. r&t
)
_
H °
tn " M
3s
3
e
i
2
3
14
5
6
7
8
9
10
11
12
13
14
*
16
17
18
19
t
20
21
22
23
f
25
450R76103
ENVIRONMENTAL PROTECTION AGENCY
LEPTOPHOS ADVISORY COMMITTEE MEETING
PUBLIC SESSION
ROOM 3906
WATERSIDE MALL
401 M STREET, S.W.
WASHINGTON, D. C. -
TUESDAY, JULY 20, 1976
9:03 0•CLOCK A. M.
-ooOoo-
-------
2
3
14
'. .a
•< c;
e
6
7
8
9
10
11
12
13
14
?
16
17
18
19
i
20
21
22
23
P
25
MEMBERS PRESENT:
ALSO PRESENT
JULIUS C001I, Chairman
SEYMOUR FRIESS
GERALD ROSEN
TETSUO FUKUTO
BERNARD McNAMARA
DAVID BOWEN
JOHN LYON
FRANKLIN GEE
WILLIAM UPHOLT
ORVILLE PAYNTER
GEORGE WHITMQRE
PETER HAMILTON
CHARLES GALA
DAVID WHITACRE
NEIL MITCHELL
CLAIRE FRANKLIN
Dr. Zweig
-------
TABLE OF CONTENTS
& o
STATEMENT OF;
3 || Introductions
David Bowen
Opening Remarks
5 II William Upholt
6 Remarks on Legal Aspects
I John Lyon
Presentation of Petition:
8 |j Chemistry Aspects
Franklin Gee
ii
9
JToxicological Overview
10 | Orville Paynter
;i? 12
11 ||Presentation of Petition:
Toxicological Aspects
George Whitmore
|e'^ Is Presentation by Velsicol
£\ Q & II»T-.J^ »»J* 1 T1 »^ JJ r.«* J
<
ssr
O y, •<
I
14
16
17
18
Neil Mitchell, David Whitacre,
Peter Hamilton, and Charles
Cala
PAGE
4
19
28
37
44
94
19
i
20
21
22
23
f4
25
-------
5
>• a 2
en S 2
Q
<
at
s
)
2
3
U
5
6
7
8
9
10
11
14
J5
16
17
18
19
i
20
21
22
23
r
MR. BOWEN: Well, this is the meeting of the Leptophos
Advisory Committee. My name is David Bowen. I am Secretariat
to the Committee and I will be assisted by Peggy Moran.
I would like, at this point, to recognize those people
that will be making presentations to the Committee today. From
the Agency, we will hear from Dr. William Upholt, Senior Science
Advisor to the Assistant Administrator for Water and Hazardous
Materials.
Following that, we will hear from John Lyon of our
Office of General Counsel; then, from Mr. Frank Gee, who is with
the Registration Division, Insecticide-Rodenticide Branch.
He will be followed by Dr. Paynter, Chief of our
Toxicology Branch, Registration Division. After that, we will
hear from Dr. George Whitmore, also a toxicologist with our
Toxicology Branch, Registration Division.
I think it would be appropriate at this time to intro-
duce the members of the Advisory Committee and perhaps each one
might wish to tell a little something about himself, his special
interest or particular expertise and area of interest.
I will start by introducing the Chairman, Dr. Coon.
CHAIRMAN COON: Thank you, Mr. Bowen. I am J. M. Coon
I am associated with the Jefferson Medical College in Philadelph
That is part of the Thomas Jefferson University.
I have been Chairman of the Department of Pharmacology
-------
u
> s%
3
-------
u o
H — «N
> S °
I S?tif
fS=S>sj
y '2 B «•>
*Sls
-------
1
2
3
J4
u
z
i-
5
6
7
8
9
10
> s§ n
SSSg
2 '. -a S .,
l*fs 12
S'S^- J
a|§s ^3
. U 5 r-
H*f~
D«^ 14
2£
1 -?5
16
17
18
19
20
21
22
23
f\A
•— N. .
r
25
Charles Gala.
I have a few matters I. would just like to discuss
before we turn the meeting over to Dr. Coon. I will pass out
an agenda so that you will see — this is a draft agenda. It
is very much like the one that you may have received at an
earlier date.
I also had a communication from the law office of
Williams, Connolly, and Califano dealing with the charge to
the Committee.
This communication is dated July the 15th and it is
marked as.AE Number 10 for identification purposes. Also
accompanying that is the agency response; also of July 15 date -
I am sorry. July 19th and that is identified as AE Number 11.
I will pass these out to the members of the Committee.
I also have a communication that was received to late
to get into the mails to you prior to this meeting. I will pass
that out. So far, it is not opened.
There is one communication here for the Velsicol Compa
and I will give it to Mr. Whitacre.
This Advisory Committee is one established under the
provisions of Section 408 of the Food, Drug, and Cosmetic Act
and is charged to consider the proposed revocation of tolerances
for leptophos on lettuce and tomatoes.
In connection with a committee of this sort, it is
required that we furnish to the Committee a copy of the certification.
-------
z
CO
5/1 ""* 8
31 £3
e <*>
fS
=2
Q
e
2
3
)4
5
6
7
8
9
10
11
12
J13
14
-i15
16
17
18
19
•t
20
21
22
23
r
25
3
of usefulness and I have that to pass out now. It is marked as
AE Number 12.
This Committee, as we are'aware from the announcement
in the Federal Register, is open to the public today. Tomorrow1
session will be closed. It will be an executive committee
deliberation tomorrow and the only ones that will be in attendan
will be the committee, the Secretariat - myself, Peggy Moran,
and the reporter.
This is a scientific advisory committee - it is not
an adversarial proceeding - and it is expected that it will be
just that.
I do not have any other special items to discuss at
this point, but if there are questions of the Secre — oh, yes.
There is one other thing.
We had an inquiry yesterday as to whether or not tape
recorders might be used by members of the public. We do not
consider that it is appropriate in this type of meeting for
tape recorders to be used by members of the public.
With that, I will now turn the meeting over to our
Chairman, Dr. Coon.
CHAIRMAN COON: Thank you, Mr. Bowen.
When I arrived in this room this morning at about ten
ninutes to nine, all of the other Advisory Committee members
already here and they had their coats off. They looked like
bhey were ready to go to work. When I left mine on, they put
-------
to
Is
to "" <•<
> S 2
at Xt *"•
<•*-
o « •<
as
5
e
o
1
2
3
>4
5
6
7
8
9
10
11
*13
-P
16
17
18
19
20
21
22
23
r
25
theirs back on. I hope that does not mean .they have given up
the idea of going to work.
(Laughter.)
CHAIRMAN COON: I left mine on on account of the tem-
perature. However, anybody on the Advisory Committee who wants
to peel off, go ahead because this is a scientific working
committee and we have to relax in a scientific atmosphere.
Well, with those remarks, the next item on the agenda
is "Remarks on Legal Aspects" by — excuse me. I am sorry.
"Opening Remarks". I got a little too far down on the agenda.
Opening remarks by William Upholt, Senior Science
Advisor to the Assistant Administrator for Water and Hazardous
Materials.
Dr. Upholt.
STATEMENT OF DR. WILLIAM UPHOLT, SENIOR SCIENCE ADVISO
TO THE ASSISTANT ADMINISTRATOR FOR WATER AND HAZARDOUS
MATERIALS
DR. UPHOLT: There are, I guess, too many opening rema;
going on at this session so far and I would not, perhaps, be
averse to leaving off some of them.
I do, though, on behalf of the Environmental Protectio
Agency want to thank this group of distinguished scientists who
take time to work on this problem and to provide us advice,
independent advice from the scientific community on this difficu
problem.
ks
-------
1
2
3
)4
5
6
7
o
10
11
12
w» -• r«
>. U O
v> a «
>J"So
£ '. .9 S
I *as
2 z .a '*> •
a |§ 13
i!!
s
14
-\5
16
17
18
19
i
20
21
22
23
r
25
10
It is inevitable, I think, in a number of decisions
that we make in this agency or any agency that some of them
will be unsatisfactory to some members of the people who are
concerned and provision has been made in this situation, as far
as setting tolerances is concerned, for a science advisory panel
to review the scientific evidence and to give us the benefit of
their opinions.
I think it is very fortunate that this is done,
because in this democratic society in which we are pleased to
operate there must be methods of reviewing the decisions of any
agency.
This seems to be one of the most satisfactory approaches,
as far as I can see, in terms of getting independent scientists
to express independent opinions based upon the evidence that is
available.
Therefore, we do appreciate very much your taking time
to devote your efforts to this problem.
I think you are aware that there are two factors,
according to our procedures, that must be considered - two ceilings
you might say, in placing tolerances on pesticides for residues
of pesticides that may occur on the raw agricultural crops at
the time of harvest and that the tolerance must not exceed eithe
of these ceilings«
The first ceiling is the maximum residue at harvest
that can be expected as a result of using the pesticide as
-------
JL*.,
z
w o
a = o o
^ '. .a S
|||S
11II
OS
8
e
i
2
3
)4
5
6
7
8
9
10
11
13
14
15
16
17
18
19
t
20
21
22
23
r
25
11
directed on the registered label.
The second ceiling might be described as the maximum
acceptable health risk as determined by toxicological evidence.
Now, in general we base this on a no observed effect level as
found in the toxicological evidence.
Then, because of uncertainties resulting from the
relatively small size of the experimental test populations andI
the interspecies differences in susceptibility that apply betwee
man and the experimental animals, we apply a safety factor to
that no observed effect level to determine the maximum level
that is, we believe, toxicologically acceptable.
Now, in the case of leptophos, we considered these two
ceilings and we came to the conclusion some time ago that certai
tolerances for tomatoes and lettuce were acceptable.
•
Therefore, we issued the tolerances. Now, some time
thereafter we realized that we had overlooked evidence that
leptophos produces neurological damage in chickens. This had no
been adequately considered when we first issued the tolerance.
When we reconsidered, in the light of the evidence of
neurotoxicity, we came to the conclusion that the tolerance shou
be revoked.
Now, I understand that the first ceiling that I mentio
ed, based upon the maximum expected residue resulting from good
agricultural practices, has not been questioned.
However, this particular ceiling based on good
-------
1
1
2
3
,4
5
6
7
8
9
UEVAL SYSTEMS, INC.
iwy.-SuitellOl
iiginu 22202
20-7680
KJ — O
§!«•« ^13
?
-------
1
2
3
)4
5
6
7
o
rf 10
Wl "• «S It
> 2 S ''
5/5 -3 £J
J^So
l^l! »
gK^g
SI 'I 13
jSt »^
^ u a
D«5 14
dS
o
u
bu
-j5
16
17
18
19
20
21
22
23
r
25
13
expected to remain on tomatoes and lettuce when leptophos is
applied in accordance with the label instructions, does this or
does it not present an acceptable or unacceptable risk to human
health.
Dr. Breidenbach, my boss, the Assistant Administrator,
who has responsibility for the water programs, including the
pesticides and others such as these, told me to express his
disappointment that he was unable to be with you this morning.
Also, he wanted to express his appreciation for your
time, for your service. If you should run into any problems
that you think warrant his consideration or, for that matter,
the attention of the Administrator, please let me know and I am
sure I can bring them to the attention of Dr. Breidenbach and
he can bring them to the attention of the Administrator.
Therefore, with that, I welcome you and encourage you
to use your best judgment in making the wisest decision you know
how.
Thank you.
CHAIRMAN COON: Thank you, Dr. Upholt.
Are there any questions from the Committee?
(No response.)
CHAIRMAN COON: If not, I would like to ask Dr. Upholt
Dr. Upholt, you said at the beginning that the neurotoxicity had
been overlooked when the tolerances were first set.
Now, by that, do you mean that they were not yet known
-------
)4
**j
u o
Wl •" «N
>. O O
-
Q « •<
3s
10
11
12
13
14
16
17
18
19
t
20
21
22
23
r
25
14
or they had been discovered but they did not come into the con-
sideration at the time?
DR. UPHOLT: I am afraid I cannot answer that guestior
Perhaps some of the toxicologists who were involved can. I
think, if I am correct, the evidence is that they had been made
available before that time, - but that for some reason or
another, and I do not know what the factors are, they were not,
as I expressed, adequately considered at the time the tolerance
was first established.
Now, whether that was because they were not known to
the individuals — you see, decisions are always made by
individuals and as it goes through the process there is no way
that we can be sure exactly what goes on in, the brain of that
particular individual.
Therefore, I cannot say whether they were aware of it
and ignored it or whether they were aware of it and evaluated it
in a different way than we did in the review or what.
All I can say is, in our opinion, it was not adequately
considered at the time the original tolerance was established.
CHAIRMAN COON7" The date of the establishment of the
original tolerances, when was that?
DR. UPHOLT: Do you have that date, Mr. Bowen?
MR. LYON: May 31, 1974 is when they were announced in
the Federal Register.
CHAIRMAN COON: Well, then we can answer my own questicjn
-------
U
a o
WJ — M
>• iJ °
. .a
<
nte f
5 JT!
o«<
3s
2
3
)4
6
7
8
9
10
II
12
13
14
16
17
18
19
20
21
22
23
r
25
15
on that basis.
DR. UPHOLT: Quite so.
CHAIRMAN COON: We have plenty of material to arrive
at our own answer.
DR. UPHOLT: Quite so.
DR. FRIESS: Dr. Upholt, you charged the Committee to
pay attention to evidence which will bear upon the definition of1
the no effect level.
Were you referring primarily to man or also to man
and other animal species in the environment?
.DR. UPHOLT: Well, as you well know, Dr. Priess, we do
not have such evidence in most cases. I am not sure about
this case, though I believe it will show in this case that we
do not have the evidence in man. We are forced to rely, in
t
general, upon the evidence in'experimental animals.
I used the term "no observed effect" which is frequently
shortened to say "no effect". We, as an agency, have pretty
much rejected the concept that you can determine the true
threshhold "no effect" by use of a limited number of experimenta:
animals.
This is part of the reason why a safety factor of some
sort is necessary, to compensate for the relatively small number
of animals on which that decision is based, as well as the fact
that it is not determined ordinarily in man which is the area
that we are most concerned with.
-------
u
2
trt*
tjj o
[EVAL SYSl
wy .-Suite 1;
ginia 22202
0-7680
DATA RETR1
S Jeff Davis H
Arlington, Vii
(703) 92
<£
OS "
u
Q
e
*
i
2
3
>4
5
6
7
8
9
10
11
12
13
14
-i5
16
17
18
19
20
21
22
23
r
25
16
CHAIRMAN COON: And would you have anything to say
about the concept of using the no effect level in the most
sensitive species?
DR. UPHOLT: I am not sure that that issue has come
up in this regard. Certainly one of the factors that must be
considered is, as I indicated, the interspecific, these deviatio
or differences in susceptibility.
The question as to how man fits into the range of
susceptibility is one that is often unknown. There may be, in
some cases, evidence to indicate that man is more or less sen-
sitive than other species and, if so, that evidence certainly
should not be ignored.
In other words, I do not believe -- to the best of my
knowledge the agency never accepted as a hypothesis that man is
always the most sensitive species nor has it rejected that in
any particular case.
So, again, this is the sort of thing that, I think,
in your judgment as scientists you need to take into considerati
The relative susceptibility of test species as compared with
man and how that affects the safety factor that should be applie
DR. FUKUTO: When you speak about man, are you speakin
about all men who might be exposed to this material, with parti-
cular reference to people who work in the manufacture of lepto-
phos or workers in the field who might be directly exposed to it
DR. UPHOLT: No. In this connection, we are concerned
n.
-------
*S
b* M ^ ^^
5 I B »
1? I8
I
1
2
3
14
5
6
7
8
9
10
11
13
14
-f
16
17
18
19
i
20
21
22
23
c
25
17
only with the tolerances on the crop at harvest, which means
that we are concerned — as a matter of fact, for this purpose
'even though conceivably workers harvesting might be exposed to
such residues, that is not a factor in our consideration of
tolerances.
The sole consideration in our establishing of tolerances
is the oral toxicity, the hazards to man through ingestion of
[the food containing this residue.
CHAIRMAN COON: You are talking about lettuce and
|tomatoes now?
DR. UPHOLT: Yes. Lettuce and tomatoes specifically.
DR. ROSEN: And are we talking, with reference to
ingestion, to dermatological absorption or .inhaling or only
oral ingestion?
DR. UPHOLT: That is correct.
DR. ROSEN: Only that route. Oral ingestion.
DR. UPHOLT: That is correct. Now, conceivably, I
suppose you could conceive of the situation where a residue on
food would become a problem to the consumer by the dermal
oute.
However, ordinarily any problems that we have with
residues at harvest are more of an occupational hazard to either
the harvester or the packer or someone like that. There have
een problems of that sort, but that is not what we are concerned
ith in the safety tolerance. It is protection of the consumer.
-------
z
Crt
Clj O
CO "* «N
> S 2
»»•••?!
kL DATA RETRIEVAL
7S5 Jeff Davis Hwy.-Su
Arlington, Virginu 11
(703) 920-7680
Q
>. — j«HM
^
i
1
2
3
)4
5
6
7
8
9
10
11
12
13
14
-i15
16
17
18
19
i
20
21
22
23
f4
25
1
1
i
18
Those factors are considered in the registration and
we are not concerned with registration at this point. This
is a tolerance setting.
DR. ROSEN: Well, were these originally looked at to
see whether perhaps the topical absorption may be greater than
an oral? Was this looked at originally?
DR. UPHOLT: I am sure that they were looked at in
connection with registration of the product. Of course, we do
not set the tolerances unless we are registering it at the same
time.
Therefore, I am sure that there was consideration
of this sort involved in registration, but that is not the issue
at point.
For this Committee, the issue here is the tolerance,
the residue on the crop and its danger to man, to the consumer.
Is that not correct, Mr. Lyon, as our attorney?
MR. LYON: Well, I think Mr. Gee could speak later to
the registration status. I would point out, however, that lepto
phos is not registered at this time and I think the charge does
get to, perhaps is a bit broader than you characterized.
I think the charge should speak for itself.
DR. UPHOLT: The registration is also the subject of
this morning's deliberations?
MR. LYON: No. I did not say that. I was trying to
larify as to the registration's status, but I think that the
-------
3
>4
o
V)
82
wi ••* rt
>• s °
I*}!
8
e
o
10
11
12
13
14
-\5
16
17
18
19
i
20
21
22
23
f
25
19
charge itself and the matters that are involved in tolerance
setting are perhaps a bit broader than you were stating them.
However, perhaps the other speakers can address that,
CHAIRMAN COON: Are there any further questions for
Dr. Upholt?
DR. McNAMARA: Yes.
Dr. Upholt, could you tell us how these tolerances are
arrived at? Does this give a certain dose in milligrams per
kilogram per day for a person consuming this, these vegetables
and so on?
DR. UPHOLT: I would prefer to have the toxicologists
in OPP speak to this question of conversion. Obviously, with
experimental animals you cannot directly go, from the concentrati
in food of animals. It cannot be directly related to the
concentration in food in man.
Therefore, there has to be jome conversion made. I
would rather have the toxicologists do it.
CHAIRMAN COON: Anything else, gentlemen?
(No response.)
CHAIRMAN COON: If not, I will call upon Mr. John Lyon
for "Remarks on Legal Aspects."
STATEMENT OF JOHN LYON, ATTORNEY, PESTICIDES DIVISION,
OFFICE OF GENERAL COUNSEL, EPA
MR. LYON: My name is John Lyon. I am an attorney in
the Pesticides Division of the Agency's Office of General Counse
n
-------
u
>. O O
U) & «
'Sfi'i
3s
P
§
10
11
13
14
I
16
17
18
19
20
21
22
23
I
o
20
I want to discuss briefly the legal background in
the appointment of this Committee and its function. We have
already touched on the fact that tolerances for leptophos on
lettuce and tomatoes were initially set by Federal Register
notice published on May 31, 1974. That is Exhibit L-2 in the
large amount of material that I know you have received.
The tolerances were set under section 408 D(2) of
the Food, Drug, and Cosmetic Act and the standards for setting
tolerances generally are set out under Section 408 B of the same
Act.
On May 27, 1975, the agency published in the Federal
Register a proposed repeal or revocation of the leptophos
tolerances. This is Exhibit L-2a in your materials.
This notice was published pursuant to sections 408 (e]
and 408 (m) of the Food, Drug, and Cosmetic Act. The notice
stated in part, quote, "Subsequent to the establishment of the
above tolerances, a reevaluation of the petition and other data
confirm that leptophos is an agent which produces delayed neuro-
toxicity in hens.
"Additional information on leptophos is necessary to
evaluate the possible hazards to man and other non-target specie
for the potential effects of its use.", unquote.
Petitioner Velsicol Chemical Corporation requested tha
the proposed revocation be referred to an advisory committee,
under Section 408 (e) of the Food, Drug, and Cosmetic Act which
-------
\ -
i. .a
*
s
8
e
o
1
2
3
)4
5
6
7
8
9
10
11
13
14
16
17
18
19
20
21
22
23
f4
25
21
provides for such referrals.
Thereafter, on May 17th, 1976, notice of the appoint-
ment of the advisory committee and its charge was published in
the Federal Register and this meeting was scheduled.
Mr. Bowen has received a letter, which has already bee
referred to, from the Assistant Administrator, Mr. Breidenbach,
concerning the charge to the Committee.
Because this is a public meeting, I feel the letter
which responds to a letter from Peter Hamilton, Counsel for
Petitioner Velsicol, should be read aloud.
. If you will allow me, I would like to take the liberty
of doing that.
CHAIRMAN COON: All right.
MR. LYON: You should all have a copy of this letter.
It is dated July 19th, 1976. It is addressed to Peter B. Hamilt
Esquire; Williams, Connolly, and Califano; 1000 Hill Building;
Washington, D. C. 20006.
"Dear Mr. Hamilton: I am writing in response to your
letter of July 15th, 1976 in which you requested charges (5) and
(6) given to the Leptophos Advisory Committee, as published in
the Federal Register on May 17, 1976, 41 FR 20210, be clarified
to conform to the tolerance setting and revocation functions
under the Federal Food, Drug, and Cosmetic Act.
"In light of your letter, I am going to clarify or
modify the charge in several respects. I first want to emphasiz
-------
z
U)
* '. .a 3
gtls
3 x •»
-------
CO
u o
>• s s
1
2
3
)4
5
6
7
8
9
10
11
12
O
-------
s
Q .o
c£ ~"
1
2
3
)4
5
6
7
8
9
10
12
14
_j15
16
17
18
19
20
21
22
23
o
25
24
Gentlemen of the Committee, any questions for Mr. Lyor
(No response.)
CHAIRMAN COON: I do not know if this is the place to
ask, but is leptophos used on any other agricultural products
besides lettuce and tomatoes?
MR. LYON: Again, I think we ought to refer questions
of that sort to the scientific people that are here. The only
tolerances are for lettuce and tomatoes, in the United States.
CHAIRMAN COON: In other words, legally it is only on
lettuce and tomatoes.
MR. LYON: Yes, in the United States. Yes.
MR. FUKUTO: Is it used elsewhere for other things?
MR. LYON: Again, I understand that it is. I would
prefer to refer you to the Registration Division personnel.
DR. PAYNTER: If I may make a comment, the pesticide
leptophos is not registered in this country. Therefore, any use
in this country is illegal.
So, right now in this country it is not usable for
anything. There are some countries that do have tolerances for
leptophos and I believe some are proposed.
This is one of the reasons that we felt that reVocatio
the proposal to revoke the tolerance had to be done in a time
nanner, because as long as those tolerances were on the books
food items from other countries could enter the country and be
distributed in our food supply.
-------
1
3-
SS3
e
i
2
3
14
5
6
7
8
9
10
11
12
14
c
16
17
18
19
20
21
22
23
r
25
25
So, right now there are no legal uses for leptophos
in this country.
DR. FRIESS: Mr. Lyon, is-the Committee to understand
that the modified charges numbers (5) and (6), as given in
this letter of July 19, are acceptable to Velsicol?
MR. LYON: I cannot speak for Velsicol. They will
have to speak for themselves. You have the correspondence from
Velsicol.
DR. FRIESS: I can compare them, of course, but it
would be comforting to know that they say and mean the same
thing. .
MR. LYON: There are some differences in the two
letters, but there is a great deal of agreement I would say as
well.
I cannot speak for Velsicol, obviously.
DR. FRIESS: Can they address this point from the
floor now?
MR. LYON: If the Committee so wishes.
CHAIRMAN COON: Go ahead. Since the question comes up
discussing the charges, I think we ought to clarify them.
MR. HAMILTON: I am Peter Hamilton. Although a copy
of the EPA's response was made available to us yesterday, due to
a communications failure between us we heard the charge for the
first time, except in a telephone communication with Mr. Lyon,
this morning.
-------
T
Iris
S:|>s
2s
u
o
e
c
i
2
3
)4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
f4
23
26
Therefore, we would like to take a look at it and
think about it before we respond to that. That is something,
perhaps, that we can mention this afternoon when we have the
time,
DR. FRIESS: Thank you.
MR. LYONj In that regard I might make one further
comment however. I think the Committee receives its charge
and must go forward with the charge that it has now received
from Dr. Breidenbach.
Obviously, it is valuable to have whatever input you
from the parties, but I think the Committee has the charge now
and should go forward with the charge as it is before you.
CHAIRMAN COON: From what Dr. Paynter said, I need a
little clarification here now. I had understood that it was
legal . to use leptophos on lettuce and tomatoes in this country
but from what you say, it is not.
DR. PAYNTER: We have two actions that are required
for pesticides which leave residues in food.or food products.
The one we are1 talking .about now is the setting of tolerances.
That is one action for that kind of a product.
The primary action, though, is the registration proces
Mr. Gee, I think, will discuss that process.
MR. GEE: Right.
DR. PAYNTER: Therefore, there are two separate action
The Agency has said that tolerances will not be set unless we ar
-------
1
2
3
6.
CO
*0
as
co — M
"Is
•J^Sg
< ". .a 3
Q .o
2£
5
10
11
12
14
16
17
18
19
20
21
22
23
r
25
27
also going to register the product.
In this case, that did not happen. Now, frequently
we set tolerances on pesticides which are not registered in
the United States simply because they are not used here.
A good example of that would be tolerances on coffee
beans, where coffee beans are not a major item in this country.
Bananas would be another one and I am sure you would think taro
root and I am sure you could think up some others that are not
grown in this country and are imported, but pesticides are used
in the country where these products are grown.
Therefore, occasionally we must set tolerances on
pesticides which are not registered in this country. Without
registration, those products may not be used legally in this
country.
Therefore, there are two actions that are involved
and this Committee is concerned with the action of setting
tolerances.
CHAIRMAN COON: So, tolerances have been established
in this country, but not registry.
•"""""/ DR. PAYNTER: That is right.
CHAIRMAN COON: The establishment permits these
products to come in from other countries where they have been
registered.
DR. PAYNTER: Yes, sir. Yes, sir.
CHAIRMAN COON: I think I have it, gentlemen. Thank
-------
i
a-
w o
C/S -" r*
^4 *> ^3
M .ti r*
Bjtfi
3-
s
O
i
2
3
)4
5
6
7
8
9
10
11
is
14
-Is
16
17
18
19
t
20
21
22
23
r
25
28
you,
Any further questions?
(No response.)
CHAIRMAN COON: If not, then we will go ahead to
Mr. Franklin Gee on the chemistry aspects under the presentatior
of the petition.
Mr. Gee.
STATEMENT OF FRANKLIN GEE, REGISTRATION DIVISION
MR. GEE: Thank you, Mr. Chairman, and other distin-
guished members of the Advisory Committee.
My name is Franklin Gee and I was the chemist who
reviewed a petition submitted by Velsicol Chemical for residue
tolerances for the chemical leptophos and its metabolites.
The petition data have already been presented to you.
That is in the basket over there for your consideration.
By way of qualifi7ations, I have a BS degree in
chemistry, some graduate work in pesticide chemistry, and 15
years of government experience, seven of which were directly
related to a review on pesticide petitions. Seven also related
to regulatory analysis, which included some work in pesticides.
At present, I am the Product Manager in the Registration
Division and leptophos is one of the chemicals that I am respon-
sible for.
What I have prepared to say does not speak to regis-
tration. However, I will speak to that if you have questions
-------
g
Q ./•>
«J }C
o
1
2
3
14
5
6
7
8
9
10
11
12
14
15
16
17
18
19
i
20
21
22
23
r
25
29
regarding that. That is a separate issue and is not a part of
the charge as I had understood it.
As indicated, I reviewed the petition for tolerances
and briefly I will tell you what that involved. As indicated
in the Federal Register notice May 17, 1976, signed by Dr.
Briedenbach, a petition has seven sections, Sections A through
G.
A brief description of each of these sections was in
that Federal Register notice. It is with Section D of the
petition that I, as a residue reviewer, was mostly/concerned.
. The petition was first submitted to EPA in 1972.
At that time residue tolerances were requested'for the following
Broccoli, Brussels sprouts, cabbage, and lettuce at five parts
per million; tomatoes at two parts per million; cottonseed at
0.3 parts per million; fat of cattle at 0.25 parts per million;
potatoes at 0.15 parts per million; milk at 0.1 parts per
million; fresh corn, including sweet corn - kernels plus cob
with husk removed - at 0.05 parts per million; eggs, meat, fat,
and meat byproducts of poultry at 0.04 parts per million.
Food additive tolerances were requested for crude oil
of cottonseed at 2.0 parts per million and sweet corn canning
waste at 15 parts per million.
Because of numerous deficiencies, such as inadequate
methodology and the need for additional residue data for some
of the commodities, the Company on December 13th, 1973 withdrew
-------
5
rf
s -
" f"l
u O
Q «
1
2
3
5
6
7
8
9
10
11
13
14
3*
16
17
18
19
20
21
22
23
r
25
30
the tolerance requests for all commodities.except for lettuce
and tomatoes.
It was also at that time that the requested tolerance
for lettuce was increased to ten parts per million. This was
done because our initial review showed that a five parts per
million tolerance was inadequate.
If the Committee wishes to see the detailed deficienci
and responses, we can make these records available.
As a residue reviewer, I reviewed the data in Section
of the petition to ascertain whether the requested tolerance
would, in.fact, be appropriate when the pesticide is used accor-
ding to the recommended rate of application. I first reviewed
the petition in March of 1973.
*
In the review of a petition/ we first begin our review
by looking at the recommended use patterns; that is, how much is
to be applied per acre; how long of an interval is recommended
between application and harvest; and whether there are restric-
tions placed on the use of items used for animal feed.
These considerations are necessary in determining how
much residue will be on the raw agricultural commodities at the
time of harvest.
Secondly, we look at the chemistry of the chemical in
order to determine the nature or the make up of the residues
expected on the crops.
The initial data presented by the petitioner was
2S
-------
'•'- - — • -•--"-^fr
o
M*
C/l
< I .aS
I r-as
Q «
I
O
1
2
3
)4
5
6
7
8
9
10
11
12
14
-I5
16
17
18
19
20
21
22
23
r
25
31
inadequate to make this determination.
However/ subsequent data enabled us to conclude that
residues of concern on the crops would be four different com-
pounds .
First would be the parent compound, leptophos, and
the oxygen analog of leptophos. Third would be a phenol which
was identified as 4-bromo-2,5-dichlorophenol. Fourth was a
photodecomposition product identified chemically as 0-(2,5-
dichlorophenyl)0-methyl phenylphosphorothioate.
The residues are expected on the crop when the pesti-
cide is applied to be on the surface of the crop and, also, some
evidence indicated that it would be within the crop, which means
that it is absorbed.
The data showed that the residues on lettuce and
tomatoes, the residues I just mentioned, are distributed as
approximately 80 to 90 percent would be the parent compound
leptophos, four to eight percent would be the phenol, less than
three percent would be the photoproduct, and about one percent
as the oxygen analog of the parent compound.
After determining the nature of the residues, we then
determine whether the analytical method is adequate to quantitat
these residues.
After a positive determination is made, we look to see
what level of residues will be present on the crops at harvest.
The review showed that a two parts per million tolerance was
-------
&kk-w '.aBaSfifc^jM
OJ
as -
5 B «
6
Seal
1
2
3
>4
5
6
7
8
9
10
11
J13
14
at.
s
O
16
17
18
19
20
21
22
23
f4
25
32
needed for tomatoes and ten parts per million was needed for
lettuce.
The petition was amended several times because of
insufficient data. However, after our many objections were
satisfied by the Company, we gave a favorable recommendation
for the establishment of tolerances on lettuce and tomatoes on
March 29, 1974.
Following a favorable recommendation, this ended our
review of the petition. The tolerances were announced in the
Federal Register on May 28th, 1974, which became effective
May 31, 1974.
Yes, sir.
DR. McNAMARA: You mentioned about raising tolerances
to ten parts per million. Was that done for analytical reasons
or is that because of toxicity considerations?
MR. GEE: It was done because from the use of the
pesticide and the review of the data, it showed that the
requested five parts per million tolerance was inadequate.
In other words, if it was used as directed, that more
than five parts per million would result in lettuce.
DR. McNAMARA: I take it someone else will tell us
how these numbers relate to toxicity of the compound?
CHAIRMAN COON: I think we will get that later on.
I take it from what you said in answer to the question
you had to have a higher tolerance because the tolerance that
-------
a
Q «•,
M > **
8
O
1
2
3
14
5
6
7
8
9
10
12
14
-f
16
17
18
19
20
21
22
23
r
25
33
had been set was always being exceeded.
MR. GEE: The tolerance that had been requested.
CHAIRMAN COON: The tolerance of five parts per millio
was not high enough because when the insecticide was used by
good agricultural practice, that tolerance was always exceeded.
MR. GEE: That is correct. We say the tolerance had
not been set. The five parts per million is what we call a
requested tolerance. Right.
DR. FUKUTO: Is there not any consideration for the
toxicity of the material when you set a tolerance of that magni-
tude?
MR. GEE: Well, from the residue point we, as I said,
set tolerances on the basis of the use pattern. We do not deal
with the toxicity of it. This is dealt with separately.
DR. PAYNTER: I will answer that question. Yes. We
pay a great deal of attention to the toxicity of a compound.
However, as most of you know, for the toxicologists to do their
particular job they really do need to know what is there and how
much is there and what is likely to be present under the conditi'
of use.
The toxicologists rely on the Chemistry Branch to do
that kind of thing for us. Before a tolerance is established,
toxicologists do get involved.
CHAIRMAN COON: Are there any further questions?
(Pause.)
ns
-------
z
"
at •* cs
>. o o
j'*So
^^'aS
O « •<
a
g
O
2
3
)4
5
6
7
8
9
10
11
12
13
14
5
16
17
18
19
t
20
21
22
23
r
25
-J
34
DR. McNAMARA: Since this schedule indicates that this
will be the end of the presentations by the EPA group, will
somebody —
DR. FRIESS: There is one more, the Toxicological
Overview.
DR. UPHOLT: There are two more.
CHAIRMAN COON: The order has been changed. We will
be coming back to Toxicological Aspects. We will come back to
the toxicological.
DR. McNAMARA: All right.
.DR. PAYNTER: I am glad the agenda is marked "draft".
(Laughter.)
DR. PUKUTO: Could you clarify for me what happens
after a tolerance is set? When registration will come into
effect and so on?
DR. PAYNTER: Well, I would like to be able to tell
you these things happen in sequence, but that is not necessarily
so. There are times when we are able to make simultaneous
reviews; that is, the chemistry review and the toxicology review
are going on simultaneously. That happens almost entirely when
you have a product that is already registered.
In a case of this sort, where it is a new compound
and is not registered, the sequence is usually chemistry's
determination of the metabolites, of what is there, the quantity
and rendering an opinion as to what quantity is likely to appear
-------
•^tt^i.'
I
CO
S -
6
7
8
9
10
11
i'Ss „
Sm J2
e?>H
!ll§ 13
^IC
o^^ 14
j C
w
a
e
O
16
17
18
.19
20
21
22
23
35
from the particular use that the manufacturers recommend.
Then, it would normally come to the Toxicology Branch
and we would take the data :that they have submitted to us and
compare that to what we believe is a safe level based on the
toxicology in our hands.
DR. FUKUTO: All the information is submitted to you
at one time, but the information is divided into two groups to
be reviewed separately?
DR. PAYNTER: Yes.
DR. FUKUTO: And then the two groups get together?
. DR. PAYNTER: Yes.
DR. FUKUTO: The tolerance is established by one
group and the registration is set after consultation between the
two groups. Is that the procedure?
DR. PAYNTER: No. The groups involved in the regis-
tration, that is the toxicologists involved in the registration
are usually the same people involved in setting the tolerances
because it is our function to recommend registration or tolerances
based on our opinion as to whether or net that product can be
safely used or the tolerances do, in fact, protect the public
health.
Therefore, the toxicology group is involved in both
processes; that is, in the registration and the tolerance settin
Maybe Mr. Gee can tell us. I am not at all sure that
the Chemistry Branch is always involved in registrations.
-------
2
to"
£°
CO —
-------
1
2
a-
w o
6
7
8
9
10
11
m'
III1"
o £ < ,14
12 -\
W
a
15
16
17
18
i
19
20
21
22
23
L
O
37
CHAIRMAN COON: Well, are there any questions to
Mr. Gee?
(No response.)
CHAIRMAN COON: If not, then we will proceed back to
Dr. Paynter for the Toxicological Overview.
Dr. Paynter.
STATEMENT OF DR. ORVILLE PAYNTER, CHIEF, TOXICOLOGY
BRANCH, REGISTRATION DIVISION
DR. PAYNTER: Thank you.
It is my purpose to communicate the concerns of the
Office of Pesticide Programs which led to the proposed revocatiofi
of tolerances for leptophos on lettuce and tomatoes.
These concerns are based on the principles used, in
this country, for determining the acceptability of tolerances.
As you have heard, a tolerance is the legal maximum
concentration of a pesticide residue in or on a raw agricultural
commodity or other human or animal food. It is a derived value
based on residue levels, toxicity data, food consumption levels,
hazard evaluation, and scientific judgment.
Since the tolerance is a derived value, based partly
on verifiable data and partly on informed judgment, it may be
established, denied, revoked or changed whenever circumstances
warrant such action.
The establishment of a "no-effect level", also sometim4s
called a "no observable effect level", based on dose effect
-------
)4
z
10
»
14
o
16
17
18
19
20
21
22
23
f4
25
38
relationships in toxicological studies, is. essential to toleranc
setting.
A no effect level is defined as the level of a
substance administered to a group of experimental animals which
demonstrates the absence of effects observed or measured at
higher levels and which produces no significant differences
between the group of animals exposed to that quantity and an
unexposed control group of animals maintained under identical
conditions .
Acute studies can demonstrate dose effect relation-
ships and yield useful toxicological information. However, as
you know, there is no consistent relationship between this type
of data and chronic toxicity data, since the cause of death or
other adverse effects after a single high dose may be entirely
different from that found after repeated administration of lower
doses .
For this reason, the no effect level from acute animal
studies is never used in the U. S. tolerance system.
The judgment used in determining the no effect level
is critical to all other aspects of tolerance acceptability
considerations and routinely only no effect levels demonstrated
by the most sensitive species tested are used for such considera
tions in the U . S .
The realization that the delayed neurotoxicity potenti
of leptophos had not been properly interpreted and weighted in
-------
y
U)
HI O
Vi ** «S
>. U O
lip
I!
w
Q
1
2
3
>4
5
6
7
8
9
10
11
12
14
O
16
17
18
19
20
21
22
23
f4
25
39
our original tolerance acceptability considerations raised
important concerns as to the appropriateness of the no effect
level and the safety factor used.
Further review of the data before us indicated that
the concerns were of such a nature that we no longer had a sound
basis for considering the established tolerances adequate to
protect the public health.
This consideration required a timely proposal to
revoke the inadvertently established tolerances until such time
as our concerns were addressed by appropriate means,
. In the acute studies in the hen, it has been shown
that leptophos produces unmistakable signs of delayed neuro-
toxicity.
This species is known to be sensitive to such effects.
and is believed to react in a manner similar to man.
The no effect levels thus far demonstrated for lepto-
phos are derived from species, the rat and the dog, known to be
comparatively insensitive to compounds producing the adverse
effects of concern in this case.
The absence of a long-term exposure no effect level
for delayed neurotoxicity in a sensitive species raises serious
questions regarding our ability to arrive at a sound judgment
that established tolerances will protect the public health.
Leptophos is an organo-phosphate compound that appears
to be persistent and have a high potential for bioaccumulation,
-------
z
tn
2E ••*
u o
>• W O
s « «
1
2
3
>4
5
6
7
8
9
10
11
.- ..
Irs 12
o ./i
14
W
a
16
17
18
19
i
20
21
22
23
r.
25
40
at least in the aquatic food chain.
It has been found experimentally that leptophos
bioaccumulates in fish, since tissue levels greatly exceed leveljs
present in water.
This propensity to bioaccumulate in tissues raises
important questions as to the appropriateness of the usual
safety factor applied to a no effect level of a compound poten-
tially capable of producing an irreversible adverse effect in
man.
These two concerns are basic to the problem posed by
tolerances for leptophos and have led to the six items presented
to this Committee for your consideration and recommendations.
That is the end of my statement.
CHAIRMAN COON: Thank you, Dr. Paynter.
Any questions from the gentlemen of the Committee?
DR. McNAMARA: I still have the same question, but
maybe we will hear an answer from other speakers. The question
that I have in mind is, in milligrams per kilogram what is the
no effect dose of these tolerances based on?
DR. PAYNTER: We will come to that and I am sure you
can get into as much detail as you want.
DR. McNAMARA: This will be Dr. Whitmore's?
reviews
DR. PAYNTER: Yes. The/will discuss those in great
defcil
DR. FRIESS: Dr. Paynter, in the work of the toxicolo-
gist with respect to analyzing data that bear on tolerances, is
-------
y
en
FEDERAL DATA RETRIEVAL SYSTI
1755 Jeff Davis Hwy. -Suite IK
Arlington, Virginia 22202
(703) 920-7680
O
i
1
2
3
)4 1
5
6
7
8
9
10
11
12
13
14
-I15
16
17
18
"
20
21 '
22
23
r
25
41
there a discreet operation of assessing hazard on one side,
the benefits on the other, and assessing the data in the form
of a risk-benefit analysis?
DR. PAYNTER: I really do not know how to answer that
correctly. In essence, the toxicologists are responsible for
an evaluation of the hazard as related to the exposure.
There are other groups in the agency which really
tackle that tough problem of benefit-risk and that is not a
function of our particular branch.
DR. FRIESS: All right. That is all I wanted to know.
Thank you.
DR. PUKUTO: What is the relationship between a no
observed effect level and a safety level? JEs there any kind of
formula for that?
DR. PAYNTER: Yes. Yes. The reason a clear-cut no
effect level is so important is that that is the level which is
used to determine the acceptable daily intake for a man and it
is that level to which the safety factors are applied.
In general, the use of a 100 fold safety factor is
used. Therefore, in essence, we are saying that we will use
ne-one hundredths of the no effect level in establishing an ADI,
CHAIRMAN COON: May I ask now, you commented on the
otential irreversibility of this neurotoxicity phenomenon. What
ou say about the safety factor, is a different safety factor
sometimes applied when there is an irreversible effect that you
-------
u
s -
10
g
14
e
o
16
17
18
19
20
21
22
23
r
25
42
are dealing with?
DR. PAYNTER: I do not believe this Agency has any
fixed set of safety factors and these can vary. Traditionally,
those that have been most often used are a safety factor of ten
for such things as cholinesterase inhibition, where it is
easily determined and we know a great deal about the similarity
of reaction in man and animals in that case.
When the cholinesterase effect is the effect we are
from
trying to protect people/and there is a spread, a good spread,
between that no effect level for cholinesterase and anything
else that we have seen, we use a factor of ten.
For many years, the usual safety factor for tolerances
and food additives has been 100. In former, years and even
now, as a .matter of fact, when we set temporary tolerances we
/
will use a safety factor of 2000.
Therefore, those are the basic three, but there is
nothing in our way of doing things that prohibits us from using
a factor of 500 or 600 or 10,000 or whatever it is that we feel
is the appropriate factor to be applied to whatever it is we are
trying to protect the people from.
However, traditionally 10, 100, and 2000 have been
factors.
CHAIRMAN COON: All right. In the case of leptophos,
was a safety factor of 100 used in those established tolerances?
DR. PAYNTER: I do not think so.
-------
2
3
)4
5
6
7
8
9
10
13
14
at
§
E
16
17
18
19
20
21
22
23
r
25
43
DR. WHITMORE: Ten.
DR. PAYNTER: It was not used. Ten was used.
CHAIRMAN COON: Ten.
DR. FRIESS: Dr. Paynter, there is a critical point
in the Chairman's question with respect to analysis of hazard
from chemicals which offerred irreversible insult to tissues,
potentially irreparable insult, and chemicals which may adverse-
ly affect functional structures and be reparable in a sense.
Does one partition, in concept, safety factors for
irreversible chemicals versus reversible ones?
DR. PAYNTER: I do not believe that is done intentionajl-
ly and I guess one of the reasons why we raise this question
before this Committee is to help us determine just how to handle
that.
There are many, many effects which can be considered
irreversible, including such things as carcinogenicity. I think
this is an area of great concern to us and we would welcome any
aid or recommendations you wish to give.
It seems to me, when a material does in fact produce
irreversible damage, you certainly must be extremely cautious
with that kind of compound and control its exposure very criti-
cally.
CHAIRMAN COON: Any other questions for Dr. Paynter?
DR. FUKUTO: It seems to me that a compound that has
irreversible effects should have no tolerance.
-------
)4
u
S 2
.« «
3s
3
e
8
9
10
11
12
13
14
O
16
17
18
19
20
21
22
23
r
25
44
DR. PAYNTER: There are several actions that can be
taken in tolerance fields. One is simply to deny a tolerance
and we can set a zero tolerance. We can set a finite tolerance
of "x" parts per million.
The other action that can be taken is to exempt the
product from a requirement of a tolerance. In many cases when w
do have serious problems, we will, if pushed to set a tolerance,
we will set it at zero.
This has some analytical problems, but we will do that
The simplest way to do it is to deny the tolerance, which is
also equivalent to zero.
CHAIRMAN COON: It is possible, is it not, to set a
zero tolerance but still allow the use of the material?
DR. PAYNTER: -Yes. If the analytical methods are
sensitive enough, that is possible.
CHAIRMAN COON: I think we ought to proceed with the
presentation of Dr. George Wiitamore on the Toxicological Aspects
under the presentation of the petition.
Dr. Whitmore.
STATEMENT OF DR. GEORGE WHITMORE, SUPERVISORY VETERAN
MEDICAL OFFICER, TOXICOLOGY BRANCH, REGISTRATION
DIVISION
DR. WHITMORE: Mr. Chairman and Committee members, I a
George Whitmore, Supervisory Veteran Medical Officer, Toxicology
Branch, Registration Division, Office of Pesticide Programs, EPA
-------
o
V)
o
•*
-------
o
£ '. .a 3
Ir-is
etf
S
E
i
2
3
M
5
6
7
8
9
10
11
12
13
14
-I5
16
17
18
19
20
21
22
23
f
25
46
Ninety-day feeding studies. We fed leptophos to rats
and dogs. We fed the phenol metabolite to rats and fed the
oxon metabolite to rats.
There was a hen demyelinization study; a two-year rat
feeding study; a two-year dog feeding study; a three generation
rat reproduction study; a rabbit teratogenic study; and a mouse
mutagenic study.
As supplemental data that was presented later in an
amendment, there was a mouse carcinogenic study and a second rat
reproduction study.
. The next thing that I wish to relate is the decisions
that were made by the primary reviewer and also by the Branch
Chief and other persons, related to the actions that were made
in respect to the data supplied and also the actions that had to
do with debating and discussing auxiliary information.
The dates I give you are the dates of the final, typed
memoranda of the reviewers or of the conference memos. These
are toxicological actions for Pesticide Petition Number 2F1228.
The 26th of April 1972, the toxicology reviewer could
not recommend it for the requested tolerances for these two
reasons. He needed additional information related to the apparent
high death loss in the rats fed for two years and also he recog
nized that the reproduction study was incomplete by reason of
totally supplied information.
The Petitioner answered that in his memo of the 20th
-------
"
Q ./>
Q
e
1
2
3
)4
5
6
7
8
9
10
.1 12
14
16
17
18
19
f
20
21
22
23
r
25
47
of June 1972, found the data supplied in respect to the repro-
duction study was satisfactory.
He referred some of the information that he had
obtained from the Petitioner to the Division Pathologist, who
asked for additional gross and histopathological data.
On the 8th of December 1972, the Division Pathologist
determined that there was adequate evidence of the lack of
carcinogenicity in the two-year study. He asked if there was a
carcinogenicity study in a second rodent species.
On the 8th of December 1972, the reviewer concluded
the establishment of the requested residue tolerance would
protect the public health.
On the 26th of January 1973 f the .reviewer examined
the additional submitted data, which was the eighteen-month
mouse carcinogenic study and information on the second repro-
duction study. He found that they were both negative.
The 20th of December 1973, that was the date of the
amendment where the lettuce tolerance was increased from five to
ten and all the other requested tolerances were dropped, except
for tomatoes at two parts per million.
The reviewer stated that the 30 parts per million
cholinesterase no effect level in rats supported the requested
ten and two parts per million residue tolerances.
On 8 April 1974, the Registration Division Conference
memo concluded there was not enough concrete evidence to delay
-------
)4
O O
a £•
< i g 8
Iris
B
O
10
11
12
14
16
17
18
19
i
20
21
22
23
r
25
48
action on Petition for establishment of tomato and lettuce
residue tolerances. If some time in the future we get data
which would lead us to feel that these tolerances should be
revoked, action will be taken at that time.
The 12th of April 1974, Conference memo, Criteria and
Evaluation Division and Toxicology Branch memo, the discussion
about water buffalo poisoning and controlled feeding study in
Buffalo, a judgment was made that the data was inadequate and
no convincing evidence that would negate TB's recommendations
for establishment of the requested tomato and lettuce residue
tolerances.
On the 28th of May 1974, the publication of residue
tolerances occurred.
The events preceding the proposed revocation .of the
leptophos residue tolerances. Subsequent to the establishment
of the tolerances, on the 28th of May 1974, in response to a
letter to the Hearing Clerk, EPA, from John E. Swift, the Univer
sity of California, that questioned the establishment of the
tolerances of phosvel on tomatoes and lettuce, a reevaluation of
the hen test presented with the petition was done.
It was recognized that clinical evidence of delayed
paralysis had been reported. In comparing this knowledge with
published hen-exposure studies, it was clear that a delayed
paralytic reaction could be produced in hens when exposed to a
single oral dose of approximately 200 milligrams per kilogram of
-------
'. .a
ss
2
3
)4
5
6
7
8
9
10
11
12
13
14
16
17
18
19
20
21
22
23
r
25
49
body weight of leptophos.
In the meantime, EPA, the Petitioner, and the labora-
tory that had produced the first hen study were cooperating in
a repeat study, with Howard Richardson, MD, Office of Pesticide
Programs, as EPA's coordinator.
Upon learning, at the completion of this test, that
demyelinization had been demonstrated as had delayed paralysis,
the Registration Division initiated action that resulted in the
notice of proposed revocation, May 27th, 1975.
That, in brief, is the Toxicology Branch actions
relating to establishment of tolerances and a synopsis of the
events that occurred related to revocation.
CHAIRMAN COON: Any questions?
DR. ROSEN: Yes, I have a couple. Is there any infor-
mation or any studies sent to EPA or done by the EPA on topical
studies or inhalations, since these pesticides will have to be
sprayed on, as by farmers?
DR. WHITMORE: In the registration there is a require-
ment for dermal, acute dermal, acute inhalation, and acute oral
and acute eye.
DR. ROSEN: And were these sent?
DR. WHITMORE: Yes, by the company registering.
CHAIRMAN COON: I understand now that it was the effect
that was used to establish the tolerance was the cholinesterase
inhibition.
-------
V) S S
i^i
|||S
iisi
e
i
2
3
)4
5
6
7
8
9
10
11
12
Is
14
-1s
16
17
18
19
t
20
21
22
23
r
25
50
DR. WHITMORE: Yes.
CHAIRMAN COON: And that the safety factor of ten
was applied to the no effect level.'
DR. WHITMORE: (Nodding head.)
CHAIRMAN COON: And tha historically as it comes to
be, why it is customary for the cholinesterase inhibitors, the
organophosphates that are used as insecticides.
DR. WHITMORE: That is right.
CHAIRMAN COON: Provided they do not have some insi-
dious effect that has been detected.
. DR. WHITMORE: That is right.
DR. PAYNTER: The tent"is-applied to fae no effect
level for cholinesterase inhibition.
CHAIRMAN COON: Right, and in rats and mice.
DR. WHITMORE: Rats. It was based upon the rats.
DR. FDKUTO: That is by oral administration and then
measuring the blood. Is that erythrocyte or plasma for cholin-
esterase?
DR. WHITMORE: It .is erythrocyte.
DR. FUKUTO: Erythrocyte. I had the impression that
/
30 parts per million was the no effect level.
DR. WHITMORE: That is right.
DR. FUKUTO: That is in food?
DR. WHITMORE: That is in food.
DR. FUKUTO: But then that is only a factor of three
-------
50 P*
>. U O
« -
S
U
It,
1
2
3
U
5
6
7
8
9
10
11
13
14
-i5
16
17
18
19
20
21
22
23
r
25
51
not ten, if it is ten parts per million.
DR. WHITMORE: Well, you see, since lettuce and
tomatoes only constitute a small portion of the diet — in other
words, you would have one-tenth of the no effect level of the
whole diet since tomatoes and lettuce only constitute a small
portion of the diet. You would have higher residues on those
crops that don't
DR. FUKUTO: That is man's diet, I take it.
DR. WHITMORE: Yes. Yes.
DR. FUKUTO: Not a diet of a rabbit or —
. DR. WHITMORE: Yes.
DR. FUKUTO: .Thank you.
CHAIRMAN COON: What were the parts per million you
used in considering the parts per million of leptophos in tlie
diet for a man consuming — or the maximum consumers?
I suppose you use maximum consumers of lettuce and
tomatoes during that time of the year when they are maximally
consumed?
What was considered to be the parts per million in the
diet under those circumstances?
DR. WHITMORE: All right. Lettuce constitutes about
1.2 percent of the daily food intake on the average, based upon
crop
USDA consumption figures, food/consumption figures.
Tomatoes constitute, on the average, about 3.4 percent
of the daily food intake based upon USDA figures.
-------
u
£73
a ^
|i|
<-> >f>
J 2
§
g
o
1
2
3
)4
5
6
7
8
9
10
11
13
•f
16
17
18
19
i
20
21
22
23
r
25
52
Therefore, we would consume 18 grams of lettuce and
52 grams daily of tomatoes. If you had a ten parts per million
tolerance on lettuce, that would figure out to be 1.8 milligrams
of leptophos that you would consume and on tomato, at two parts
per million, you would consume 0.1 milligram of phosvel or
leptophos. Add them together and it would be 0.28 milligrams
available.
DR. McNAMARA: Did you say that was 1.8 milligrams
per man or is that per kilo?
DR. WHITMORE: Well, if you take the USDA consumption
figures on food and whatever percent that divides in your daily
intake for that particular crop, we would calculate how much
will be contributed on that particular crop, in the daily diet.
DR. PAYNTER: There is an assumption here that is
made in all of the calculations, which is not always correct,
and that is that you must assume in doing these calculations
that the tolerance level in fact represents the quantity of
residue that the person would receive when he consumes that.
In many cases this is not so, but that is an assumption you must
make to go through these calculations.
CHAIRMAN COON: That gives you a little more safety yot
night say.
DR. PAYNTER: In many cases that is true.
DR. McNAMARA: Forgive me. I still do not have this
straight. If you have two parts per million on tomatoes and a
-------
u
CO •* (S
>. U O
1
2
3
)4
5
6
7
8
9
10
11
12
14
16
17
18
19
i
20
21
22
23
r
»
53
man's intake is a tenth of a milligram per,day or is that a
tenth of a milligram per kilogram of body weight per day?
DR. WHITMORE: Let me start the other way. Allowable
amount of leptophos in the diet, based upon a ten-x safety
factor with a rat, 30 parts per million no effect level.
Thirty parts per million in the rat is equivalent to
1.5 milligrams per kilogram of body weight per day. So, one-tenth
of that would be 0.15 milligrams per kilogram per body weight
per day for man.
We calculate it on the basis of an average weight
adult and it is a long time that we have said a 60 kilogram man.
A 60 kilogram man consumes, on the average, 1500 grams of food
a day.
Well, if you multiply 60 times 1.5, you get 9.0
milligrams allowable daily, based upon the 30 parts per million
no effect rat diet with a 10-x safety factor.
All right?
Then you come over here to the leptophos contribution
to the diet, based on the ten parts per million lettuce and two
parts per million tomato residue tolerances.
The ten parts per million level is equivalent to
0.01 milligram per gram and the two parts per million is equiva-
lent to 0.002 milligram per gram on tomatoes.
Therefore, if lettuce is 1.2 percent times 1500 gram
intake for a 60 kilogram human being, 18 grams of lettuce times
-------
z
Cfl"
w o
*" " ij
taj ul f^ O
•< i 3 °°
1 r-'is
iL DATA RETI
755 Jeff Davis 1
Arlington. V
(703) 9
1
-
^
1
f
1
2
3
)4
5
6
7
8
9
10
11
12
14
15
16
17
18
19
20
21
22
23
r
25
54
the amount of leptophos per gram gives you 1.18 milligrams of
leptophos.
Now, 3.4 percent constitutes the average consumption
of tomatoes based upon USDA consumption figures. So, 3.4 percen
of 1500 is 52 grams of tomatoes containing, potentially, 0.002
milligrams of leptophos per gram, and that is 0.1 milligrams
of leptophos. Add it together and you get 0.28 milligrams,
provided the contribution in the diet, with ten parts per milli
on lettuce and two parts per million on tomatoes - 0.28 quota,
daily. That is potential.
.Relate it to 9.0 milligrams based upon a 10-x safety
factor, which I think if you divide 0.28 into the 9.0 you come
out with 32 and you already have a 10-x safety factor.
Therefore, roughly you have a 320-x safety factor-
Do not get misled by these out to second place. I do not think
that these things are that accurate, but nevertheless it has to
be done some way and we do it this way.
CHAIRMAN COON: Are all these figures available? I
do not recall running across them in the material that we
received.
I think they might be of some importance in our future
wrestling with this problem.
MR. BOWEN: We can make them available I am sure.
DR. FRIESS: Dr. Whitmore, you did raise one point in
detailing the process; that is, that when several crops or
-------
>• S 2
CO « 2
d^So
It
Q £
is-
U4
Q
e
1
2
3
)4
5
6
7
8
9
10
11
12
14
:?5
16
17
18
19
20
21
22
23
r
25
55
products are simultaneously having residue .numbers attached to
them, you consider always simultaneous intake of all?
DR. WHITMORE: Yes. Yes.' In other words, we make the
assumption that wherever the residue tolerance is applied, yes,
using the USDA consumption figures, that amount of food and for
that particular crop will be consumed daily.
DR. FRIESS: This gives an additional factor of safety
for those who do not simultaneously consume all products at
the same time.
DR. PAYNTER: We are frequently criticized that this
is — the.way we do this is a good example of over-conservatism.
In essence, it probably is because when you compare many of the
market basket survey figures of actual measurements of residues
in the food supply and you go back and compare that quantity,
the maximum quantity found - over the last, since 1963 I think
the Food and Drug has been running Uiose things - when you do th
and you compare it to the no effect level of the compounds, many
times you will find a 12,500 fold safety factor because the
residue that is represented by the tolerance is seldom ever
there when you consume it.
It is most likely there when you eat fruit pulled from
a tree. Very seldom is that tolerance residue quantity identica
to what you receive as a consumer, because of weathering, food
processing, peeling, washing, and that sort of thing.
However, that assumption is always made and that,
-------
w
>, w O
»> irS
1
2
3
14
5
6
7
8
9
10
11
5Sf
i8
14
16
17
18
19
20
21
22
23
r
25
56
obviously, is going to create some problems sooner or later.
DR. FRIESS: But in the assessment of hazards, you do
have to take the worst case estimate, which is simultaneous
ingestion.
DR. PAYNTER: Yes. Yes. Right. A good example of
the kinds of problems you get into when you do that, I think,
malathion has seven parts per million tolerance on about 90
food crops.
There is no way you and I are going to come into
contact with these 90 food crops in any one day. Nature does
not allow.it and, secondly, you cannot eat that much.
DR. WHITMORE: One thing that I need to mention, when
we establish tolerances based upon no effect cholinesterase,
we do not establish tolerances above the no effect on any single
food item.
This is added assurance that somebody that wants to
eat a single food item for a day that that particular no effect
level not be exceeded. This is just another added safety factor
In other words, this 30 parts per million no effect
level cholinesterase, we would not establish any tolerances
above 3Q parts per million.
If it is a one part per million no effect cholinestera
level, we would not establish the tolerance above one part per
million on any single food item.
DR. FUKUTO: Do you have a no effect level for
-------
1
2
3
u
rf
S 2
WS "* N
>. O O
55 .a «N
C*
§
9
10
12
14
,15
16
17
18
19
j
20
21
22
23
24
25
57
neurotoxicity?
DR. PAYNTER: Not in this particular case. No.
DR. WHITMORE: In the hen'test, if that is what you
are asking about —
DR. FUKUTO: For any animal. I want to know on what
you based your decision to revoke.
DR. WHITMORE: On the hen tests and there were no
effect levels demonstrated. Yes. As best I know. I am not
the primary reviewer. I was not a supervisor and so forth and
I am not — Dr. Richardson. Dr. Richardson, unfortunately, got
killed in an accident and some of the materials are a little bit
obscure.
forth.
Therefore, I do not know the whole history and so
Light microscopic — examination with visible light
demonstrated no tissue damage and they also had some electron
examination of the tissues.
I do not know what that is, but it is in your material]
MR. BOWEN: Mr. Chairman, is there still a question on
what Dr. McNamara wants us to furnish in the way of these
calculations?
Could we have specifically what it is that you want?
DR. McNAMARA: There is still a question in my mind.
CHAIRMAN COON: Would you not like these numbers on
paper so that we will have them in black and white?
-------
1
2
3
>4
5
6
7
SYSl
ite 1 1
202
10
11
3»8
lit!»
c; .— ••»
Irfs
; B £ y
FEDERAL DATA RE
1755 Jeff Davis H
Ailington, Vir
(703)
13
14
16
17
18
19
t
20
21
22
23
r
25
58
DR. McNAMARA: Yes.
CHAIRMAN COON: So that we can extrapolate to make up
our own extrapolations from these. '
MR. BOWEN: These will be furnished by Dr. Whitmore.
DR. PAYNTER: We will supply that data.
DR. ROSEN: Mr. Chairman, may I ask one more question?
CHAIRMAN COON: Go ahead.
DR. ROSEN: So that the no effect level in chickens
is the ppm's necessary so that you do not see any delayed oral
toxicity under light microscope effects. Is that correct?
DR.. WHITMORE: I do not quite follow you/ sir. .
DR. ROSEN: When you are setting the no effect level,
what you are doing is going to the nerve and looking at demyelin
ation. You are using that as the test?
DR, WHITMORE: No. Most of the situations I have seen
the clinical evidence of paralysis is the determining factor
rather than any —
DR. ROSEN: So, it is paralysis and not light micro-
scope tests.
DR. WHITMORE: Yes. That is correct.
CHAIRMAN COON: Or even less than that. Ataxia.
DR. PAYNTER: Yes. In all of these determinations we
look at the behavior of the animal as well as any of the other
factors - necropsy, light microscopic determinations - but it is
the total picture you are looking at.
-------
Z
I. .9
3*
s
e
)4
10
11
1 12
14
-f
16
17
18
19
i
20
21
22
23
25
59
If an animal is down and cannot get up and all the
pathologists in the world tell me that they cannot find any
lesions, I do not care. The bird is down.
DR. ROSEN: That is what I was interested in, because
in this case there is definitely a definitive difference between
a no effect level with the light microscope and what you are
going to see with the pathological studies versus ataxia.
DR. FUKUTO: This is with chronic feeding studies, I
take it?
DR. PAYNTER: No. This is the point that I really
wanted to- make. In this case, we have acute studies in the hens
which obviously have some no effect levels, but these levels
are never used.
Acute no effect levels are never used in tolerance
setting. Never, and were not used in this case.
.DR. WHITMORE: The no effect level is based on the
two-year rat study.
DR. FUKUTO: Two-year rat study?
DR. WHITMORE: Yes. Two-year rat study.
DR. FUKUTO: But rats are insensitive animals though.
DR. PAYNTER: Keep in mind now what we are talking abo
is the .no. effect level; that' >was used here was' cholinesterase
inhibition. They are not insensitive to that.
DR. FUKUTO: Not for neurotoxicity .
DR. PAYNTER: To answer your question, we do not have
-------
u
t/l"
o
gtsi
Irp
£5*^51
Q .o <
8
u
u.
1
2
3
)4
5
6
7
8
9
10
11
12
14
O
16
17
18
19
20
21
22
23
r
25
60
a clear-cut no effect level in a sensitive animal for delayed
neurotoxicity.
DR. FUKUTO: On a chronic'basis .
DR. PAYNTER: Right.
CHAIRMAN COON: By clear-cut, no level has been shown
not to produce this effect?
DR. PAYNTER: To my knowledge, the rat and dog two-
year studies did not show delayed neurotoxicity, but we have to
recognize that these species are not very sensitive to that kind
of thing.
.Since we know that chickens and cats are sensitive to
this kind of a problem, these effects, we much prefer when we
know that a species is sensitive, we would prefer to use that
species and we do not have those studies here.
CHAIRMAN COON: Well, you mean there has been no
no effect level observed in chickens?
DR. PAYNTER: In chickens in long-term studies. There
are some levels and I do not remember what they are, but when
you do an acute study, just as you were doing an LDW, there are
some levels that produce no effect. However, we never, never
/
use those. Never.
CHAIRMAN COON: Oh.
DR. PAYNTER: We use an acute no effect level in
tolerance setting.
CHAIRMAN COON: I did not understand.
-------
tO
s
)4
5
6
7
8
9
10
S 11
si is
Ic
< ' 14
>•* .
I
e
16
17
18
19
20
21
22
23
r
25
61
DR. PAYNTER: Now, we take those, things into consider.
tion in registration, but not in tolerance setting.
CHAIRMAN COON: Well, wha't I was trying to get at,
EPA is not satisfied that a no effect level has been establishe
in the chickens?
DR. PAYNTER: That is right.
DR. WHITMORE: That is correct.
CHAIRMAN COON: In an appropriate study.
DR. WHITMORE: or if you can use a no effect level
or if you can or cannot use a no effect level.
CHAIRMAN COON: Does this leave open the possibility
that in a future satisfactory study, if a no effect level is
established to your satisfication, that a tolerance could be
set using an appropriate safety factor?
DR. PAYNTER: Yes. I think that is the general
principle we have used in setting all tolerances. The only
consideration then is, will the no effect level be high enough
to support, in this case, a ten parts per million tolerance in
lettuce?
If the data is not sufficient to support that quantity
that quantity would not be established. That quantity would be
denied.
Therefore, yes, I see no reason at this stage of the
game for leptophos to be any different than any other kind of
compound that comes in here.
-------
o
is
i;
o
(*
£
1
2
3
)4
5
6
7
8
9
10
11
13
14
16
17
18
19
i
20
21
22
23
r
25
62
In other words, we will take the. data; we will
evaluate it and make a judgment as to whether or not a new
tolerance can be set.
CHAIRMAN COON: What kind of a safety factor would
you think of in this case?
DR. PAYNTER: Dr. Coon, that is really one of the
things that we wanted this Committee to consider, because I
think it is crucial that this Agency have some guidance from
experts in the field as to whether or not the safety factors
aPPlied to all tolerances are static and set by tradition or
whether we should be thinking about a dynamic system where a
judgment is used as to what the safety factor should be on the
basis of what we see in the animals.
If this is a reversible factor and it disappears with
withdrawal of the compound, we might be able to use a lower
safety factor than when we are confronted with, in this case or
with cancer, what appears to be an irreversible effect.
DR. FRIESS: Dr. Paynter, this question came up before
and it has to be repeated now. Is there not such a thing as a
no effect level for a chemical which produces an irreversible
tissue effect at some level in a sensitive species?
DR. PAYNTER: There must be. I do not know what it
is, but there must be such a level because all that we know
about chemicals thus far indicates that there are such levels.
DR. FRIESS: Well, can I push it a little further?
-------
w)
u O
"s
I
)4
9
10
11
14
-f
16
17
18
19
20
21
22
23
f4
25
63
If indeed you have produced an irreversible effect by some dose
in some sensitive species, inferentially can you say that there
is some level at which no effect is' produced in an insensitive
species or must you always assume that there is the chance that
there will be the beginning of an irreversible effect even in
an insensitive species?
It is a rough one. I do not think science has an
answer to this.
DR. PAYNTER: Right.
DR. FRIESS: It is what Agency practices that counts
at this point.
- DR. PAYNTER: I am not at all sure that I understand
the Agency practice at this stage of the game, because I really
do not believe that the Agency has come to .grips with that in
any serious way.
I think that this one apparently builds in degrees.
DR. UPHOLT: Well, I just wanted to make a statement
that we have stated as an Agency policy - Mr. Train has stated
it publicly even in regards to carcinogens - that we do not
prescribe to the concept that our responsibility is to reestablish
a"zero risk situation, that there are always some potential
risks in any efforts we take, and that we must always balance
the benefits of do we achieve a reduced risk against the cost
to society in making that regulation.
Therefore, the question as to whether or not it is
possible to guarantee absolute safety is not one with which we
-------
WJ "* N
W " ®
-------
o
> u O
51 a
J BJ «
<2 »&
SeSl
9
10
11
12
J
13
14
f
e
16
17
18
19
20
21
22
23
25
65
DR. PAYNTER: I really do not know the answer to that
I do not know whether we import lettuce or tomatoes at all, as
a matter of fact.
I think there might have been some confusion raised
when I said that frequently we have to set tolerances on
pesticides which are not registered in the United .States, simply
because the food is not grown here. I used bananas and coffee
beans as an example.
However, I do not know what other tolerances have
been set by other countries on what products. Therefore, it is
possible.- I do not know if there is someone here —
DR. WHITMORE: Canada has.
DR. PAYNTER: If there is someone" here from Canada,
they would know. What tolerances do you folks have on whcit?
DR. FRANKLIN: Two ppm, cabbage, lettuce, and tomato.
DR. PAYNTER: Therefore, I guess it is possible if
these tolerances remain in effect, those items can cross the
Canadian border.
CHAIRMAN COON: Well, now I would suppose that consump
tion of lettuce and tomatoes in this country is at least 99
percent homegrown. I am just grabbing a percentage figure off
the top of my head.
DR. UPHOLT: Homegrown, you mean domestically within
the United States?
CHAIRMAN COON: Yes, and I heard earlier this morning
-------
t/5
bJ C3
>• «» 2
'. .a 3
2s
5
6
7
8
9
10
11
12
J13
14
u
O
16
17
18
19
20
21
22
23
r
25
66
that it is not legal to use leptophos on lettuce and tomatoes
in this country.
, DR. WHITMORE: That is correct.
CHAIRMAN COON: So, I am asking, is there any consump
tion of leptophos in this country?
MR. LYON: You seem to be looking at me, Dr. Coon.
(Laughter.)
DR. UPHOLT: There is a difference, Dr. Coon, between
legally
saying that it can/be consumed and saying that it is consumed.
In other words, there is no way that anybody can guarantee
there are. not people breaking the law.
However, I take it your question is in terms of our
legal regulation. Our regulations do not permit it, if our
regulations are enforced.
*
Am I not correct, John?
MR. LYON: The only tolerances are on lettuce and
tomatoes. Now, I do not have information as to the amount of
these commodities that are coming into the United States. They
legally can.
Would the Registration Division be able to furnish
such information to the Committee?
DR. PAYNTER: I suppose somebody in there can. I
am not familiar with this.
MR. BOWEN: You mean on quantity?
DR. UPHOLT: We do import tomatoes from Mexico. I do
-------
S-
w o
fi = «
> » g
>4
5
6
7
8
9
10
11
J
-
If
13
14
16
17
18
19
20
21
22
23
r
25
67
not know how many or what the circumstances are.
CHAIRMAN COON: Well, we would not have to talk about
fresh tomatoes. It could be canned'tomatoes. Could they not?
DR. UPHOLT: Sure.
DR. ZWEIG: Dr. Coon, if I may make a comment?
CHAIRMAN COON: All right. May we have contributions
from around the room, whoever might have a little something to
say in answer to a question or pertaining to a question.
DR. ZWEIG: I am Dr. Zweig from EPA. Just to clarify
this point that you have just raised, I would like to say that
the role of the Food and Drug Administration is in the regulator
portion of it and at this moment I do not know, to answer your
questions specifically, if indeed phosvel is on the list of
pesticides that they are monitoring.
It would be their responsibility to monitor for
illegal residues and, as I hear from my colleagues, a phosvel
residue in imported crops would be illegal.
Therefore, the food would have to be seized, but I
do not know and I not think that at this moment FDA is monitorin
for phosvel.
DR. ROSEN: May I ask one question? How about on
cotton or other, since it is used in the Middle East. You were
mentioning cotton a little earlier.
So, if it is sprayed on the plants, how about this
coming in here? Do we import cotton?
-------
u
c/l
1
2
3
J4
5
6
7
8
9
10
11
13
14
16
17
18
19
20
21
22
23
25
68
DR. PAYNTER: I am sure we do, but that is not a
food item. Therefore, cotton fiber per se would not have a
tolerance.
However, cotton meal, cotton seed, used for animal
feeds would require, if there is a residue, it would require a
tolerance.
MR. MITCHELL: I am Neil Mitchell of Velsicol. The
Company only sells leptophos for export at the moment. There
would be no way, unless someone reimported it, for them to use
our product in this country. We do not have a registration.
- We are concerned with imports both from Canada and
Mexico. Of course, we are also interested in the tolerance and
how the Committee treats it in that it's the first step, obviously,
in a registration process.
I guess that is the end of my comment.
DR. FUKUTO: Dr. Whitmore, if the no effect level for
leptophos in chickens, on a chronic basis, is, say, one milligra
per kilogram or less, how does this extrapolate in terms of part
per million in lettuce or whatever kinc? of crop?
Can you give me a quick answer?
DR. WHITMORE: The only requirement in respect to this
type of delayed paralytic reaction has been this acute hen test.
It has been a requirement, as long as I can remember, related to
these organophosphates.
In my knowledge, this is the first one that has presen
ed
-------
i. .flS
1
2
3
U
5
6
7
8
9
10
12
a:
8
14
-?s
16
17
18
19
i
20
21
22
23
r
25
69
a reaction that is similar to the reaction in the TOCP that is
generally given as a positive control.
Therefore, we have not been put in a position to have
to consider other means of arriving at a decision related to
this type of thing.
So, when you ask about a chronic feeding study in
chickens at a certain level and what would we do and how would
we respond, I cannot answer that.
DR. FUKUTO: However, we could use — I presume you
are going to give us your calculations to the cholinesterase.
We can use the formula there to calculate for neurotoxicity.
Can we not? Am I correct in that?
DR. UPHOLT: Using a different safety factor. Do not
use the ten for the safety factor.
DR. FUKUTO: Well, to get at some number and then
throw in a safety factor later. Am I correct in that?
DR. PAYNTER: Well, I want to be sure I understand
what you are going to do with it.
DR. FUKUTO: What I am trying to establish is the
relationship between the no effect level — there have been
reports where the no effect level is, say, half a milligram per
kilogram in chickens on a 60-day feeding study.
Now, how do we extrapolate this in terms of parts per
million on some kind of crop?
DR. PAYNTER: All right. We can supply that to you
-------
u
2
a-
u o
•SSS
•d «» S g
^ 1 <•
> j,;|S
DATA RETRI
S Jeff Davis Hi
Arlington ,Vii]
(703) 92C
<5
§
S
^
t
•
i
2
3
• 4
5
6
7
8
9
10
11
12
13
14
-I5
16
17
18
19
20
21
22
23
r
25
70
and we will go into some detail. As a matter of fact, if you
wish, we could supply the whole steps, all the steps we go
through in establishing tolerances related to levels of food
factors and body weights, et cetera.
If you wish, we will do that.
DR. FUKUTO: I would like to see that.
CHAIRMAN COON: Any other questions?
(No response.)
CHAIRMAN COON: I would like to ask a question. I
think it has already been answered, but I would like to pin it
down.
Dr. Upholt or Mr. Lyon, either one of you might
answer, our Committee is to consider only the risk of the
consumption of lettuce and tomatoes containing these amounts,
specified amounts of leptophos.
We are not to consider the risk of use of leptophos
or the hazard to the producer, the worker or the farmer or any
of those factors. Is that true?
DR. UPHOLT: I would defer to Mr,. Lyon on what is
charged.
MR. LYON: I think first, let me say, that the charge
has to stand for itself in terms of exactly what your role is.
That was a rather lengthy question. I am not sure I
can give a quick answer. Is there one particular part of the
charge?
-------
\
V)
1
2
3
5
6
7
8
9
10
U
> '• -IS to
I r-as 12
£S*|S ,
ilss 13
Q 2
14
I
e
16
17
18
19
20
21
22
23
r
25
71
CHAIRMAN COON: Well, to shorten.the answer, are we
to consider the hazard of use or just the risk of consumption
of the food containing leptophos? Or'both?
MR. LYON: I think the answer to that — I am sorry
we lost Dr. Paynter for a moment. Is he going to return?
I think what you are to consider here is what is
considered in light of setting a tolerance. This is a tolerance
setting committee.
If various factors are considered in setting a toleran
then it is appropriate for your Committee to look at those
factors. •
I would really like to hear Dr. Paynter on that, as to
all the various considerations that go into, their considerations
when they set a tolerance.
I do not want to arbitrarily limit this down. At the
same time, I recognize that this is a Committee under the Food/
Drug, and Cosmetic Act not an advisory committee under the
FIFRA.
CHAIRMAN COON: Well, in referring to our original —
the charge that was submitted to us originally and, number two,
as we are supposed to express an opinion on the following, "(2)
Whether there are toxic effects from the use of leptophos."
MR. LYON: Yes.
CHAIRMAN COON: A broad interpretation of that is that
a man goes out and sprays leptophos in the field or if the farme
ce,
if
-------
)4
,
9
10
11
12
e
ill
5
16
17
18
19
20
21
22
23
r
25
72
is out in the field picking lettuce or tomatoes and becomes
exposed, is there a hazard in connection with these activities?
MR. LYON: I think my answer is that you should con-
sider the kinds of factors that they would consider in setting
a tolerance on that.
If they would take into account, in the Toxicology
Branch, effects beyond strictly consumption, ingestion of the
insecticide through eating, then you should consider those.
Is Dr. Paynter expected to return?
DR. WHITMORE: I do not know. I did not even know he
was gone.
DR. UPHOLT: His jacket is here, so I assume he would
return.
. CHAIRMAN COON: Yes.
MR. LYON: I perhaps am giving an answer that you
would rather have more specific, but I think that I have to be
somewhat broad in my answer there.
CHAIRMAN COON: Well, I would submit the question to
the Committee. Is there a connection between — an established
tolerance on lettuce and tomatoes, is there any connection
between that and any consideration of hazard in applying the
insecticide to those crops?
DR. FRIESS: Mr. Chairman, if I can address it in term
of the six pieces of the charge, piece number four relates
directly and pointedly to the hazard to man from ingestion. One
-------
o
-------
£~M
>• 0 O
" -3 8
1
2
3
J4
5
6
7
8
9
10
11
il? 12
14
16
17
18
19
20
21
22
23
r
25
74
Five, where it says whether leptpphos bioaccumulates
in tissue, it does not define as to the route by which it gets
there or the species - whether it happens to be in fish or
whether it happens to be absorbed through the skin of a farmer
who happens to have sprayed it in the wrong direction and the
wind happens to have sprayed it onto him or it is inhaled, as
well as in the food chain which he might eventually eat and it
get into the tissue that way.
I think it is exceptionally broad and I would like to
put that into the record.
. CHAIRMAN COON: All right.
I take it we are supposed to substitute five and six
of the original list with the five and six we got this morning.
DR. ROSEN: Right.
DR. ROSEN: Yes. That is what I am looking at. Five
and six, with respect to the remaining four from the old. I am
suggesting that five is sufficiently broad in combination with
four, especially since four specifically defines one very small
area, I can assume that five, defining a very broad area, would
be an additional factor we should look at and look at the bio-
accumulation in tissues from other routes outside of ingestion
and in other"things such as lettuce and tomatoes.
DR. PAYNTER: Mr. Chairman, I am sorry I had to leave
the room, but coming back, I suspect that somehow we are botherejl
with lettuce and tomato. Obviously, those are the tolerances
-------
z
co"
&i§
£ "SI
If IS
! lit
1
2
3
)4
5
6
7
8
9
10
11
13
14
i
16
17
18
19
i
20
21
22
23
r
25
75
we have. Not a very good set.
However, I would remind you of Mr. Gee's testimony,
where he was saying that the original proposals included such
things as broccoli, brussels sprouts, cabbage, lettuce, tomatoes
cottonseed, fat of cattle, potatoes, milk, fresh corn including
sweet corn, eggs, meat, fat, and meat byproducts of poultry,
et cetera.
There is no reason why this Committee should assume
that this product will be confined to lettuce and tomatoes, but
we are talking about foods of all the agricultural products; in
some cases, probably processed foods.
Therefore, it is not just limited to lettuce and
tomatoes.
DR. FRIESS: Dr. Paynter, the Chairman's question
while you were gone pertained to whether exposure of man or
other biota in the environment to other routes than ingestion,
oral ingestion, might not pose scientific questions that are
within the elements of the charge.
DR. PAYNTER: Well, if I may address that, I think it
does in the sense that fish are food items. Now, no tolerance
has been requested for fish, but I think that you will find in
reviewing the data that there is clear evidence that fish, fish
tissue contains quite a large amount of residue over and above
that which is found in the water.
Here is a case of a food that might need a tolerance
-------
V)
u o
to -« rt
>. « O
3s
u
a
1
2
3
)4
5
6
7
8
9
10
11
12
14
|5
16
17
18
19
20
21
22
23
r
25
76
simply because it gets into the water somehow. Obviously, in
the case of fish you have all routes of exposure. You have
immersion, dermal, of course the oral, and I guess you can
exaggerate the gill system and say even the inhalation type of
process. So, we would have total immersion to the exposure in
that case.
DR. FRIESS: Or the skin contact problem, because
species, as in charge one, may contact leptophos by the skin
route.
DR. PAYNTER: (Nodding head.)
. DR. FUKUTO: Will there be a statement made on the
benefits of this material? Would that be made by the Company?
DR. PAYNTER: I do not believe EPA is prepared to do
that.
*
DR. UPHOLT: As far as I know, that is correct.
DR. FUKUTO: This is usually done by the USDA, is it?
DR. UPHOLT: No.
MR. LYON: Let me say that this is an advisory commit-
tee and if you wish to obtain information - you mentioned the
FDA and other agencies - you are free to request of Mr. Bowen
more information.
Therefore, our —
DR. FUKUTO: I am not sure whether that is relevant
or not.
DR. UPHOLT: In terms of the tolerance or benefits are
-------
f 13
•g ^ £• •<
Ili 1
1
2
3
)4
5
6
7
8
9
10
11
12
o « <
I
14
16
17
18
19
20
21
22
23
r
25
77
expressed in terms of the need, the usefulness, I believe you
were given a statement of — what was it called?
MR. BOWEN: Certification'of Usefulness.
DR. UPHOLT: Certification of Usefulness and this is
the way the benefit side of the benefit side of the equation
comes in.
So, that is before you. I have not reviewed it, but
I would assume from the evidence that I have heard that it woulc
show that it is, in fact, useful to use leptophos at levels up
to these levels - ten parts per million in lettuce and two parts
per million in tomatoes.
This is sort of implied in the fact that we have
considered this as a legitimate level. Had. it not been certifiejd
as useful, there would be no particular benefit in using it at
these levels and we would not have.
MR. LYON: Pardon me. Dr. Coon, might I also add
this. We have been talking a lot about the charge and benefits
really are not something that are addressed by this charge.
This is strictly an advisory committee. They are
really not at issue here.
CHAIRMAN COON: We are supposed to offer advice only
in regard to the charges submitted to us?
MR. LYON: Yes.
CHAIRMAN COON: Gentlemen, do you have any questions
that you want to ask anybody around the room?
-------
>. O O
V) •— <*•
«J 5 S o
^ t ^ BO
Ir!
jsSi1
iif
Is
I
1
2
3
i4
5
6
7
8
9
10
12
14
16
17
18
19
t
20
21
22
23
r
25
78
DR. ROSEN: Mr. Lyon, a couple questions from the
legal standpoint. Since the EPA is concerned with the Federal
Water Pollution Control Act and since this is a pesticide which,
theory, can get into the water sources through runoff, should
we at least think about this problem or is this not, even though
it is not per se part of our charge it is a broader view which
should take into consideration because this is the way it can
eventually get into the streams and eventually be eaten by fish?
MR. LYON: I guess my answer to that would be I think
as Dr. Paynter has said, if it is getting into the food source
in some way then I think it would be appropriate to consider it.
DR. PAYNTER: We have occasionally set tolerances for
pesticides in water. That occasionally happens.
DR.' UPHOLT: Yes. There is a section on the Food,
Drug, and Cosmetic Act available to us, Section 406, in which
we can set tolerances for pesticides that occur inadvertently.
What we have been talking about is Section 408 in
which the pesticide is certified to be useful in the protection
of. that crop. It provides the benefit side of it.
Then, we have to decide whether or not this level that
accurs has adequate safety. However, we may also — frequently
» come to a serious problem with a pesticide that has been used
for a long time. We find that it does accumulate in other food,
such as fish, for which it is not necessary. It does not come
ander the Section 408 category and yet we must set tolerances
-------
u
c/j"
.a
ss
a*, «
35
g
e
1
2
3
U
5
8
9
10
11
? 12
3
13
14
16
17
18
19
20
21
22
23
f
25
79
to determine, on a slightly different basis - there is a little
different criteria there - the benefits in this case come in
terms of the benefits of being able- to use that fish or not to
use the fish. Not in production of fish, but in the use of the
fish.
We have to set a level which is considered sufficient]
safe so that it can be used, the fish can be consumed, even
though the pesticide is not applied to the fish directly for
any purpose.
Therefore, in this sense, why, we might very well
eventually be. faced with the problem and I suspect that infor-
mation would be useful to EPA.
DR. ROSEN: The reason I asked the question in parti-
cular is that the FDA setting standards is different than the
Federal Water Pollution Control Act standards.
You are familiar with the 201's and 208 problems.
They are different directives and I wonder how the interrelatioi
ship is established here and how it directly affects us.
Could you clarify that, please?
MR. LYON: I am not able to comment on that.
DR. ROSEN: All right. I can talk to you about it
later maybe.
DR. UPHOLT: I think I can say that it does not affect
us directly in terms of this Committee.
DR. ROSEN: All right.
-------
s
Wl"
>. u o
^iS
«J
-------
o
V)
Z -
w o
e
1
2
3
• 4
5
6
7
8
9
10
11
\t
14
-f
16
17
18
19
20
21
22
23
r
25
81
compound?
CHAIRMAN COON: That 80 to 90 percent was the parent
MR. GEE: That is correct;
CHAIRMAN COON: And the other figures for various
other things, like the phenol and the oxygen analog and a photo-
decomposition product, now this is at what time? As these
products go to market?
MR. GEE: This is at the time of harvest.
CHAIRMAN COON: At the time of harvest.
MR. GEE: The label recommends, I think, maybe seven
to fourteen days harvest interval after application. The figure
I gave you reflect that particular interval.
CHAIRMAN COON: Well, what is the relation between
the content at time of harvest and at the time they are in the
grocery store? If any.
MR. GEE: Well, the tolerance is set at the time of
harvest, from the use pattern of it. We set the tolerance on
that basis. That would tell us the maximum amount that is there
CHAIRMAN COON: Then the assumption is that some peopl
will consume the material in the same condition in which it is
harvested?
MR. GEE: That is a fair assumption. We do not genera
ly assume that, but that is a fair assumption. We assume that
that level is going to be there when it enters into commerce.
CHAIRMAN COON: When it enters into commerce. Well,
-------
Cfl
•j
s
a «
3s
5 -
1
2
3"
M
5
6
7
8
9
10
11
12
13
14
16
17
18
19
20
21
22
23
r
25
82
that is an expression that —
DR. PAYNTER: That is the control point for us.
DR. UPHOLT: The Food, Drug, and Cosmetic Act applies
to crops moving in interstate commerce. FIFRA does not. FIFRA
applies to wherever it may be used.
The Act under which these tolerances are set can be
enforced only if the food moves in interstate commerce. Some
states have parallel tolerances, but they are not set by us.
They are set by the state.
DR. ROSEN: Interstate commerce is very broad. I
think you- can be traveling on the highways and if you stop in
a restaurant and eat food, that is considered interstate
commerce.
DR. UPHOLT: Yes, sir. That is true. From an enforci
ment standpoint which is the place that this comes into effect.
From a regulatory standpoint, as Mr. Gee has said, we set the
tolerance on the basis of the residue at harvest and this has
not been challenged so far as I know.
The enforcement takes place when it moves in interstatja
commerce and FDA will have to answer questions about how they
do that.
However, the tolerance, itself, is set on the basis
under
of what is there and this / Section 408 tolerance standards.
CHAIRMAN COON: That is the same thing I think you
referred to as the raw agricultural product.
-------
2
3
U
1
8
9
10
11
12
14
-f5
16
17
18
19
20
21
22
23
P
25
83
MR. GEE: Yes.
DR. UPHOLT: Correct. Correct.
CHAIRMAN COON: Has anybody ever made any surveys
of the relation between the raw agricultural product content
of a pesticide and the market basket content?
DR. UPHOLT: There has been a great deal of study in
this. I do not have all the results.
DR. PAYNTER: Yes. Going back as long as, I believe
it started around 1963 and we have no values for leptophos,
because that is not registered. Therefore, the values are not
there.
However, the long history of that market basket survey
and the enforcement surveys indicate that i^t is seldom, it is
rare that the residues consumed by the public are at the
tolerance required squared.
CHAIRMAN COON: Well, what I am getting at is that in
general is not the market basket concentration a lot less than
the raw agricultural product concentration?
DR. PAYNTER: Yes, it is by many, many fold. I am not
just talking about one or two. I am talking in some cases as
much as a thousand fold.
However, the point I think we are trying to make is,
it is not at that level. It is not at the consumer's level whic
is the enforcement point. It is the raw agricultural product
at harvest.
-------
-------
1
2
3
»4
5
6
7
8
9
10
11
ills 12
PP i3
sSf
14
16
17
18
19
20
21
22
23
r
25
85
I can come up with some more questions, but it is now 11:30 and
our agenda calls for lunch at 12:00.
MR. BOWEN: It can be flexed/ certainly, to suit your
pleasure there, Mr. Chairman.
CHAIRMAN COON: The agenda calls for a 1:30 start with
the presentation by Velsicol. I think it would probably be best
not to start the Velsicol presentation before lunch and interrup
it for lunch, unless I am disagreed with on that point.
MR. BOWEN: Mr. Chairman, the Petition is made availab
to you. There may be particular parts of it that you may have
a special.interest in and, of course, Mr. Gee and Dr. Whitmore
will be more than happy to describe in further detail for you
any portions there that you might consider to be appropriate
for you to peruse.
CHAIRMAN COON: Yes.
MR. BOWEN: This is the place where the Petition is
being presented to you and that is what starts the file.
CHAIRMAN COON: Well, perhaps we could use a little
bit more time in the presentation of the petition. I noticed
that Dr. Whitmore mentioned Section C of the Petition.
I interpreted his reference to that as meaning that
that was the critical section from the standpoint of toxicology.
DR. UPHOLT: Mr. Chairman, may I be excused? If there
is anything further I can do, I will be glad to return. My
secretary can get me.
-------
u
!=L
sis
. 3 r<
1
2
3
14
5
6
7
8
9
10
U
> ,
'l c « 13
3 § o IJ
M «• t-
e
16
17
18
19
i
20
21
22
23
r
86
CHAIRMAN COON: Thank you, Dr. Upholt.
Now, how many other sections are there?
MR. BOWEN: Well, I might'just show, if I may, the
Petition consists of Sections A through G. A and B is one secti
They name the identity and the composition of the product here
and the frequency and time of application are always contained i
Section B.
Section C, which is the toxicology portion, we have
made a copy of the index of that petition to give you an idea of
its contents. If that would be of particular interest to you,
we have that.
CHAIRMAN COON: I think it would, would it not gentle-
men?
DR. FRIESS: Yes.
MR*.BOWEN: -I would be happy to pass out an index to
Section C of the petition. This is all contained within the
Petition, itself.
Section D, dealing with residues, I have taken a copy
of the introductory portion of that, which would give the Com-
mittee some further indication of just what is contained in that
section.
Section E is so short, I will just pass that around
for you to look at. Then, I will make copies of it if it is
desirable. However, that is the practical methods of removing
the residue.
n.
-------
1
2
3
)4
z
ta
'--s
8
9
10
11
12
> * )
e« 13
l3
U
e
16
17
18
19
20
21
22
23
r
25
87
Section F is here. It is very short also and that is
the proposed tolerances, the leptophos and its metabolites.
Section G is the general,'the reasonable grounds for
the establishment of tolerances. That is contained in Section G
That is all here.
Section C consists of three volumes of this size.
Section D is about the same size. It is all here and it will
be available for us to peruse at your pleasure or to get any
further clarification from Mr. Gee or Dr. Whitmore.
DR. ROSEN: Excuse me. Was the dermal administration,
inhalation administration, and skin irritation done on rats in
low doses? This is found in Section C.
DR. WHITMORE: The dermal is generally done on the
rabbit and I imagine this was done on the rabbit. Inhalation is
generally on the rat and I imagine this was done on the rat.
Skin irritation, I imagine, was done on the rabbit. It is a
pretty competent test to tell. I imagine that was it.
CHAIRMAN COON: I would assume to a considerable exten
Section C is similar to the material that was sent to the Com-
mittee in advance or there is undoubtedly considerable overlap,
but —
MR. BOWEN: Well, since the Petition would be presente
to you today, there was no effort made to have the material that
was submitted to you embrace everything that is in Section C
and it may not embrace more than just a portion of that which is
-------
U O
™3
V) •* r*
>• u O
irli
g = £2
Q .o
8
i
2
3
14
5
6
7
8
9
10
11
14
4s
16
17
18
19
i
20
21
22
23
i4
25
88
contained in Section C.
I would be reluctant to say that there was considerabl
overlap.
MR. LYON: May I just make a comment?
CHAIRMAN COON: Certainly.
MR. LYON: Mr. Bowen, of course, put together those
materials and I am not clear on all of the materials, but it was
my understanding that no part of the Petition was included in
the material that was sent out.
Therefore, I do not think there would be an overlap
between these materials and the materials that were sent out by
you.
MR. BOWEN: In working up the initial bibliography,
there may have been sources of material that came to our atten-
tion that might be duplicated in the Petition's Section C. We
did not check it against Section C to make sure that there was
no possible overlap.
MR. LYON: I see. Well, let me just suggest, then,
that if there is a part of Section C that interests the Committe
you should not assume that it is contained somewhere else in the
other material.
MR. BOWEN: That is right.
MR. LYON: Perhaps that is a better way to state it.
CHAIRMAN COON: I have a suggestion from Dr. Friess on
the side here that perhaps the meeting could adjourn to give the
-------
u
a)
•j _
10
11
12
14
16
17
18
19
»
20
21
22
23
f4
25
89
Committee the opportunity of referring to the Petition for a
little while before the Committee goes to lunch.
The others could be excused, then, during'that time.
Now, before that, the question has entered my mind
in connection with what is included in the tolerance, the parent
compound and the other products that form the total residue, I
take it that the tolerance includes all of the other products
other than the parent compound, calculated back to the parent
compound.
Is that right?
-MR. GEE: That is correct. That is the way this
tolerance was established.
DR. WHITMORE: Does the method pick out the phenol
metabolite and the oxon metabolite? Is there a method for that?
MR. GEE: Yes. There has to be a method for all of thfese
residues'before.the tolerance is established. All residues.
The tolerance is established on the basis of the residues
calculated as the parent compound.
DR. FUKUTO: Even though they are degraded products?
DR. PAYNTER: As in general, he is talking specifically
about this, in general tolerances are based on the parent
compound and the major breakdown or metabolic metabolites.
We frequently have had some residue that is completely
of no concern to us. You know, you end up with some acetic
acid or something of this sort, which is not of toxicological
-------
z
CO
u —
WJ — g
< "? M »
FA RETRIEV
ff Davis Hwy.
ngton, Viigini
(703) 920-7<
< — » *3
a «•> •<
j jc
^"
u
0
e
^
<
4
1
2
3
)4
5
>
6
7
8
9
10
11
12
i3
14
• J C
J
~~'
16
17
18
19
i
20
21
22
23
r
25
90
concern.
So, the tolerances, the way they are written into the
Federal Register, would include the'parent compound and the
major breakdown or metabolic products.
DR. FUKUTO: You mean anti-cholinesterases or potentic
anti-cholinesterases and not things —
DR. PAYNTER: They would be included in the —
DR. FUKUTO: — but not things like, say, in this
particular case, phenolphosphonic acid or some hydrolytic or
degraded product?
(Pause.)
CHAIRMAN COON: So, the tolerance is expressed fully
on the basis of the parent compound, though^ in this case part
, -i
of that would be calculated back from, say, the phenol which
may constitute, say, ten percent of the residue or it will be
equivalent to —
DR. PAYNTER: There are many ways of expressing these
things. I think that is why you are getting blank looks from
us. There are so many ways you can set a tolerance. A number o
them.
For instance, you might say the tolerance is "x" of
"y", but no more than "x", no more than some factor of "x" shoul1
be — is included.
Maybe if we read this one, it would give us a key to
what we are talking about. The actual language in the Federal
-------
6*3 O
Cfl *"* • u O
" -
** ^
'S -• m
1
2
3
)4
5
6
7
8
9
10
11
12
14
r
16
17
18
19
20
21
22
23
r
25
91
Register that sets the tolerances can sometimes get pretty
complicated.
However, in general they are set so that they take
care of all residues of concern in some fashion.
MR. GEE: To answer your questions/ yes, the Federal
Register notice of May 28th says this, "The tolerances are
established for combined residues of the insecticide leptophos
And it names the parent and the three metabolites I mentioned,
calculated as leptophos.
CHAIRMAN COON: And that is done in spite of the
fact that, the phenol product, for example, has much lower
toxicity than leptophos.
. DR. PAYNTER: Yes. I think that there is another
factor here that perhaps has not surfaced. You just have to
keep in mind that the tolerance number is simply a legal number.
It may or may not be related to toxicity. There are
other factors that go into the same thing.
In general, when an enforcement chemist finds something
in a plant that he cannot identify, his first concern is to redo
it. If he still gets it, then he says, "ftell, exceed that becau
we do not know what it is."
if
Therefore,/the tolerance is written only for leptophos
and he finds phenolics in there and it is not written into the
regulation that they should be there or they are allowed to be,
then that crop would have to be seized.
-------
tn •" «N
>. « o
1
2
3
)4
5
6
7
8
9
10
11
mi »
3s
8
14
16
17
18
19
20
21
22
23
f4
25
92
So, things are put into the tolerance for legal
reasons which may not be of concern from the toxicological
reasons.
Therefore, keep in mind that the tolerance number is
simply a legal number and it may only be indirectly related to
the toxicity, because of the other factors that go in.
That is, we do not set tolerances any higher than is
needed with agricultural products. So, the relationship of that
tolerance number to all of the things that would be considered
is not necessarily always direct.
CHAIRMAN COON: In other words, the tolerance level
may be, it may provide a safety factor of 1,000 where you do not
need it more than a ten, more than ten?
"""DR. PAYNTER: Yes.
CHAIRMAN COON: So, the tolerance is based on what
is left. It is based on the residue when the material is used
to produce the effective insecticidal function.
DR. PAYNTER: It must do whatever it claims and that i
the level at which no more should be applied after it has reache1
that level, whether it is two pounds per acre, three pounds per
acre or six ounces per acre.
So, if you try to calculate from the tolerance number
back to the toxicology, you may not always find a direct relatiofi
ship. Something which has a no effect level of 100,000 parts pe
million may only require a tolerance of only one-tenth part per
-------
en
W o
o O
.«
. -
1
2
3
)4
5
6
7
8
9
10
11
e
s
16
17
18
19
t
20
21
22
23
r
93
million and that is all it would get.
CHAIRMAN COON: Are there any other questions that ha\
arisen in your minds in the last few minutes?
(No response.)
CHAIRMAN COON: If not, let us declare the meeting
adjourned until 1:30.
(Whereupon, at 11:40 o'clock a.m., the meeting was
recessed, to reconvene at 1:30 o'clock p.m. this same day.)
-------
1
2
3
'4
5
6
7
8
9
10
11
Irp »
c£ 35 «S
-------
W O
III .
irfs
Q ,n
I
g
5
6
7
8
9
10
11
12
13
14
-------
-
(jj O
ta "* «*•
>, u O
VI •- M
358
' -a
Q «
1
2
3
J4
5
6
7
8
9
10
11
II
.,
12
14
r
16
17
18
19
20
21
22
23
f4
25
96
was raised earlier. Are we to make our judgment on the basis
only in respect to tolerance?
This question came up and•I do not know whether that
was clearly defined. This has to do with the charges, the six
charges that we have been given.
Does that include effects on people who are working
with the spray operator and the other people who might come in
contact with leptophos or are we to consider only the residues
and the amount that the public may take upon eating various
kinds of crops?
. DR. PAYNTER: I think some of the confusion comes from
the fact that we are really concerned with public health. That
is our basic concern.
- - ,-T. -.--.-, .,...,.„
The confusion, I think, arises when we have to deal
with two separate and distinct laws, both covering the same
subject with regard to the public health.
So, even those of us in the Agency frequently have to
step back and take a look at what we are really doing. The laws
and the legal minds say that you should consider this sort of
thing under this law and this sort of thing under that law.
However, in fact, what the toxicologist has to do is
take the total picture of toxicology, whether he is talking abou
tolerances or registration, and look at the total picture.
I can conceive of situations where a product may be a
very strong sensitizer, skin sensitizer. I may choose not to
-------
u
«s
o
.j
it
1
2
3
i4
5
6
7
8
9
10
U
12
aife
I
e
14
16
17
18
19
20
21
22
23
r
25
97
set a tolerance for that compound, which really has nothing to
do with ingestion at this stage of it.
So, I think I cannot answer the legal question on
whether you have to stick to that charge or not. That is some-
body else's responsibility.
I would suggest that the Committee has to look at the
total picture of toxicology and take that into consideration.
MR. MITCHELL: If I can add to that, Velsicol did not
mean to imply that there was a portion of the toxicology that
you should not review.
You should look at the entire toxicological picture.
The questions that you have to answer, however, based on that
toxicological picture I think relate to ingestion, to food
residue as opposed to the worker safety and that area.
DR. FUKUTO: It seems to me that you would be highly
concerned about worker safety in the manufacturing plant in
the production of these materials.
MR. MITCHELL: Indeed we are.
We feel like the law has prescribed this Committee's
functions to a role which relates to ingestion or whatever route
that man, the public, would receive
MR. LYON: Dr. Coon, if you would just let me make my
brief statement, I think the answer to this is that you should
take user or occupational safety into account just to the extent
that that would be considered in setting a tolerance.
-------
)4
W O
< i. .a 3
Ir-is
2*^5
Hi t! «
* £ a <=>
U
o « •<
8
9
10
11
12
13
14
16
17
18
19
20
21
22
23
r
25
98
Now, that would be my judgment as to how you should
handle this question.
MR. MITCHELL: -I would agree, but you get two lawyers
in a room talking and it is hard to adopt the adversary when
we are agreeing.
CHAIRMAN COON: I find it difficult to see the
connection between the level of a tolerance and the hazards
that are connected with the use of an insecticide.
MR. MITCHELL: Well, if I can comment?
CHAIRMAN COON: All right.
- MR. MITCHELL:* The hazard -connected with the use may,
from field experience, give some additional toxicological infor-
mation which you should apply with the othejr reservoir of
information in determining whether or not there is a safe,
acceptable daily intake at this point in time.
As a scientific question, it may or may not be appli-
cable. That is for the Committee to choose, but the information
will be provided.
CHAIRMAN COON: Yes. I understand that you can get
biotoxicological information from workers involved in the pro-
duction of the chemical that might give you an idea of what to
look for in your toxicological, experimental work. I can under-
stand that.
I would submit in that connection that there are un-
certainties as to just what we are charged to do; that these
-------
sn •"• r<
£• a o
5 '..93
Irfs
i
2
3
)4
S
6
7
8
9
10
11
12
8
90
Bugas
14
r
16
17
18
19
*
20
21
22
23
r
99
five charges or six charges are now down in black and white and
we can take it upon ourselves to interpret those charges and
pursue the matter accordingly.
MR. LYON: Yes. I would say that is right. I would
also say, as Mr. Mitchell has stated, that the charge is made
and it is not subject to modifications at this point.
CHAIRMAN COON: In connection with what I have just
said, I have trouble with charge number six, merely the wording
of it.
The phrase, "to the extent necessary to protect the
public health", I do not see how it fits in.
If that phrase was put at the end of the sentence,
instead of sort of parenthetically where it is, it would read,
"make it unsafe.for use to the extent necessary to prctect the
public health."
I do not follow the syntax. I think it is merely a
matter of — do you gentlemen have similar troubles?
MR. HAMILTON: It is a phrase taken from the Food and
Drug and Cosmetic Act and it is the standard accepted under the
Act, as an articulation of safety for added substances or food
additives or pesticide residues in food.
CHAIRMAN COON: Well, I will accept it as a rather
inscrutable articulation.
(Laughter.)
------- |