Pronamide: Position Document 1
EPft/sPtS - 86/(, 7
Pronamide Working Group
Richard Troast, Project Manager
U.S. Environmental Protection Agency
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Pronamide: Position Document 1
CONTENTS
Page
I. Background
A. General Chemistry 1
B. Residue Chemistry 1
C. Environmental Chemistry 2
D. Toxicology 6
E. Uses and Production 9
F. Alternative Pesticides 11
G. Hunan Exposure 11
II. Regulatory History 12
A. Tolerances 12
B. Previous EPA Reviews 13
III. Summary of Scientific Evidence to
Support Rebuttable Presumption on
the Basis of Chronic Toxicity 14
A. Chronic Feeding Studies in
Which Oncogenic Effects Were
Observed 15
B. Chronic Feeding Studies Reporting
No Oncogenic Effects 20
1. "Toxicology Study on the
Effect of Adding RH-315 to the
Diet of Rats for a Period
of Two Years" 20
2. "Toxicologic Study on the
Effect of Adding RH-315 to
the Diet of Beagle Dogs for
a Period of Two Years 23
List of Appendices 24
t 9
(I
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I. Background
A. General Chemistry
Pronamide (N-(1,1-dimethyl-2-propynl)3,5-dichloroben-
zamide) was patented as a herbicide in 1964 by Dr. A. Crovetti
of Abbott Laboratories, Northbrook, 111.— The proprietary
rights to the compound were transferred to Rohm and Haas
Company, Inc., in 1968. Abbott Laboratories still receives
a royalty from Rohm and Haas from pronamide production.
There are no currently registered pesticides that
are chemically similar to pronamide. Rohm and Haas has
indicated that pronamide is probably the most biologically
active compound of its type (1).
0 CH
II ¦ 13
C-N-C-C=CH
I I
H |
CI ch3
Pronamide
Physical characteristics of this compound are:
Melting Point 155°C
2
Solubility in H 0 15 ppm
Vapor Pressure 8.5 x 10~5 mm
— U.S. Patents 3,534,098 and 3,640,699 granted on October
13, 1970, and February 8, 1972.
-------
Pronamide is synthesized as a solid. The technical
chemical is packaged as a coarse powder formulation.
Pronamide products that are ready for application are
wettable powders or granules.
B. Residue Chemistry
In a study of pronamide metabolism, cows and rats
fed pronamide excreted over half the amount they ingested
directly through the- gastrointestinal tract in the feces.
Radioisotope studies in the cows and rats indicated that
only a slight percentage of the ingested pronamide is
metabolized in the gastrointestinal tract. However, once
pronamide is absorbed through the intestinal lining, at
least seven metabolites can be identified in the urine
(2) .
Pronamide metabolism in mammals is similar to fatty
acid metabolism in that the aliphatic chain is modified by a
series of carboxylic acid transformations. Since these
chemical transformations follow fatty acid metabolism, which
is a liver function, pronamide metabolism may also largely
be a function of the liver.
Metabolism of pronamide by plants was demonstrated
by Yih and Swithenbank in 1971 (3). A plant study using
alfalfa revealed that at least ten metabolites could be
-2-
-------
FIGUBE 1. Pronamide Metabolites
Metabolite
No.
Compound A
(Pronamide)
Structure
0 CH
if H I 3
R-C-N-C-C-CH
I
CH,
VII
0 CH
II H I 3
R-C-N-C-CH COOH
I 2
CH,
II
O-C-CH
R-C I 2
\ 1
N-C-CH
I 4
CH,
3
0 CH
H H I 3
R-C-N-C-COCH
i 3
CH,
VIII
IX
0 CH
II H | 3
R-C-N-C-OOOH
I
CH-,
0 CH
0 H I 3
R-C-N-C-COCOOH
CH,
III
IV
VI
H
D-C-CH OH
r\ r*
TJ-C-CH
I 3
ch3
0 CH
II H ! 3
R-C-N-C-COCH OH
i 2
CH_
0 CH
II H I 3
R-C-N-C-CH CH OH
I 2 2
ch3
0 CH
U H I 3
R-C-N-C-CHOHCH OH
I 2
CH,
XI
XII
XIII
XIV
R-C-R.
4
0
II
R_C"R2
0 CH
II H I 3
R-C-N-C-CHOHCOOH
I
CH,
0
II
R-C^
0
II
R-C-R,
TO
are unknown
-3-
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TABLE 1. Occurrence of Pronamide Metabolites Ln Soil, Plants,
and Mammals
Metabolite
Mec ia
Soil
Alf al
fa Rat Feces
Rat Urine
Cow Urine
Pronamide
+
+
+
+
-
I
+
+
+
-
-
II
+
+
+
-
-
III
+
+
+
-
IV
+
+
+
+
-
V
+
+
+
-
VI
+
+
+
+
-
VII
+
+
+
+
+
VIII
+
+
+
+
IX
+
-
-
-
X
-
+
-
-
-
XI
-
-
+
+
-
XII
-
-
-
+
+
XIII
-
-
-
+
+
XIV
•
•
•
+
NOTE: Structures of
the
metabolites are
given in Figure 1.
present
— 3
absent
Sources: Appendices 3 and 4.
-4-
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identified in the alfalfa tissue after treatment with
pronamide. This study indicated that the treated crop
should not be harvested until 120 days after the last
pronamide application. A list of pronamide metabolites and
media in which they occur may be found in Figure 1 and Table
1.
C. Environmental Chemistry
Soil degradation patterns of pronamide follow pathways
similar to the metabolic pathways found in plants and
animals. Residues of pronamide in soil were detectable
in amounts of 0.27 ppm for up to 112 days after field
14
application (3). In a study using C-pronamide, Fisher
14 — -
found that 13% of the pronamide changed to CO2 after 33
days. Fisher speculates that this change was accomplished
14
by soil bacteria since there was no significant CO2
liberation in a similar test in sterilized soil (4).
Walker (5), Yih et al. (6), and Leistra et al. (7)
conducted additional studies of the persistence of pronamide
in soil. All of these studies indicated that pronamide may
persist in soil. The half-life of the molecule is wholly
dependent on soil temperature and moisture. At 10% soil moisture
Walker reported half-lives of 29 days at 23°C, 63 days at
15°C, and 140 days at 8°C. Reducing the soil moisture to 5%
increased half-life by a factor of almost two at 23°C.
Leistra et al_. additionally found that the mobility of
pronamide is slight beneath the top 5 cm of soil and is
totally dependent on the breakdown kinetics of the herbicide.
-------
Data submitted by Rohm and Haas on the hydrolysis
of pronamide in water indicated that pronamide is relatively
14
stable when the pH is nearly neutral. Little if any C-
1 4
pronamide was converted to C02- Other studies of pronamide
in aqueous systems showed that it is slowly degraded by light
and microorganisms in water and sludge (8).
D. Taxicology
On the basis of toxicological data submitted by
Rohm and Haas, pronamide products are in Toxicity Category
III (40 CFR 162.10) because pronamide exhibits only slight
to moderate irritation to the skin and eye and has an acute
toxicity in excess of 500 mg/kg. A complete chart of
reported toxicological values is included in the Tables 2
and 3.
Since pronamide and most of its identified metabo-
lites (3) contain an amide functional group with one amino
hydrogen, the question of N-nitroso formation must be raised
since N-nitroso compounds are extremely potent animal
carcinogens. Dr. David Severn, Chemist, Chemistry Branch,
Criteria and Evaluation Division (CED), stated "...pronamide
could be nitrosated... This appears unlikely during manufac-
ture...but could occur subsequent to application" (9).
The potential for N-nitroso formation is especially
likely since some pronamide is marketed in a formulation
with nitrogen fertilizers. N-nitroso formation may also
-6-
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TABLE 2. Acute Toxicity of Pronamide Products
Test
Species,
Sex
Product
LD
50
Oral
Oral
Oral
Oral
Dermal
Dermal
Primary
skin ir-
ritation
Percu-
taneous
Eye Ir-
ritation
Rat-male
Rat-male
female
Rat-male
female
Dog
Rabbits
Rabbits
Rabbits
Kerb 75 WP (RH-315 75 WP)
Kerb - Technical (RH-315)
Kerb - 50W (RH-315 50 WP)
Kerb - Technical (RH-315)
Kerb - Technical (RH-315)
Kerb - 5QW (RH-315 50 WP)
Kerb 50W (RH-315 50 WP)
Rabbits-male Kerb 75 WP (RH-315 75 WP)
Rabbits
Eye Ir- Rabbits
ritation
Inha- Rats
lation
Kerb — Technical (RH-315)
Kerb 50W (RH-315 50 WP)
Kerb 50W (RH-315 50 WP)
4125 mg/kg
8350 mg/kg
5620 mg/kg
16,000 mg/kg
16,000 mg/kg
> 10 gAg
> 3-16 gAg
> 10 gAg
Not considered
primary irritant
at 0.5 g.
> 20 gAg-
Slight conjuntual
redness at 3 mg;
no corneal damage
Slight irritant
to unwashed eye
at 100 rag.
No mortality, but
spots on lungs at
3.32 mg/1 air.
Source: Section C of Pesticide Petitions 1F1139 and 9G0821.
-7-
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TABLE 3. Wildlife Toxicity of Pronamide Products
Test
Species,
rsex
Product
LD50/LC 50
Oral
Japanese
Kerb
75
WP
8770 mg/kg
quail
male
Kerb
75
WP
9540 mg/kg
female
Kerb
75
WP
8000 mg/kg •
Mallard
Kerb
75
WP
>14,000 mg/kg
duck
Tank
Goldfish
Kerb
75
WP
LC * 350 ppm
Water
50
Guppies
Kerb
75
WP
LC^q = 150 ppm
Rainbow trout
Kerb
75
WP
LC50 = 72 ppm
Catfish
Kerb
75
WP
LC^g > 200 ppm
Treat-
Honey bee
Kerb
75
WP
24 hr mortality
ed Fo-
1 iage
Leafcutter
Kerb
75
WP
24 hr mortality
(2 lb/
bee
(control = 4%)
0%
5%
acre)
Source: Section C of Pronamide Petitions 1F1139 and 9G0821.
-8-
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occur after the pesticide is applied if there are nitrates
present. This formation is therefore possible in soil,
water, air, plants, and animals including man.
While some data show that pronamide does metabolize,
the metabolites have essentially the same molecular structure
except for the last two carbons. Thus it is unclear which
part of the molecule is oncogenic. If the amide moiety of
the molecule undergoes nitrosation to form an N-nitrosoamide,
which is in a class of compounds shown to be potent oncogens
in laboratory animals, then some pronamide metabolites may
be oncogens. Moreover, there are no experimental data that
demonstrate clearly that pronamide breaks down or is metabo-
lized to harmless substances. Presence of CC^as a byproduct
does not constitute sufficient evidence that this has
occurred.
Other Rohm and Haas data show that pronamide is a
low order toxicant in cold and warm water fish, waterfowl,
and game birds. Pronamide had no effect on pollinating
bees (10) .
E. Uses and Production
Rohm and Haas is the only registered producer of
technical grade pronamide and is also the largest formulator
of pronamide products. Most of the technical grade pronamide
manufactured and sold in the U.S. is formulated into Rohm
and Haas Kerb 50 W (EPA Reg. No. 707-98). Rohm and Haas
-9-
-------
produces most of the pronamide products registered for
agricultural uses. Because production data are confidential,
they are available for internal use within EPA only (Table
4) .
Ornamental turf weed and grass control is the
major nonagricultural pronamide use. All formulators hold
registrations for this use. Pronamide is marketed in formula-
tions for turf grass weed control in several concentrations
and occasionally with fertilizers in the formulation as
nutrients for the remaining grass. Other ornamental uses
include weed control in commercial forest plantings. However,
the ^use of pronamide on ornamental turf appears minor when
compared to the agricultural uses.
Rohm and Haas exports approximately 200 tons of
formulated pronamide each year. Use patterns abroad are.,
similar to those in the United States. Countries to which
pronamide is exported include Canada (alfalfa), South Africa
(pasture management), Spain (citrus), Italy (orchard crops,
lettuce), United Kingdom (beans, peas, lettuce) , France
(lettuce), and Japan (pasture management) (1).
Pronamide is available to the agricultural consumer
in quantities sufficient to meet their demands. Rohm and
Haas plans to develop additional uses for pronamide.
-10-
/
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F. Alternative Pesticides
Alternative pesticides are registered for most of
the uses and sites but not all the target organisms covered
by pronamide registrations. Of the 41 alternatives currently
identified, five are candidates for RPAR (three arsenicals,
paraquat, and pentachlorophenol). In addition several other
chemicals have been referred to the Office of Special
Pesticide Reviews but have not yet been reviewed and accepted
as candidates.
G. Human Exposure
Humans are most likely to be exposed to pronamide
from the ingestion of treated lettuce. Residue data provided
in the Rohm and Haas tolerance petitions for lettuce indicate
that residues range from <0.01 to 1.8 ppm with a mean
level of 0.3 ppm (10).
Other raw foods treated with pronamide which"
humans may ingest directly are cane fruits blueberries,
blackberries, boysenberries, and raspberries). Use patterns
for these crops indicate that pronamide is applied in the
winter and 100 days or more before berries are harvested
for human consumption.
While alfalfa has the highest permissable pronamide
tolerance of all raw agricultural commodities, the amount of
alfalfa that humans consume directly is probably very small.
-11-
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Residues from alfalfa ace usually ingested via secondary
routes of exposure: consuming meat, milk, and eggs of
animals fed treated alfalfa. Levels of pronaraide found in
chickens fed field-aged alfalfa ranged from 0.02-0.09 ppm in
the kidney <0.01-0.04 ppm in the liver, <0.01-0.02 in the
gizzard, and <0.01-0.03 in fat (11).
Pronaraide levels found after feeding cows alfalfa
treated with pronamide also showed a wide variance. Concen-
trations in the liver varied from 0.02-0.17 ppm and those in
the kidney were from <0.01 to 0.04 ppm. In a study performed
in 1975, L. E. St. John and D. J. Lusk fed cows pure pronamide
and found residues in milk ranging from 0.01-0.08 ppm (12).
FDA has not reported pronamide residues in
samples from in their Market Basket Survey. However they
have not been specifically examining food for pronamide
residues (13).
II. Regulatory History
Since the first pronamide product was registered, there
have been no restrictive or enforcement actions taken by
EPA.
A. Tolerances
Registration Division has established the following
tolerances for residues resulting from the direct application
of pronamide: 10 ppm, alfalfa? 5 ppm, clover and forage
-12-
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legumes; 2 ppm, lettuce and endive (escarole) ? 0.05 ppin,
cane fruits (blackberries, blueberries, boysenberries, and
raspberries).
The following tolerances for secondary residues
resulting from feeding treated material to animals that
produce meat, milk, and eggs were also established:
0.2 ppm Kidney and liver of beef cattle, goats,
hogs, poultry, horses, and sheep,
0.02 ppm Eggs, milk, meat, fat, and meat byproducts
{except kidney and liver) of cattle,
goats, hogs, horses, poultry, and
sheep.
A temporary tolerance based on an experimental use permit
was granted for the use of pronamide on almonds, apples,
apricots, cherries, grapes, nectarines, peaches, pears,
pistachio nuts, plums, prunes, and walnuts. The experimental
permit was for the 1974-75 growing season and was limited to
1500 lb pronamide. Rohm and Haas withdrew this permit in
July 1976.
B. Previous EPA Reviews
On November 29, 1974, Mr. Robert Coberly of the
Toxicology Branch, Registration Division (RD), reviewed
an 18-month feeding study submitted with a tolerance petition
-13-
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for alfalfa (14). Because of the increased frequency of
hepatic carcinomas in male mice in this study, he concluded
that pronamide might be a carcinogen (15).
On the basis of this evaluation Dr. Martin
Rogoff, Pesticide Science Officer, RD, requested the opinion
of Dr. Leonard Axelrod, Director, CED. In his reply dated
December 18, 1974, Dr. Axelrod stated, "...we do not antici-
pate a human toxicological problem with carcinogenicty"
(16) .
Upon receipt of Dr. Axelrod's memo the Toxicology
Branch, RD, reexamined the petition. In a review dated
October 10, 1975, Mr. David Ritter, Pharmacologist reaffirmed
Mr. Coberly's conclusion that pronamide may be a carcinogen
(17). In his review Mr. Ritter stated, "The evidence
submitted ...is very strong that (pronamide) is a potential
human carcinogen...It does produce...cancers... in the
mouse." The Registration Division referred pronamide
to the Office of Special Pesticide Reviews for further
study.
III. Summary of Scientific Evidence to Support Rebuttable
Presumption on the Basis of Chronic Toxicity
40 CFR 162.11(a)(3) provides that a rebuttable presump-
ion shall arise if a pesticide's ingredient(s), metabolite(s),
or degradation product(s) meet or exceed (i) acute toxicity
risk criteria relating to hazards to humans, domestic
-14-
-------
animals or wildlife, or (ii) chronic toxicity risk criteria
relating to oncogenic, mutagenic, and delayed toxic effects
in man and/or test animals, or relating to population
reductions in nontarget organisms or fatality to members
of endangered species.
The Pronamide Working Group has concluded .that
pesticide products containing pronamide meet the chronic
risk criteria relating to oncogenic effects in test animals
set forth in this Section.
A. Chronic Feeding Study in Which Oncogenic
Effects Were Observed
The Working Group recommendation to presume
against pronamide because of its oncogenic effects is
based on data presented in a chronic feeding study submitted
with a petition for tolerances for alfalfa and fresh hay:
"Eighteen Month Study on the Carcinogenic Potential of Kerb
(RH-315; Pronamide) in Mice" (14) . Rohm and Haas, who
submitted the study, holds that the results indicate that
pronamide is not a true carcinogen and does not represent a
substantial hazard to humans. However, three groups within
EPA have reviewed this data and each has concluded that
pronamide is a carcinogen.
The first reviews occurred in 1974-75 when
Toxicology Branch specialists in the Registration Division
evaluated these petitions and concluded that pronamide was a
-15-
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potential human carcinogen. (See discussion in section II
B). Later, in connection with the current RPAR review of
pronamide, a CED contractor, Battelle Memorial Laboratories,
Columbus, Ohio, reviewed this data and concluded that prona-
mide is an oncogen (18). Dr. Robert Potrepka of CED stated,
"Based on the assumption that an adequate histopathology....
was conducted ....it may be concluded that pronamide is a
carcinogen in (C57BL/6) x (C3HAnf) Fl male mice (19) . The
EPA Carcinogen Assessment Group (CAG) also concluded that
the study indicated that pronamide is a carcinogen. CAG
wrote "The mouse study showed a statistically significant
excess of liver carcinomas in males associated with a 78
week exposure to 1000 and 2000 ppra of pronamide in the Diet"
(20) .
Data from the chronic feeding studies upon which
these conclusions are based are presented in Tables 5, 6,
and 7. The data in Table 5 indicate that 19% of 100 mice
ingesting 1000 ppm pronamide daily in the diet developed
malignant tumors, and that 28% of 99 mice ingesting 2000 ppra
pronamide developed malignant tumors. By contrast, malignant
tumors were found in 8% of 100 control animals.
-16-
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TABLE 5. Tumors at.All Sites in Male Mice Ingesting Pronamide a/
Dose,
ppm
Mice with
Benign Tumors
Mice with
Maiignant
Tumors
Total. Mice
with Tumors
NO.
%
No.
% •
No. %
0
1000
2000
0/100
0/100
1/99
0
0
1
8/100
19/100
28/99
8
19 b/
28
8/100 8
19/100 19
29/100 29
a/ This table records the number of mice with tumors and
not the total number of tumors. Thus a mouse with more
than one tumor is counted only once,
b/ Three questionable tumors are not included.
The CAG review also noted other liver lesions
found in male mice that included adenomatous hyperplasia,
degeneration, hyperplasia, intrahepatic cholestasis, necrosis,
and/or fatty change (Table 6). Mice which had cholestasis,
an extremely rare lesion, did not have carcinomas of the
liver. There were no lesions of the liver reported for
female mice in the control group and only 1 and 2% in the
liver of female mice ingesting 1000 and 2000 ppm pronamide,
respectively (Table 7).
-17-
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TABLE 6. Liver Lesions in Male Mice Ingesting Pronamide a/
Dose,
Mice with
Mice with
Mice
Total
ppm
Hyperplasia
Adenomatous
with
Mice with
Hyperplasia
Carcinomas
Lesions
No. % No. % No. % No. %
0
0/100
0
0/100
0
7/100
7
7/100
7
1000
0/100
0
3/100
3
b/
18/100
18
21/100
21
2000
5/99
5
6/99
6
c/
24/99
24 d/
36/99
36
a/ Twenty-eight mice had intrahepatic cholestasis which were not
tabulated. The number of mice in each group would be slightly
higher if results were corrected for survival time,
b/ Includes two mice with questionable carcinomas*
c/ Includes two mice with questionable carcinomas.
-------
Metastases of the liver tumors were not observed
in this study. CAG explained that because this study was
terminated at 18 months, the animals had not lived long
enough for metastases to develop. Therefore, although there
were no reported metastases by the conclusion of the
study, this data does not conclusively demonstrate that
metastases would not have occurred if the study had gone to
24 months, i.e., the full life expectancy of the mouse.
Moveover, CAG predicted that if the study had not terminated
after 18 months and if known histological trends were
followed, mice that had hyperplasia would most likely have
developed carcinomas. CAG characterized the nonhepatic
tumors as lymphomas.
In summary, both CED and CAG reported that
pronamide- increases hepatic carcinomas in male (C5-7BL/-6- x
C3HAnf) Fl mice. CAG also identified additional tumors
which cannot be properly evaluated because of the method of
tissue collection.
Thus the Working Group concludes that a rebuttable
presumption against the registration of pronamide products
should be issued based on its oncogenic potential as demon-
strated in the Rohm and Haas 18-month mouse feeding study.
-19-
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B. Chronic Feeding Studies Reporting No
Oncogenic Effects
1. "Toxicologic Study on the Effect of Adding
RH-315 to the Diet of Rats for a Period of Two
Years"
Rohm and Haas fed groups of 30 rats pronamide
in their diet at levels of 30, 100, and 300 ppm for 2 years
(21). Results of the study are reported in Tables 8-11.
Rohm and Haas concluded that no toxic effects were shown.
CAG reported that male and female rats developed tumors in
both the controland treated groups but that no trend or dose
response relationship could be observed (20). The CED report
noted the tumor formation but could not offer comment
without a complete histopathologic reexamination. CED
recommended that future feeding studies included a tissue
residue analysis for proper assessment of potential toxic
effects (19) . For these reasons neither CED nor CAG could
conclude that pronamide caused oncogenic effects. However,
because CAG also noted that a reexamination of organs
containing tumors would be worthwhile, the Agency has
requested that Rohm and Haas submit slides of thse tissues
for examination.
-20-
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TABLE 8. Benign and Malignant Tumors in Male Rats Ingesting
Pronaraide a/
Dose t
Rats
with
Rats with
Total Rats
with
ppm
Ben ign
Tumors
Maiignant
Tumors
Tumors
No.
%
No.
%
No.
%
0
2/22
9
0/22
0
2/22
9
30
3/22
14
1/22
5 b/
4/22
18
100
0/21
0
0/21
0
0/21
0
300
2/19
15
0/19
0
2/19
15
a/ Tumors of the mammary glands and pituitary are listed in
another table and are not included here,
b/ Reticulum cell sarcoma of the lung.
TABLE 9. Benign and Malignant Tumors in Female Rats Ingesting
Pronamide a/
Dose
Rats
with
Rats with
Total Rats
with
ppm
Benign
Tumors
Maiignant
Tumors
Tumors
NO.
%
NO.
%
No.
%
0
1/22
5
0/22
0
1/22
5
30
0/17
0
0/17
0
0/17
0
100
3/22
14
0/22
0
3/22
14
300
4/21
19
1/21
5 b/
5/21
24
a/ Tumors of the mammary glands and pituitary are listed in
~~ another table and are not included here.
b/ Carcinoma of the uterus with metastases to the adrenals.
-21-
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TABLE 10. Tumors of the Mammary Glands and Pituitary in
Female Rats Ingesting Pronamide
Dose,
Rats with
Rats with
Total Rats
with
ppm
Mammary
Gland
Pituitary
Tumors
b/
Tumors
£/
Tumors
No.
%
No. %
No.
%
0
12/22.
55
6/22 27
• 15/22
68
30
9/17
53
4/17 24
12/17
71
100
11/22
50
4/22 18
13/22
59
300
11/21
52
1/21 5
11/21
52
a/ Tumors were described as fibromas or adenomas. This
Table records the number of mcie with tumors and not the
total number of tumors.
b/ Rats that had both types of tumors are counted only once
in this column.
TABLE 11. Tumors of the Mammary Glands and Pituitary in Male
Rats Ingesting Pronamide
Dose, Rats with Mammary Rats with Pituitary Total Rats with
ppm Gland Tumors a/ Tumors Tumors
No. % No. % No. %
0 1/22 5 2/22 9 3/22 14
30 1/22 5 0/22 0 1/22 5
100 2/21 10 0/21 0 2/21 10
300 2/19 11 0/19 0 2/19 11
a/ Tumors were described as fibromas or adenomas. This
Table records the number of mice with tumors and not the
total number.
b/ Rats that had both types of tumors are counted once in
this column.
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2. "Toxicologic Study on the Effect of Adding RH-315
to the Diet of Beagle Dogs for a Period of Two
Years"
This study, which was submitted by Rohm and Baas
(22) could not be used to assess oncogenic or other chronic
effects since the dogs were fed pronamide for only 2
years which is not "the greater part of the animal's life
span" as required by the National Cancer Institute guide-
lines. In addition the number of animals tested was small.
Dr. Robert Potrepka of CED concluded "...with the sacrifice
of one dog at the end of one year statistical differences
would be difficult to obtain with only the remaining animals
of each sex per dose" (20). The CAG report on this study
reached the same conclusion. Therefore, EPA will not request
the opportunity to reevaluate these tissue slides.
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LIST OF APPENDICES
(1) Troast, R. January 14, 1977. Biological Activity of
Kerb, Export Uses of Kerb. Memorandum to files of
telephone conversation with Dr. E. Swisher, Rohm and
Haas, Co. 1 p.
(2) Yih, R.Y., and C. Swithenbank 1971. Identification
of metabolites of N-(l,l-dimethylpropynyl)-3,5-dichloro-
benzamide in rat and cow urine and rat feces. J. Agr.
Food Chenu 19(2):320-324^
(3) Yih, R.Y. and C- Swithenbank 1971. Identification of
metabolites of N^(l,l-dimethylpropynyl)-3,5-dichloroben—
zamide in soil and alfalfa. J„ Agr. Food:Chem. 19(2):314—
319-
(4) Fisher, J.D. 1974. Metabolism of the herbicide pronamide
in soil. J. Agr. Food Chem. 22(4):606-608.
(5) Walker, A. 1970~ Persistence of pronamide in soil.
Pestic. Sci. 1:237:239.
(6) Yih, R.J., C. Swithenbank, and D.H. McRae. 1970. Transforma-
tions of the herbicide N-(1,1-dimethylpropynyl)-3,5-
dichlorobenzamide in soil. Weed Sci. 18(5):601-6Q7.
(7) Leistra, M., J.H. Smelt, J.G. Verlaat, and R. Zandvoort. 1974
Measured and computed concentration patterns of propyza-
mide in field soils. Weed Res. 14:87-95.
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(8) Rohm and Haas Company. May 1972. KERB: 3,5-Dichloro-N-
(1,l-dimethyl-2-propynyl)-benzamide. Environmental Data
on Soil, Water, Fish and Wildlife Based on PR Notice
70-15. (Data in support of EPA pesticide registration
707-98.) 436 pp. CONFIDENTIAL.
(9) Severn, D. December 1, 1976. Pronamide. Memorandum to
R. Troast, OSPR. 1 p.
Severn, D. December 10, 1974. Pronamide-Further Comments
on Possible Nitroso Derivative. Memorandum to R. Troast,
OSPR. lp.
(10) Rohm and Haas Company. April 1971. Permanent Tolerance
Petition for Kerb - 3,5-Dichloro-N-(1,l-dimethyl-2-propynyl)
benzamide: Lettuce. Vol 1 and 2 (Pesticide Petition
1F1139) 1155 pp. CONFIDENTIAL.
(11) Adler I.L., L.D. Haines, and J.P. Wargo, Jr. 1972.
Studies with dairy cows and laying hens fed alfalfa
containing field-aged residues due to 3,5-dichloro-N-(1,
l-dimethyl-2-propynyl)benzamide. J. Agr. Food Chem.
20 (6):1233—1235.
(12) St. John, L.E., and D.J. Lusk. 1975. A feeding study
with the herbicide, Kerb (N-(1,1-dimethylpropynyl)-3,5-
dichlorobenzamide, in the dairy cow. Bull.Environ.
Contam. Toxicol. 13 (4):433-435.
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(13) Troast, R. March 25, 1977. FDA Market Basket Survey for
Pronamide Residues. Memorandum to the files of telephone
conversation with P. Corneliussen, FDA. 1 p.
(14) Medical College of Viriginia. 1974. Eighteen Month
Study on the Carcinogenic Potential of Kerb (RH-315;
Pronamide) in Mice, EPA Pesticide Petition 5F1552.
242 pp. CONFIDENTIAL,
(15) Coberly, R. November 29, 1974. 3,5-Dichloro-N-(1-1-
dimethyl-2-propynyl)benzamide (Kerb). Memorandum to
J.E. Mayes, Acting Chief, Coordination Branch, Registra-
tion Division. 12 pp.
(16) Axelrod, L. December 18, 1974. Petition No. 5F1552 -
Kerb. Memorandum to M.H. Rogoff, Pesticides Science
Officer, Registration Division. 1 p.
(17) Ritter, D. October 10, 1975. PP #5G1618 KERB; 3,5-
dichloro-N-(1,l-dimethyl-2-propynyl)benzamide and its
metabolites calculated as KERB. Proposal for temporary
tolerances in or on sugar beet tops at 0.75 ppm,
sugar beet roots at 0.1 ppm. Memorandum to L. Zink,
Assistant Product Manager and Chemistry Branch.
7 pp.
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(18) Freudenthal, R.I., and P. Leber February IX, 1977.
Evaluation of Pronamide Toxicity Data to Determine Its
Potential Health Hazards to Man or Domestic Animals.
42 pp. Unpublished.
(19) Potrepka, R.F. February 17, 1977. Validation of
Pronamide (Kerb) Chronic Feeding Studies. Memorandum
to R. Troast, Project Manager, OSPR. 1 p.
(20) Albert, R.E. March 17, 1977. The Carcinogen Assessment
Group Preliminary Review of Oncogenicity of Pronamide.
20 pp. Unpublished.
(21) Department of Pharmacology, Medical College of Virginia.
1968. Toxicologic Study on the Effect of Adding RH-315
to the Diet of Albino Rats: (Two-Year Feeding Study)
First Month Report, EPA Pesticide Petition 1F1139. 313 pp.
CONFIDENTIAL.
(22) Department of Pharmacology, Medical College of Virginia. 1970
Effect of Adding Technical Kerb (RH-315) to the Diet of Dogs
for Two Years. EPA Pesticide Petition 1F1139. 239 pp.
CONFIDENTIAL.
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