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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
-------
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.
-------
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
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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
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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
-------
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
-------
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
-------
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
-------
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
-------
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.
0124d -21- 09/19/88
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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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t
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Lundh, H., 0 Nllsson and I. Rosen. 1979. Effects of 4-am1nopyr1d1ne In
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I
/
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0124d -49- 10/21/88
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/
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0124d -50- 09/19/88
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i
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0124d -51- 10/21/88
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0124d -52- 02/08/89
-------
U.S. EPA. 1986a. CBI Appendix for Review and Evaluation of ADI for: POOS
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mental Criteria and Assessment Office, Cincinnati, OH.
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i
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U.S. EPA/NIH (Environmental Protection Agency/National Institute of Health).
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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
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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
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Hed. 310: 988-989.
0124d -54- 10/21/88
-------
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
-------
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
-------
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
------- |