTIS PB84-209907.

 U.S. EPA.   1984.   Methodology and  Guidelines for Ranking Chemicals  Based  on
 Chronic ToxicUy  Data.   Prepared by the  Office  of Health and  Environmental
 Assessment,  Environmental Criteria and  Assessment  Office, Cincinnati,  OH  for
 the Office of Solid Waste and Emergency  Response, Washington,  DC.

 U.S.  EPA.    1985.   Notification  Requirements;   reportable  quantity  adjust-
ments; final rule and proposed rule.   Federal  Register.   50(65):  13456-13522.
0124d                               -52-                            02/08/89

-------
U.S.  EPA.   1986a.  CBI Appendix  for  Review and Evaluation of  ADI  for:  POOS
4-Amlnopyrldlne.   Prepared by  SRC  under  Contract  No.  68-03-3228 for Environ-
mental Criteria and Assessment Office, Cincinnati, OH.

U.S.  EPA.   1986b.   Guidelines   for   Carcinogen  Risk  Assessment.   Federal
Register.  51(185): 33992-34003.

U.S.  EPA.   1986c.  Reference  Values  for Risk  Assessment.   Prepared by  the
Office  of  Health  and Environmental  Assessment,  Environmental   Criteria  and
Assessment Office, Cincinnati, OH  for  the Office  of  Solid Waste, Washington,
DC.

U.S.  EPA.   1987.   Graphical  Exposure  Modeling  System  (GEMS).   PCCHEM.
Version April T987.

U.S.  EPA.   1988.   Reference  Dose  (RfD):  Description  and Use In Health  Risk
Assessments.    Integrated   Risk   Information   System   (IRIS).    Online.
Intra-Agency  Reference   Dose   (RfD)   Work   Group,   Office  of   Health   and
Environmental  Assessment,  Environmental  Criteria  and  Assessment  Office,
Cincinnati, OH, February.

U.S.  EPA.   1989.   Integrated  Risk  Information  System  (IRIS).   Online.
                i
Office  of  Health  and  Environmental  Assessment,  Environmental   Criteria  and
Assessment Office, Cincinnati, OH.

U.S.  EPA/NIH  (Environmental  Protection Agency/National  Institute of Health).
1988.   OHM-TADS  (011  and  Hazardous  Materials-Technical   Assistance   Data
System).  Online: May, 1988.
0124d                               -53-                             02/08/89

-------
Vohra,  M.H.,  S.N. Pradhan,  P.C.  Jain,  S.K. Chatterlee and  N.  Anand.   1965.
Synthesis  and structure-activity relations  of  some amlnopyrldlne  -  Imldazo
pyrldlnes  and trlazole  pyrldlnes.   J.  Hed.  Chem.  8:  296-304.   (CUed  In
Schafer et al., 1973a)

Wakabayashl,  K.,  T.  Yahagl,  M.  Nagao and  T.  Suglmura.   1982.   Comutagenlc
effect  of norharman  with amlnopyrldlne  derivatives.   Hutat. Res.   105(4):
205-210.
                                                  •
Weast,  R.C.,  Ed.   1985.   CRC Handbook  of Chemistry  and  Physics, 66th  ed.
CRC Press, Inc., Boca Raton, PL.   p. C-462, D-160.

Hessellng,  H.,  S.  Agoston, G.B.P.  van  Dam,   et al.   1984.   Effects  of
4-am1nopyr1d1ne  1n elderly  patients  with Alzhemlers  disease.   N. Engl.  J.
Hed.  310: 988-989.
0124d                               -54-                             10/21/88

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                                  APPENDIX A

                              LITERATURE  SEARCHED



    This  HEED  1s  based  on  data  Identified  by  computerized  literature

searches of the following:

              CHEHLINE
              TSCATS
              CASR online (U.S. EPA Chemical Activities Status Report)
              TOXLINE
              TOXLIT
              TOXLIT 65
              RTECS
              OHM TADS
              STORET
              SRC Environmental Fate Data Bases
              SANSS
              AQUIRE
              TSCAPP
              NTIS
              Federal Register
              CAS ONLINE (Chemistry and Aquatic)
              HSDB


These  searches  were  conducted  1n Hay  1988, and  the  following  secondary

sources were reviewed:
    ACGIH  (American  Conference of Governmental  Industrial  Hyg1en1sts).
    1986.   Documentation  of the  Threshold  Limit Values and  Biological
    Exposure Indices, 5th ed.  Cincinnati, OH.

    ACGIH  (American  Conference of Governmental  Industrial  Hyg1en1sts).
    1987.   TLVs:  Threshold  Limit Values for Chemical Substances  In  the
    Work  Environment  adopted   by   ACGIH   with   Intended   Changes   for
    1987-1988.  Cincinnati,  OH.  114 p.
                I
    Clayton,  G.D.  and  F.E.  Clayton,  Ed.   1981.   Patty's  Industrial
    Hygiene  and Toxicology,  3rd rev.  ed., Vol.  2A.   John  Wiley  and
    Sons, NY.  2878 p.

    Clayton,  G.D.  and  F.E.  Clayton,  Ed.   1981.   Patty's  Industrial
    Hygiene  and Toxicology,  3rd rev.  ed., Vol.  28.   John  WHey  and
    Sons, NY.  p. 2879-3816.

    Clayton,  G.O.  and  F.E.  Clayton,  Ed.   1982.   Patty's  Industrial
    Hygiene  and Toxicology,  3rd rev.  ed., Vol.  2C.   John  Wiley  and
    Sons, NY.  p. 3817-5112.
0124d                               -55-                             09/19/88

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     Grayson,  H. and  D.  Eckroth,  Ed.   1978-1984.   Klrk-Othmer Encyclo-
     pedia of  Chemical Technology, 3rd ed.  John Wiley and Sons, NY.  23
     Volumes.

     Hamilton,  A.  and H.L.  Hardy.  1974.  Industrial Toxicology, 3rd ed.
     Publishing Sciences  Group,  Inc.,  Littleton, HA.  575 p.

     IARC   (International  Agency  for  Research  on  Cancer).   IARC  Mono-
     graphs on  the  Evaluation  of Carcinogenic  Risk  of Chemicals  to
     Humans.   IARC, WHO,  Lyons,  France.

     Jaber, H.H.,  W.R.  Mabey,  A.T.  L1eu, T.W.  Chou and  H.L. Johnson.
     1984.   Data   acquisition  for  environmental   transport  and  fate
     screening  for  compounds  of  Interest  to the Office  of Solid Waste.
     EPA   600/6-84-010.   NTIS  PB84-243906.   SRI  International,  Menlo
     Park.  CA.

     NTP  (National  Toxicology Program).   1987.   Toxicology Research and
     Testing   Program.   Chemicals  on  Standard  Protocol.   Management
     Status.

     Ouellette,  R.P.  and  J.A.   King.   1977.   Chemical  Week  Pesticide
     Register.   McGraw-Hill Book Co., NY.

     Sax,  I.N.   1984.   Dangerous Properties  of Industrial Materials, 6th
     ed.   Van Nostrand Relnhold  Co., NY.

     SRI  (Stanford Research   Institute).  1987.   Directory  of Chemical
     Producers.  Menlo Park, CA.

     U.S.  EPA.   1986.   Report  on  Status  Report In  the  Special  Review
     Program,   Registration  Standards  Program  and  the  Data  Call  1n
     Programs.   Registration   Standards  and  the  Data  Call 1n  Programs.
     Office of  Pesticide  Programs, Washington, DC.

     USITC  (U.S.  International  Trade  Commission).   1986.    Synthetic
     Organic Chemicals.   U.S.  Production  and Sales,  1985,  USITC  Publ.
     1892,  Washington, DC.

     Verschueren, K.   1983.   Handbook  of  Environmental   Data  on  Organic
     Chemicals,  2nd ed.   Van Nostrand Relnhold Co.,  NY.

    Worthing.   C.R.  and  S.B.  Walker,  Ed.   1983.  The Pesticide  Manual.
     British Crop Protection Council.  695 p.

    Wlndholz,  M., Ed.  1983.  The  Merck  Index,  10th  ed.   Merck and Co.,
     Inc.,  Rahway, NJ.
0124d                               -56-                             09/19/88

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    In  addition,  approximately 30  compendia of aquatic  toxldty data were

reviewed. Including the following:


    Battelle's  Columbus  Laboratories.   1971.   Water  Quality  Criteria
    Data  Book.   Volume  3.  Effects  of  Chemicals   on   Aquatic   Life.
    Selected  Data  from the Literature  through  1968.   Prepared for  the
    U.S. EPA under Contract No. 68-01-0007.  Washington,  DC.

    Johnson,  W.W.  and H.T. Flnley.   1980.   Handbook  of  Acute  Toxldty
    of  Chemicals  to  Fish and  Aquatic  Invertebrates.   Summaries  of
    Toxldty  Tests  Conducted  at  Columbia  National  Fisheries  Research
    Laboratory.   1965-1978.   U.S.  Dept.  Interior.  F1sh  and  Wildlife
    Serv. Res. Publ. 137,  Washington, DC.

    McKee, J.E. and  H.W.  Wolf.  1963.  Water Quality Criteria, 2nd  ed.
    Prepared  for  the  Resources   Agency  of  California, State   Water
    Quality Control Board.  Publ.  No. 3-A.

    Plmental, D.  1971.  Ecological  Effects  of  Pesticides  on  Non-Target
    Species.  Prepared for the U.S.  EPA, Washington, DC.   PB-269605.

    Schneider, B.A.   1979.  Toxicology  Handbook.  Mammalian and Aquatic
    Data.  Book 1: Toxicology  Data.   Office  of  Pesticide  Programs, U.S.
    EPA, Washington, DC.   EPA  540/9-79-003.  NTIS PB 80-196876.
0124d                               -57-                            09/19/88

-------
IS)
                                                   APPENDIX B
                                        Summary Table for 4-Amlnopyrldlne
                                 Species
                                            Exposure
                             Effect
    RfD or q-|*
Reference
in
CO
Inhalation Exposure
Subchronlc
Chronic
Carclnogenlclty
Oral Exposure
Subchronlc

Chronic

Carclnogenlclty
rat      0.15 mg/kg/day    NOAEL for
                           CNS effects
                                   rat       0.15 mg/kg/day     NOAEL  for
                                                              CNS effects
                                                                                     ID
                                                                                     ID
                                                                                     ID
0.0002 mg/kg/day
or 0.01 ng/day
for a 70 kg human*
0.00002 mg/kg/day
or 0.001 mg/day
for a 70 kg human*
       ID
                                                                                                    Kohn, 1968
                                                                 Kohn. 1968
   REPORTABLE QUANTITIES
   Based on chronic toxlclty       100
   Based on Carclnogenlclty        ID
VO
CD
CO
                                                                                                 Kohn. 1968
tThese RfDs should be considered tentative and should be reviewed when additional data are available.
ID » Insufficient data

-------