of  the

                                       A M I T R 0 L E


                                         March 12,  1971
EPA 540/5-71-001



      The Committee recommends continuation of the cancellation  of regis-

 tration of ftmitrole for  use on food crops as listed on Page 25  of the

 USDA  Summary of Registered Agricultural Pesticide Uses (2nd Edition);  it

 does  not recommend reclassification of these listed uses as non-food



      Amitrole (Aminotriazole) was registered as a herbicide under  the

 Federal Insecticide, Fungicide and Rodenticide Act in 1956.  In 1958

 Amitrole was registered  for use on cranberry bogs after harvest.   In

 1957, 1958 and  1959 the  herbicide was misused by being applied prior to

 harvest, and cranberries were found contaminated by Amitrole.   In  1959

 Amitrole was reported to be a highly potent goitrogen and to induce can-

 cers  of the thyroid of rats when it was contained in their diets.   In

 1963  the post-harvest use of Amitrole on cranberry bogs was withdrawn

 because detection of residues in berries was claimed by regulatory agen-


      In 1965 the National Academy of Sciences,  National Research Council,

at the recommendation of the President's Science Advisory Committee,  ap-

pointed a Pesticide Residues Committee  specifically to study the concepts

of "no residue" and "zero tolerance"  as they relate  to pesticide use.

The Committee recommended that the concepts  of "no residue" and "zero

tolerance," as employed in the registration  and regulations of pesticides,

are scientifically and administratively untenable and should be  abandoned,

Amitrole Advisory Committee                                           2

especially since continually improving analytical techniques are capable

of detecting smaller and smaller residues.  Based on the Committee's

findings, the USDA and the DHEW published a joint statement in the

Federal Register on April 13, 19&6, providing that all uses of pesti-

cides involving reasonable expectation of small residues on food or feed

at harvest in the absence of a finite tolerance or exemption should be

discontinued as of December 31, 196?.  The joint statement led in Febru-

ary,  1968, to the cancellation of  registration of Amitrole for all uses

listed on Page 25 of the USDA Summary of Registered Agricultural Pesti-

cide  Chemical Uses.  In May, 1969, the FDA, answering a petition, indi-

cated that no finite tolerance could be  established for Amitrole under

the Federal Food, Drug and Cosmetic Act  since it produces cancer in ex-

perimental animals.

      The  firms having registration of products containing Amitrole for

use on food crops filed petitions  (March, 1968) requesting that the

matter be referred  to an advisory  committee as provided under Title 7,

 Chapter  III, Part 36^ of the Code  of Federal Regulations.  Under these

provisions the National Academy  of Sciences, National Research Council,

was asked to  suggest potential candidates for the Advisory Committee,

 and the  Department  of Agriculture  then appointed the following individ-


                         Dr. William A.  Meissner, Chairman
                         Dr. Chester L.  Foy
                         Dr. James G. Hilton
                         Dr. William B.  House
                         Dr. Svend W. Nielsen

      The Committee  was  requested to consider all relevant factors and

 submit a report and recommendations as to the registration of the

 articles (USDA Reg. No.'s  26U-68,  26U-12U, 26U-135,  and 2^1-60)  in Exhib-

Amitrole Advisory Committee                                            3

it 2, for use on food crops, together with all underlying data and a

statement of the reasons or basis for the recommendations.  Committee

function began on November 16, 1970, when the Chairman acknowledged

receipt of registrants' petitions and other exhibits.  On January 7,

1971, an extension of 60 days for submission of the report was granted.

     The Advisory Committee met in Washington, B.C., on December 16 and

17, 1970.  After reviewing its charge, the Committee considered the Ex-

hibits and References (Appendices 1 and 3)*.  Presentations by the

registrants were heard and discussed (Additional Exhibits—Appendix 2)*.

Technical information and advice was obtained from representative mem-

bers of the Pesticide Regulation Division, Environmental Protection

Agency, and the Food and Drug Administration.  The Committee concluded

its two-day meeting in executive session with discussion leading to a

concensus for recommendations.   Further investigations were assigned to

respective Committee members, and the meeting adjourned with the intent

of handling future business by mail if possible.   Mr. David L.  Bowen of

the Environmental Protection Agency, Pesticides Regulation Division,

served as Committee Secretariat and kept notes of the meeting.



     Amitrole administered orally to rats enters  the blood through the

gastro-intestinal tract and probably mostly through the gastric mucosa

(R-l ).  It is fairly rapidly distributed throughout the tissues and

eliminated through the kidneys.  It inhibits liver and kidney catalase,

* E = Exhibit
  R = Reference
 AE = Additional Exhibit

Amitrole Advisory Committee                                            k

liver peroxidase, and thyroid peroxidase.  The site of metabolism is in

the liver where a metabolite is formed which might be responsible for

catalase inhibition since such inhibition persists even after Amitrole

itself is no longer present  (R-l).

     In animal experiments Amitrole has shown a low acute toxicity after

oral, intravenous or intraperitoneal injection (R-2 ).  For example, the

LD50 for mice after oral administration was found to be lU,700 mg/kg.

There have been no long-term adverse effects in rats from chronic skin

applications or chronic inhalation  (AE-3).

     Amitrole is a fairly potent antithyroid agent (R-3).  The goiter

production by Amitrole results from the inhibition of thyroid peroxidase

which participates in the iodination reactions involved in the biosyn-

thesis of thyroid hormone  (R-U).   The amount of inhibition is dose re-

lated.  Diminished hormone output elicits an increased secretion of

Thyroid Stimulating Hormone  (TSH) by the pituitary which stimulates the

thyroid to hyperplasia in  order to  synthesize at a more rapid rate.  A

compensated hypothyroidism as well  as a goiter results.  Fregley (AE-3g)

reports that 0.5 ppm  in food had no effect  in the rat on any of seven

separate measures of  thyroid function studied.  At 2 ppm in food, two of

sixteen separate measures  of thyroid function were affected significantly.

Strum and Karnovsky (R-U ) found early changes in the thyroid after ad-

ministration of Amitrole for only one week  and reduction in thyroid ac-

tivity within  three days.  Most experimental goiters induced by Amitrole

have been the  result  of long-term and continuous administration.

      The  Committee  noted with  interest that the ingredient designated as

T in Cytrol  Amitrole-T and Amitrol-T is ammonium thiocyanate.  The name

Amitrole Advisory Committee                                           5

ammonium thiocyanate is not included on the labels and apparently is

considered as an inert substance by both the registrants and the Pesti-

cide Control Division.   However, the thiocyanate ion has in itself a

goitrogenic effect and could be a contributing factor to the development

of goiter, especially when intake of iodine is low (R-5).  Thus, two of

the four products involved (E-l6) potentially have a double goitrogenic

activity.  Also, it is known that in plants ammonium thiocyanate poten-

tiates and/or prolongs the persistence of Amitrole by slowing down its

normal metabolic degradation (AE-6, AE-7).  Whether such could also hap-

pen in animals is unknown, but the distinct possibility exists.

     The carcinogenic effect of Amitrole was first reported in 1959

(E-9, E-10), subsequently by Russian observers (AE-3) and more recently

by Innes et al (AE-3f).  The Food and Drug Administration noted in 1959

that feeding high dosages of Amitrole stimulated abnormal growth of the

thyroid gland (E-9).  A summary of subsequent research conducted by

American Cyanamid Company showed that, with chronic feeding studies in

rats, thyroid tumors began appearing at the 68th week of feeding at ICO

parts per million; after two years thyroid tumors were present in more

than half of the rats examined which had been fed 100 parts per million.

These tumors were diagnosed as various types of adenoma and carcinoma.

At lower levels of feeding, 50 and 10 parts per million,  thyroid tumors

also appeared in decreasing number.  A "no effect level"  was not estab-

lished (E-9).

     Innes et al (AE-3f) in 19&9 used Amitrole as a positive control

against which carcinogenic activity of other pesticides and industrial

compounds were compared.  The Amitrole was administered at a daily

Amitrole Advisory Committee                                           6

dosage of 1000 mg/kg.  The Amitrole-fed mice were carried for 53 to 60

weeks with 6k of the 72 animals developing thyroid carcinomas and 67 of

the 72 animals developing hepatomas.

     The mode of action of Amitrole in producing thyroid tumors is pre-

sumably related to  its goitrogenic effect and resultant TSH stimulation.

Other antithyroid agents, such as thiouracil, produce experimental

thyroid cancers in  a similar manner through TSH stimulation of the

thyroid and, in fact, TSH itself has produced thyroid tumors experimen-

tally  (R-6).  In this sense Amitrole acts in a  different manner from

the classic  carcinogenic hydrocarbons, such as  methylcholanthrene, inas-

much as its  effect  is mediated by hormonal stimulation.  It should be

noted  that in either type of carcinogenic stimulation, hyperplasia

usually precedes neoplasia.  The fact that Amitrole  is carcinogenic

because it induces  exaggerated physiologic stimulation and hyperplasia

makes  it  no  less a  carcinogen.

     Plant Physiology

     Amitrole is a  herbicide, plant growth inhibitor, and defoliant.  It

is a foliarly-applied,  readily translocated, nonselective spray chemical

for control  of annual and perennial grasses and broadleaved weeds (R-7>

R-8).  The major phytotoxic effect is to  interfere in some presently un-

specified way with  the  normal metabolism  of purines, pyrimidines, nucleic

acids  and related compounds leading to the disorganization and inhibition

of new, active  growth  (R-8, AE-9a).   The  appearance  of chlorotic or albino

tissue is the most  striking symptom of Amitrole phytotoxicity.  The typical

 chlorotic lesions  result from the  failure of plastids  (self-replicating

organelles rich in  protein) to  reproduce  properly.   Thus the effect of

Amitrole Advisory Committee                                           7

Amitrole on protein appears to be indirect.  Although similar biochem-

ical lesions may be produced in different species, the particular

lesion which is critical may be different for different organisms.

Amitrole apparently attaches to amino acids and protein by forming a

free radical and may become bound in an insoluble form.

     The present method of analysis, developed by Storherr and Burke

of FDA (AE-9) has a claimed sensitivity of 0.02 ppm for Amitrole and

"all known metabolites."  By this and other methods, "disappearance"

from certain plant species has been reported.  However, dissipation or

removal from ready detection does not necessarily mean complete degra-

dation.  For example, the possibility that Amitrole was bound in in-

soluble form or was lost from roots, similar to other mobile herbicides,

has not been critically evaluated.

     Dalgaard-Mikkelsen and Poulsen (R-2) have emphasized (l) that atten-

tion not be confined to toxicity of original herbicide compounds, but

should include the influences on plant metabolism which perhaps might

lead to accumulation of endogenous products and (2) that little is

known regarding toxicity of metabolites of herbicides formed either in

soil or plants.

     The triazole nucleus is highly stable; hence it is not surprising

that conclusive evidence of ring cleavage under physiological conditions

has not been reported.  Rather, rapid metabolism of Amitrole in higher

plants appears to be restricted principally to conjugation.  Conjugation

with other plant constituents has also been proposed.  Technically, these

conjugates are not "degradation" products because they still contain the

intact triazole nucleus which may be regenerated by chemical treatment.

Amitrole Advisory Committee                                           8

     The Committee was impressed by the lack of detailed information

available on the metabolites of Amitrole or ammonium thiocyanate,

and on the influence of environmental and chemical factors on the

metabolism in plants.  For example, Smith et al (AE-7) reported that

Amitrole metabolism in leaves of two species was more rapid in the

light than in dark; also, at 28° C than at 15° or 22° C.  In the same

study, pre-treatment with benzyladenine enhanced metabolism, but

ammonium thiocyanate markedly retarded or reduced metabolism of Ami-

trole, thus acting as a potentiator for Amitrole in plant tissues.

Yet, the Committee was led to understand that virtually all of the

earlier residue data reviewed in the case pertained to Amitrole alone,

not Amitrole plus ammonium thiocyanate  (Amitrole-T, which comprises

two of the  four commercial products under consideration).

     Persistence in Soils

     Since  Amitrole  is not applied directly  to  food crops, but to the

 soil in which these  crops are grown, the question of  the persistence

and degradation in soils  is  of  prime importance.  In  some soils the

 chemical disappears  rapidly while  in others  the applied Amitrole may

persist  for months.   The  factors  governing the  rate of  degradation of

Amitrole are not satisfactorily understood at present.  Sund (R-9) re-

ported that Amitrole becomes tightly bound to  soil particles  and has

 a tendency to complex with metals.  Ashton (R-10) and Ercegovich and

 Frear (R-ll) have also reported the complexes  of Amitrole with metals.

 Several investigators (R-10, R-ll, R-12) have proposed that  soil micro-

 organisms are responsible for the degradation of Amitrole, but have not

 been able to isolate or identify the microorganisms  responsible.  More

Amitrole Advisory Committee                                            9

recently Kaufman  et al  (K-13) have reported that the degradation of

Amitrole in  soil  is largely a chemical process only indirectly related

to microorganisms.  Plimmer et al (R-l^) have studied the reactions of

Amitrole in  several isolated systems and propose the decomposition of

this  substance by free radical-generating systems.  These investigators

have  proposed the breakdown of Amitrole to carbon dioxide, urea and

cyanamide.   In light of these different possibilities for the degradation

of Amitrole, it is not surprising that the persistence of the chemical

appears to vary greatly with the soil type and composition.  For example,

the Herbicide Handbook (R-7) reports a duration of two to three weeks

in warm, moist soils while Riepma (R-15) has reported that two thirds

of the applied Amitrole remained after 60 days in high clay, low organic

matter soil.

      The degradation of Amitrole by either microorganisms or by free-

radical generating systems raised questions about the persistence and

fate  of this chemical in surface waters.  There appears to be a lack

of information about this area.  The Committee could visualize situa-

tions where high  concentrations of Amitrole might be present in surface

waters either from run-off or from treatment of weeds growing on the

banks of ditches and dikes.

     Under these conditions information about the toxicity of this  sub-

stance on marine life and other wild life that might be ingesting the

water would be essential.  This would be particularly true if the

Amitrole persisted in the surface water for any period of time and  was

transported from location to location by the water.

Amitrole Advisory Committee                                          10

     Residue in Food or Feed Crops

     The current method of analysis  for Amitrole  residues  (Storherr and

Burke) has claimed  sensitivity of 0.02 ppm and is said to  account not

only for Amitrole,  but also all known metabolites of Amitrole in plant

tissue  (AE-9).  Amitrole  is picked up from soil and is systemic in

plants  so while  it  is not used directly on food or feed  crops, its close

proximity to such crops raises the question  of potential residue.

Amitrole is  no longer registered for use  on  cranberries, but the ability

of the  chemical to  be retained in plants  was demonstrated  by Onley  (R-l6)

who found residues  in the berries harvested 12 months after application.

Other investigators using direct application of radioactive C1^ Amitrole

to corn plants (E-15)  and tokay grapes  (R-l?) have reported detectable

 radioactivity ^5 days  and 112 days  after treatment.

      From current registered uses of Amitrole and when used according to

 directions, no reports of residues  in'food or feed crops have  been  demon-

 strated in abundant residue data.  Market-basket surveys since 196U have

 not shown detectable residues in crops grown on land treated with Ami-

 trole .

      Other Items

      The Committee was presented with voluminous material for considera-

 tion, consisting of oral and written reports, copies of correspondence,

 reprints, etc.  (See Exhibits).  While all of this material was studied

 by the Committee,  only the more pertinent items  leading to the Committee's

 conclusions have been discussed above, and  no attempt has been made to

 cite each reference and  report.

CONCLUSIONS                                                         11

     Amitrole is a highly effective herbicide of considerable agricul-

tural importance.  It has been widely used for over a decade, and no

evidence was presented to the Committee that Amitrole, used as now

registered, has had any harmful effects on man or animals.  Available

data indicate no detectable residues on food products when it is used

as currently registered.  The 1968 decision to cancel registration,

which the Committee has been asked to arbitrate, was based on reevalua-

tion of policy, rather than on new evidence of residues or harmful

effects.  The Committee was particularly concerned that both the re-

evaluation of policy and Committee deliberations were partially dependent

on  usage of scientifically vague terms such as, "reasonable expectation

of residues"; and "applications highly remote from food crops."  If

such terms were more specifically defined, actions of this and future

committees would be sharpened.

     The Committee, however, also appreciates that Amitrole has been

accepted as a carcinogen.  Although it seems highly unlikely that

Amitrole could contaminate a human diet in sufficient quantities to

produce cancer, the carcinogenicity of the chemical must necessarily

influence the conclusions and recommendations of the Committee.   This

is evident in the following statements:

     (A)  Section hQ9 (3W) (c) (3) (A) of the Federal Food, Drug and

Cosmetic Act, as Amended (R-l8):   "No additive shall be deemed safe if

it is found to induce a cancer when ingested by man or animal ..."

Amitrole Advisory Committee                                          12

      (B)  FDA, 1959  (E-9):  "It has not been determined  scientifically

whether it is possible to  establish  a safe  level  of use for a  carcinogen

in human food."

      (C)  A. H. Fleming, Secretary of HEW,  1959 (E-7):   "The FM has

declined to  set any tolerance for any amount of a chemical in  foods if

the  chemical produces  cancer when fed to test animals.   This principle

is set down  in the  Food Additives Amendment enacted last year  in a

specific provision  prohibiting the FDA from setting any tolerance for

any  such chemical.

           "While  in theory there may be  a minute  quantity of a carcino-

gen  which  is safe in foods,  in actuality our scientists do not know

whether this is true or how  to establish a  safe tolerance."

      (D)   Pesticide Residues Committee,  1965 (E-ll):   "Although it is

reasonable to assume that  a  no-effect level could be  demonstrated for

a compound with respect to carcinogenic  potential, approval of such a

compound for use  when it might leave a residue on food would require

most extraordinary  justification."

      (E)   Pesticide Program, USPHS,  1969 (E-13):   "We cannot recommend

reregistration of this Reg.  No.  Amitrole/  because we do not believe that

a compound which  produces  cancer in  experimental animals should be em-

ployed as  a  pesticide."

      (F)   Secretary's Commission on  Pesticides and their Relationship

to Environmental  Health,  19&9 (E-lU): "It  is recommended that the ex-

posure of  human beings to pesticides in  this Category "B" /includes

compounds  judged  "positive"  for  tumor induction and specifically men-

 tions Amitrole_7 t)e minimized and that use  of these pesticides be re-

Amitrole Advisory Committee                                           13

stricted to those purposes for which there are judged to be advantages

to human health which outweigh the potential hazard of carcinogenicity."

     In the present climate of ecologic concern, with such policy state-

ments made by statute, agencies and committees, as above, the Committee

feels that it would be difficult to recommend continued use of an ac-

cepted carcinogen, even if no residue has been demonstrated.

     While the available residue data on Amitrole indicate that when

used according to current registrations and directions no residues have

been detected, it is clear that the USDA (EPA) feels that there is a

reasonable expectation of some level of residues in harvested crops.

     The Committee, as noted above in discussion, was concerned by the

relative lack of information, not of tests for residual Amitrole, but

regarding its metabolism, metabolites, degradation and ultimate fate in

soils, plants and water.

     Despite the fact that Amitrole is not registered for direct spray

on crops and label directions call for spraying on the soil before

planting or when no fruit is present,  the Committee does not feel that

such applications can be considered as "remote" from food crops.   It

does not seem to the Committee that with existing knowledge it is pos-

sible to conclude dogmatically that there is  no "reasonable expectation"

of a residue, even though no residues  have been demonstrated using cur-

rent analytical techniques.

     Because of these considerations,  the Committee unanimously adopted

the following recommendation?

          The Committee recommends continuation of the cancel-

     lation of registration of Amitrole for use on food crops

Amitrole Advisory Committee

     as listed on Page 25 of the USDA Summary of Registered Agri-

     cultural Pesticide Uses (2nd Edition); it does not recommend

     reclassification of these listed uses as non-food uses.
                            -4 <-
                                             March  12, 1971
     William A. Meissner,  M.D.,  Chairman    Date

Amitrole Advisory Committee                                          15


     The names of individuals who contacted the Chairman or members of

the Committee outside of the meeting and the substance of the conver-

sations were, as follows:

     1.  Dr. Frank Stark of the American Cyanamid Company called the

Chairman by telephone on 11/25/70 to ask if the Advisory Committee

planned to have a meeting and, if so, about what date.  He also asked

if the American Cyanamid Company and Amchem Products, Inc. would be in-

vited.  The Chairman informed him that there would be a meeting about

the middle of December and that they definitely would be invited to

present data to the Committee.

     2.  On 12/7/70, Dr. Stark, representing the American Cyanamid

Company, called the Chairman by telephone to request that representa-

tives of the American Cyanamid Company and Amchem Products, Inc., be

allowed to appear before the Committee on the afternoon of December l6

instead of the morning of December 17, as planned.   The Chairman granted

the permission for this change provided it would not interfere with the

agenda or function of the meeting as far as the Secretariat was con-

cerned.  Permission was also granted to have the representatives  of the

two companies meet jointly with the Committee,  rather than separately.

     3.  On 2/8/71 a reprint on Pesticide Residues  in Total Diet  Sam-

ples (V) by P. E.  Corneliussen (1970) was received from C. Boyd Shaffer,

Ph.D , American Cyanamid Company,(R-19).

Amitrole Advisory Committee                                           16


 E-l  Notice of cancellation of  registration of certain products bearing
      directions for use on food in the absence of finite tolerances or
      exemptions (PR Notice 68-6, February  1, 1968).

 E-2  Labeling of Amitrole products bearing food crop uses.

 E-3  Petitions for an advisory  committee filed in behalf of the regis-
      trants, March 13 and lk, 1968.

 E-k  Federal Insecticide, Fungicide,  and Rodenticide Act, 196k.

 E-5  Rules governing  the appointment, compensation, and proceedings of
      an advisory committee, and rules of practice governing hearings
      under the Federal Insecticide, Fungicide, and Rodenticide Act,
      August 29, 1969.

 E-6  Interdepartmental coordination of activities relating to pesticides,
      by the Department of Agriculture, the Department of Health, Educa-
      tion and Welfare, and the  Department  of the Interior, 1964.

 E-7  Statement by Arthur S. Felmming, Secretary of Health, Education, and
      Welfare, at nevs conference, November 9» 1959-

 E-8  Department of Health, Education, and  Welfare release announcing speed-
      up of  cranberry  analysis for aminotriazole, November 16, 1959-

 E-9  Portion of statement showing scientific background for Food and Drug
      Administration action against aminotriazole in cranberries, Novem-
      ber  17, 1959.

 E-10  Department of Health, Education, and  Welfare report on actions taken
      with respect to  aminotriazole and stilbestrol, January 26, 1960.

 E-U   "No  residue" and "Zero  tolerance" report by Pesticide Residues Com-
      mittee, National Academy of Sciences, National Research Council, 1965.

 E-12  Notice to manufacturers, formulators, distributors and registrants
       regarding abandonment of "Zero  tolerance" and "No residue" concepts,
      with attached National  Research Council Pesticide Residues Committee
      Report, April 13, 1966.

 E-13   Interdepartmental referral comments from United States Public Health
      Service, regarding  reregistration of  Amitrol T, June 13, 19&9*

 E-lU  Excerpts from the Report of the Secretary's Commission on Pesticides
      and their Relationship  to  Environmental Health, December, 1969.

Amitrole Advisory Committee                                           17

E-15  Letter from Amchem Products, Inc., with residue data regarding use
      of Amitrole on crop land, March 13, 1968.

E-l6  List of products involved in the advisory committee proceedings.

Amitrole Advisory Committee                                          18


                           ADDITIONAL EXHIBITS
AE-1   Presentation of information on Amitrole to the Advisory Committee
       on December 16, 1970, by representatives of Amchem Products, Inc.
       and American Cyanamid Co.

AE-2   Chronology of Amitrole development and key registration actions.

AE-3   Statement by Dr. C. Boyd Shaffer, Director of Toxicology, Ameri-
       can Cyanamid Company, before the Amitrole Advisory Committee—
       16 December, 1970.

AE-3a  One-year status report to American Cyanamid Company.  Two-year
       sub-acute dermal toxicity study on Amitrole 3-AT in Albino rats.

AE-3b  IBT No. N7640 - two-year chronic inhalation toxicity study with
       Amitrole 3-AT in Albino rats.

AE-3c  Project #16.  Carcinogenesis assay studies (12/15/66).

AE-3d  Project #16.  Carcinogenesis assay studies (5/8/67).

AE-3e  Letter of 10/24/68 to Dr. Harry W. Hays from C. Boyd Shaffer,

AE-3f  Bioassay of pesticides and  industrial chemicals for tumorigenicity
       in mice:  a preliminary note.

AE-3g  Effect of Aminotriazole on  thyroid function in the rat.

AE-3h  Antithyroid effects of Aminotriazole.

AE-4  Statement by Dr. Robert M.  Clyne, Corporate Medical Director,
       American Cyanamid Company,  before the Amitrole Advisory Committee—
        16 December, 1970.

AE-5  Position statement of American Cyanamid Company and Amchem Pro-
        ducts, Inc., regarding Amitrole  registrations.

AE-6  Metabolism of Amitrole  in excised leaves  of Canada thistle eco-
        types and bean.

AE-7   Influence of environmental  and chemical factors on Amitrole metabo-
        lism in excised leaves.

AE-8   Guidelines  for  Selected Use of Amitrole (issued by the working
        group of  the Subcommittee on Pesticides,  President's Cabinet Com-
       mittee on  the Environment,  February  kt  1970).

Amitrole Advisory Committee                                           19

AE-9   Statement by Mr. Richard J. Otten, Program Coordinator, State
       and Federal Labeling, Amchem Products, Inc., before the Amitrole
       AMsory Committee, 16 December, 1970.

AE-9a  Some physiological and phytotoxicological properties of Amitrole.

AE-9b  Pesticide residues in total-diet samples.

AE-9c  Residues in food and feed.  Assessments include raw food and
       feed commodities, market basket items prepared for consumption,
       meat samples taken at slaughter.

AE-9d  Residues in food and feed.  Pesticide residues in total diet
       samples (ll).

AE-9e  Residues in food and feed.  Pesticide residues in total diet
       samples (IV).

AE-9f  Letter of 5/29/59 to Mr. R. W. Gannon, Amchem Products, Inc.,
       and Mr. F. Ray Barren, American Cyanamid Company, from F. J.

AE-9g  Letter of 1/23/68 to Amchem Products, Inc., from Harold G. Alford.

AE-9h  Letter of 2/15/68 to Mr. R. J. Otten, Amchem Products, Inc., from
       Harold G. Alford.

AE-9i  Amizine advertisement by Amchem Products, Inc.

AE-9J  Weedazol advertisement by Amchem Products, Inc.

AE-9k  Amitrol-T advertisement by Amchem Products, Inc.

AE-91  Weedazol advertisement by Amchem Products, Inc.

AE-10  Tests on mice for evaluating carcinogenicity.

Amitrole Advisory Committee                                          20


R-l  Fang, S.  C.,  George. M. ,  and Yu,  T.  C.:  Metabolism of 3-Amino-
     l,2,U-triazole-5-Ciqby Rats,  J. Agr.  and Food Chem. , 12:219-223,
 R-2  Dalgaard-Mikkelsen,  S.  and Poulsen,  E.:   Toxicology of Herbicides,
     Pharm.  Rev.,  1^:225-250,  1962.

 R-3  Alexander,  N. M. :  Antithyroid Action of 3-Amino-l,2,l*-triazole, J.
     Biol.  Chem. ,  23U:lU8-150, 1959-

 R-1*  Strum,  J. M.  and Karnovsky, M. J.:   Aminotriazole Goiter.   Fine
     structures  and Localization of Thyroid Peroxidase Activity, Lab.
     Investig.,  2^:1-2,  1971.

 R-5  Goodman,  L. and  Oilman,  A. :  The Pharmacological Basis of Thera-
     peutics,  New York:   Macmillan Co.,  1970.

 R-6  Sinha,  D.,  Pascal,  R.  and Furth, J.:  Transplant able Thyroid Car-
     cinoma Induced by Thyrotropin:   Its Similarity to Human Hurthle Cell
     Tumors, Arch. Path. , 79:192-198, 1965.

 R-7  Herbicide Handbook of the Weed Science Society of America, 1967.

 R-8  Carter, M.  C.:  "Amitrole," in Kearney, P.  C. and Kaufmann, D. D. :
     Degradation of Herbicides, New York:  Marcel Dekker, Inc., 1969,
     pp 187-206.

 R-9   Sund, K.  A.:   Residual Activity  of 3-Amino-l,2,U-triazole  in Soils,
     J. Agr. and Food Chem. , k: 57-60, 1956.

R-10  Ashton, F.M.:  Fate of Amitrole  in Soil, Weeds, 11:167-170, 1963.

R-ll  Ercegovich, C. D. and Frear, D.  E. H.:  The Fate of 3-Amino-l,2,U-triazole
      in Soils, J. Agr. and Food Chem., 12:26-28, 196^.

R-12  MaeRae, I. C. and Alexander, M. :  Microbial Degradation of Selected
      Herbicides in Soil, J. Agr. and Food Chem., 13:72-76, 1965.

R-13  Kaufman,  D. D., Plimmer, J. R.,  Kearney, P. C., Blake, J.  and Guardia,
      F. S.:  Chemical Versus Microbial Decomposition of Amitrole in Soil,
     Weed Sci., 16:266-272, 1968.

R-lU  Plimmer,  J. R., Kearney, P. C.,  Kaufman, D. D. and Guardia, F. S.:
     Amitrole Decomposition by Free Radical Generating Systems  and Soil,
      J. Agr. and Food Chem. , 15:996-1000, 1967.

Amitrole Advisory Committee                                           21

R-15   Riepma,  P.:   Preliminary Observations on the Breakdown of 3-Amino-
       1,2,4-triazole  in Soil,  Weed Res., 2:4l-50, 1962.

R-l6   Onley, J.  H.  and Storherr,  R. W.:   An Oregon Cranberry Bog Study for
       3-Amino-l,2,4-triazole Residues,  1961-1962, Jour. A.O.A.C., H6:996-
       1001,  1963.

R-17   Leonard, 0. A.  and Weaver,  R. J.:   Absorption and Translocation of
       2,U-D and  Amitrole in Shoots of the Tokay Grape, Hilgardia, J31-327-
       368, 1961.

R-l8   Federal Food, Drug, and  Cosmetic Act, As Amended, U. S. Dept. Health,
       Ed. and Welfare,  Public  Health Serv., Food and Drug Administration,
       April, 1970.

R-19   Corneliussen, P.  E.:  Residues in  Food and Feed.  Pesticide Residues
       in Total Diet Samples (V),  Pesticides Monitoring J., ^:89-92, 1970.