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                                  DISCLAIMER           '

    This report  1s  an external draft  for  review purposes only  and  does  not
constitute  Agency  policy.   Mention of  trade names  or  commercial  products
does not constitute1 endorsement or recommendation for use.
                                      11

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                                    PREFACE
    Health and  Environmental  Effects  Documents (HEEDs) are prepared  for  the
Office of  Solid  Waste  and Emergency Response  (OSWER).  This  document  series
Is Intended to support listings under  the  Resource  Conservation  and  Recovery
Act  (RCRA) as  well as to  provide health-related limits and  goals  for  emer-
gency  and  remedial actions under  the Comprehensive  Environmental  Response,
Compensation   and - Liability  Act  (CERCLA).   Both  published  literature  and
Information obtained  for  Agency Program Office  files are evaluated  as  they
pertain to potential human health,  aquatic  life  and environmental  effects of
hazardous  waste  constituents.   The  literature searched for 1n  this  document
and  the  dates  searched  are  Included In  "Appendix:  Literature  Searched."
Literature search  material  1s current up  to 8 months previous  to  the  final
draft  date listed  on  the front  cover.   Final  draft document  dates  (front
cover) reflect the date the document 1s sent to the Program Officer  (OSWER).

    Several quantitative  estimates  are  presented  provided  sufficient  data
are available.   For systemic  toxicants,  these  Include Reference  doses (RfDs)
for  chronic  and  subchronlc  exposures  for  both  the Inhalation  and  oral
exposures.  The  subchronlc or  partial  lifetime  RfO, Is  an  estimate of an
exposure  level   that  would not  be expected  to  cause adverse  effects  when
exposure occurs  during a  limited  time  Interval  I.e., for an  Interval  that
does  not  constitute a  significant portion  of the  Hfespan.  This  type of
exposure estimate  has  not been  extensively used,  or rigorously defined as
previous risk assessment efforts  have  focused  primarily  on lifetime  exposure
scenarios.  Animal data   used  for  subchronlc  estimates  generally  reflect
exposure durations of 30-90  days.   The general  methodology  for  estimating
subchronlc RfDs  Is  the same as  traditionally  employed for  chronic  estimates,
except that subchronlc data are utilized  when available.

    In the case  of suspected  carcinogens,  RfDs are  not  estimated.   Instead,
a  carcinogenic  potency   factor,  or   q-|*   (U.S.  EPA,  1980),  Is   provided.
These  potency  estimates  are  derived  for both  oral  and  Inhalation  exposures
where possible.  In addition, unit  risk  estimates for air  and drinking water
are presented  based on Inhalation and oral  data, respectively.

    Reportable quantities  (RQs)  based on both chronic toxlclty  and  cardno-
genlclty are derived.  The RQ  Is  used  to determine the quantity of a hazard-
ous  substance  for  which  notification  Is required 1n  the  event  of  a release
as  specified  under  the  Comprehensive  Environmental  Response,  Compensation
and  Liability  Act  (CERCLA).    These two  RQs  (chronic toxlclty  and  carclno-
gerilclty)  represent two of six scores developed  (the remaining  four reflect
1gn1tab1l1ty,   reactivity,  aquatic  toxlclty,  and acute mammalian  toxlclty).
Chemical-specific  RQs reflect the lowest of  these six primary criteria.   The
methodology for  chronic  toxlclty and  cancer  based  RQs  are  defined  1n  U.S.
EPA, 1984 and  1986a, respectively.
                                      111

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                               EXECUTIVE  SUMHARY

    Methomyl  1s  a  colorless,  crystalline  compound  with  a  sulfurous  odor
(Hartley  and  K1dd,  1985).   It  1s  used as  a  broad-spectrum  Insecticide  on
vegetables,   soybeans,   cotton,   other  field  crops,   certain   fruits   and
ornamental  plants (Melster,  1987).   The  only  current  U.S. manufacturer  of
methomyl  1s  DuPont  (SRI,  1987).   Production  of  methomyl   1n  1983  was
estimated  to  be—4.5-7.5  million pounds.   Methyl Isocyanate  Is used  as  a
chemical  Intermediate  In the  manufacture  of methomyl  (Martin  and  Worthing,
1977).
    The dominant  environmental  fate  process  for methomyl 1n air  Is  expected
to  be  vapor-phase  photooxldatlon with  hydroxyl  radicals.   In  an  average
ambient  atmosphere,  the methomyl-hydroxyl  radical  reaction  half-life  was
estimated  to  be  6   hours  (Atkinson,  1987).    If  released   to  environmental
waters, methomyl  may be degraded by blodegradatlon,  hydrolysis and  photoly-
sis.   B1odegradat1on may  be  the  most  Important  transformation  process  1n
water  based upon  the dominance of blodegradatlon  1n  soil.   Aqueous  hydroly-
sis occurs, but at  a relatively slow  rate.   Hydrolysis  half-lives  of 54,  38
and 20  weeks  were experimentally determined at respective  pH  values  of  6,  7
and  8  at  25°C  (Chapman  and  Cole,  1982).   Exposure to  sunlight  has  been
reported  to accelerate  the decomposition  of  methomyl  In   aqueous  solution
(Worthing and Walker, 1983).   Blodegradatlon  1s the dominant fate process  1n
soil  (Harvey  and  Pease, 1973;  Johnson and  Cox,  1985;  Fung and  Uren,  1977;
Heywood,  1975;  Aly  et  al.,  1979).  Field  studies 1n Delaware,  Florida and
North  Carolina  found   that  at  least  98.2% of   soil-applied  methomyl  had
disappeared after a  1-month  exposure  (Harvey and  Pease,   1973).   Although
methomyl  may  adsorb weakly to  moderately  In  soil  (Lelstra  et  al.,  1984;
                                      1v

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Kenaga,  1980),  leaching  may not  become  Important  since  the compound  may
degrade  faster   than  significant   leaching  can  occur.   Leaching  was  not
significant during field and runoff studies (Harvey and Pease, 1973).
    Methomyl 1s released  primarily  and directly to the  environment  from Us
application  as  air  Insecticide.   An  analysis  of  food  products  collected
between  1980 and  1983  by  U.S.  FDA  laboratories  detected  me thorny!   In  a
variety  of  vegetable  and  fruit   samples  at  concentrations  ranging  from
<0.01-0.41 ppm (Krause, 1985).  With the  possible  exception  of data from the
U.S.  EPA  STORET  Data  Base (U.S.  EPA,  1988),  environmental  monitoring  data
for methomy1 are  limited.
    Channel  catfish,  I.,   punctatus.   were  among  the  most  sensitive  fish
species  to any  formulation of   methorny! on  an acute  basis.  The  96-hour
LC5_  for  this species  exposed to  a  24% liquid  formulation was  0.30  mg/a
(Mayer and  Ellersleck,  1986).   Results from one test  with  blueglll sunflsh,
L_.  macrochlrus.   produced  the  highest  LC5Q  (least   toxic)   among  fish
(96-hour  LC5Q = 7.7  ppm), although  the  majority of  test results  with  this
species  ranged  from 0.43-2.8  mg/a  (Mayer  and  Ellersleck, 1986).   Salmo
clarkl  demonstrated   tolerance almost  as  high  as   that  of  the  blueglll
(96-hour   LCcQ =  6.8  mg/a).    There    was   little   evidence  that   water
chemistry significantly affected the toxldty of methomyl to fish.
    Aquatic  Invertebrates  expressed  greater   sensitivity  to  exposure  to
methomyl  than fish.   Water flea,  D. maqna. were among the  most  sensitive to
methomyl  on an  acute  basis  (48-hour  EC50 = 8.8  ppb).   Copepods,  Acartla
jtorisa.,  scud,  G.  pseudollmnaeus.   and  fiddler  crabs  were  among   the  least
sensitive  Invertebrates,  with  96-hour  LC5Qs  of  0.41,  1.05  and   2.38  mg/a,
respectively  (Kaplan and  Sherman,  1977;  Roberts  et  al.,  1982;   Mayer  and
Ellersleck, 1986).

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    Algae were  very  tolerant  to exposure to methomyl  compared  with  fish and
Invertebrates.  The  96-hour EC5Qs  with  respect to  growth  for A.  falcatus.
S.  quadrlcauda and  £.  trlcornutum  were 4.5,  67  and  82.0  mg/i,  respec-
tively.  Growth 1n £. fragile was Inhibited only at concentrations >225 ppm.
    Methomyl appears to  be  absorbed rapidly and completely from  the gastro-
intestinal tract of  rats (Huhtanen  and Dorough,  1976).   At  24-72  hours after
gavage  treatment  with  14C-methomyl,  -10% of the  administered  radioactivity
can be  recovered  from the  body  (Harvey  et al., 1973).   The  largest amounts
are located  In the eviscerated carcass,   hide,  gastrointestinal tract, blood
and  liver.    Metabolism  of  syn-methomyl,  the  Isomer   used  In  Insecticide
formulations, begins with partial  1somer1zat1on  to the  ant1-Isomer,  followed
by rapid hydrolysis  of the  ester  linkage  to  liberate the carbonyl moiety and
form  the  corresponding  syn- and  ant1-ox1mes  (Huhtanen  and Dorough,  1976).
The  carbonyl  carbon Is  rapidly and  nearly  completely expired  as  carbon
dioxide.  The  syn- and  ant1-ox1mes  undergo Beckmann  rearrangement   to  form
more  slowly  metabolized Intermediates  1n the  production of  carbon  dioxide
and acetonltrlle,  respectively.  The  carbon dioxide  and acetonUMle  thus
formed  are  expired  rapidly.   Together,   respiratory  excretion  accounts  for
-31-36% of  the dose of radioactivity.   Urinary metabolites, which  account
for -25-35%  of  the administered radioactivity,  may consist primarily  of the
oxlmes and acetonltrlle.
    Methomyl  was   not  carcinogenic  In   rat  feeding  studies   (Kaplan  and
Sherman, 1977) or  mice feeding  studies (Hazelton Laboratories,  1981)  and was
negative  1n  a  transplacental  hamster   fetal   cell . transformation  assay
(Quarles et al., 1979).  Results of mutagenlclty tests  were largely  negative
1n microorganisms   (Simmon et al.,  1976,  1977;  Blevlns  et al.,  1977a;  Waters
et al., 1980,  1982;  Morlya et  al., 1983; Klopman  et  al.,  1985;   Garrett  et
                                      v1

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al.,  1986),   but  were  mixed  In  Drosophlla  (Waters  et  al.,  1980,  1982;
Valencia, 1981; Hemavarthy  and Krlshnamurthy, 1987a)  and  various mammalian
systems  (Simmon et  al., 1977;  Blevlns  et  al.,  1977b; Waters  et  al., 1980,
1982; Wojdechowskl  and Kaur,  1980;  Wojdechowskl  et  al.,  1982; Debuyst and
Van  Larebeke,  1983;  Garrett  et  al.,  1986;  Hemavarthy and Krlshnamurthy,
1987b).   NHrosomethomyl,   however,   was   positive  In   cell  transformation
(Quarles  et  al.,  1979)  and  mutagenldty  tests  (Blevlns  et  al.,  1977a,b;
Seller,  1977)  and  Induced   forestomach  tumors   1n  rats  treated  by  gavage
(LlJInsky and Schmahl,  1978).
    The  acute  tox1c1ty  of   methomy1  appears to  be  equivalent  among  most
laboratory species;  however, the mouse Is noticeably more sensitive than the
rat  or  dog.   Single-dose  oral LD5_  values  ranged  from 8.5-40 mg/kg  (Kaplan
and  Sherman,  1977;  Fahmy et al., 1978;  Antal  et  al.,  1979;  Dashlell  and
Kennedy,  1984; Galnes  and  Under, 1986).  Gender and  age  appear  to have no
effect  on toxic  potency.   Doses  of  12-15 mg/kg  have been  fatal  to  humans
(Uddle  et   al.,  1979;  Arakl   et  al.,  1982).    Deaths  are  preceded  by
chol1nerg1c  signs (Kaplan  and Sherman, 1977).  Other  effects  attributed to
methomy1  Include  altered pancreatic  (Bedo and  deleszky,   1980) and liver
enzyme  activities (Iverson,  1977; El-Sewedy  et  al.,  1982), effects  on the
erythrocyte  and hematopolesls (Nakamura et  al.,  1977;  N1sh1da et al.,  1980),
and  sldn  sens1t1zat1on  (Kambe et  al.,  1976;  Matsushita and Aoyama,  1979).
Methomyl  has  not  been  associated with  neurotoxldty 1n  hens (Kaplan  and
Sherman, 1977;  U.S.  EPA,  1986b).
    A number of subchronlc  and chronic dietary studies  have been performed
using rats,  dogs  and mice.   In  the  subchronlc  studies, 400 ppm  (10  mg/kg/
day,  the  highest  level tested) was  considered  a  NOAEL  In  dogs (Kaplan and
Sherman,  1977), and 50  ppm  (2.5 mg/kg/day) (Kapland and Sherman,  1977), 100

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ppm  (5  mg/kg/day)  (Bedo and deleszky, I960) and  3  mg/kg/day  (Homan et al.,
1978) were considered NOAELs  1n- three  studies  using  rats.   At  higher dosages
rats  showed  body  weight  gain  depression,  decreased erythrocyte  counts  and
Increased  erythropolesls,  depressed  erythrocyte  or  brain  chollnesterase
activities,  minor • serum  or   liver  biochemical  alterations,  and  elevated
relative  kidney weights.   In  a  chronic  rat  study   with  dietary  levels  of
50-400  ppm  (Kaplan and  Sherman,  1977),  100 ppm  (5  mg/kg/day) was  a  NOAEL,
and  depressed growth  rate,  reduced  blood  hemoglobin  concentration, Increased
splenic  erythropolesls   and mild  kidney  lesions were observed  at  higher
levels.  In dogs chronically exposed to  50-1000 ppm,  100 ppm (2.5 mg/kg/day)
was  a  NOAEL,  and  anemia  and  mild lesions  of  the kidney,  liver,  spleen  and
bone  marrow  were  observed  at  higher  levels  (Kaplan   and  Sherman,  1977).
Mortality preceded by chollnergic  signs  was observed at 1000  ppm (25  mg/kg/
day).   Increased  mortality was  observed  In all  groups of  mice  chronically
exposed  to  diets   containing  50-800  ppm  (Hazelton Laboratories,  1981).   The
50  ppm  level  (6.5 mg/kg/day)  was  judged  a LOAEL  associated with  reduced
longevity.
    Methomy1   has   been   tested  for  developmental  toxlclty  In  rabbits  at
dosages up to 16 mg/kg/day  (Kaplan  and Sherman, 1977; Feussner  et al., 1983)
and  1n rats fed diets containing <400  ppm (U.S. EPA,  1986b)  with no evidence
of   teratogenldty.   No  effects   on   reproduction   were  observed   1n   a
3-generat1on   study where  rats  were  fed  diets  containing up  to  100  ppm
(Kaplan and Sherman,  1977).
    Me thorny!  was  classified  In EPA Group  0,  not classifiable as  to human
carc1nogen1c1ty, because  of no human data and Inadequate  animal  data.  Data
were Insufficient  for estimation of cancer  potency  factors for  either  oral
or Inhalation exposure.   Data  were  also  Insufficient for  estimation of  RfDs

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for subchronlc or  chronic  Inhalation  exposure.  An RfD of  0.025  mg/kg/day  (2
mg/clay  for  a  70  kg human)  was  calculated  for  chronic  oral  exposure  to
methomyl from the  NOAEL  of  2.5 mg/kg/day In the chronic  dog  study  by  Kaplan
and Sherman (1977).  The chronic oral RfD was adopted  as  the  subchronlc  oral
RfD.   A  chronic  -toxldty-based  RQ of  100  was  derived   from  the effect  of
reduced  survival  of  male  mice  1n  a  chronic  dietary study  (Hazelton
Laboratories,   1981).  Data  were  Insufficient   to  derive an  RQ  based  on
carclnogenldty.
                                      1x

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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
    2.2.   WATER	     4

           2.2.1.   Hydrolysis	     4
           2.2.2.   Oxidation 	  	     5
           2.2.3.   Photolysis	     5
           2.2.4.   MUroblal Degradation	     5
           2.2.5.   Volatilization	     5
           2.2.6.   Adsorption.  	     5
           2.2.7.   B1oconcentrat1on	     6

    2.3.   SOIL	     6

           2.3.1.   Degradation  	     6
           2.3.2.   Adsorption/Leaching 	     7

    2.4.   SUMMARY	     8

3.  EXPOSURE	     9

    3.1.   HATER	     9
    3.2.   FOOD	     9
    3.3.   INHALATION	    10
    3.4.   DERMAL	    10
    3.5.   SUMMARY	    10

4.  AQUATIC TOXICITY	    11

    4.1.   ACUTE TOXICITY	    11
    4.2.   CHRONIC EFFECTS	    22
    4.3.   PLANT EFFECTS	    22
    4.4.   SUMMARY. .	    23

5.  PHARMACOKINETCS	-	    24

    5.1.   ABSORPTION	    24
    5.2.   DISTRIBUTION	    24
    5.3.   METABOLISM	    25
    5.4.   EXCRETION	    29
    5.5.   SUMMARY	    30

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                           TABLE  OF  CONTENTS  (cont.)

                                                                        Page
 6.  EFFECTS	   31

     6.1. "  SYSTEMIC TOXICITY	   31

            6.1.1.- -  Inhalation Exposure	   31
            6.1.2.   Oral Exposure	   33
            6.1.3.   Other Relevant Information	   38

     6.2.   CARCINOGENICITY	   42

            6.2.1.   Inhalation	   42
            6.2.2.   Oral	   42
            6.2.3.   Other Relevant Information	   43

     6.3.   MUTAGENICITY	   44
     6.4.   TERATOGENICITY	   47
     6.5.   OTHER REPRODUCTIVE EFFECTS 	   48
     6.6.   SUMMARY	"	   48

 7.  EXISTING GUIDELINES AND STANDARDS 	   51

     7.1.   HUMAN	   51
     7.2.   AQUATIC	   51

 8.  RISK ASSESSMENT	   52

     8.1.   CARCINOGENICITY.  .	   52

            8.1.1.   Inhalation.  ..... 	   52
            8.1.2.   Oral	   52
            8.1.3.   Other Routes	   52
            8.1.4.   Weight of Evidence	   52
            8.1.5.   Quantitative Risk Estimates	   53

     8.2.   SYSTEMIC TOXICITY.	   53

            8.2.1.   Inhalation Exposure 	   53
            8.2.2.   Oral Exposure	   53

 9.  REPORTABLE QUANTITIES	   56

     9.1.   BASED ON SYSTEMIC TOXICITY 	   56
     9.2.   BASED ON CARCINOGENICITY	   58

10.  REFERENCES	   61

APPENDIX A:  LITERATURE SEARCHED	   78
APPENDIX B:  SUMMARY TABLE FOR METHOMYL 	   81
                                      x1

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                               LIST OF  TABLES
No.                               Title                               Page
4-1     Median Lethal  and Effective Concentrations  for  Fish  Exposed
        to Methomyl  (Lannate)  	   12
4-2     Medial Lethal  and Effective Concentrations  for  Aquatic
        Invertebrates  Exposed  to Methomyl  (Lannate)  	   19
6-1     Acute Oral  Toxldty of Methomyl	   39
6-2     Genotoxldty Testing of Methomyl	   45
9-1     Dietary Toxldty of Methomyl:  Data  Considered for
        Derivation  of  Composite Score  	   57
9-2     Methomyl: Minimum Effective Dose  (MED)  and  Reportable
        Quantity (RQ)	   59

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                             LIST  OF  ABBREVIATIONS
AChE
BCF
BHA
CAS
CS
DNA
dpm
DUEL
EC50
HA
Koc
Kow
LC50
LD50
LEL
LOAEL
MED
MTO
NOAEL
NOEL
ppb
ppm
RFO
RQ
RVd
«ve
SNARL
TLM
TLV
TWA
UV
Acetylchollnesterase
Bloconcentratlon factor
Butylated hydroxyanlllne
Chemical Abstract Service
Composite score
Deox1r1bonucle1c acid
Disintegrations per minute
Drinking water effect level
Median effective concentration
Health advisory
Soil sorptlon. coefficient
Octanol/water partition coefficient
Concentration lethal to 50% of recipients
Dose lethal to SOX of recipients
Lowest effect level
Lowest-observed-adverse-effect level
M11mum effective dose
Maximum tolerated dose
No-observed-adverse-effect level
No-observed-effect level
Parts per billion
Parts per million
Reference dose
Reportable quantity
Dose-rating value
Effect-rating value
Suggested no-adverse-reponse level
Median threshold limit
Threshold limit value
Time-weighted average
Ultraviolet

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                               1.  INTRODUCTION
1.1,   STRUCTURE AND CAS NUMBER
    Methomyl Is a common chemical name  for  the  compound  currently referenced
by  the  Chemical  Abstracts  Service  as  ethan1m1doth1o1c  add,  N-(((methyl-
am1no)carbonyl)oxy~}-,  methyl  ester.    It   1s   also  known  by  the  synonyms
S-methyl  N-(methylcarbamoyloxy)th1oacet1m1date,   methyl   N-[[(methylam1no)-
carbonyl]oxy]ethan1m1doth1oate   and   2-methylth1oprop1onaldehyde   0-methyl-
carbamoyloxlme  (Hartley and K1dd,  1985).   Methomyl   1s  marketed  by  E.I.
DuPont de  Nemours  and Co.  under  the trade names  Lannate  and Nudrln  and  by
Crystal  Chemical  Inter-America  Co.   under  the trade  name  Lanox  (Melster,
1987).   The  structure,  molecular weight, empirical formula and  CAS  Registry
number for methomyl  are as  follows:
CH3

CH3
                                        0 H
                                 \      II I
                                  C=N-0-C-N-CH3
Molecular weight:  162.21
Empirical formula:  C^-N^S
CAS Registry number:  16752-77-5
1.2.   PHYSICAL AND CHEMICAL PROPERTIES
    Methomyl  1s   a  colorless,  crystalline  compound  with  a  sulfurous  odor
(Hartley and  K1dd,  1985).   The commercial  product  1s a mixture of  the  syn-
and ant1-1somers  of methomyl  with  the  syn-lsomer  predominating  (Worthing and
Walker,  1983).   At 25°C,  methomyl  1s  soluble In  water  (58 g/kg),  acetone
(720 g/kg),  ethanol  (420 g/kg), methanol  (1000 g/kg) and  toluene  (30 g/kg)
(Worthing and Walker,  1983). Selected physical properties  are listed below:
    Melting point:       78-79°C.
    Water solubility     58 g/kg
      at 25°C:
                  Worthing and Walker, 1983
                  Worthing and Walker, 1983
0121d
      -1-
06/08/88

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    Vapor, pressure       0.00005 mm Hg          Worthing and Walker, 1983
      at 25°C:
    Log Kow:             0.60                   Hansch and Leo, 1985
    A1r conversion       1 mg/m3 = 0.148 ppm
    factors at 20°C:     1 ppm = 6.76 mg/m3

    Aqueous  solutions  of  methomy1  decompose  slowly  at room temperatures.
The  decomposition  can  be  accelerated with  aeration, exposure  to  sunlight,
alkalinity or higher temperatures (Worthing and Walker, 1983).
1.3.   PRODUCTION DATA
    Methomyl  Is   currently   manufactured  1n  the   United   States   by  the
Agr1chem1cals Dept. of  E.I. DuPont de  Nemours  and  Company,  Inc.  1n La Porte,
Texas  (SRI,  1987).   Production  of  methomyl   1s   accomplished  by  reacting
methyl Isocyanate with  methyl  N-hydroxyth1oacet1m1date (Martin and Worthing,
1977).
    In 1971,  an  estimated 2 million  pounds  of methomyl was  produced  1n the
United States  (Ouellette  and  King,  1977).   Current production volumes  are
not available, but  production  volumes  for 1983 can  be approximated.   It has
been  estimated  that  10% of methyl  Isocyanate production  Is used  to  manu-
facture  methomyl  and  that 15-26  million pounds  of  methyl   Isocyanate  was
produced  In 1983  (U.S. EPA,  1986b).    Using  these  figures, production  of
methomyl   1n  1983  can  be roughly  estimated  to  have  been  4.5-7.5  million
pounds.
1.4.   USE DATA
    Methomyl 1s used as  a  broadspectrum  Insecticide on vegetables,  soybeans,
cotton,  other  field  crops,  certain  fruits  and  ornamental plants  (Melster,
1987).  According  to  statistics compiled  by  the  U.S. Dept.  of  Agriculture,
the quantities  of  methomyl applied  to major  field  and  forage crops  1n  the
United States  1n  1971,  1976   and  1982  totaled   0.3,  2.5 and  1.7  million

0121d                               -2-                              07/14/88

-------
pounds,  respectively  (USDA,  1983).   In  1982,   the  major  crops  receiving
1nsect1c1dal  applications  of  methomyl  were  soybeans,  cotton,  peanuts  and
tobacco (USOA, 1983).
1.5.   SUMMARY
    Methomyl  1s  a "colorless,  crystalline  compound  with  a  sulfurous  odor
(Hartley  and  Kldd,  1985).    It  1s used  as  a  broadspectrum  Insecticide  on
vegetables,   soybeans,  cotton,   other   field  crops,  certain   fruits   and
ornamental  plants  (Melster,   1987).   The only current  U.S. manufacturer  of
methomyl  1s  DuPont  (SRI,   1987).   Production   of  methomyl   1n  1983  was
estimated  to  be -4.5-7.5  million pounds.   Methyl  Isocyanate  1s  used as  a
chemical  Intermediate  In  the manufacture of  methomyl (Martin and  Worthing,
1977).
0121d                               -3-                           .   06/08/88

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                     2.  ENVIRONMENTAL FATE AND TRANSPORT
2.1.   AIR
    Organic  compounds  having  vapor  pressures >0.0001  mm  Hg  should  exist
almost  entirely  1n  the  vapor phase  1n  the  ambient atmosphere,  while  com-
pounds  having  vapor pressures  
-------
2.2.2.   Oxidation.  Pertinent  data  regarding the oxidation  of  methomyl  1n
water were not located 1n the available literature dted 1n Appendix A.
2.2.3.   Photolysis.   Methomyl  absorbs  UV  light  at   environmental   wave-
lengths (Chen et a!., 1984), which Indicates  a  potential  for  direct photoly-
sis 1n sunlight. "The photodegradatlve  half-life  for a  thin  film of methomyl
applied to a  glass  slide and exposed to  laboratory  UV  light  of  environment-
ally significant wavelengths  (>295 nm)  was 48.41  hours  (Chen  et  al.,  1984).
Extrapolation of these data  to  predict  environmental photolysis  rates  1s  not
possible  without  additional  experimental  data;  however,  1t  does  Indicate
that photolysis may  be  a viable mechanism  by which  methomyl may  be degraded
In  the  environment.   When a dilute  aqueous solution of  methomyl  1s  Irradi-
ated with  UV  light  at  254  nm, acetonHMle,  dimethyl  dlsulflde,  acetone,
N-ethyl1denemethylam1ne  and  carbon  dioxide are  produced  (Freeman  and  Ndlp,
1984).
    The decomposition rate of methomyl  1n  aqueous  solution has been reported
to accelerate with  exposure to sunlight (Worthing  and Walker,  1983).
2.2.4.   Mlcroblal  Degradation.   Based  upon  the  soil  mlcroblal  degradation
data presented In Section 2.3.1., methomyl  may  be susceptible  to significant
blodegradatlon  1n  natural water  because  It  has  been  shown  to  be  degraded
primarily by blodegradatlon 1n soil.
2.2.5.   Volatilization.  Based  upon a  water solubility  of   58  g/kg  and  a
vapor  pressure  of  0.00005 mm Hg at  25°C  (Worthing and Walker,  1983),  the
Henry's  Law  constant  for  methomyl  can  be  estimated  to   be  1.84xlO~10
atm-mVmol,  which  Indicates  that  volatilization  from  environmental  waters
1s not significant  (Thomas, 1982).
2.2.6.   Adsorption.   Based  upon  the  soil  adsorption  data   presented   1n
Section 2.3.2., methomyl  1s  not expected  to partition  significantly from  the
water column to sediments or  to suspended organic  material.

0121d                               .5-                           .   06/08/88

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2.2.7.   B1oconcentrat1on.  The  BCF  of an organic chemical  can be estimated
from the following recommended regression-derived equations (Bysshe, 1982):
                         log BCF  = 0.76 log KQW - 0.23                   (2-1)
                    log BCF  =  2.791  - 0.564 log WS (1n  ppm)              (2-2)
For methomyl,  the' BCF values  calculated  from Equations 2-1 and  2-2  are 1.7
and 1.3,  respectively, based  on a  log  K   of  0.60  (Hansch and  Leo,  1985)
and a  water solubility  of  58,000  ppm (Worthing and Walker,  1983).   Kenaga
(1980)  estimated  the  BCF  for methomyl  to  be 8, based  on an experimental
K    of  160.   These  calculated  BCF  values  suggest  that   environmental
 oc
bloconcentratlon 1s not significant.
2.3.   SOIL
2.3.1.   Degradation.  Harvey  and  Pease  (1973)  conducted  soil  degradation
studies  of  14C  radlolabeled  methomyl  under  both  laboratory  and  field
conditions.  In the  laboratory,  31-48% of  applied methomyl  remained 1n  three
different  soil  types after  a  42-day exposure period.   The  primary degrada-
tion  product  was  C0_,  which  the authors  attributed  to mlcroblal  degrada-
tion.   A  small  amount of methomyl's  hydrolysis  product  (S-methyl  N-hydroxy-
th1oacet1m1date) also  remained 1n the  soils  In addition to polar residues.
Under   field  conditions   In  Delaware, only   1.8%  of  applied  radlolabeled
methomyl remained  1n the soil after a 1-month  exposure.   Approximately  71%
of  the applied  radioactivity was   lost  from  the soil,  presumably as  CO-.
After   1  year,  methomyl  and  Us hydrolysis  product completely  disappeared
from the  soil.   Similar  field results were obtained from  Florida and  North
Carolina.   Johnson and Cox  (1985)  found  methomyl degradation   In  soils  from
Georgia, Texas  and California  to be consistent  with the  results  reported by
Harvey and Pease (1973).
0121d                               -6-                           ;   06/08/88

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    Fung and Uren  (1977) examined  the  degradation  of  methomyl  1n two tobacco
growing soils using  perfuslon  studies.   Mlcroblal  degradation  was  determined
to  be  the  major  transformation process  based on  dissipation  results  from
sterile (using  sodium azlde) vs.  nonsteMle  soil.   In both  tobacco growing
soils,  mlcroblal •  degradation  occurred  after a  lag  period  of 7-14  days;
however, no lag period was  observed when  these soils  were previously exposed
to methomyl.  Other  authors have also determined  that  mlcroblal degradation
Is  the  primary  path  by  which methomyl  Is  degraded 1n soil  (Heywood,  1975;
Aly et al., 1979).   Lelstra  et  al.  (1984)  found  the degradation half-life of
methomyl 1n three greenhouse soils  to range from 3-14 days.
    In a compilation of  foliage  persistence data,  methomyl  has been reported
to have plant persistence  half-lives  ranging from  0.4-8.5  days  with respect
to cotton, mint  and Bermuda grass (Willis and McDowell, 1987).
2.3.2.   Adsorption/Leaching.   Harvey  and Pease  (1973)  applied 14C  radio-
labeled methomyl to  field  soils  1n  Delaware,  Florida  and  North Carolina, and
monitored  the  radioactivity  at depths  <15  Inches.   After  1-12  months  1n
Delaware,  3 months In Florida and  5 months  In North Carolina,  the  percent of
applied radioactivity at depths below 7  Inches  was a maximum of  0.2%.   The
remaining radioactivity was  found predominantly 1n  the  upper  3 Inches of the
soils.  Under farm use conditions, methomyl did not transport  laterally  Into
untreated  areas  with  runoff water  to  any   significant  degree (Harvey  and
Pease, -1973).
    Lelstra et  al.  (1984)  observed weak  to  moderate adsorption of  methomyl
to  three  greenhouse  soils,  and Kenaga  (1980)  reported an  experimental  K
value of  160 for  methomyl,  which   Is  Indicative  of moderate  soil  mobility.
These  results  suggest  that  significant  leaching  of  methomyl 1n   soil  1s
possible;  however, under conditions where  rapid degradation 1s occurring [as


0121d                               -7-                              07/14/88

-------
was  the  case In the Harvey  and  Pease (T973) field study],  leaching  may  not
be Important since the compound Is degrading faster than It Is leaching.
2.4.   SUMMARY
    The dominant environmental fate  process for methomyl  1n  air  1s  expected
to  be vapor-phase • photooxldatlon with  hydroxyl  radicals.   In  an  average
ambient  atmosphere,  the  methomyl-hydroxyl  radical   reaction half-life  was
estimated  to be  6  hours  (Atkinson,  1987).   If .released  to  environmental
waters, methomyl may  be degraded by  blodegradatlon,  hydrolysis and  photoly-
sis.   Blodegradatlon  may  be  the  most  Important  transformation  process  In
water based  upon the  dominance of blodegradatlon  1n  soil.   Aqueous  hydroly-
sis occurs,  but at  a  relatively  slow  rate.  Hydrolysis  half-lives of 54,  38
and 20 weeks were experimentally determined at respective  pH values  of 6,  7
and  8 at  25°C  (Chapman  and  Cole,  1982).  Exposure to  sunlight  has been
reported  to accelerate  the  decomposition  of  methomyl  1n  aqueous  solution
(Worthing and Walker, 1983).   Blodegradatlon 1s  the dominant fate process  1n
soil  (Harvey  and  Pease,  1973;  Johnson and  Cox,  1985;  Fung  and  Uren,  1977;
Heywood,   1975;  Aly  et  al.,  1979).    Field  studies 1n Delaware,  Florida  and
North  Carolina  found   that  at  least 98.2% of   soil-applied  methomyl   had
disappeared  after  a  1-month  exposure  (Harvey and  Pease,  1973).   Although
methomyl   may adsorb weakly  to  moderately  1n  soil   (Lelstra et  al.,  1984;
Kenaga,  1980),  leaching  may  not  become  Important  since  the compound  may
degrade  faster   than   significant  leaching can   occur.   Leaching  was   not
significant during field and runoff  studies (Harvey and Pease, 1973).
0121d                               -8-                           .   06/08/88

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                                 3.  EXPOSURE

    As  an  Insecticide,  methomyl  1s  applied to  plants  and son by  spraying
(CPP, 1987).   Release  to the environment  occurs  directly from  Its  applica-
tion as  an  Insecticide.   Environmental  releases resulting from  Us  manufac-
ture or  formulation  Into 1nsect1c1dal products  are  expected to be  minor  1n
relation  to   the  quantities   released  by  Insecticide   applications.    At
present, some  or all  applications of methomyl may be classified by  the  U.S.
EPA  as   Restricted  Use  Pesticides  (Melster,  1987).   Improper  disposal  of
methomyl wastes Is  a  violation of Federal  law  (CPP,  1987).
3.1.   HATER
    The gross analysis of the water  monitoring  data  from  the U.S.  EPA STORET
Data Base cites 1837 reporting  stations for methomyl with a  minimum, maximum
and mean  concentration  of 0.0,  500.0 and  7.2  ppb,  respectively  (U.S.  EPA,
1988).
    Methomyl was not  detected  (analytical  detection  limit not  reported)  In
any groundwater during  a monitoring  survey conducted  In  the early  1980s  of
1174 community wells and 617  private  wells  In Wisconsin (KM 11  and Sonzognl,
1986).  Methomyl was not detected  (analytical detection limit of 1.0 ppb)  In
water  samples  collected  from  91 farm  wells   1n  southern  Ontario  1n  1984
(Frank et al., 1987).
3.2.   FOOD
    Krause  (1985)  reported  the  results of  an  analysis  of food  products  for
residues  of carbamate  pesticides conducted  by the  U.S. FDA  laboratories.
Between 1980 and 1983, 39 different  fresh  crops, dehydrated  apples,  crackers
and wines  were analyzed  for  methomyl.   Methomyl was detected  In  15  of  319
food samples analyzed at  the  following concentrations (by weight):   cabbage,

0121d                               -9-                              07/14/88

-------
0.02-0.41  ppm;  cantaloupe, 0.02  ppm;  cucumber,  0.04 ppm;  grapes,  0.01-0.04
ppm; lettuce, 0.12 ppm;  romalne,  0.02  ppm;  squash,  0.06 ppm;  potatoes,  <0.01
ppm.   One  market  basket from  the  U.S.  FDA's  Total Diet  Program  for  1983
contained 0.07 ppm methomyl 1n  boiled  collards and  0.067 ppm methomyl 1n raw
strawberries (Krau'se, 1985).
3.3.   INHALATION
    The  average  concentration of methomyl  In the  ambient  air of  a storage
room of  a  commercial  pest control  building was  13.7   ng/m3  over  a  3-hour
monitoring period (Yeboah and  Kllgore,  1984).
3.4.   DERMAL
    Pertinent monitoring data regarding dermal  exposure were  not  located  In
the available literature dted 1n Appendix A.
3.5.   SUMMARY
    Methomyl 1s  released primarily  and directly  to  the  environment  from Us
application  as   an   Insecticide.   An  analysis   of   food products  collected
between  1980 and  1983  by U.S.  FDA  laboratories  detected   methomyl   1n  a
variety  of  vegetable  and fruit  samples  at  concentrations  ranging  from
<0.01-0.41  ppm (Krause,  1985).  With the  possible exception of data from the
U.S. EPA  STORET  Data  Base (U.S.  EPA,  1988),  environmental monitoring  data
for methomyl are  limited.
0121d                               -10-                          .   06/08/88

-------
                              4. AQUATIC 'TOXICITY
4.1.   ACUTE TOXICITY
    The results of an extensive series of  studies  1n  which  fish were exposed
to methomyl 1n a  variety of  formulations  for  <96  hours  are  reported 1n Table
4-1.  Most  of  the- studies were  reported  by Mayer and  Ellersleck  (1986)  and
were published previously  by Johnson and  Flnley  (1980).  The  96-hour  LC5_s
for  channel catfish,  Ictalurus  punctatus.  exposed   to methomyl   In  three
different formulations In  tests  conducted at three temperatures  ranged from
0.30-0.76 mg/l.   Catfish  yolk-sac fry were  less  sensitive  than  sw1m-up  fry
or  flngerllngs  (1.8  mg/l).   Temperature  appeared to  have  a minimal  effect
on  the  toxldty  of methomyl  to  blueglll  sunflsh, Lepomls macrochlrus.   The
96-hour  LCggS   at  12  and  22°C  were  2.0  and   0.86  mg/i,   respectively.
Schneider   (1979)  reported   the  highest   LC5Q   for   bluegllls  exposed   to
methomyl  (7.7  ppm);   the  lowest   LC5Q  for bluegllls  In a  96-hour  test  was
0.37 mg/8,  (Mayer  and Ellersleck,  1986).  The  results of  all other  acute
studies with fish  were comparable to those reported  for channel  catfish  and
blueglll  sunflsh.   Rainbow   trout,  Sal mo  galrdneM.  eggs  were   the  least
sensitive  fish  stage  among   studies  reported.    The  96-hour  LC5Q  for  eyed
eggs was 32 mg/l (Mayer and Ellersleck,  1986).
    Hashimoto and  Fukaml  (1969)  assessed the toxldty  of Lannate  (methomyl)
to carp,  Cyprlnus  carplo  Llnne,  by three routes  of exposure:   oral, topical
and  contact.   Oral  exposure  was achieved  by adding  pesticide to powdered
fish feed  that  was mixed  with  distilled water to  form a  paste.   The paste
was molded  Into  a small  pellet and offered  to the  test fish.   Mortality  was
determined  48  hours  after feeding.   Topical application  of   pesticide  was
achieved  by applying solutions directly  onto the gill  lamella  of anaesthe-
tized  fish.  The anaesthetic  was a 0.1X aqueous solution  of  MS-222 SANDOZ
0121d                               -11-                           .  08/24/88

-------
                                   1ABLE 4-1
Median Lethal and Effective  Concentrations  for Fish Exposed to Methoayl  (Lannate)
rw
Q.











1
rvi
i












V

o
o»
>*
o
CO
v*
CO
CO
Median Response Concentration
Species
Cyprlnodon
varlegatus
Ictalurus
punctatus
Channel catfish
Ictalurus
punctatus
Channel catfish
Ictalurus
punctatus
Channel catfish
Ictalurus
punctatus
Channel catfish
(flngerllng)
Ictalurus
punctatus
Channel catfish
(swla-up fry)
Ictalurus
punctatus
Channel catfish
(yolk-sac fry)
Channel catfish
(species not
specified)
Cyprlnus carplo
Carp
Chemical
24X Lannate
In aethanol
95X technical
aatertal

24X liquid


29X liquid


24X liquid



24X liquid

'

24X liquid



nethoayl
lest
Method
S

S


S


S


S



S



S



S
24-Hour
(95X
NR

0.72 ag/t
(0.535-0.967)

0.45 ag/t
(0.30-0.65)

0.46 ag/t
(0.225-0.938)

0.76 ag/t
(0.635-0.909)


0.56 ag/t
(0.445-0.705)


2.4 ag/t
(2.0-2.9)


0.92 ag/t
48-Hour 96-Hour
confidence Halts)
NR 0.96 ag/t
(0.82-1.26)
NR 0.53 ag/t
(0.375-0.748)

NR 0.30 ag/t
(0.20-0.43)

NR 0.32 ag/t
(0.275-0.371)

NR 0.76 ag/t
(0.635-0.909)


NR <0.56 ag/t



NR 1.8 ag/t
(1.3-2.4)


NR NR
Comments
LC50. teap. = 22*C.
salinity = 10V»
IC50. teap. = 22*C.
pH = 7.4. hardness =

LC50. teap. * 22«C.
pH <= 7.4. hardness =

LC50. teap. = 17-C.
pH = 7.4. hardness •

LC50. teap. <• 22*C.
pH = 7.4. hardness «


LC50. teap. = 25-C.
pH = 7.4. hardness =


LC50. teap. = 25'C.
pH = 7.4. hardness =


LC50. teap. = 26«C
i

•

40 ng/t


40 ng/t


44 ag/t


40 ng/t



40 ng/t



40 ng/t



Reference
Roberts et
1982
Mayer and
Ellersleck,

Mayer and
E Hers leek,

Mayer and
Ellersleck.

Mayer and
Ellersleck,


Mayer and
Ellersleck.


Mayer and
Ellersleck,


Carter and
al..


1986


1986


1986


1986
.


1986



1986



Graves. 1973

Lannate


S


3.16 ag/t
(2.76-3.62)

2.96 ag/t NR
(2.54-3.54)

UH. teap . 22-25«C;
reported as ag/t of

results
active

El-Refal et
1976

al..

Ingredient; fish size = 1.75 g

Cyprlnus carplo
Carp

Lannate


S


1.55 ag/t
(1.02-2.35)

1.21 ng/t NR
(0.8-1.85)

11H, teap . 22-25'C;
reported as ng/t of

results
active

El-Refal et
1976

al.,

Ingredient; fish size = 31.5 g

-------
TABLE 4-1 (cant.)
_i Median Response Concentration
M
0.



1
CO
1



o
o
CO
Species
Lepoals
aacrochlrus
Blueglll sunflsh
Lepoals
aacrochlrus
Blueglll sunflsh
Lepoals
aacrochlrus
Blueglll sunflsh
Lepoals
aacrochlrus
Blueglll sunflsh
Lepoals
aacrochlrus
Blueglll sunflsh
Lepoals
aacrochlrus
Blueglll sunflsh
Lepoals
aacrochlrus
Blueglll sunflsh
Lepoals
aacrochlrus
Blueglll sunflsh
Lepoals
aacrochlrus
Blueglll sunflsh
>'tepoa1s
aacrochlrus
Blueglll sunflsh
Lepoals
aacrochlrus
Chemical
95X technical
aaterlal
95X technical
aaterlal
95X technical
aaterlal
9SX technical
aaterlal
95X technical
aaterlal
95X technical
aaterlal
95X technical
aaterlal
29X liquid
29X liquid
24X liquid
24X liquid
Test
Method
S
S
S
S
S
S
S
S
S
ET
S
24-Hour 48-Hour 96-Hour
(95X confidence Halts)
3.3 ag/t NR
(2.11-4.51)
0.93-1. 8 ag/t NR
1.0 ag/t NR
(0.825-1.21)
1.55 ag/t NR
(1.11-2.16)
1.2. 0.94 ag/t NR
0.92 ag/t NR
(0.67-1.26)
1.3 ag/t NR
(1.01-1.67)
2.4 ag/t NR
(1.572-3.663)
2.4 mg/t NR
(1.572-3.663)
NR NR
0.76-0.79 ag/t NR
2.0 ag/t
(1.43-2.80)
0.6-1.2 ag/t
0.86 ag/t
(0.644-1.15)
0.84 ag/t
(0.53-1.34)
0.94. 0.48 ag/t
0.62 ag/t
(0.37-1.04)
1.05 ag/t
(0.859-1.28)
0.67 ag/t
(0.428-1.048)
0.67 ag/t
(0.428-1.048)
2.8 ag/t
(2.5-3.2)
0.37-0.71 ag/t
"50
pH =
Comments
. teap. = 12-C.
7.4. hardness =
: Reference
40
LC50. temp. = 17»C.
pH * 7.4. hardness = 40
results from 3 studies
"50
pH =
"50
pH =
. teap. = 22-C.
7.4. hardness =
. teap. = 17*C.
7.4. hardness -
LC50. temp. « 17«C.
pH = 6.0. 6.5.
hardness - 40 ag/t
LC50. teap. = 17«C.
pH = 8.5. hardness =
"50
pH =
"50
pH =
"50
pH =
"50
pH =
"50
pH =
. teap. = 20*C.
7.2, hardness =
. teap. = 22"C.
7.4. hardness =
. teap. = 17«C.
7.4. hardness =
. teap. - 22-C.
7.4. hardness =
40
mg/t
rag/I.
mg/t
320 mg/t
40
40
40
44
mg/t
mg/t
mg/t
mg/t
272 mg/t
. teap. = 20-22*C.
7.2-7.4. hardness =
. Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck,
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck,
Mayer and
Filers leek.
1986
1986
1986
1986
1986
1986
1986
1986
1986
1986
1986
_  Blueglll sunflsh
CO
                                  40 ag/t. results from
                                  4 studies

-------
                                                                          TABLE 4-1 (cont.)
2 ' Median Response Concentration
i\> Species
Q.
Lepoals
aacrochlrus
Blueglll sunflsh
Lepoals
. aacrochlrus
Blueglll sunflsh
Lepoals
aacrochlrus
Blueglll sunflsh
Lepoals
aacrochlrus
Blueglll sunflsh
Lepoals
, aacrochlrus
— • Blueglll sunflsh
Blueglll sunflsh
(species not
specified)
Menldla aenldla
Mlcropterus
salmoldes
Largeaouth bass
Mlcropterus
salmoldes
Largeaouth bass
Plmephales
ooromelas
Fathead alnnow
g> Plmephales
\ promelas
Chemical
24X liquid
24X liquid
24X liquid
90X active
Ingredient In
wettable powder
24X liquid
methomyl
24X Lannate In
aethanol
95X technical
material
24X liquid
99X technical
material
24X liquid
Test
Method
S
S
S
S
S
S
S
S
S
S
S
24-Hour 48-Hour 96-Hour
(95X confidence limits)
>3.2 mg/t
2.5 mg/t
(1.69-3.3)
0.48 ag/t
(0.37-0.62)
2.35 ppa
12.0 ppa
NR
NR
1.25 mg/t
(0.956-1.63)
0.76 ag/t
(0.589-0.979)
3.8 ag/t
(2.6-5.6)
2.0 mg/t
(1.5-2.7)
NR
NR
NR
2.15 ppa
9.10 ppm
NR
NR
NR
NR
NR
NR
1.8 ag/t
(1.2-2.7)
1.2 ag/t
(0.924-1.56)
0.43 ag/t
(0.31-0.59)
2.15 ppa
7.70 ppa
2 ag/t
0.34 ag/t
(0.29-0.39)
1.25 ag/t
(0.971-1.61)
0.76 ag/t
(0.589-0.979)
2.8 ag/t
(1.8-4.3)
1.8 ag/t
(1.2-2.7)
Comments
I
LC50. teap. = 12-C.
pH = 7.4. hardness = 40 mg/t
LC50. teap. = 17-C.
pH - 7.4. hardness - 40 ag/t
LC50. temp. = 27 -C.
pH = 7.4. hardness = 40 ag/t
LC50. teap. « 18-C
LC50. teap. = 18'C
LC50. teap. * 23*C
LC50. teap. = 22'C,
salinity = 10V—
LC50. teap. = 22-C.
pH = 7.2. hardness = 40 mg/t
IC50. teap. » 22«C.
pH = 7.2. hardness = 40 mg/t
LC50. teap. = 17«C.
pH = 7.4. hardness = 45 mg/t
LCS0. temp. = 12*C.
pH = 7.2. hardness = 40 mg/t
Reference
Mayer and
Ellersleck
Mayer and
Ellersleck
Mayer and
Ellersleck
Schneider,
. 1986
. 1986
. 1986
1979
Schenlder. 1979
Carter and
Graves, 1973
Roberts et
1982
Mayer and
Ellersleck
Mayer and
Ellersleck
Mayer -and
Ellersleck
Mayer and
Ellersleck
al..
. 1986
. 1986
, 1986
. 1986
CO
CO

-------
TABLE 4-1 (cont.)
0
•J
PO
o.
Median Response Concentration
Species
Chemical
Test
Method
24 -Hour
48-Hour 96-Hour
Comments
Reference
(9SX confidence 1 tails)












i
en














0
c*
0
00
>x
CD
00
Ploephales
promelas
Fathead minnow
Salop dark!
Cutthroat trout
Saloo galrdnerl
Rainbow trout
Salao galrdnerl
Rainbow trout
Salao qalrdnerl
Rainbow trout
Salao galrdnerl
Rainbow trout

Salao galrdnerl
Rainbow trout
Salao galrdnerl
Rainbow trout

Salao galrdnerl
Rainbow trout
Salao galrdnerl
Rainbow trout
Salgg galrdnerl
Rainbow trout

>*Sa1ao galrdnerl
Rainbow trout
Salao qalrdnerl
Rainbow trout



29X liquid


95X technical
material
95X technical
material
95X technical
material
95X technical
material
95X technical
material

95X technical
material
95X technical
material

29X liquid

24X liquid

24X liquid


24X liquid

24X liquid




S


S

S

S

S

S


S

S


S

FT

S


NR

S




2.8 og/l
(2.0-3.9)

>3.f> og/t

2.8 og/ft
(1.98-3.96)
2.1 og/l
(1.6-2.8)
1.45 mg/l
(0.93-2.26)
4.0 mg/l
(2.92-5.47)

1.3 mg/l
(0.96-1.75)
2.00-4.2 mg/l


1.8 mg/l
(1.32-2.45)
>2.5 og/l

1.8-5.0 og/l


3.8. 3.9,
3.0 og/l
2.7 og/l
(2.08-3.51)



NR


NR

NR

NR

NR

NR


NR

NR


NR

NR

NR


NR

NR




1.5 mg/l
(0.9-2.5)

6.8 og/l
(2.18-7.53)
1.4 og/l
(0.95-2.0)
1.5 mg/l
(1.1-2.0)
1.2 mg/l
(0.78-1.86)
2.0 mg/l
(1.43-2.79)

0.86 ag/l
(0.59-1.26)
1.05-1.7 ag/l


1.2 ag/l
(0.76-1.88)
>2.5 ag/l

1.2-2.3 ag/l


1.4. 1.4. 1.5
mg/l
1.4 og/l
(1.1-1.79)



i
LC50. temp. = 12*C.
pH = 7.2. hardness = 46 rog/i

LC50. teop. = 10-C.
pH «= 7.4. hardness = 162 bg/l
LC50. teop. = 12'C,
pH = 7.4. hardness = 320 og/l
LC50. teap. = 12-C.
pH - 6.5, hardness = 40 mg/l
LC50. teap. = 12-C.
pH «= 8.5. hardness = 40 og/l
LC50. test temp. = 7'C.
pH = 7.4. hardness - 40 og/l

LC50. test teap. = 17*C.
pH = 7.4. hardness = 40 mg/l
LC50. test teap. <= 12*C.
pH " 7.2-7.5. hardness = 40 og/l,
results from 4 studies
IC50, teap. = 12-C.
pH = 7.4. hardness = 40 og/l
LC50. temp. = 12-C.
pH = 7.4. hardness = 272 og/l
LC50. test teap. » 10-12*C.
pH = 7.2. hardness = 40 og/l.
results froo 5 studies
LC5Q values after 1. 3. 7 days
of degradation, respectively
LC50. temp. = 17'C.
pH - 7.2. hardness = 40 og/l



Mayer and
E Her sleek.

Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.

Mayer and
Ellersleck,
Mayer and
Ellersleck.

Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.

Mayer and
Ellersleck,
Mayer and
Ellersleck.




1986


1986

1986

1986

1986

1986


1986

1986


1986

1986

1986


1986

1986




-------
                                                                          TABLE 4-1 (cont.)
0
_j
o.



i
o*
1




06/08/
Median Response Concentration
Species
Salmo galrdnerl
Rainbow trout
Salao galrdnerl
Rainbow trout
Salao galrdnerl
Rainbow trout
(eyed egg)
Salao galrdnerl
Rainbow trout
(swim-up fry)
Salao galrdnerl
Rainbow trout
(yolk-sac fry)
Salmo salar
Atlantic salaon
Salao salar
Atlantic salaon
Salao salar
Atlantic salaon
Salmo salar
Atlantic salaon
Salvellnus
"Font anil Is
Brook trout
Salvellnus
fontanllls
Brook trout
Chemical
90X active
Ingredient In
wettable powder
90X active
Ingredient In
wettable powder
24X liquid
24X liquid
24X liquid
95X technical
material
99X technical
material
99X technical
material
24X liquid
99X technical
aaterlal
24X liquid
Test
Method
S
S
S
S
S
S
S
S
S
S
S
24-Hour 48-Hour
(95X confidence
3.1 ppa 2.7 ppa
2.95 ppn 2.95 ppn
>10 ag/t NR
1.5 ag/t NR
(1.2-1.9)
>10 ag/t NR
0.8 ag/t NR
(0.7-0.92)
1.63-1.72 ag/t NR
0.82, 0.94 ag/l NR
1.6. 1.5 ag/t NR
2.25, 1.75 ag/t NR
NR NR
96-Hour
Halts)
2.38 ppa
2.60 ppa
32 ag/t
(18-55)
1.3 ag/t
(0.96-1.6)
3.2 ag/t
(2.3-4.5)
0.56 ag/t
(0.46-0.69)
1.0-1. 22 ag/t
0.64. 0.70 ag/t
1.4. 1.2 ag/l
2.2. 1.5 ag/t
1.22 ag/t
(0.86-1.73)
Comments
LC50. teap. = 12°C
tC50. leap. = 12«C
LC50. teap. = 10-C.
pH = 7.2. hardness = 40
LC50. teap. . 12«C.
pH = 7.4. hardness = 40
LC50. teap. = 12'C.
pH = 7.2. hardness = 40
LC50, test temp. = 17"C.
pH = 7.5, hardness = 40
LC50, teap. = 12'C,
pH = 7.5. hardness = 40
results from 5 studies
• 1


mg/t
ng/t
ng/t
mg/t
ng/t,
LC50. teap. . 12'C. pH = 6.0.
6.5. respectively, hardness =
40 ag/t. results from 2 studies
IC50. teap. = 12'C.
pH = 7.5. hardness = 40
results from 2 studies
LC50, teap. = 12'C.
pH = 7.5. hardness = 40
results from 2 studies
tC50. teap. = 12°C.
pH = 7.5. hardness = 40
ng/t.
ng/l.
ng/t
Reference
Schneider,
Schneider,
Mayer and
Ellersleck
Mayer and
Ellersleck
Mayer and
Ellersleck
Mayer and
Ellersleck
Mayer and
Ellersleck
Mayer and
Ellersleck
Mayer and
Ellersleck
Mayer and
Ellersleck
Mayer and
Ellersleck
1979
1979
. 1986
. 1986
. 1986
. 1986
. 1986
. 1986
. 1986
. 1986
. 1986
CO
CO

-------
                                                                            TABLE 4-1  (cont.)
o
— ' Species Chemical
Median Response Concentration
Test
Method 24 -Hour
48 -Hour 96 -Hour

Comments
Reference
(95X confidence Units)
Tllapla nllotlca Lannate
Tllapla

Tllapla nllotlca Lannate
Ttlapla

S 1.0S4 ng/t
(0.983-1.13)

S 1.301 mg/t.
(0.855-1.980)

0.916 ng/t MR
(0.848-0.989)

0.884 ng/t MR
(0.570-1.37)

TLH. te«p.
reported as
Ingredient;
TLH. teap.
reported as
Ingredient;
= 22-25-C; results
ng/t of active
fish size = 1.5 g
= 22-25-C; results
mg/t. of active
fish size = 13.8 g
El-Refal et al..
1976

El-Refal et al..
1976

     FT « Flowthrough; LCjQ = nedlan lethal concentration; NR = not reported; S = static
o
oo
CO
CO

-------
 (methanesulphonate   of   meta-am1nobenzo1c   add   ethylester).   F1sh   were
 observed  for  48  hours  after the application of pesticide.   Contact  exposure
 was  achieved by  holding  fish  1n  10  I  of  test   solution  at 20-22°C.   The
 duration  of  exposure  was  not  specified.    Hashimoto  and  Fukaml  (1969)
 reported  LD5Qs   for  all   treatments  Including  the   contact   studies   by
 assuming  that all  of  the  pesticide  In  the  test  solutions  was  "completely
 accepted  by  the  test  fishes."   They reported an  oral  L05Q  of  4.2  mg/flsh,
 a  topical  LD5Q of  0.036 mg/f1sh and  a contact LD5Q  of 2.0  mg/flsh.   F1sh
were an average of 6.0 cm In total length and 2.5  g 1n weight.
    Carter (1971)  reported a 24-hour IC™ of  0.92 ppm  for  channel  catfish,
 Ictalurus  punctatus. exposed  to methomyl.   Other  than  fish size  (mean =
 8.54 g),  experimental   conditions  were  not  reported.   Kaplan  and  Sherman
 (1977) reported the  results  of  acute studies with blueglll  sunflsh,  rainbow
 trout  and   goldfish.    The   96-hour   LC5Qs   were  0.875,   3.4   and  >0.10,
 respectively.
    The  results  of  studies  In  which aquatic  Invertebrates  were exposed  to
methomyl  for  acute  periods  are  presented 1n Table 4-2.  Most of  the studies
were  reported  by  Mayer and  Ellersleck  (1986)  and were  published  previously
by  Johnson  and  Flnley  (1980).   In general,  aquatic  Invertebrates,  mainly
crustaceans and Insects, demonstrated greater  sensitivity  to acute  exposures
 to methomyl  than  fish,  although  the toxldty  was  not  dependent  on  water
chemistry.   The   96-hour  LC5Qs   generated with  copepods  and shrimp  ranged
from  0.29-0.41  and  0.03-0.064   mg/l,   respectively,  and  were not  signifi-
cantly  affected  by  differences  1n  salinity  (Roberts  et  al.,  1982).   The
48-hour  ECcg  levels  with  Daphnla  maqna  were  0.0076   and  0.0088   mg/8.
despite  differences  1n  water  hardness  or  methomyl  formulation (Mayer  and
0121d                               -18-                          .   06/08/88

-------
                                            TABLE 4-2



Median Lethal and Effective Concentrations for Aquatic  Invertebrates  Exposed  to Nethonyl  (Lannate)
INJ 	 : 	 	 	 — 	
°- Median Response Concentration




i
i



o
0
CD
CD
CD
Species
Acartla tonsa
Copepod
Eurytemora afflnls
Copepod
Mysldopsis bah la
Mysld shrlap
Neomysts aaerlcana
Mysld shrimp
White River crawfish
(species not specified)
Daphnta aagna
Water flea
Daphnta aagna
Water flea
Gaaaarus
pseudollanaeus
Scud
Gaaaarus
pseudollanaeus
Scud
^Gajnarus
pseudol Imnaeus
Scud
Gaaaarus
pseudollanaeus
Scud
Chemical
24X Lannate
In aethanol
24X Lannate
in aethanol
24X Lannate
In nethanol
24X Lannate
In methanol
methomyl
95X technical
material
24X liquid
24X liquid
24X liquid
24X liquid
24X liquid
Test
Method 24-Hour 48-Hour 96-Hour
(95X confidence Halts)
S NR NR
S NR NR
S NR NR
S NR NR
S NR NR
S 0.012 ag/t 0.0088 ag/t
(0.0073-0.02) (0.0041-0.019)
S NR 0.0076 mg/t
(0.0048-0.0121)
FT >2.5 ag/t NR
NR NR 1.05. 0.075.
0.034 ag/t
S NR 1.05 ag/t
(0.424-2.60)
S >1 mg/t NR
0.41 ag/l
(0.26-0.62)
0.29 ag/t
(0.09-0.50)
0.050. 0.064
•9/t
0.034. 0.030
ag/t
1.0 ag/l
NR
NR
1.05 ag/l
(0.839-1.315)
NR
NR
0.72 ag/t
(0.572-0,907)
Comments
i
LC50. temp. = 22°C.
salinity = 10°/*«
LC50. temp. = 22'C.
salinity = 10V»
LCso. temp. = 22»C,
salinity = 20V. o.
results from 2 studies
LCjo. temp. = 22"C,
salinity = 20V-«.
results from 2 studies
LC50. temp. = 26°C
EC50. temp. = 21eC. pH =
7.4. hardness = 272 ag/t
ECjQ, temp. = 20*C. pH =
7.2. hardness = 40 mg/t
LCso. temp. = 12*C. pH =
7.4. hardness = 274 mg/t
LC50. temp. = 12-C, pH =
7.2. hardness = 40 mg/t;
values represent LCjo
after 1. 3 and 7 days of
degradation of active
metabolites In liquid
LC50. temp. = 12-C. pH =
7.2. hardness = 40 mg/t
LCc0. temp. = 17*C. pH =
7.4. hardness = 40 mg/l
Reference
Roberts et
1982
Roberts et
1982
Roberts et
1982
Roberts et
1982
al..
al..
al..
al..
Carter and
Graves. 1973
Mayer and
Ellersteck.
Mayer and
Ellersleck.
Mayer and
Ellersleck,
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
1986
1986
1986
1986
1986
1986

-------
                                                                          TABLE 4-2  (cent.)
O
I
Median Response Concentration
Species
Saaaarus
pseudollanaeus
Scud
Chlronoaus plumosus
Nidges
Chlronoaus pluaosus
Nidges
Isogenus sp.
Stonefly
Isogenus sp.
Stonefly
Pteronarcella badla
Stonefly
Pteronarcella badla
Stonefly
Chealcal Test
Method
99X technical S
aaterlal
24X liquid S
95X technical S
material
9SX technical S
material
24X liquid S
95X technical S
material
24X liquid S
24-Hour 48-Hour 96-Hour
(95X confidence Halts)
>.«/.
0.105 ag/l
(0.071-0.156)
NR
0.49 ag/l
(0.368-0.653)
0.066 ag/l
(0.046-0.095)
0.168 ag/l
(0.125-0.226)
0.067 ag/l
(0.056-0.080)
NR
0.032 ag/l
(0.013-0.080)
0.088 ag/l
(0.060-0.129)
NR
NR
NR
NR
0.92 ag/l
(0.68-1.24)
NR
NR
0.343 ag/l
(0.268-0.440)
0.029 ag/l
(0.021-0.041)
0.069 ag/l
(0.044-0.108)
0.060 ag/l
(0.045-0.080)
Comments
"!?•
5ci!'
"50.
7.4.
£?•
icl?'
icl?'
£?•
temp. =
hardness
temp. =
hardness
temp. =
hardness
teap. =
hardness
temp. =
hardness
teap. =
hardness
temp. =
hardness
17
20
22
T
T
T
s
T
•c
40
i
, PH =
mg/l
•C.'pH=
272 rag/l
°C
40
C.
42
C.
42
c.
40
C.
40
. PH =
mg/l
pH =
mg/l
pH =
mg/l
pH =
mg/l
pH =
Reference
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
1986
1986
1986
1986
1986
1986
1986
    £650 « Median effective concentration; FT » flowthrough; LCjQ = aedlan lethal concentration; NR = not reported; S - static
o
CO
^K
CO
CO

-------
Ellersleck,  1986).   The 96-hour LCcns  obtained  with' scud,  Gammarus  pseudo-
                                   3U                        ___^^__  	
Hmnaeus.  ranged  from 0.72-1.05 mg/j,  despite differences 1n  water  hardness
and  methomyl  formulation  (Mayer  and   Ellersleck,  1986).   The  toxldty  of
methomy1  to  aquatic  Insect  larvae,  however,  was  significantly affected  by
formulation.    The' 95%  technical  material was  more than  twice  as  toxic  to
midges  than  the 24%  liquid,  and 10-fold more  toxic  to a stonefly  Isoqenus
sp;  however,  these  same  formulations   did  not differ  1n  their toxldty  to
another  stonefly   genus,  Pteronarcella  badla.  after   96  hours  (Mayer  and
Ellersleck, 1986).
    Kaplan and  Sherman (1977)  reported  the  results  of  acute studies  with
grass  shrimp,  pink  shrimp,  mud crab  and fiddler  crab.   The 96-hour  LC5Qs
for  these   organisms  were  0.049,  0.019,   0.41   and   2.38,   respectively.
N1sh1uch1  and  Yoshlda (1972)  exposed  four  species of  snail  to methomyl  at
22°C  for  48 hours,  and reported  TL s of  6.6,  12,  25 and  18  ppm  for  the
snails,  Indoplanorbls  exustus.  Sem1.sulcosp1ra  Hbertlna.   C1panqopalud1na
ma 1'I eat a and  Physa acuta. respectively,  exposed to methomyl  as a  wettable
powder.  The  Investigators  also reported that I.,  exustus and S.  Hbertlna
experienced a loosening of body  muscle  at 1.2 and  0.60  ppm methomyl  after 48
hours of exposure at 22°C.
    Slmonet  et  al.  (1978)  used the  negative phototaxls  response  of  first
Instar  larval  mosquitoes,  Aedes aeqyptl.  to estimate  an  EC5Q for  exposure
to methomyl.   Groups  of  25  larvae were placed  Into stacking dishes  contain-
ing  100  ma of test  solution  for 8 hours.  Photomlgratlon tests were run In
a multi-unit apparatus consisting  of four glass  chambers  (4x4x4.7 cm) with a
moveable  gate; the  maximum  migration  distance  was  30  cm.  The  EC5Q  was
defined  as  the concentration  of methomyl reducing migration  1n 50% of  the
0121d                               -21-                          .   06/08/88

-------
test  larvae  as  compared  with  the  controls.   The  8-hour  EC5Q  (and. 95%
confidence  limits)  was  0.39  mg/8.  (0.85-1.70).    Strlckman  (1985)  exposed
second  Instar  larvae of  the  mosquito, Hyeomyla  smithll,  to methomyl  1n  30
ma  of  aged tap water  1n  7-day static  tests.   There were no mortalities  at
1  ppm,  but 100% mortality after  7 days at  5  ppm.  The  Investigators  noted
delayed development of larvae at 1  ppm.
4.2.   CHRONIC EFFECTS
    Carter  (1971)  reported an  EC5Q  (Inhibition)  of  0.016  ppm  for  channel
catfish  exposed  to  methomyl  1n a  static  test  conducted In  5000 l  pools.
Brain AChE,  Inhibited 80-90%,  recovered  to  80%  of normal activity  In  6-10
days  following  treatment  for  fish that were  left  1n the treatment  pools.
Carter  (1971)  also  reported  that scol1os1s,  a  lateral  curvature  of  the
spine, usually  with  localized hemorrhaglng,  was produced  In  channel  catfish
by methomyl at sublethal  concentrations.
4.3.   PLANT EFFECTS
    Khalll  and  Hostafa   (1986)  exposed   the  freshwater  blue-green  algae,
Phorm1d1um fragile,  to methomyl  to assess  effects  on  growth  and  physiologi-
cal behavior.  Algal cultures  (6-7  days old) were  exposed  to  methomyl 1n 100
mi  of  experimental medium for  7 days  at  28-30°C.  Concentrations <225 ppm
did not produce any  significant effects on the growth  of  P.  fragile.   Growth
(blomass  yield)  was  reduced  significantly  at concentrations  ranging  from
225-900 ppm.  Exposure to  methomyl  at concentrations  >225 ppm  also produced
reductions  1n  the  levels  of  chlorophyll  a,  carotenes   and   carbohydrate
contents.  Ibrahim (1984)  determined  the  EC5Qs for exposure of  the  chloro-
phytes,  Anklstrodesmus falcatus and Scenedesmus guadrlcauda.  and  the  diatom,
Phaeodactylum  trlcornutum.  to  methomyl  (Lannate).   The   96-hour   ECcls,
0121d                               -22-                             07/14/88

-------
defined as the calculated concentration of  Lanhate  that  would  Inhibit  growth
by  50%   as   compared   with  control  growth,  were  4.5,   67.0   and   82.0,
respectively.
4.4.   SUMMARY
    Channel  catfish,  l_.   punctatus.   were  among   the  most  sensitive  fish
species  to  any  formulation  of methomyl  on   an  acute  basis.   The  96-hour
LCcQ  for  this species  exposed  to  a  24%  liquid formulation  was  0.30  mg/a.
(Mayer and Ellersleck,  1986).   Results from one test with  blueglll  sunflsh,
L.  macrochlrus.  produced the  highest 1C.,  among  fish  (96-hour   LC5Q =7.7
ppm),  although  the majority of test  results  with  this species ranged  from
0.43-2.8  mg/i  (Mayer   and   Ellersleck,  1986).   Salmo  clarkl  demonstrated
tolerance  almost  as    high  as  that  of  the  blueglll  (96-hour  LC5Q = 6.8
mg/i).   There  was  IHtle  evidence  that  water   chemistry   affected   the
toxIcHy of methomyl to fish.
    Aquatic  Invertebrates  expressed  greater   sensitivity  to  exposure  to
methomyl than fish.  Water  flea, D. maqna.  were among  the  most sensitive to
methomyl  on  an  acute  basis  (48-hour  EC™ = 8.8  ppb).   Copepods,  Acartla
tonsa.  scud, G.  pseudollmnaeus.  and fiddler  crabs  were  among  the  least
sensitive  Invertebrates,  with  96-hour  LC5Qs   of  0.41,  1.05  and   2.38  mg/l,
respectively  (Kaplan  and  Sherman,  1977;  Roberts   et  al.,  1982;  Mayer  and
Ellersleck, 1986).
    Algae were very  tolerant to exposure to methomyl compared  with  fish and
Invertebrates.  The  96-hour EC5Qs  with  respect to  growth  for A.  falcatus.
£.  quadrlcauda   and  P_.  trlcornutum  were   4.5,  67  and 82.0  mg/i,  respec-
tively.  Growth 1n £. fragile was Inhibited  only at  concentrations  >225 ppm.
0121d                               -23-                             07/14/88

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                             5.  PHARHACOKINETICS
5.1.   ABSORPTION
    Metabolism   studies   with   orally  administered   [14C=0]-and   [14C=N]-
methomyl  provide  excretion  data  from which  Information regarding  gastro-
intestinal  absorption  can be  Inferred.  The  most useful Information  comes
from  studies  using the  [14C=0]  label, because  metabolism and  excretion  of
the  [C=0]  moiety  1s more rapid than  metabolism and  excretion  of  the  [C=N]
moiety.
    Huhtanen  and  Dorough  (1976)  administered  single  oral  1-2 million  dpm
doses  of  syn-[14C=0]-methomyl  1n corn  oil  to  two  male  and  two  female
Cox-SO  rats and  measured the  radioactivity  excreted  1n urine,   feces  and
expired carbon dioxide at various  times during  24  hours.  Fecal radioactiv-
ity accounted for  only 0.2% of  the administered  dose  In both sexes.  Urinary
radioactivity accounted  for  4.8-4.9% and expired  radioactive  carbon  dioxide
for  83.0  and 87.7% of  the dose 1n  males  and females,  respectively.   Total
recovery  was 88.0%  1n  males and 92.8%  In  females.   Radlolabeled  carbon
dioxide  appeared  within  the  first hour  of  treatment;   Us  excretion  was
nearly  complete   within   10  hours.   These  data  suggest  that  methomyl  Is
rapidly and nearly completely  absorbed from  the gastrointestinal  tract  of
rats.   U.S. EPA  (1987a)  mentioned  an unpublished  study from  the OPP  CBI
files  (Andrawes  et al.,  1976)  and a  paper  presented  at an  International
symposium  on  pesticide   terminal   residues   (Baron,  1971),  both  of  which
suggest that gastrointestinal  absorption In rats  Is nearly complete.
    Data were not located regarding the absorption of  Inhaled methomyl.
5.2.   DISTRIBUTION
    Harvey  et  al.  (1973) administered a  1.2  mg  (5.0-5.5  mg/kg) dose  of
[14C=N]-methomyl   1n  peanut oil  by gavage to  two rats  that  had been  main-
tained on a diet containing 200  ppm  cold methomyl  for 8 days.   Radioactivity
0121d                               -24-                          .  06/08/88

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was  measured  1n  expired  air, urine,  feces, several  Individual  organs  and
tissues  and  the  eviscerated  carcass  upon  sacrifice  at  72 or  24  hours.
Collectively, the organs  and  eviscerated  carcass contained 10 and  9% of  the
administered  dose of  radioactivity  after   72  and  24  hours,  respectively.
Radioactivity  was  expressed   as  yCl  per  organ  rather   than  1n  terms  of
concentration,  obscuring  tissue  affinities  for  methomyl  or  Its  radioactive
metabolites.   The  largest  amounts  of  radioactivity  were  located  In  the
carcass, hide,  gastrointestinal  tract, blood and  liver,  -0.2, 0.14,  0.014,
0.084  and   0.04 yd,  respectively.   Amounts  In  other  organs  ranged  from
0.000-0.014  yd.   The  amount of  radioactivity  In  the   blood  was  greater
after 72 hours  (0.084 yC1) than after 24 hours  (0.034 yC1).
    In  rats  treated  with a single  oral  5 mg/kg dose of  [14C=N]-methomyl,  a
total  of  10X of  the dose of  radioactivity  was  recovered  from tissues  upon
sacrifice at 24 hours  (Baron,  1971).  No  tissue  site demonstrated  a tendency
to  accumulate  radioactivity.   Tissue  levels were  nearly  Identical  In  rats
sacrificed  3  days  after .treatment,  suggesting  that the  radlolabel  had  been
Incorporated Into tissue components.
5.3.   METABOLISM
    Huhtanen and  Dorough (1976)  and  Oorough (1977) reported  extensively  on
the metabolism  of  orally-administered radlolabeled 1-2 million dpm doses  of
methomyl  1n corn  oil  1n male  and  female  Cox-SD rats,  and proposed  the
metabolic  scheme  presented  1n  Figure  5-1  and discussed below.   Methomyl
exists  1n   two  geometric  forms,  syn-methomyl  and  ant 1-methomyl;  the  syn-
Isorner  1s  the  more  stable  and 1s the  form  present 1n Insecticide formula-
tions.   Following  absorption, syn-methomyl  undergoes  partial  1somer1zat1on
to  the  anti-form.   Hydrolysis of the  ester  linkage liberates  the  carbonyl-
contalnlng  moiety and  the corresponding  syn- and  ant1-ox1mes.  The carbonyl


0121d                               -25-                          .   06/08/88
                                                                  r

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                    CM3
                    CH
                            I
                                                 $-CH3
                                                      FIGURE  5-1




§?                                  Proposed Metabolic Pathway for Hethonyl  In  Rats


o

\                                        Source:  Huhtanen and Dorough,,  1976

CO
oo

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carbon Is metabolized  rapidly  to carbon dioxide, which  Is  eliminated  1n the
expired air.  The  oxlmes  are partially excreted In  the  urine;  the remaining
syn- and  ant 1-oxlmes  undergo  Beckmann rearrangement  to form  Intermediates
that  are  further  metabolized  to  carbon  dioxide  and acetonltrlle,  respec-
tively.  These  Intermediates may be  metabolized slowly,  as  Indicated  by the
continued expiration of labeled  carbon  dioxide  and  acetonltrlle  for  at least
3 days after a single dose of labeled methomy1.
    The pathways  proposed above were  supported  by  the  results  of  several
experiments.  When [14C=0]-syn-methomyl  was given  to  rats,  83-88%  of  the
administered  radioactivity  was  recovered as  14C-carbon  dioxide  within  24
hour,  Indicating   that  hydrolysis of  the ester  linkage  with   formation  of
carbon dioxide  and the  oxlme 1s  rapid  and nearly  complete.   Further support
for  extensive  hydrolysis  of  the ester  linkage comes  from  the observation
that  <5%  of  the  administered   dose  of  radioactivity  from  [14C=N]-syn-
methomyl was recovered 1n  the urine as an  Intact carbamate compound.
    Administration  of   either   Isomer   of   [14C=N]-methomyl   resulted   1n
recovery  of14C-carbon   dioxide   within   2   hours.   14C-AcetonHr11e   was
recovered within  2 hours when  the ant1-1somer was  given,  but  not  before  6
hours when  the  syn-1somer was given.   The  Investigators theorized  that  the
delay  between  administration  of  syn-methomyl  and  recovery of  14C-aceto-
nltrlle represented  the  time required  for  1somer1zat1on of  the syn-  to  the
ant1-1somer,  because   oral   administration   of   [14C=N]-ant1-methomyl   or
l4C-aceton1tr1le   resulted   1n   prompt recovery   of  l4C-aceton1tr1le  from
expired air.  When the ant1-1somer  was given  14C-carbon  dioxide, excretion
was  rapid but  essentially complete  by 14 hours, suggesting  that  Its  source
was actually  syn-methomyl, which contaminated the ant1-Isomer up  to a level
of  20%.   Administration of  a purified  ant1-1somer  preparation  (5% syn-form)


0121d                               -27-                           .  06/08/88

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resulted  In  substantially  less expiration of  14C-carbon  dioxide,  suggesting
that  the  syn-lsomer  was  the  source  of  the  carbon  dioxide  and  that  the
ant1-1somer  does  not  1somer1ze to  any  extent  in  vivo.   Experiments  with
[4C=N]-syn   and   antl-methomyl   oxlme   confirmed   their   conversion   to
14C-carbon dioxide -and l4C-aceton1tr1le, respectively.
    Although  the   radioactive  urinary  metabolites  were   not   Identified
precisely, Huhtanen and Dorough (1976)  speculated  that  they  consisted  of the
oxlme and  a  highly volatile  fraction,  possibly acetonltMle.  In a  briefly
reported  unpublished   study   1n  rats,  urinary excretory  products  Included
unchanged  methomyl,  free  and  conjugated acetonltrlle,  the  oxlme  and  the
sulflde  oxlme  and  unidentified  polar metabolites  (Andrawes  et al.,  1976).
In  a  similar study In rats,  Harvey et  al.  (1973) established that  urinary
excretion  products  did  not   Include  unmetabollzed methomyl,  N-hydroxyth1o-
acetlmldate,  or sulfoxldatlon products  or their glucuronlde  conjugates.   In.
vitro  studies   with  hepatic   flavlne  adenlne  dlnucleotlde-dependent  mono-
oxygenase  (Hajjar  and  Hodgson,  1980, 1982) confirmed that methomyl was not a
substrate  for sulfoxldatlon,  which  occurs commonly with  thloether-containing
carbamate  Insecticides.
    There  1s considerable  Interest  1n  the ability of pesticides  containing
secondary amlne groups to undergo nltrosatlon  In the acid environment  of the
stomach  to form N-nltroso  derivatives,  several of which  (Including  nltroso-
methomyl)  have  been  shown to*be carcinogenic  In  gavage studies using  rats
(L1J1nsky  and Schmael, 1978). Although methomyl has  been nltrosated  1n  the
laboratory  (Lljlnsky  and  Schmahl,   1978;  IARC, 1983),  nltrosatlon  did  not
occur  In one experiment  under simulated  stomach  conditions  using  nitrite-
containing cured meats Incubated at  pH  2  (Han,  1975).   Additional  studies of
the 1n vivo nltrosatlon of  methomyl  are  1n progress (NTIS,  1988).


0121d                               -28-                             07/14/88

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5.4.   EXCRETION
    Huhtanen  and  Dorough  (1976)  orally administered  radlolabeled  syn- or
antl-methomyl  to rats  and  measured  expired 14C-carbon  dioxide and  aceto-
nltrlle and  urinary  radioactivity  over  a 24-hour period  as  described  above.
When  [14C=0]-syn-methomyl  was  given,  total  recovery  of radioactivity  was
>88% (>83.0% as  expired  carbon  dioxide, <5% as  urinary metabolites  and 0.2%
1n the feces), suggesting that excretion of  the  metabolites  of the carbonyl-
contalnlng  moiety  was  rapid   and   complete.    When  [14C=N]-methomyl  was
given, 24-hour  recovery  of  respiratory  radioactivity ranged  from  31-36% and
urinary  radioactivity ranged  from  25-35%   of  the  administered dose.   For
syn-methomyl, carbon  dioxide  accounted  for  19.5 and acetonltrlle  for  11.3%
of the dose  of radioactivity.  For the  ant1-1somer,  carbon  dioxide accounted
for 7.6  and  acetonltrlle for 27.9%  of  the   dose  of  radioactivity.   Respira-
tory  excretion   continued  for at  least  3  days following  treatment.   The
Investigators concluded  that  the extended  period of  excretion observed with
[14C=N]  methomyl  compared   with  [14C=0]   methomyl   resulted  from  persis-
tence  of  the  carbon dioxide  and  acetonltrlle  precursors  formed  from  the
ox1 me rather than  delay  In  the excretion of carbon  dioxide  and acetonltrlle
themselves.
    Similar  observations were reported  by Harvey  et  al.  (1973), who adminis-
tered  [14C=N]-methomyl   orally  to  rats at  3.6-5.5  mg/kg/day  and  measured
excretion  of  radioactivity   as  expired carbon  dioxide  and  acetonltrlle,
urinary metabolites  and fecal metabolites  for  24-72 hours.   Expired  carbon
dioxide ranged from  15-23%, acetonltrlle accounted for  -33%, urinary metabo-
lites for 16-24% and fecal  radioactivity for <2% of  the dose.
0121d                               -29-                          .   06/08/88

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5.5.   SUMMARY
    Methomyl appears  to  be absorbed rapidly and completely  from the gastro-
intestinal tract of rats  (Huhtanen  and  Dorough,  1976).   At  24-72 hours after
gavage  treatment  with 14C-methomyl,  -10% of the  administered  radioactivity
can be  recovered  "from the  body  (Harvey et al., 1973).   The  largest amounts
are located  1n  the eviscerated carcass,  hide,  gastrointestinal  tract, blood
and  liver.  Metabolism   of  syn-methomyl,  the  Isomer   used  1n  Insecticide
formulations, begins  with  partial  1somer1zat1on  to the  ant1-1somer,  followed
by rapid hydrolysis of the  ester  linkage  to liberate the carbonyl moiety and
form  the  corresponding  syn- and  ant1-ox1mes (Huhtanen  and Dorough,  1976).
The  carbonyl carbon  1s  expired   rapidly and  nearly completely as  carbon
dioxide.   The  syn- and  ant1-ox1mes  undergo Beckmann  rearrangement  to  form
more  slowly  metabolized  Intermediates  1n  the  production of carbon  dioxide
and acetonltrlle,  respectively.    The  carbon dioxide  and acetonUrlle  thus
formed  are expired rapidly.   Together,  respiratory  excretion   accounts  for
-31-36X of the dose  of  radioactivity.   Urinary metabolites, which  account
for -25-3554  of  the administered  radioactivity,  may consist primarily  of the
oxlmes and acetonltrlle.
0121d                               -30-                          .   06/08/88

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                                 6.   EFFECTS
6.1.   SYSTEHIC TOXICITY
6.1.1.   Inhalation Exposure.
    6.1.1.1.   SUBCHRONIC — In the only  repeated exposure Inhalation  study
located, Ta'naka et  al.  (1987) exposed groups of 10  young  adult  male  Wlstar
rats  In  an  Inhalation  chamber to  a   dust  generated  from  a  formulation  of
methomy1.  Exposures were 4  hours/day, 5  days/week  for  3  months.   Concentra-
tion  of  dust  was   0  or  14.8+4.2 mg/m3.    The  formulation  contained  45%
methomyl; Identity of  the  Inerts  present  was not reported.   Presumably,  the
concentration of methomyl  In  the chamber atmosphere  was  14.8 mg/m3 x  0.45,
or  6.7  mg/m3.   The  mass   median  aerodynamic  diameter  was  estimated  at
4.4 p. with  a  standard  deviation  of  2.9  M.   Body weights  of exposed  rats
were  slightly below those  of  controls  from week  4  to  termination of  the
study, but  the  differences  were  not  statistically significant.   There  were
no effects on absolute or  relative weights of lung,  liver, kidney or  spleen
compared with controls.   H1stopatholog1c  examination, limited to  the  organs
listed above  as well as  the  upper  respiratory tract,  the  brain and organs of
sight and hearing,  revealed  focal  hemorrhages In the lungs of  three exposed
rats and scattered  foam cell aggregations In the lungs of  three  exposed and
one control  rats,  but  the  Investigators  concluded that  these effects  were
not related to methomyl  exposure.  Exposure had  no  significant  effect  on the
concentration of I1p1ds, or  the fatty  add  content  of Uplds  1n lung tissue.
Plasma  choilnesterase   activity determined  at  sacrifice was  depressed  1n
exposed  rats  compared  with  controls,  but the extent of depression was  not
greater  than  that  measured   In  rats   following  only one 4-hour  Inhalation
exposure  at  9.9   mg/m3.    Erythrocyte  choilnesterase  activity  was   not
depressed.

0121d                               -31-                          .   07/14/88

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   .6.1.1.2.   CHRONIC — Pertinent  data  regarding  the  toxldty  In  labora-
tory animals  of  chronic  Inhalation exposure to methomyl were  not  located 1n
the available literature cited in  Appendix  A.   Morse et  al.  (1979) performed
a health effects  study In August,  1976,  on  101  workers In  a  methomyl  produc-
tion and packaging -plant.  Until  June,  1976,  the  plant had also produced the
herbicide  propanll  from  3,4-d1chloroan1l1ne, so  that exposure  to  a  mixture
of chemicals  was  likely.  Workers were  divided by  job  category as follows:
packaging  (n=ll),  production  (n=28), safety, laboratory (safety and  labora-
tory together,  n=15), maintenance,  other  (maintenance  and  other  together,
n=31) and  office  (n=16).  According  to Morse et  al.  (1979), a separate OSHA
Investigation  revealed  that  highest  atmospheric  levels  of  methomyl  were
located  In the packaging area,  but  concentrations  were not  reported.   The
Investigators  stated  that   differences  1n  demographics   between  the  job
category groups  were  minor.   Average  length  of  employment was  24  months.
Data on  health effects were  obtained from  a questionnaire,  hospital  records
and a complete physical  examination  Including hematology,  urlnalysls,  plasma
and erythrocyte  chollnesterase  activity and vibratory sensation tested with
a tuning fork.   Symptoms  of  methomyl toxldty  recorded  were mlosls,  nausea.
vomiting,  blurred  vision, muscle  weakness,  fatigue  and Increased salivation.
Expressed  1n terms  of  the  mean  number  of methomyl  symptoms/worker,  the
greatest Incidence of  symptoms was observed In packaging  (2.55) followed by
production  (1.11), maintenance (0.78),  safety (0.60),  office  (0.25),  labora-
tory (0.20)  and  other (0.13). There  were no measurable effects on urlnaly-
sls,  hematology,  acetyl  chollnesterase activities of  plasma or  erythrocytes
or  sensitivity  to  vibration.    The   Incidence  of  methomyl-related  health
effects   decreased  after  cleaning  procedures were Improved In  the packaging
area (Morse et al., 1979).

0121d                               -32-                             06/08/88

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6.1.2.   Oral Exposure.
    6.1.2.1.   SUBCHRONIC — Kaplan  and   Sherman   (1977)   summarized   the
results of  3-month  dietary studies with  methomyl  (>90% purity)  1n  rats  and
dogs.  Groups of 10 male and  10  female  ChR-CD rats  were fed diets containing
methomyl at  0,  10, 50,  125  or  250  ppm  for  90 days.   The 125  ppm dietary
concentration was Increased to 500 ppm  after  6  weeks.   There were no effects
on  general   appearance or  behavior  and  no  mortality.    Body  weight  gain
depression accompanied  by  a depression  1n  food consumption was  observed  1n
males  at  250 ppm and  In both sexes  at 500  ppm.   There were no  effects  on
urlnalysls,   or  on  plasma  or  erythrocyte chollnesterase activities  measured
at 2 months  1n  five rats/sex  In  the  group Initiated at 125 ppm and Increased
to 500 ppm,  or  measured at  termination  In five  rats/sex from the 250 and 500
ppm groups  compared with controls.  Hematologlc examination revealed slight
depressions   1n  blood hemoglobin  concentrations  In  50 ppm  females  at 1  month
and  In 250  ppm males   at  2  months.   Depressed erythrocyte  counts  compared
with controls were observed 1n 250 ppm females, although  values were within
normal  limits.   There  were no effects on  organ  weights  or hlstopathologlc
appearance of the  tissues   (>20) examined,  with the exception  of moderately
Increased hematopolesls  1n the  bone marrow  1n unspecified  treated groups.
U.S. EPA (1987a) considered 50 ppm a NOAEL and 250 ppm a  LOAEL  for rats  In
this study.
    In the dog  study,  groups  of one male and one female beagle dog  were fed
diets  containing 0, 50,  100 or 400 ppm methomyl for  92-101 days (Kaplan and
Sherman, 1977).   There were no effects  on food  Intake,  body weights, general
appearance,   hematology,   urlnalysls,   unspecified   biochemical  parameters,
organ  weights or  the   hlstopathologlc examination of >30  tissues.   U.S.  EPA
(1987a) considered the 400 ppm level a NOAEL for dogs In this study.


0121d                               -33-                             07/14/88

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    U.S.  EPA (1987a)  summarized  a  13-week  unpublished dietary  study  where
F-344  rats  were  fed  methomyl  of  unspecified purity  (Roman et  al.,  1978).
Dosage  levels  were estimated  at  0,  1,  3,  10.2  and  30.2 mg/kg/day  for  the
males  and  0, 1, 3, 9.9  and 29.8 mg/kg/day  for  the females.   There  were no
effects on  survival  or clinical appearance.  Body weight  gain  was depressed
significantly In  all  treated groups  of  females  at >4  weeks.   The magnitude
of the  weight gain depression was not reported,  and  It 1s not  known  whether
the effect  occurred  In a dose-related fashion.   Effects  on  body weight gain
were  not  observed  1n males.  Organ  weight  determinations  of  7  organs  and
hlstopathologlc examinations  of >30  tissues  from representative control  and
high-dose  animals  revealed  elevated relative kidney  weights   In  females  at
9.9  and  29.8  mg/kg/day,   but  no   hlstopathologlc  effects  at  any  level.
Erythrocyte  chollnesterase  activities were  depressed  In  both   sexes  In  the
high-dose groups,  but  there was no  effect on  plasma  or brain  chollnesterase
activities.  Despite the effects on  body  weight  gain  In treated female rats,
U.S.  EPA  (1987a)   judged  3  mg/kg/day a  NOAEL and 9.9  mg/kg/day  a LOAEL  1n
this study.
    Antal et al.  (1979)  fed  a  semi-synthetic  diet containing 90% methomyl at
0  or  200  ppm  to  groups  of 10 male and 10  female  Lean  R/Amsterdam  albino
rats, a strain  that resists  excessive weight  gain, for  12 weeks.  There were
no  effects  on  food  or  water  consumption  or   growth.   The  Investigators
estimated  the Ingested dosage at 1.08 mg/100 g   (10.8  mg/kg/day)  1n  treated
males and  1.29  mg/100  g  (12.9 mg/kg/day) 1n  treated  females.   There  were no
effects on  hematocrlt  or  fasting  blood glucose.    Treated  males had elevated
relative  spleen weights  and treated females had elevated relative  kidney
weights compared  with controls,  but there  were  no  hlstopathologlc  effects
(examination limited to  liver,  kidney, adrenal,  heart  and spleen).  Elevated

0121d                               -34-                              07/14/88

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liver  trlglycerlde  content and  reduced  liver  free fatty  acid content  was
observed  1n  treated  males,  but  there  were no  effects  on  liver  glycogen
content.   Reduced  hepatic glucose-6-phosphate dehydrogenase activities  were
observed  1n  treated  rats  of  both  sexes,   but  there  were  no  effects  on
glucose-6-phosphafase or  two  drug  metabolizing  enzyme  activities.   Acetyl-
chollnesterase  activities,  measured  only In  the  brain,  were  depressed  In
treated rats of both sexes.
    Male  and  female  rats  (strain  and  groups sizes not reported) were  fed
diets  containing  100  or  200  ppm 90%  methomyl  for   3  months  (Bedo  and
deleszky,  1980).   There  were  no  effects  on  body weights,  food or  water
consumption, oral glucose  tolerance or  hexobarbHal  sleeping  time.   Compared
with controls,  females  at 200 ppm had significantly decreased  brain  cholln-
esterase  activity and elevated  serum I1p1d  and cholesterol  levels,  although
the cholesterol  levels  were within  the normal range, and  slightly  decreased
liver glucose-6-phosphatase activity.   Other effects attributed.to  exposure
to  methomyl,  but of  uncertain  toxlcologlc  significance,   Included  slightly
altered activities of two drug-metabolizing  enzymes  and  vitamin A  content 1n
the  liver  and altered  activities of pancreatic enzymes.   The  Investigators
stated that histology was normal  and concluded that 100 ppm was  a  no-effect
level 1n this study.
    6.1.2.2.   CHRONIC — Kaplan and  Sherman (1977)  briefly summarized  the
results of  chronic  dietary  studies with  methomyl   (>90%  pure) In rats  and
dogs.   Six groups  of  35 male and 35  female ChR-CD   rats were  fed  diets
containing  0,  0,  50,  100, 200 or 400  ppm for 22 months.   Mortality  was  not
affected  by  exposure  to  methomyl.  The  authors  noted that  early  In  the
study,  methomyl  1ngest1on at  400  ppm  was  ~60  mg/kg/day,   >3  times  the
reported  oral  LD5Q,  without  any   deaths.   They  theorized that  when  rats


0121d                               -35-                          .   06/08/88

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Ingested methomyl  gradually 1n  the  diet, they  were able to  metabolize  the
pesticide at  a rate  sufficient  to prevent death.   Body weights of  400  ppm
males were  significantly less  than  controls  for  the  first  52 weeks  of  the
study.  This  trend  was also observed  1n  males  at 200 ppm and  1n  females  at
400 ppm, but  was  -not  statistically  significant.   Food  consumption  1n males
at 200  and  400 ppm was  reduced  significantly  for the first 26 weeks  of  the
study.  There were  no  effects  on urlnalysls,  biochemistry  or  hematology,
with  the exception  of a  dose-related  reduction 1n  blood  hemoglobin  concen-
tration 1n female rats at 18 and 22 months,  particularly evident at >200 ppm
(statistical  analysis  not  reported).   Specific  data  were not reported  for
effects on  plasma,  erythrocyte  or  brain chollnesterase  activities  measured
at  12  months  and   at  termination.   Elevated   relative  testlcular  weight
unaccompanied  by  hlstopathologlc alteration was  observed at  400  ppm.  Rats
of both sexes  at 400 ppm had  mild   kidney  lesions  (protein  accumulation,
tubular dilatation and hypertrophy and vacuollzatlon  of tubular  epithelium)
and females  at 200  and  400 ppm  had  Increased  hematopolesls  1n  the  spleen.
In  this study,  100  ppm was  considered  a  NOEL  and  200 ppm  a  LOAEL  for
methomyl 1n rats (U.S. EPA,  1987a).
    The dog  study was  performed with groups  of  four  male  and four  female
young adult beagles fed  diets containing  methomyl  at 0,  50,  100,  400 or 1000
ppm  for 24  months  (Kaplan and Sherman,  1977).   Mortality  attributed  to
exposure to methomyl  claimed  two females at 1000  ppm:   one  after  8 weeks  of
exposure and  the other  (her  replacement)  after  18 days of  exposure.   The
latter  death   was  preceded by   convulsive  seizures  and  coma.   Chollnerglc
signs occurred 1n two  males at  1000 ppm,  but  no deaths occurred.   There were
no effects  on appetite,  body weights, urlnalysls or  biochemistry  Including
chollnesterase activity  1n  plasma and erythrocytes  measured 1n  controls  and

0121d                               -36-                              08/24/88

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high-dose dogs at  9  weeks and In high-dose dogs only at  13  weeks.   A slight
to  moderate  anemia  was  observed 1n  five high-dose  dogs at  3 months  that
persisted 1n one male  throughout the study.   There were  no  effects  on organ
weights.  Hlstopathologlc  lesions observed 1n  the  kidneys Included  Increased
pigmentation In  the  proximal  convoluted  tubule 1n males  at 400 ppm  and  1n
females at 1000  ppm.   Tubular epithelial  cells exhibited  slight  swelling  In
both  sexes  at  1000  ppm  only.   Increased  hematopolesls   In  the spleen  was
observed  In  both  sexes  at 1000  ppm;  pigment  deposition  In the spleen  was
observed  1n  both  sexes  at 400  ppm.   A minimal to  slight  Increase  1n  bile
duct  proliferation  In  the   liver  and  a slight  Increase  In  bone  marrow
activity was observed  1n  both sexes at 1000 ppm.  The  100 ppm dietary level
was a NOAEL and 400 ppm was a LOAEL  1n this study.
    U.S. EPA (1986c) mentioned a 1981 2-year dietary study  with  methomyl  In
rats  1n which  100  ppm  (5 mg/kg/day)  was a  NOEL and  400 ppm  was  an  LEL
associated with  growth retardation  and Inhibited  chollnesterase  activities.
No  further  Information was provided  and  the  study was not  discussed  In  the
methomyl  Registration  Standard  (U.S.  EPA,   1981)   or  the  recent  Health
Advisory (U.S.  EPA, 1987a).
    Hazelton Laboratories  (1981)  fed  diets  containing 0,   50,  100 or 800  ppm
methomyl of unspecified  purity to groups  of 80 male and  80  female  CD-I  mice
for 104 weeks.  Significantly  reduced  survival  1n  mice  of both sexes at  week
26  at  800 ppm led to  reducing dietary concentration to  400 ppm at week  28
and to  200 ppm at  week 39.  Also at week  39,  the 100 ppm diet  was reduced to
75  ppm.  Survival  was  reduced  1n all  treated  groups  of  males at termination,
although  there  were  no  hlstopathologlc  lesions  attributed  to exposure  to
methomyl.  The  lowest  dietary level  of  50 ppm was considered  a  LOAEL based
on decreased survival  In males (U.S. EPA,  1987a).


012'ld                               -37-                          .   06/08/88

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6.1.3.   Other Relevant  Information.   Acute  oral  toxldty data  for  me thorny!
1n  several  species  are  presented  1n  Table 6-1.   Oral  LD50. dietary LC™,
approximate  lethal  dose  and  minimum  lethal  dose  values  (the  last  two
criteria  are  equivalent)  suggest  that  mice are  moderately more  sensitive
than  other   laboratory  species   to  the  acute  oral  toxldty  of  methomyl.
Gender  and  age  appear  to  have  little  Impact  on  the  lethal  potency  of
methomyl.   Methomyl  appears  to  be sightly  more  toxic  1n  fasted  than  In
normally fed  rats.   Exposing mice  to  dietary  BHA for 4 days  before Intuba-
tion  with  methomyl  reduced  the  toxldty  of methomyl  (Jao  and  Hsu,  1981).
BHA  possibly  Induced  drug-metabolizing  enzyme  activities,  as  suggested  by
the observation of decreased pentobarbltal sleeping time.
    Mortality was  preceded by  signs  of  acute chollnergic poisoning (Kaplan
and  Sherman,  1977;  Dashlell and  Kennedy,  1984)  1n rats at  doses as  low  as
5.1  mg/kg  (Kaplan  and Sherman,  1977).  Kaplan and Sherman  (1977)  reported
that  decedents  exhibited  no  hlstopathologlc signs  attributed  to  exposure.
In an abstract, however, H1gash1hara  (1987)  reported  biochemical  evidence  of
Impaired liver and kidney  function and hlstopathologlc lesions  In  the lungs
of  rats  treated  orally  with  5  mg/kg,  and hlstopathologlc  lesions  of  the
liver and kidney at  15 mg/kg.   In a 2-week study  In which  six male rats were
treated  by  gavage  with  5.1  mg/kg/day on  5  days/week,  the Intensity  of  the
chollnergic  signs decreased  during the second week of treatment  (Kaplan  and
Sherman,  1977).   There  were  no  deaths,  no hlstopathologlc  lesions  and  no
effects  on plasma  chollnesterase  activities  at  4 hours  or 14  days  after  the
last treatment.
    Studies  of accidental and suicidal deaths In  humans  poisoned orally with
methomyl suggest  that  doses  of  12-15 mg/kg are  fatal  (Arakl et al.,  1982;
0121d                               -38-                             07/14/88

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1
CO
                                                                                TABLE 6-1


                                                                     Acute Oral Toxlclty of Hethoayl
Spec les/Stra In/Sex
Rat/ChR-CD/H
Rat/ChR-CD/F
Rat/NR/NR
Rat/Sheraan/N.F
Rat/Sheraan/F
Rat/Crl-CD/H


Rat/Wlstar/N.F
Rat/ChR-CD/H
Nouse/SwIss/NR
House/Swlss/F
Guinea plg/NR/N
dog/Beagle/M
Honkey/rhesus/N.F
Purity/Vehicle
90X/peanut oil
90X/peanut oil
NR/NR
technical/peanut oil
technical/peanut oil
99X/corn oil
99*X/corn oil
99»X/corn oil
NR/corn oil -diet
90X/peanut oil
purified/corn oil
NR/water
90X/peanut oil
90X/capsule
90X water
Concentration
or Dosage
17 ag/kg
23.5 ag/kg
37 ag/kg
25 ag/kg
27 ag/kg
25 ag/kg
40 ag/kg
26 ag/kg
5000 ppa In diet
for 5 days
5.1 ag/kg
10 ag/kg
8.5 ag/kg
15 ag/kg
30 ag/kg
40 ag/kg
Effect
LDjo In fasted rats
LDjo In fasted rats
LOjo In fed rats
LDso In adult rats
1050 In weanling rats
LOso In fasted rats
1050 In fed rats
approxtaate lethal dose,
fed rats
LC5Q for growing rats
chollnerglc signs
LD5Q
LDjQ
alnlaua lethal dose
alnlaua lethal dose
alnlaua lethal dose
Reference
Kaplan and Shernan, 1977;
Antal et al., 1979
Kaplan and Sheraan, 1977
Antal et al.. 1979
Antal et al.. 1979
Galnes and Under, 1986
Galnes and Under. 1986
Dashlell and Kennedy. 1984
Oashlell and Kennedy. 1984
Kennedy et al.. 1986
NcCann et al.. 1981
Kaplan and Shernan, 1977
Fahmy et al.. 1978
El-Sewedy et al.. 1982
Kaplan and Sheraan. 1977
Kaplan and Shernan, 1977
Kaplan and Shernan, 1977
            NR =  Not  reported
o
00

CO
CO

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Llddle  et  al.-,  1979).  Symptoms  reported  were those of  classic  chollnerglc
toxldty.   Survivors  of accidental  poisoning  responded  to  atroplne  (Llddle
et al., 1979).
    Methorny!  has  been  shown  to  be  acutely  toxic  to  rats  exposed  by
Inhalation.   Kaplan  and Sherman  (1977)  reported a  4-hour  LC5Q of 76.8 ppm
(510 mg/m3)  using a mist  created  from an aqueous  solution.   Plasma  cholln-
esterase Inhibition was observed  In rats exposed for 4 hours  to a  dust  of a
formulation  containing  45% methorny!  (Ta'naka  et al.,  1987).  The  exposure
concentration of methomyl  was estimated at 4.5  mg/m3.
    Galnes  and  Under  (1986)  reported that  the  dermal  LD5Q  for methomyl  1n
rats was  >2400 mg/kg.   For  rabbits,  the  dermal LD5Q  was  determined to  be
>5000 mg/kg  (Kaplan and Sherman,  1977).   Kaplan and  Sherman  (1977)  reported
that methomyl was mildly Irritating  to the  skin  and eyes  of guinea  pigs, but
was  not a  sensitizing  agent when  administered  topically  or  Intradermally.
Brief abstracts  of  Japanese  studies, however, reported  that  methomyl-sensl-
tlzed guinea  pigs cross-reacted with  blnomyl  (Matsushita and  Aoyama,  1979,
1980).    Humans  occupatlonally  exposed  to methomyl  responded  positively  to
the  patch   test   (Kambe  et al.,  1976)  and  cross-reacted  to  the  pesticide
blnomyl (Matsushita and Aoyama,  1979).
    In  other  experiments  In  which  animals  were  acutely  exposed to  methomyl
by  various  routes,  Increased activities  of  pancreatic  digestive enzymes  1n
rats (Bedo  and  deleszky.  1980),  decreased hepatic  kynurenlne  hydrolase and
kynurenlne  amlnotransferase activities  In  mice (El-Sewedy et al.,  1982) and
decreased hepatic carboxylesterase  and amldase activities  In  rats  (Iverson,
1977)  were   reported.   Nakamura  et al.  (1977)  and  Nlshlda  et  al.  (1980)
reported hematologlc  changes  Including  Increased  numbers  of  retlculocytes
and punctate  basophlUc erythrocytes  and decreased  erythrocyte  resistance  to
0121d                               -40-                          .   06/08/88
                                                                  9

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osmotic pressure 1n rabbits  (and  possibly  other  species)  exposed to methomyl
or  other  pesticides  by  1ntraper1toneal Injection.   Similar  changes  In  the
blood were  observed 1n farmers who  used pesticides.  A  single  Intraperlto-
neal dose of  methomyl  of  8.3 mg/kg had  no effect  on Immune  function In mice
as evaluated  by humoral response  to  sheep  erythrocytes  or to  mouse hepatitis
virus 3 (Fournler et al.,  1986).
    Methomyl  did  not  cause evidence  of  delayed  neurotoxldty   1n  Red-Rock
Cross hens  treated  orally  with 28 mg/kg  and held  for  22 days  (Kaplan  and
Sherman,  1977).   Without  providing  any  additional  data,  U.S.   EPA (1986c)
stated  that methomyl  was   not  a  neurotoxln  In hens  at dosages  up  to  200
mg/kg/day.
    Bracy et  al.  (1979)   Investigated  the  effect  of   dietary  exposure  to
methomyl, ethanol or  the  combination of chemicals  on plasma  and erythrocyte
chollnesterase activity  and three parameters of  behavior  In male  Sprague-
Dawley rats. The test  substances  were  mixed  1n  corn syrup,  which was used to
coat pellets  of  standard  laboratory  rat diet.  The  corn  syrup  contained  200
ppm methomyT,  but  data were not  provided  that  permitted estimation  of  the
Ingested dosage.  Control  diet  was prepared  using  corn  syrup  alone.   Sucrose
was  added   to  the   control  and methomyl  diets   to  equalize  caloric Intake.
Response to handling  and  open-field activity was  recorded on exposure days
4, 7,  10 and  13.   A  mouse-killing  test was performed  on exposure day  13.
The  rats were  sacrificed   for  measurement  of  erythrocyte  chollnesterase
activity  on  day  14.   Plasma  and  erythrocyte  chollnesterase  activity  1n
methomyl-treated rats  was  depressed to ~25X of  that of controls.   Cholln-
esterase activity In ethanol and  methomyl-ethanol  rats was  depressed only to
-50% of  that   of  controls.   None of  the  treatments had  any effect  on  the
parameters of  behavior evaluated.

0121d                               -41-                          .   06/08/88

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    Selmed-Antal  et  al.  (1980)  Investigated  the effects of  methomy1 alone
at 200  ppm  In the diet  or with  caffeine  at 30 mg% or  ethanol  at  10% 1n the
drinking water  1n  rats  exposed for 12 weeks.   Compared with methorny! alone,
methomyl  and ethanol  markedly  depressed  the  growth  rate  of  rats  of  both
sexes and  methomyV and  caffeine depressed the  growth  rate of  female rats.
The combination  of methomyl  and caffeine  elevated  the relative  weights  of
the kidney,  liver, spleen and  heart  .In  female  rats  and of the  adrenals  1n
rats of both  sexes.  Methomyl  and  ethanol  elevated  fasting glucose levels  In
females,  and  liver   trlglycerlde  and  free   fatty  add  levels  In  males.
Ethanol was  considered  to have  exacerbated the disruption  of  I1p1d  metabo-
lism observed with methomyl  alone  (Antal  et  al.,  1979).  Altered  hepatic
enzyme  activities  were  observed 1n  female rats treated  with methomyl  and
caffeine.   Ethanol  In  combination  with  methomyl  depressed brain  chollnes-
terase  activities  1n  male  rats  beyond the  slight  depression  observed  with
methomyl alone.
6.2.   CARCINOGENICITY
6.2.1.    Inhalation.   Pertinent  data  regarding  the  carcinogenic  potential
of  Inhalation  exposure  to   methomyl  were not  located  1n  the  available
literature cited In Appendix A.
6.2.2.    Oral.   Kaplan   and  Sherman  (1977) reported  a  22-month  study  In
which rats were  fed diets  containing  50-400 ppm methomyl  (Section 6.1.2.2.).
There were  no effects  on  survival,  but growth was  delayed  In  males  at  >200
ppm and  1n  females at  400 ppm,  and  hlstopathologlc  lesions  were  observed  1n
the kidneys  of  both  sexes at 400 ppm and  1n  the spleens of females  at  >200
ppm.  The  authors  reported  that the Incidence  of  neoplasms at 400  ppm was
similar to that  observed 1n controls.
0121d                               -42-                          .   06/08/88

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    Hazelton Laboratories  (1981)  fed  CD-I  mice diets containing  methomyl  at
50-800  ppm  for 104  weeks  (see Section  6.1.2.2..).   Survival was  reduced  1n
male mice,  motivating a reduction  1n the  dietary  levels as  the experiment
progressed.     H1stopatholog1c   examination   revealed   no   compound-related
effects on the Incidence of tumors.
6.2.3.    Other Relevant Information.   Quarles  et  al.  (1979)  tested  methomyl
for activity  In  the transplacental  hamster fetal cell  transformation  assay.
In  this  test,  a  1.0 mg/kg dose  of methomyl  1n  an unspecified  solvent  was
administered by  IntraperUoneal  Injection  to  hamsters  on  day 10 of  gesta-
tion.   Solvent controls  and positive  controls, known carcinogens represent-
ing several  different  classes  of compounds,  were also  Included.  On  gesta-
tion day  13,  cell   suspensions  were  made  of  the  decapitated,  eviscerated
fetuses from which  the limbs had  been  removed.  Primary liquid cultures were
prepared  from  cells  that were  washed,   trypslnlzed  and  suspended  In  a
complete  medium.    Subcultures  were  prepared and  plated  from  the  primary
culture every  4-6  days.   Colonies  were  scored  for  plating  efficiency  and
transformations at  the third,  fifth, sixth  or  seventh,  and  tenth  subcul-
tures.   At  the same  time  that subcultures  were  prepared for  evaluation  of
transformation, growth  (cloning  efficiency) 1n soft agar was  also evaluated
as  further  Indication of  cellular  transformation.   Cells,   usually  from  the
sixth  subculture, were Injected  subcutaneously  Into  young  adult  nude  mice,
which  were  observed for  6 months to  1 year for  the appearance of Injection
site tumors.
    Solvent   controls  yielded  negative  results   1n  the  cell  transformation
test,  the growth  1n  soft agar  test  and the  tumor1gen1dty 1n nude mice test.
012'ld                               -43-                          .   06/08/88

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Positive  controls  responded appropriately  with positive  results  In one  or
more  of  the  above  tests.  Methomyl  yielded negative  results  1n all  three
tests,  and  nltrosomethomyl  yielded  consistently  positive results  1n  all
three tests.
    As  mentioned  "1-n  Section  5.3.,  there  1s  considerable  Interest  1n  the
ability of  pesticides  containing secondary amlne groups to  undergo  nltrosa-
tlon  In  the add environment  of the  stomach.   L1j1nsky and Schmahl  (1978)
reported  that  nltrosomethomyl  Induced  forestomach tumors In male  and  female
Sprague-Dawley  rats,  treated  by  gavage   for   10   consecutive   weeks   with
once-weekly doses of 50 mg/kg.
6.3.   MUTAGENICITY
    Results of  reverse  mutation  tests  1n  five  strains of  Salmonella  typhl-
murlum and Escher1ch1a coll WP2, differential toxlclty  tests  (DNA  damage)  1n
E_.  coll and  Bacillus  subtnis.  and  enhanced mltotlc recombination  tests  In
Saccharomyces cerevlslae D3 have been  largely negative  (Simmon et  al.,  1976,
1977; Waters et al., 1980, 1982; Klopman  et al.,  1985;  Garrett et  al.,  1986;
MoHya  et  al., 1983;  Blevlns  et al.,  1977a),  as  summarized  In  Table  6-2.
Positive results  1n  the reverse mutation  test  1n S. typhlmurlum  (Njagl  and
Gopalan, 1980) and 1n an  unspecified test  1n S.  cerevlslae  (Guerzonl  et  al.,
1976) were reported, but  these data were  available  only In  abstract  form and
1t  was  not  possible  to  evaluate  the studies  and  explain  these  apparent
contradictions.  Minor  discrepancies appeared  1n the  reports  by Simmon  et
al.  (1976,  1977), Waters  et  al.  (1980,  1982),  Klopman et  al.   (1985)  and
Garrett et  al. (1986), all  of  which  appeared  to  summarize  the  results  of
tests performed  at  Stanford Research  Institute under  contract  to the  U.S.
EPA.  Not all  reports  Included  S.  typhlmurlum strain TA98  1n the  Ames  test,
some reported purity as technical grade and others  as  99.0%,  and  most  stated


0121d                               -44-                          .  06/08/88

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            TABLE  6-2



Genotoxtclty Testing of Nethoayl
ISJ
£ Assay
Reverse Mutation


i
V
i

Differential
toxlclty
(DNA damage)
v-
§ Enhanced Ml t otic
>* recombination
o
00
00
CD 	 : 	
Indicator/Organist Purity
Salmonella NR
typhlmurluM
S. typhlMurlua technical grade.
TA1535, TA1537. 99. OX
TA1538. TA100.
TA98
S. typhlMurluM NR
TA1535. TA1537.
TA1538. TA100,
TA98
S. tvphlmurlua technical grade
TA1535. TA1537.
TA1538. TA98.
TA100
Escherlchlae coll technical grade
UP2
i. coll UP2 NR
E. coll H3110. technical grade.
P3478 99. OX
Bacillus subtllls technical grade,
H17. N45 99. OX
Saccharomvces technical grade.
cerevlslae 03 99. OX
Application
NR
plate
Incorporation
plate
Incorporation
spot test and
plate Incorpo-
ration
plate
Incorporation
plate
Incorporation
spot test
spot test
plate
Incorporation
Concentration Activating
of Dose System
NR
6 concentrations » S-9
at 1-1000 ng/plate
>1 concentration » S-9
at <5 ag/plate
50 nM solution NR
6 concentrations «• S-9
at 1-1000 Vg/p1ate
>1 concentration * S-9
at <5 Mg/plate
1 mg/dlsh none
1 Mg/dtsh none
0.1-3X In aedla » S-9
Response Reference
i
» NJagl and Gopalan.
1980
Slmnon et al.. 1976.
1977; Haters et al..
1980. 1982; Klopman
et al.. 1985; Garrett
et al.. 1986
Horlya et al.. 1983
Blevlns et al.. 1977a
Haters et al.. 1980,
1982; Garrett et al..
1986; Simmon et al..
1977
Horlya et al.. 1983
Haters et al.. 1980.
1982; Garrett et al..
1986; Slimon et al..
1976. 1977; Klopman
et al.. 1985
Haters et al.. 1980.
1982; Garrett et al..
1986; Sloraon et al..
1976. 1977; Klopman
et al.. 1985
Haters et al.. 1980.
1982; Garrett et al..
1986; Slmnon et al..
1976. 1977

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TABLE 6-2 (cont.)
o
o.





i




06/08/88
Assay
NR
Sex-linked
recessive lethal


Chromosomal
translocatlon
Chromosome loss,
rearrangement and
non-disjunction
Nutation to
ouabaln resis-
tance
Sperm morphology
assay
Chromosomal
aberration
Induction of
sister chroma t Id
exchanges
Unscheduled DNA
synthesis
DNA strand
breaks
NR = Not reported;
Indicator /Organism Purity
S. cerevlslae NR
Orosophlla NR
melanogaster
0. melanoqaster technical grade
Canton-S wild type
0. melanoqaster 20X formulation

D. melanoqaster 20X formulation

D. melanogaster technical grade
Chinese hamster NR
V79 cells
Swiss mouse 20X formulation
Swiss mouse 20X formulation
human lymphocytes NR
human lung flbro- technical grade.
blast MI -38 cells 99. OX
human skin flbro- -95X
blast
NA = not applicable
Application
NR
NR
adult feeding
continuous
larval feeding
continuous
larval feeding
NR
cell culture
oral once dally
for 5 consecu-
tive days
oral once dally
for 5 consecu-
tive days
cell culture
cell culture
cell culture

Concentration
or Dose
50 ppm
NR
4 or 10 ppm
2-6 ppb In food
2-6 ppb In food
10 ppm
1.0. 5.0 and
10.0 mN
0. 20. 40 or 60
mg/kg total dose
0. 20. 40 or 60
mg/kg total dose
NR
10"' to 10'« N
10'* H

Activating
System
NR
NA
NA
NA
NA
NA
» Irradiated
fetal Syrian
hamster cells
NA
NA
± S-9
± S-9
none

Response Reference
«• Guerzonl et al.. 1976
Gopalan and NJagt.
1981
Haters et al.. 1980.
1982; Valencia. 1981
* Hemavarthy and
Krlshnamurthy. 1987a
Hemavarthy and
Krlshnamurthy. 1987a
Valencia. 1981
Uojclechowskt and
Kaur, 1980;
Hojctechowskt et al..
1982
+ Hemavarthy and
Krlshnamurthy. 1987b
<• Hemavarthy and
Krlshnamurthy. 1987b
f Debuyst and
Van Larebeke. 1983
Simmon et al.. 1977;
Haters et al.. 1980.
1982; Garret t et al..
1986
Blevtns et al.. 1977b


-------
that  the  metabolic  activation system was  derived  from Aroclor 1254-treated
male Sprague-Dawley rats, while Simmon et al. (1977) stated that  the activa-
tion system was derived from Aroclor-treated  male mice.
    Mixed results were  reported  1n  sex-linked recessive tests In DrosophUa
me'lanoqaster (Gopalan and  Njagl,  1981;  Hemavarthy and Krlshnamurthy, 1987a;
Waters  et   al.,   1980,   1982)  and  In   several   mammalian   test  systems
(Woj dec hows k1  and  Kaur, 1980;  Wojdechowskl  et al.,  1982;  Hemavarthy and
Krlshnamurthy,  1987a; Oebuyst  and  Van Larebeke, 1983;  Simmon  et  al.,   1977;
Waters et al.,  1980, 1982;  Garrett  et  al.,  1986;  Blevlns et al., 1977b).
    NUroso  derivatives  of me thorny!  caused  mutations  In   S.   typhlmurlum
(Blevlns et  al.,  1977a;  Seller,  1977)  and  caused DNA strand breaks 1n  human
skin flbroblasts  (Blevlns et al.,  1977b), whereas methomy1  Itself  did not.
6.4.   TERATOGENICITY
    Kaplan and Sherman (1977) briefly described a teratogenlcHy  study  using
New Zealand  white rabbits.  Diets  containing  methorny!  at 0.  50  or 100 ppm
were  fed  to pregnant rabbits  on  days 8-16  of  gestation.   Dams  were sacri-
ficed on  gestation  day  29  or 30 or were allowed  to deliver  at term.   Fetal
body weights,  gross malformations and uterine  resorptlon  sites  were evalu-
ated,  and  skeletal  examination  was  performed  on  about  one-third of the
fetuses.  The  Investigators  reported  no  evidence of a  teratogenlc  response,
but did  not mention  maternal  effects or  effects  on fetal body  weights or
uterine resorptlons.
    A second developmental  toxldty study 1n rabbits (Feussner et al.,  1983)
was reviewed briefly  by  U.S.  EPA (1987a).   Groups of five New Zealand  white
rabbits were treated with  98.7% methomyl   (route  unspecified)  on  gestation
days  7-19  at  dosages  of 0,  2,  6  or 16 mg/kg/day.   Maternal  toxldty was
0121d                               -47-                             07/14/88

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restricted to choHnerglc signs and death of one dam at  16  mg/kg/day.  There
were  no  effects  on  embryo  survival  or  the  Incidence  of soft  tissue or
skeletal malformations.
    U.S.  EPA  (1981,  1986c)  mentioned  a teratogenlcHy  study where rats  were
fed diets  containing 0,  50, 100 or 400  ppm  methomyl on  days 6-15 of gesta-
tion.  Maternal toxldty was  reported at 400 ppm,  but there was no  evidence
of embryotoxldty or teratogenlcHy.
6.5.   OTHER REPRODUCTIVE EFFECTS
    Kaplan and  Sherman  (1977) briefly described a 3-generatlon  reproduction
study  where  groups  of 10  male and  20  female  ChR-CD  rats were  fed diets
containing methomyl at 0, 50  or 100 ppm.  Hating commenced  after 3 months of
feeding.  Two Utters were delivered  In  each generation.  Several Indexes of
reproduction  and  lactation were calculated  and hlstopathologlc examination
was performed  on  10  male  and 10  female weanlings from  the  F-.  Utters of
controls  and  both  test  groups.   There  were no effects  on reproduction or
lactation  and  no  gross  or  hlstopathologlc  lesions  1n   F3b  weanlings   that
were associated with exposure to methomyl.
6.6.   SUMMARY
    Methomyl  was  not carcinogenic  In feeding  studies  1n  rats  (Kaplan  and
Sherman,  1977) or mice  (Hazelton Laboratories,  1981),  and was negative  1n a
transplacental  hamster  fetal  cell  transformation assay (Quarles  et   a!.,
1979).   Results  of  mutagenldty tests were  largely  negative In microorgan-
isms  (Simmon et al.,  1976,  1977;  Blevlns et al.t 1977; Maters et al., 1980,
1982; Morlya et al.,  1983;  Klopman et al., 1985; Garrett et al., 1986), but
were  mixed  In  DrosophUa   (Waters  et  al.,  1980,  1982;   Valencia,  1981;
Hemavarthy and  Krlshnamurthy,  1987a)  and  various  mammalian systems  (Simmon
et  al.,   1977;   Blevlns   et  al.,   1977b;  Waters   et   al.,  1980,  1982;
0121d                               -48-                             07/14/88

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Wojclechowskl and  Kaur,  1980; Wojdechowskl  et  al., 1982;  Debuyst  and Van
larebeke, 1983; Garrett  et  al.,  1986;  Hemavarthy and Krlshnamurthy, 1987b).
NHrosomethomyl,  however,  was positive  1n  cell  transformation  (Quarles et
al., 1979)  and mutagenldty tests (Blevlns et  al.,  1977a,b; Seller, 1977),
and  Induced fore-stomach  tumors   1n  rats  treated by  gavage  (L1j1nsky and
Schmahl, 1978).
    The  acute  toxlclty  of methomyl  appears  to be  equivalent  among   most
laboratory species; except  that  the  mouse  1s  noticeably more sensitive  than
the  rat or  dog.    Single-dose  oral LD5Q  values  ranged  from  8.5-40   mg/kg
(Kaplan and  Sherman, 1977;  Fahmy  et  al., 1978; Antal et al., 1979;  DashlelT
and Kennedy, 1984;  Galnes  and Under,  1986).   Gender and age appear to  have
no effect on toxic  potency.   Doses  of  12-15 mg/kg have been fatal to humans
(Llddle  et  al.,   1979;   Arakl   et   al.,  1982).   Deaths  are   preceded by
cho11nerg1c  signs  (Kaplan  and Sherman,  1977).   Other  effects  attributed to
methomyl  Include  altered  pancreatic  (Bedo and  deleszky,   1980)  and   liver
enzyme  activities  (Iverson,  1977; El-Sewedy  et  al., 1982), effects on the
erythrocyte and hematopolesls  (Nakamura et al., 1977; Nlshlda et al., 1980),
and skin  sensltlzatlon  (Kambe et al.,  1976;  Matsushita  and Aoyama, 1979)..
Methomyl  has not  been  associated  with  neurotoxldty  In hens  (Kaplan and
Sherman, 1977;  U.S. EPA,  1986c).
    A number of  subchronlc and chronic  dietary  studies  have been performed
using rats,  dogs  and mice.   In  the subchronlc  studies,  400 ppm (10 mg/kg/
day, the  highest  level   tested)  was  considered a NOAEL  In  dogs (Kaplan and
Sherman, 1977), and 50  ppm (2.5  mg/kg/day)  (Kaplan  and Sherman, 1977), 100
ppm (5  mg/kg/day)  (Bedo  and deleszky,  1980)  and 3 mg/kg/day (Homan et  al.,
1978) were  considered NOAELs  1n  three studies  1n rats.  At higher  dosages,
rats showed  body  weight  gain depression, decreased  erythrocyte counts and


0121d                               -49-                              07/14/88

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Increased  erythropolesls,  depressed  erythrocyte  or   brain   chollnesterase
activities,  minor  serum  or  liver  biochemical   alterations   and   elevated
relative  kidney  weights.   In  a  chronic study where  rats were  dosed  with
dietary  levels of  50-400 ppm  (Kaplan  and  Sherman,  1977),  100 ppm  (5  mg/kg/
day)  was  a  NOAEtj  and  depressed  growth  rate,  reduced  blood  hemoglobin
concentration,  Increased  splenic erythropolesls and mild kidney lesions  were
observed at higher  levels.   In dogs chronically exposed to 50-1000  ppm,  100
ppm (2.5 mg/kg/day) was  a NOAEL,  and anemia and mild lesions  of  the kidney,
liver,  spleen  and  bone  marrow were  observed  at higher  levels  (Kaplan  and
Sherman,  1977).   Mortality  preceded by  choHnerglc  signs was  observed  at
1000 ppm  (25 mg/kg/day).   Increased mortality  was observed 1n all  groups  of
mice   chronically   exposed  to   diets  containing  50-800   ppm   (Hazelton
Laboratories,  1981).   The 50  ppm  level  (6.5  mg/kg/day)  was  judged a LOAEL
associated with reduced longevity.
    Methomyl   has  been  tested for  developmental  toxldty  1n  rabbits  at
dosages <16 mg/kg/day  (Kaplan  and  Sherman,  1977;  Feussner et  al.,  1983)  and
1n rats fed diets containing <400  ppm  (U.S. EPA,  1986c), with  no  evidence of
teratogenldty.   No effects  on reproduction were  observed 1n  a 3-generat1on
study In rats  fed diets containing  <100 ppm (Kaplan  and  Sherman, 1977).
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                     7.   EXISTING  GUIDELINES AND  STANDARDS
7.1.   HUMAN
    ACGIH  (1987)  recommends  a TLV-TWA  of 2.5  mg/m3  for  methomyl.   ACGIH
(1986)  reported  a  4-hour   LC.-   of  0.30  mg/l  (300  mg/m3)  for  methomyl
mist  1n an  unnamed- species  and concluded that the  factor of  120  between the
TLV  and  the   LC5Q  should  be adequately  protective.   There  are  no  NIOSH
criteria or OSHA standards for methomyl.
    U.S.  EPA  (1982,  1985a,  1987b,c)  established tolerances  for  methomyl  on
or  1n raw  agricultural  commodities.   For  Items grown  as  food  for  humans,
allowed  tolerances  range  from 0.1-7  ppm.   For  livestock  feed,  tolerances
range  from  0.1-40  ppm.   World  Health  Organization  recommendations  for
methomyl  residues  range from  0.02 ppm,  considered at  or  near the  limit  of
detection,  for  meat and milk, to 5 ppm  1n  various  fruits   and  vegetables
(WHO,  1976a,b,  1977).   Recommendations  for   livestock forages  range  from
0.1-10 ppm.
    NAS  (1983)  derived  a  SNARL  for  methomyl  of  0.175 mg/l,  based on  the
no-effect  level  of 2.5  mg/kg/day In  the 2-year  study In dogs described  In
Section  6.1.2.2.   (Kaplan  and  Sherman,  1977).   Based  on  the NOEL of  2.5
mg/kg/day In the same  study  In dogs,  U.S.  EPA  (1986c) derived an  oral RfD of
2 ing/day.   One-day,  10-day  and  longer-term HAs of  0.25 mg/l  were  based  on
the  DWEL   for  a  child  of  0.25  mg/l.   A  lifetime  HA of 0.175 mg/l  (175
ug/l) was also recommended.
    U.S. EPA (1985b) listed an RQ for methomyl  of 100.
7.2.   AQUATIC
    Guidelines  and  standards  for the protection  of aquatic  organisms  from
the effects of methomyl were not  located 1n the available literature.
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                              8.   RISK ASSESSMENT
8.1.   CARCINOGENICITY
8.1.1.   Inhalation.   Pertinent   data   regarding   the  cardnogenlcUy  of
Inhalation exposure to methomyl were not  located In  the  available  literature
dted 1n Append1x-A.
8.1.2.   Oral.   Kaplan  and Sherman  (1977) reported  no  Increased  Incidence
of  tumors  In  groups of  35  rats/sex  fed diets containing methomyl  at  50-400
ppm for 22 months.  Although  there were  no effects  on mortality,  growth rate
was depressed  at >200 ppm  and  lesions  of  the kidneys were observed at  400
ppm,  suggesting  that  the MTD may  have  been reached.  Hazelton  Laboratories
(1981)  reported  no compound-related  effect on  the  Incidence  of  tumors In
groups  of  80  mice/sex  fed  diets  containing 50-800  ppm  methomyl  for  104
weeks.  Increased  mortality  was  observed  1n  all  treated  groups  of males.
Because only a brief  report was available, H 1s not known whether  a  suffi-
cient  number   of  animals   remained  at  risk  for   late   developing  tumors;
therefore,  confidence 1n the negative results  of  this study  Is  low.
8.1.3.   Other Routes.  Methomyl was  negative  1n  the transplacental hamster
fetal  cell  transformation assay (Quarles et al.,  1979).
8.1.4.   Weight  of Evidence.   U.S.   EPA  (1987a)  evaluated  the weight  of
evidence for  the  carclnogenlcUy  of methomyl and  characterized both  human
and animal  data as  "Inadequate," resulting  In classification In  EPA  Group D,
not classifiable as to human  cardnogen1c1ty  (U.S.EPA, 1986d).   Because data
were not located regarding  the  cardnogenlcHy  of  methomyl  In humans,  human
evidence may more  appropriately be characterized as  "no data."  The animal
data  are  best characterized  as "Inadequate," because  the  complete  studies
were  not  available for  thorough  review.   Particularly  In question 1s  the
adequacy of the mouse study (Hazelton Laboratories,  1981),  because  1t  1s  not


0121d                                -52-                             07/14/88

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known whether  decreased  survival  resulted In  Inadequate  numbers of mice  at
risk  for  late  developing  tumors,   the  most  appropriate classification  for
methomyl continues to be EPA Group  D.
8.1.5.   Quantitative Risk  Estimates.   The  lack of  Inhalation cancer  data
and  the  negative-results of  the  oral  studies  1n  rats (Kaplan  and  Sherman,
1977) and mice (Hazelton Laboratories,  1981) preclude derivation  of  potency
factors for  either route of  exposure.
8.2.   SYSTEMIC TOXICITY
8.2.1.   Inhalation  Exposure.   The  only  repeated  exposure  Inhalation  study
located was  a 13-week experiment  In  which  rats were exposed  to dust  of  a
formulation   of methomyl  containing  45% active  Ingredient  (Ta'naka et  al.,
1987).  The  only  effect attributed  to methomyl  was plasma  chollnesterase
Inhibition.   This  study  1s  not suitable  for  use In  risk assessment  because
of  the  large  proportion of  uncharacteMzed  Inert  substances  1n the  test
material.   Therefore, no subchronlc or  chronic RfD 1s estimated  for  Inhala-
tion exposure to methomyl.
8.2.2.   Oral  Exposure.   In  the  dietary studies  discussed  below,   trans-
formed dosages  expressed In mg/kg/day have  been estimated  from  the  dietary
concentrations expressed 1n ppm by multiplying  the  dietary  concentrations  by
reference food factors  adopted by  the Agency.   In   the absence of  actual
Intake  data,  the  Agency assumes  dally  food consumption by  rats, dogs  and
mice equivalent to  5,  2.5  and 13% of their  body weights, respectively (U.S.
EPA,  1986e).   For example,  a  dietary  level  of  50  ppm Is equivalent  to 2.5
mg/kg/day In rats, 1.25 mg/kg/day In dogs and 6.5 mg/kg/day  In mice.
    8.2.2.1.    LESS   THAN   LIFETIME   EXPOSURES   (SUBCHRONIC)  -- Subchronlc
dietary studies using rats  Identify NOAELs of  50 ppm  (2.5 mg/kg/day)  (Kaplan
and  Sherman,  1977)  and  3 mg/kg/day (Homan et  al.,  1978).   LOAELs Identified


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1n  different  studies  Include  12.5  mg/kg/day  associated  with  reduced  food
consumption,  body  weight  gain  and  blood  hemoglobin  1n  males,  and  reduced
erythrocyte  count  1n females (Kaplan  and  Sherman,  1977), and  ~10 mg/kg/day
associated  with  elevated  relative  kidney weight  In  females  (Homan et  al.
1978)  and  elevated   relative   spleen  and  kidney weights,  decreased  brain
chollnesterase activity,  and other biochemical effects of  uncertain  toxlco-
loglcal  significance (Antal et  al.,  1979; Bedo  and deleszky,  1980).   The
NOAELs  and  LOAELs observed 1n  subchronlc  rat studies  are virtually  Iden-
tical  to those  observed  In chronic  studies  (Section 8.2.2.2.),  suggesting
that the thresholds  for subchronlc and chronic exposure are very similar.
    Adverse  effects  were  not observed  In  dogs  fed diets containing  400  ppm
(10 mg/kg/day)  for 3 months, although  mild  kidney  lesions were observed  at
this dietary level In dogs exposed for 24 months (Kaplan  and Sherman,  1977).
    An  RfD   for  subchronlc  oral  exposure to  methomyl could  be  derived  by
applying an  uncertainty  factor  of 100 (10 for  animal  to  human extrapolation
and 10  to  provide additional protection  for  more sensitive  Individuals)  to
the NOAEL of 3 mg/kg/day  1n rats In the  13-week  dietary study  by  Homan  et
al. (1978).  This  would  result  In an RfO  of  0.03 mg/kg/day,  equivalent  to 2
mg/day  for  a  70  kg human.   Because  the  subchronlc and chronic thresholds  of
methomyl are  similar, an  equally sound approach would be  to adopt  the  RfD
for  chronic oral  exposure  as  the  RfD  for   subchronlc  oral   exposure.   The
latter  approach  1s preferred,  because the RfD  for chronic  oral  exposure  has
been  verified  by  the Agency  and  Is  available  on  IRIS  (U.S.   EPA,  1986c)
(Section 8.2.2.2.).  Accordingly,  the  RfD  for  subchronlc exposure to  methomyl
1s 0.025 mg/kg/day,  equivalent  to 2  mg/day  for a 70 kg human,  derived  from
the Kaplan  and Sherman  (1977)  2-year dog  study.  Confidence  1n  the  critical
study  1s medium,  but confidence In  the data  base  and  RfD  are high,  as
discussed 1n Section  8.2.2.2.

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    8.2.2.2.   CHRONIC EXPOSURES — Chronic  studies  available  1n  sufficient
detail to  warrant  consideration for derivation  of  an RfO for  oral  exposure
Include  studies  using  rats   (Kaplan  and  Sherman,  1977), dogs  (Kaplan  and
Sherman,  1977) and  mice (Hazelton Laboratories,  1981).   In  rats  exposed  to
dietary  levels of- 0,  50,  100, 200 or 400 ppm (0, 2.5, 5.0,  10  and 20 mg/kg/
day), 5.0 mg/kg/day was a NOAEL and  10  mg/kg/day was  a LOAEL associated with
reduced  blood  hemoglobin concentration  and  Increased splenic  hematopolesls
1n females.   In  dogs exposed  to  dietary levels of 0,  50,  100, 400  or 1000
ppm  (0,  1.25,  2.5,  10 and  25 mg/kg/day), 2.5  mg/kg/day  was a NOAEL  and  10
mg/kg/day was a  LOAEL  associated  with mild kidney lesions In males.   In the
mouse study,  the lowest dietary  level,  50 ppm  (6.5 mg/kg/day), was  a LOAEL
associated with decreased survival In males.
    In earlier  analyses, the U.S. EPA  (1986c, 1987a) conservatively chose
the dog  NOAEL  of 2.5 mg/kg/day (Kaplan  and  Sherman,  1977) as  the basis for
derivation of an RfO.   Application of an uncertainty  factor  of 100 resulted
1n an RfD of 0.025  mg/kg/day.   Multiplication by 70  kg results  In  an RfD for
a  70 kg human  of   1.75  mg/day,   which may  be  rounded  to  2  mg/day.   The
previously derived  oral  RfD  of 2  mg/day  1s adopted for the  purposes  of this
document.  U.S.  EPA (1986b)   placed medium  confidence 1n  the critical study
and high confidence In the data base and RfD.
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                           9.   REPORTABLE  QUANTITIES
9.1.   BASED ON SYSTEMIC TOXICITY
    The  systemic  toxldty of  methomyl  discussed  1n  Chapter 6  Includes  one
repeated  exposure  Inhalation  study  using  rats  and several  dietary  studies
using rats, dogs and mice.   In the Inhalation study,  rats exposed to dust of
a  formulation  of methomyl  containing 4554 active  Ingredient  for  13 weeks  had
depressed  plasma  chollnesterase  activity.   This  study  Is not  suitable  for
derivation of  a CS because of  the large proportion of the test material that
consisted of unidentified Inerts.
    Table 9-1  presents  data  from the dietary studies  considered for  deriva-
tion of  CSs.   Kaplan  and Sherman  (1977)  reported  a study In which rats were
fed diets containing 50-400 ppm  methomyl  for  22  months.   Mild kidney lesions
were observed  In  rats of both sexes  at 400 ppm  (20 mg/kg/day),  and  reduced
blood  hemoglobin  concentration  and  Increased   splenic  hematopolesls  were
observed  In  females  at  200  ppm  (10 mg/kg/day).   Because an RV   ranking of
5  Is  appropriate for  the  effects observed  at  both  dietary concentrations,
only the  effects  on  females at  10 mg/kg/day 1n this  study  are  presented In
Table 9-1.   In subchronlc dietary studies using  rats,  Homan et  al.  (1978)
reported  elevated  relative kidney weight  1n  females at  -10 mg/kg/day  and
depressed erythrocyte  chollnesterase  activities  In both  sexes at  -30  mg/kg/
day.  Antal et al.  (1979) and Bedo  and  deleszky  (1980)  reported depressed
brain chollnesterase activities and other biochemical  effects  1n rats  at  200
ppm (10  mg/kg/day)  1n the diet.   Because these effects  occurred  at  dosages
>10 mg/kg/day  associated with reduced  blood hemoglobin and  splenic  effects
In  the  Kaplan and  Sherman  (1977)  study and  rate an  RV  ranking <5,  they
are not Included In Table 9-1.
0121d                               -56-                             07/14/88

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o
ro
o.
                                                                                TABLE 9-1
                                             Dietary Toxlctty of Hethomyl:  Data  Considered  for Derivation of Composite Score


en
-j
r
Species/
Strain
Rat/ChR-CD
Dog/beagle
Nice/CD-I
No. at
Start/
Sex
35/f
4/N
80/N
Average
Body Height
(kg)
0.35*
12. 7d
0.03e
Purity Exposure
>90X 200 ppm diet
for 22 Months
>90X 400 ppm diet
for 24 aonths
NR SO pp» diet
for 104 weeks
Trans forMed
An low 1 Dose*
(ng/kg/day)
10
10
6.5
Trans forMed
Human Doseb
(Mg/kg/day)
1.7
5.7
0.49
Response
Reduced blood hemo-
globin concentrations.
Increased splenic
hematopotesls
Mild kidney lesions
Reduced survival
Reference
Kaplan and
Sherman. 1977
Kaplan and
Sherman. 1977
Hazelton
Laboratories.
1981
             Calculated  using  reference  food  Intakes (U.S. EPA. 1986d) as described In Section 8.2.2.
             ^Calculated  by Multiplying the animal transformed dose by the cube root of the ratio of animal  to reference human body weight  (70 kg).
             Reference body weight  for rats (U.S. EPA. 1986d)
             ^Reference body weight  for dogs (U.S. EPA. 1986d)
             'Reference body weight  for mice (U.S. EPA. 1986d)
             NR  =  Not  reported
 o
 CO
 •^
 CD
 00

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    Kaplan and  Sherman  (1977) also  reported  a study In which  dogs  were  fed
diets  containing  50-1000  ppm  methomyl.   The  highest  dosage  level   (25
mg/kg/day) resulted  In  acute  signs  of chollnerglc toxldty and death  of  2/5
females within  18  days  to 8 weeks of  Initial  exposure.  The  acute nature of
these  effects  precl-udes the use of  this  dosage for  dogs  In  derivation of  a
CS  for  methomyl.   The  authors  also  reported  Increased  pigmentation  In  the
proximal  convoluted  tubules  of   male   dogs  (RV  = 5)  at   400  ppm   (10
mg/kg/day).   These  data   are presented   1n   Table  9-1.   No  effects were
observed  1n  dogs  fed  diets  containing  <400  ppm  for 3  months  (Kaplan  and
Sherman, 1977).
    Hazelton  Laboratories  (1981)   fed mice   diets  containing  methomyl   at
50-800 ppm  for  104 weeks.  Reduced  survival   (RV  =  10)  was  observed  1n  all
treated  groups  of  males,  and   this  effect  at 50  ppm  (6.5 mg/kg/day)   1s
presented In  Table 9-1.  From the data  presented  1n Table 9-1,  1t  1s clear
that the most  severe effect,  reduced survival, occurred at  the lowest human
equivalent dosage,  0.49 mg/kg/day.   Therefore, 1t 1s necessary to calculate
a CS only for this  effect.  The  human equivalent  dosage  of 0.49 mg/kg/day 1s
multiplied by  70  to calculate a  human MED of  34  mg/day for a  70 kg  human,
which  1s  equivalent to an  RV.  of 3.2.   A CS  of  32 corresponding  to an RQ
of  100  1s  calculated  by  multiplying  the  RV. of  3.2  by  the  RVg  of  10.
This CS 1s presented 1n Table 9-2.
9.2.   BASED ON CARCINOGENICITY
    Carclnogenlclty  data  for  methomyl  consist of negative  dietary  studies
using rats (Kaplan and  Sherman,  1977)  and mice (Hazelton Laboratories, 1981)
and negative results  In the transplacental  hamster fetal  cell transformation
assay  (Quarles  et  al.,  1979).   U.S.  EPA  (1987a) assigned  methomyl  to  EPA
Group D, not  classifiable as  to  human cardnogen1c1ty,  because  the  negative
0121d                               -58-                             08/24/88

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                                  TABLE 9-2
                                   METHOMYL
          Minimum  Effective Dose  (MED) and Reportable Quantity (RQ)


Route:                  oral
Dose*:                  34 mg/day
Effect:                 reduced survival
Reference:              Hazelton Laboratories,  1981
RVd:                    3.2
RVe:                    10
Composite Score:        32
RQ:    .100

^Equivalent  human dose
0121d                               -59-                             06/08/88

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studies  for  differing  reasons  were  Inadequate  and weakened  the  negative
observations.   Because  quantitative  data  are  not available  from which  to
derive  a  potency  factor,  derivation   of  a  cardnogen1c1ty-based  RQ  1s
precluded.
0121d                               -60-              •       '      i 09/20/88

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0121d                               -65-                             07/14/88

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0121d                               -66-                          .    06/08/88

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mutagenldty of nitrogenous pesticides.  Mutat.  Res.   48: 225-236.

Selmed-Antal,  M.,  M.  Barta-Bedo,  G.   Constant1nov1ts,   K.   Nagy   and   J.
Szepvolgyl.   1980.   Nutritional  toxlcologlcal  studies  with Lannate:  Inter-
actions with caffeine and ethanol.  Arch. Toxlcol.  Suppl.  4:  443-445.

0121d                               -72-                              07/14/88

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Simmon,-V.-.F., O.C. Poole and G.W. Newell.  1976.   In  vitro  mutagenlc  studies
of twenty pesticides.  Toxlcol.  Appl.  Pharmacol.   37(1):  109.

Simmon,  V.F.,   A.D.   Mitchell  and  T.A.  Jorgenson.   1977.   Evaluation  of
selected pestlddss  and  chemical mutagens.   ln_ vitro and  In vivo  studies.
NTIS PB268647.   p. 4-5, 12-27,  100-101,  129,  143,  149,  161.

Slmonet, D.E.,  W.I.  Knausenberger,  L.H. Townsend,  Jr.  and  E.G.  Turner,  Jr.
1978.   A  b1omon1tor1ng  procedure  utilizing  negative phototaxls  of  first
Instar Aedes aeqyptl  larvae.   Arch.  Environ.  Contam. Toxlcol.   7(3):  339-347.

SRI  (Stanford  Research   Institute).    1987.    1986  Directory  of   Chemical
Producers:  United States  of America.   SRI International,  Menlo Park.   p.  851.

StMckman,  D.   1985.   Aquatic bloassay  of 11 pesticides using larvae  of the
mosquito,  Myeomyla  smlthll   (D1ptera:Cul1c1dae).    Bull.   Environ.   Contam.
Toxlcol.  35: 133-142.

Ta'naka,  I., H.  Iglsu,   J.  Haratake,  et al.   1987.   Cumulative  tox1c1ty
potential of methomyl  aerosol by repeated Inhalation.  Am.  Ind. Hyg.  Assoc.
J.  48(4):  330-334.

Thomas,  R.G.   1982.    Volatilization  from water.   In.:  Handbook  of  Chemical
Property Estimation Methods, W.J. Lyman, W.F.  Reehl  and  D.H.  Rosenblatt, Ed.
McGraw-Hill Book Co.   p.  15-1 to 15-34.
0121d                               -73-                             07/14/88

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USDA  (U.S.  Department  of  Agriculture).   1983.   Inputs  Outlook and Situation.
Oct.  1983  IOS-2.   U.S.  Department  of  Agriculture,  Washington,  DC.   p. 6,
9-11.

U.S.  EPA.  1980.- • Guidelines and  Methodology  Used  In  the Preparation  of
Health  Effect  Assessment Chapters  of  the  Consent   Decree Water  Criteria
Documents.  Federal Register.  45(231): 49347-49357.

U.S.  EPA.    1981.    Pesticide   Registration   Standard  S-Methyl  N-(Methyl-
carbamoyl)  Oxy-Th1oacet1m1date  (Methomyl).   U.S. EPA, Washington,  DC.   NTIS
PB82-180738.  p. 2-2, 6-1 to 6-3.

U.S.  EPA.  1982.   Tolerances and  exemptions  for  tolerances  for  pesticide
chemicals 1n or on raw agricultural commodities.  Methomyl.  40 CFR 180.253.

U.S.  EPA   1984.  Methodology and  Guidelines  for Reportable  Quantity  Deter-
minations Based on  Chronic  Toxlclty  Data.  Prepared by  the  Office of  Health
and Environmental  Assessment,  Environmental Criteria and  Assessment  Office,
Cincinnati, OH  for  the Office of  Solid Waste  and  Emergency Response,  Wash-
ington,  DC.

U.S.  EPA.   1985a.    Methomyl;   Renewal   of  Temporary  Tolerances.   Federal
Register.  50(176): 37052-37053.

U.S.  EPA.   1985b.   40 CFR 117  and 302.  Notification Requirements;  Report-
able  Quantity  Adjustments;  Final Rule and Proposed Rule.   Federal  Register.
50(65):  13475, 13491.


0121d                               -74-                             07/14/88

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U.S. EPA.   1986a.   Methodology  for Evaluating Cardnogenldty  In  Support  of
Reportable  Quantity  Adjustment  Pursuant  to CERCLA Section 102.   Prepared  by
the  Office of  Health and  Environmental  Assessment,  Carcinogen  Assessment
Group,   Washington,   DC  for  the  Office   of   Solid  and  Emergency  Response,
Washington, DC.  ' •

U.S.  EPA.   1986b.    Health  and  Environmental   Effects  Profile  for  Methyl
Isocyanate.  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.   p.  2-3.

U.S., EPA.   1986c.   Integrated Risk  Information System  (IRIS):  Reference Dose
(RfD) for  Oral Exposure for Methomyl.  Online.  (Verification  date 04/22/86).
Office  of  Health and Environmental Assessment,  Environmental Criteria  and
Assessment Office, Cincinnati, OH.  p.  1-7.

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

U.S. EPA.   1986e.   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.   1987a.   Health Advisories for  50  Pesticides:  Methomyl.  Office of
Drinking Water, Washington,  DC.   NTIS PB86-118338.  p.  1-19.
0121d                               -75-                             07/14/88

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U.S.  EPA.    1987b.   Pesticide  Tolerances  for  Methomyl.   Federal  Register.
51(184): 35730-35731.

U.S.  EPA.    1987c.   21  CRF   193.   Methomyl;  Pesticide  Tolerance.   Federal
Register.  52(218):- 43324.

U.S. EPA.  1988.  STORET Water Quality Data Base.   Online:  February,  1988.

Valencia,  R.   1981.   Mutagenesls  Screening  of Pesticides Using  Drosophlla.
NTIS P881-160848.  EPA 600/1-81-017.  p. 1-15, 40.

Waters,  M.D.,  V.F.  Simmon,  A.D.  Mitchell, T.A. Jorgenson  and R.  Valencia.
1980.   Overview  of  short-term  tests  for  the mutagenlc  and  carcinogenic
potential of pesticides.  J.  Environ.  Sd.  Health  Part B.   15:  867-906.

Waters,  M.D.,  S.S.  Sandhu,  V.F.  Simmon,  et  al.   1982.   Study of  pesticide
genotoxldty,  Basic  Life Sd.  21: 275-326.

WHO  (World  Health Organization).   1976a.  Pesticide Residues  In  Food  Report
of  the  1975  Joint Meeting of  the  FAO Working Party of Experts on  Pesticide
Residues and  the WHO  Expert  Committee  on Pesticide  Residues.   WHO,  Tech.
Rep. Ser. No. 592.  p.  1-45.

WHO  (World  Health   Organization).    1976b.    Evaluation  of  Some  Pesticide
Residues 1n Food.  WHO Pestle. Res. Ser.  p.  289-312.
0121d                               -76-                          .   07/14/88

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WHO  (World Health  Organization)   1977.   Pesticide Residues  1n Food.   WHO
Tech. Rep. Ser. 612.  p. -1-35.

Willis,  G.H.  and  L.L.  McDowell.   1987.   Pesticide persistence on  foliage.
Rev. Environ. Contam. Toxlcol.  100:  23-73.

Wojc1echowsk1,  J.P.  and  P.  Kaur.  1980.   Cell-mediated  mutagenesls of  V79
cells with four carbamates.  In VHro.  16: 235-236.

'Wojcleehowsk1,  J.P.,  P.   Kaur and   P.S.  Sabharwal.   1982.   Induction  of
ouabaln  resistance  In  V-79  cells  by  four  carbamate  pesticides.   Environ.
Res.  29(1): 48-53.

Worthing,  C.R.  and  S.B.  Walker,  Ed.    1983.   The Pesticide Manual,  7th  ed.
The British Crop Protection Council,  Croydon, England,   p.  363.

Yeboah,  P.O.  and  W.W.  Kllgore.  1984.  Analysis  of  airborne  pesticides  In a
commercial pesticide storage  building.   Bull.  Environ.  Contam.  Toxlcol.   32:
629-634.
0121d                               -77-                             07/14/88

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                                  APPENDIX A

                '              LITERATURE  SEARCHED



    This  HEED  Is  based  on  data  Identified  by  computerized  literature

searches of the following:

              CHEMLINE
              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  February 1988, and  the  following  secondary

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

    ACGIH  (American  Conference of Governmental  Industrial  Hyglenlsts).
    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.

    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.  2B.   John  Wiley  and
    Sons, NY.  p. 2879-3816.

    Clayton,  G.D. and  F.E.  Clayton,  Ed.   1982.   Patty's  Industrial
    Hygiene  and  Toxicology,  3rd  rev.  ed., Vol.  2C.   John  WHey  and
    Sons, NY.  p. 3817-5112.
0121d                               -78-                          .   06/08/88

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

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

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

    Jaber, H.M.,  W.R.  Mabey,  A.T.  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.
0121d                               -79-                           .  06/08/88

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    In  addition,  approximately  30  compendia of  aquatic  toxldty  data  were

reviewed, Including the following:


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

    Johnson,  W.W.  and M.T.  Flnley.   1980.  Handbook of  Acute  Toxldty
    of  Chemicals  to  F1sh  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.
OlZld                               -80-                          .   06/08/88

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o
CO
00
00
                                                     APPENDIX B

                                             Summary Table for Methomy1
0
rj
Species
Inhalation Exposure
Subchronlc ID
Chronic ID
Carclnogenlclty ID
Oral Exposure
( Subchronlc dog
CD
1
Chronic dog
Carclnogenlclty ID
REPORTABLE QUANTITIES

Exposure

ID
ID
ID

100 ppra In diet
for 24 months
(2.5 rog/kg/day)
100 ppro In diet
for 24 months
(2.5 mg/kg/day)
ID


Effect

ID
ID
ID

mild kidney lesions
In males at 400 ppra
mild kidney lesions
In males at 400 ppm
ID


RfD or qi*

ID
ID
ID

0.025 mg/kg/day
or 2 mg/day for
a 70 kg human
0.025 mg/kg/day
or 2 mg/day for
a 70 kg human
ID


Reference
1

ID
ID
ID

Kaplan and
Sherman. 1977
Kaplan and
Sherman, 1977
ID

    Based on chronic toxlclty:
    Based on Carclnogenlclty:
100
ID
Hazelton
Laboratories,
1981

ID
    ID = Insufficient data

-------