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ENVIRONMENTAL PROTECTION AGENCY
LEPTOPHOS ADVISORY COMMITTEE MEETING
PUBLIC SESSION
,' /. . ROOM .3906
WATERSIDE MALL
" 401 M STREET, S.W.
WASHINGTON, D.C.
WEDNESDAY, July 21, 1976
2:00 O'CLOCK A.M.
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E. Brenner
EPA 7-21-76
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(2:00 p.m.)
CHAIRMAN COON: I would like to convene the
opening session, ladies and gentlemen. The purpose of this
opening session, if you will recall from yesterday, was to
submit to the to submit any questions to the Velsicol
people the committee may have on its minds, as a result of
the committee's deliberations in the last few hours. !
And, I should add, I should say that the committe
is really not loaded with questions at this point, but in
r
answer to the few questions that we do have, there might be
.other questions generated in.that we can proceed on that
basis. -
Gentlemen.of the committee, would you ask any \
questions that you might have.
"" DR. FRIESS: Gentlemen of Velsicol, a question
raised in the course of the committee work this morning,
t
which really bears on the need for information relative to ;
the toxic effects on humans by whatever routes or modalities*
j
Of exposure these humans have experienced, you did tell us |
yesterday that information exists with respect to peripheral
neuropathy in the human from certain kinds of exposures that
have occurred.
We feel that it would be extremely important for
the committee within the next month, which is between now anc
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the time that we are going to put the report out, for us to
have rough data on these relating to the following points,
as much as you have and in as crude a form as you have is
okay with the committee.
What we would really like to know is items relat
ing to the airborne concentrations that personnel might be
exposed to in the course of manufacture, over long periods
of time, and rough estimates of time intervals of contactT;
'*
for personnel with these airborne concentrations, and how-«-;
ever rough you give it to us, indications of peripheral
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neuropathy in these operational personnel as a function of^','
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: ."the integrated dosage that they might have gotten. V J"-"'1;' ^'
;': - /*, = vl -It is asking for a lot, and it may not be in pol-
ished form at this stage, but what we would really like to j
know in the earliest possible form for release, is the .,;|!
effect in the human, this peripheral neuropathy as a functioj
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of dose that the human has been exposed to by the inhalation]
route. That is a primary need, because the human is the j
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ultimate target that we are worried about and the animal >
9
models are great, but if there is this opidemiological infor-
mation on the human, and if it is reaching report form in a
month, what we would like to ask is a preliminary peek at th
rough data, before the month is out. This would help us a
good bit, especially in terms of the timetable for the pro-
duction of the report, in which the committee would benefit
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by having the data at the earliest time to have the longest
consideration time. So we would very much appreciate that
kind of information if possible, in the earliest part of
August.
Secondly, it would be of some interest and consi-|
derable interest if data exists relating to single incident]
or group incidents of accidental skin exposure, percutaneoi
i
exposure of the human perhaps in the manufacturing situa-
tion as much as possible relating to time and dose, and net
peripheral neuropathy/ this would be information of extrem
importance to the committee, in looking at the biological
-. ,- _ .-. -
situation in man, vis-a-vis that in the. animal,
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: y. So, we really are saying that we would very much
appreciate having inhalation and skin contact information
in the human, in however crude a form you wish so t'^at the '-,.
committee members might have it as the earliest possible
date.
And, we would thank you very much for such informa-i
-
tion. I
i
CHAIRMAN COON: You are welcome to make any comment
that you wish in connection with those requests.
MR. CALO: I think really the only comment that
I could make at this time is I really don't know what infor-
mation is available. I would have to ask for exactly what
you asked us for.
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MR. WHITACRE: Any 'aspects having to do with
the manufacturing process.
DR. FRIESS: Just in terms of being able to
sequester data, is all manufacturing done in one location --
all manufacturing of Leptophos done in one location?
MR. WHITACRE: Leptophos is manufactured in two :
I
i
places, in the world. It has been manufactured in Japan
since about 1969, and in Texas, near Houston since 1971.
There has been no incident well, maybe I
shouldn't say that, I am not familiar with the program, but,
in Japan there has never been any reports at all concerninc
. '*'
.that 'due'to. the manufacturing of the material,, is that true
-. ' r - "--47-'/- :.--".-- " -'"<":--. . " ""- ;
MR. CALO: That is correct.
DR. FRIESS: But, in this country, there is just
the single plant in Houston?
MR. WHITACRE: Right.
DR. FRIESS: And, are the populations relatively
stable of workers so that one might have expected certain
workers to have prolonged and continuous exposure?
MR. WHITACRE: We have asked the manufacturing
people to gather all of those data, and that is the report
that I am referring to.
It might seem to you that we know a lot about that
but in fact, we do not, simply because it is their responsi-
bility in the company. We have asked them with the help of
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consultants to put together everything they can. They have
conducted a monitoring program within the last year and a
half or so, data from which should be available. I have
not made any report or anything from that experience, and
so when I see it, I am going to see it, and we will probably
see it about the same time. ]
I
DR. FRIESS: Thank you.
CHAIRMAN COON: Are there any other questions? Di
McNaniara, did you have another question?
I
DR. McNAMARA: Yes, I had another question, one *
that is definitely in mind. And, I was wondering, with-'a
compound that is not registered, why would you want a toler'
f
ance level conducted? ':M
MR. WHITACRE: For the sake of registering the
compound principally. It is the first step, or at least
after certification of usefulness is made by the agency,
for this compound, the next step is to establish a tolerance,
whereupon, if everything else is adequate, the registration
can be obtained. Our intent in originally submitting the
application for registration in this country, is for that
!
purpose, to get the registration. It has just so happened
certain occurrences have not permitted registration be issue<
Obviously, if the tolerances will not stand, we
will not have the basis to ask for the basis upon which
to issue a registration. >;
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8
So, very simply, the reason that we want toleranc
is the first or second step to obtaining registration.
DR. McNAMARA: This is the general sequence in
getting registered?
MR. WHITACRE: I would stand cdrrected by anyone^
from EPA, but that's the sequence for food items. j
DR. ROSEN: I'm finished, I have no questions.
CHAIRMAN COON: I would like to ask one questio
in connection with your plans for a cholincstcrasestudy
in chickens. I want to be sure is this a feeding study,
or a single dose per day administration? .' "
V: ;'' MR. WHITACRE": It'would please us greatly if the
committee would take that proposal, which we have written,
and look through it. It would answer two questions, and
perhaps it would answer the question that you are asking,
first, but second, you might want to make a suggestion befo
it gets under way. j
CHAIRMAN COON: This proposal hasn't been made
available to us, yet.
MR. WHITACRE: That is right. Would you like it,j
that is the question? I don't think that it has been made
available, although I would be more than pleased to submit
it, for your information and for your comments.
CHAIRMAN COON: I think that it would be important
for the committee to have, yes.
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MR. Will TAG RE: Incidentally in answer to your ques-
tion, it was going to be well, we haven't decided in facf
absolutely whether we should give -- whether it should be
a feeding study, in which the material is incorporated intc
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the feed, or whether we should administer the dose by gelaii
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capsules, so that we would know absolutely what each bird ^
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is getting. Did we decide finally?
MR. CALO: No, we have not decided that.
MR- l'?II ETACRE: Everything else being equal, I thit
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that we would like to go to the geletin capsule unless it is
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The only advantage, it is easier and cheaper to
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doing it with the feed, incorporate it into the feed, and it
is adequate. Butr the advantage of administering the capsulj
1
is that you know exactly what each bird has ingested, and fo
control purposes, it might be a little bit better, I'm not!
sure.
DR. FRIESS: Mr. Chairman, could I address this i
point? [
CHAIRMAN COON: Yes, go ahead.
DR. FRIESS: This has been the subject of some
discussion with the committee, and I think that points can
be made in favor of the feeding experiment, that this is
more realistic in terms of the time sequence of ingestion,
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as related to man's experience in eating food.
And, secondly, the absorption problems with respec
to compound tissue, rates of dissolution, carrying and meta-
bolism are much better approximated by the feeding experimer
than by the gelatin capsule experiment.
MR. WHITACRE: Incidentally what we normally do for
feeding experiments of this type is we use gelatin capsules
well, what I do, we try to absorb the material in the
grain so that it shouldn't be a major factor in terms of >*
in other words, it is the same material
,V; J--. DR., ERIES3: But in a small bolus of relatively
high concentration, which contrasts with taking in a-larger^
volume of food, with a smaller specific structure, and one
wants the model which is closer to man, eating food in bulk.
MR. WHITACRE: But, it is your recommendation that
it should be a feeding experiment? I
DR. FRIESS: Personally yes, and I think that this4
is reflected by the committee. i
CHAIRMAN COON: This was our practically the
i
assumption of the committee, when it was discussing this
matter. It just entered my mind the possibility that you
might be considering the capsule approach to the administra-
tion, so I thought that I would ask questions, and that
conventionally in long term toxicity studies with food addi-j
tives and pesticide residues in food, conventionally they all
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proceed by incorporating the material in the diet. And, Dr
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MR. WHITACRE: I would like to do it that way.
CHAIRMAN COON: You mentioned the theoretical
advantage of knowing exactly how much of the chemical the
chicken is getting.
I suppose as time goes on, and the weight of the
chicken changes, so that the amount administered would be
on a pretty low basis to keep that constant. Well, of coui
as the chicken grows, it eats more too, and so there is
sort of built in an automatic increase in the amount pro-
portionate, to the weight of the chicken. Of course, .that i
not exact, because sometimes the chicken will not eat, but
what he eats would be variable, but in the chronic J
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mouse and rat studies, they have an estimate of how much ;;
^
the animals eat per day. In some tests they actually measur
the daily intake of the food, and know the concentration of
the chemical in the food, and they can calculate exactly
how much was consumed.
I suppose that there are other estimates of the
consumption, the food consumption of the chickens, on a woicjl
basis for the type of food that they are taking.
MR. WHITACRE: There is yes, it is a matter
of the number of animals being used, if they show any measur
able or significant variation in intake, then there will be
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an error there which will not be easily defined, but it
should not be excessive on that basis.
I am not really concerned that the study involvii
the feeding of the compound would be inadequate in any way,
if everything goes according to the schedule we would like
to define.
CHAIRMAN COON: Well, committee, is there anythinc
further?
(No response.)
CHAIRMAN COON: Well, I might invite questions or
comments from the observers, who Jiave arrived today, if thq
wish to, ask questions or make comments, I would urge that
if they do, identify themselves, and indicate whether they
are speaking for themselves, or for the agency that they
represent.
DR. CORODA: Dr. Rosen brought up a point
yesterday about accumulation in fish, and in this regard I .'
would like to ask Leptophos if they have completed their (
egg to egg feedingof the study of brook trout, and if not, ',
" ./ i
I think that the data would be very interesting to the
committee. I think that it should be turned over to them.
MR. CALO: The study is completed. We have every
intention of turning the information over to the EPA and the
committee. I understand that the report will be completed
within the ne^t three weeks. As soon as it is available, we
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will pass on the report to appropriate channels.
DR. CORODA: This was done by Ken Macy.
MR. CALO: It was done by Rionomics, that is
correct.
DR. CORODA: I have one other comment. I heard
that through the grapevine that Phosvel was banned in
Egypt, do you have any comment?
MR. CALO: I guess really I can only give an
unofficial answer. I have not heard that. The information
that I have is that if they had an infestation as they hav
had.in past years, they would probably request the material
again.1 r know that it is actively being considered by a ";
number of people in Egypt.
DR. CORODA: When you speak of infestations, are j
you implying that this compound is only used during periods
of infestation and at other times when there is not an in- \
festation it is not used?
MR. CALO: Relative to the efficacy of the compound
i
I really can't comment. I just am not that familiar with j
!
these patterns whether they be here in the U.S. or overseas.
DR. FRANKLIN: Dr. Claire Franklin, Health and
Welfare, Canada.
Could you tell me are there any other pesticides
produced in the plant in Texas other than Phosvel?
MR. WHITACRE: I am not certain because again, I am,'
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not really involved with the manufacturing situation, but
my impression is that Phosvel is the only labeled
Methylparathion.
I think that there was a Methylparathion con-
verted plant in *
5-j
DR. FRANKLIN: And, they are still actively I
\
producing it now
MR. WHITACRE: Well, let me finish. I think that
*
that was a Methylparathion converted plant that produced '*
Phosvel up until early 1976, and it has been converted for *
EPN production, by Velsicol. : .
. :^V=:.;;>/.MR^ ROSEN: Does that mean that you will no longed
be producing it in the States? " .
MR- WHITACRE: I really don't know. I really do
not know what the plans are for that plant, or far the
compound until we go further.
DR. FUKUTO: This is jumping out of the pot and ;_
into the fire, EPN is a neurotoxic agent, and from what
information we have, how seriously has the company consider^
this?
MR. WHITACRE: I am sure that they'have considered
it, and I really can't answer it from the corporate standpoi^
I'm just not in the position to do that, because I am not
*
involved in their decision making, perhaps it seems so, and *
it may be so, but I can't really answer the question with an}'
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assurity .
tion?
DR. ZWEIG: Are you phasing out tho Phosvel procluc
MR. WHITACRE: I don't know if that is the case.
You've got me in an area in which I know little about it
from the company's standpoint. Phosvel is not now being
produced in the United States, and it hasn't been for some
months. That is all that I know.
DR. ZWEIG: It is being produced overseas?
MR. WHITACRE: As far as I know it is being pro-
duced in Japan, but I really don't know. It is not one of 1
the considerations thatl'm required to look at or which
:.'-'-. .' ' " ""'':&
Charlie is required to look at. And, we haven't.
DR. ZWEIG: Questions can be answered if they are
cogent and the committee wishes to have them addressed.
MR. WHITACRE: Well, I can't answer with any degre
of certainty, because I just don't know. t
DR. FRIESS:What did come to mind though, is that
the interval in which workers might have been exposed during
manufacture is now limited from 1971 to 1975, right, there
is a four year interval?
MR. WHITACRE: That was when the compound was
produced, domestically, that is what I understand, through
1975.
DR. FRIESS : That is the interval of course, for
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which we would like exposure data.
MR. WHITACRE:
DR. FRIES S:
workers with respect to
under the Occupational
MR. CALO: I
MR. WHITACRE:
Indeed, yes.
Is there any intent to follow up
long-term delayed
Safety and Health
don't know.
neuro toxicity,
type regulations?
. i
I don't know what their long range
plans are. We have not, at least I have
to give ray opinions on that, and I don't
not been asked
*
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know what their lor
1
range plans are. 1
CHAIRMAN COON: Does EPN have a registration now?*.'
> ; MR. WHITACRE: It is a registered product in the"!
United States. . ll
DR.. CORODA:
It is on the presumption against
registration, .it is on the RPAR list for delayed toxicity, .'
so it is going to be examined for that property.
DR. ZWEIG: It is registered though? {
DR. CORODA:
DR. ROSEN:
Do you have any kind of
MR. CALO: I
Yes, it is registered, yes. ,
1
Could you describe the fish study? '\
1
.information?
can describe it in
don't have any of the data. It is an egg
general terms. I
to egg study, whic
encompasses probably 13 months of work, wherein you expose
mature fish to the chemical, during their
during the period of time when they are
*
adult stages, and
reproducing. You
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then follow through the egg of the first generation until
they reproduce. In general terms that is the whole idea of
this study. It is a laboratory study, not a field study.
CHAIRMAN COON: The point of that is a reproducti'<
study?
. MR. CALO: Yes. ;
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CHAIRMAN COON: You say that that is going to be ,
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available shortly in about three weeks? ^
MR. CALO: Yes, I believe the date given by Dr. ,
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Whitacre was the 20th of August, which is approximately a
month..
, .,. ^:%fe?!v, MR.. WHITACRE: I don't think that I mentioned
that, report yesterday, even though it was in that manuscript:
that I talked about, but that is true, it is available, it !j
will be submitted.
DR. FRIESS: We hadn't heard about it.
DR. FUKOTO: That's the third study that you are }
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talking about? .
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MR. WHITACRE: I don't know what happened. I don'1:
think that I mentioned it yesterday, because I don't remembei:
it, but on the other hand it was in the thing that I read
from, I think that when the charges were restricted on the
environmental aspect came out, I cut it, and we got back
into that yesterday, it broadened again.
DR. FRIESS: Because it is broadened.
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DR. ROSEN: Are there any other studies that are
going on that might be pertinent to this?
MR. WHITACRE: There are no other studies goin<
on to my knowledge.
DR. FRIESS: The question that I have is with
respect to the increasing need to have mutogenic data on *;
all chemicals in the food chain as well as the environment
I wondered, does the company have any plan to include Velsi-
col in systematic and vitro screening for nmtogencsis?
MR. CALO: The whole area of mutogencsity is right
now a very difficult one for us. We have spent tons of houi
discussing what we should do.- Routinely we.have been doing**
at least a dominate lethal study, and in some cases we have
gone beyond this. In terms of the in_vitro studies, we have
not made a decision as to what we will be doing. We have
been told by EPA that some time this year, there will be
some guidelines out as to what tests would be appropriate. j
Really, we are waiting for some direction in that area. '
4
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DR. FRIESS: It hasn't been done yet to the best
of your knowledge,and the in vitro system, there is no plan
at the moment?
HR. CALO: For Leptophos?
DR. FRIESS: For Leptophos, right. Speaking of
in vitro system.
MR. CALO: It has not been done. The mutogenisity ,
4
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MR. GEE: When you say it is available?
MR. WI11TACRE: To the committee in the basket.
MR. GEE: It is not part of the basket?
MR. WHITACRE: No, we have it in our files. It is
not part of the petition. '
DR» FUKU.TO: We have some items there are some
items that came fairly recently like the degradation studies
in water, and is that the thing that you are talking about?
MR. WHITACRE: It would have to be from Vclsicol.
DR. FUKUTO: It is from Velsicol, and it is
called a report, we have those things.
'-,".."-.-- MR. WHITACRE: What I am trying to determine i
if something was submitted that was not part of the peti-
tion, or the amendment to the petition, it was submitted
simply to fill the file, is it available to the committee's
review, or must we submit it separately to the committee ort
must you submit it separately to the committee? ']
MR. GEE: Let me say the files there contain all
petition information, the information that you are talking '
$
about recently we received and I know what you are talking {
about, and we've added it to the file. It is not part of
our basket. We have it in our files here in the main office
If the committee wishes to see it, it can be made
available.
DR. FRIESS: Mr. Gee, if you do indeed have those
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four studies on mutogenesis, if you can submit it, and they
are in the file, the committee would like those.
MR. GEE:If you have submitted them -- you have
submitted them -to us?
«
MR. WHITACRE: As I recall, they have been sub-
mitted in the last four or five months. I
MR. GEE: We have them. i
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MR. WHITACRE: The host mediated study is an »
old one. Right? *
DR. FRIESS: Isn't the dominate lethal the first '*
one filed?
. CALO: Yes,, the other three were submitted^]
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MR. WHITACRE: So, the three studies should be
available, all except the dominate lethal.
DR. FRIESS: Right, the dominate lethal infor- '.
mation is available,that is out, the other three are not.
MR. CALO: That is correct.
MR. BOWEN: The three studies that have been
sent to the Registration Division is what the committee
desires to have.
DR.-FRIESS: Right.
MR. BOWEN: And, Mr. Frank Gee will furnish those
to the Secretariat when they are given to the committee.
CHAIRMAN COON: I take it that these results came
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in too late to be entered in the petition, is that right?
MR. WHITACRE: These were studies that were run
in 1975.
MR. CALO: Yes, 1975.
MR. WHITACRE: Just to update our information on
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the compound, we were not required to do them, but they were
done as part of the accumulation of information on the
behavior of the compound.
CHAIRMAN COON: I don't understand fully why they
are not in the petition.
* .p
, ,. MR. WHITACRE: Because we were not required by
EPA to submit thenv in support of the petition or in the
amendment to the petition. We conducted them on our own,
but yet submitted them to the file, to the EPA file, after
the petition was submitted and amended. ,
CHAIRMAN COON: So, it was a matter of timing,
it was too late for the petition.
MR. WHITACRE: And, in addition to that, it was
not information which was specifically required by EP?T~to
support to support. \
CHAIRMAN COON: Is there anything further?
DR. FUKUTO: I would like to ask a question, and
Dr. Painter might be the appropriate person. Why are not
chronic feeding studies requested for delayed neurotoxicity?
DR. PAINTER: Why are they not requested? I think
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the best answer that I can give to that is that this is the
first compound for an extremely long time where we have face
this kind of a problem.
I am going to say something now that I do not have
a direct involvement in. On some of those compounds which
are currently registered, which show this effect at extreme!
high levels, and I believe Food & Drug did require long term
chicken studies. I say that because I have been personally
involved with some of those chicken studies. -
So, I guess the answer is when you come up agains
it, that is what you ask for, and in fact I have been per-
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sonally involved with some of these gentlemen from Velsicpl'f
in recommending that chain study. , «
DR.. ZWEIG:
I would like to call to the attentio
of the committee, unless at least it wasn't clear to me
when the representatives from Velsicol yesterday were men- *
tioning studies on water buffalo, there are two reports in
your'possession, one is'47 and the other is'68. I don't
know which one is which, but as I recall the very first
study which was carried in 1971, although the report is not
signed by anybody, and I agree that it probably would not
could not be scrutinized as closely as published reports,
but at least in that report, from an observer, there were
some delayed neurotoxicity symptoms in the water buffalo at
the highest level fed, and there were, as I recall, four
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levels, IX, 2X, 3X, and 4X. When that experiment was re-
peated, apparently under the auspices of the Egyptian Govern
ment, and partially from Velsicol, is that correct?
MR. WHITACRE: That is correct, yes.
DR. ZWEIG: These animals were only fed, 1 and 2X
level. In other words, they did not repeat the experiment
I
as had been done before, and as I recall, they did not
observe any neurotoxic effects. I would just like to call
to your attention that there were two separate water buffalo
studies and neither of them are very well authenticated,
as far as authorship is concerned. , ;
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made aware that there are two separate studies, one was ;
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positive and the other negative. And, the only difference
that I could see was the positive one was at a higher level
fed than the negative one. ;
CHAIRMAN COON: Thank you. Are there any other
questions, or comments?
(No response.)
CHAIRMAN COON: If not, we then declare the open
session adjourned. And, I want to thank the Velsicol
representatives for making themselves available today, and I
am sorry that we didn't make more use of it to justify it
better, but so be it.
Thank you very much.
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MR. WHITACRE: Thank you.
(Whereupon, the open session was adjourned at
2:39 p.m.)
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