/SPtZX)- £0/at
TRIFLPRALIN (THEFLAN)
POSITION DOCUMENT 17171
Special Pesticide Review Division
Office of Pesticide Programs
AUG 2 2 1979
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50777-1QI
REPORT DOCUMENTATION
PAGE
1. REPORT NO.
EPA/SPRD-80/21
3. Roclpient's Accession No.
213937
4. Title and Subtitle
Trifluralin (Treflan): Position Document 1/2/3
| S. Report Date
i 8/22/79_
7. Author(s'/
. 8. Porforming Organisation Rept No
9. Performing Organisation Nime and Address
10.
Pro|ect/Te$l*/Work Unit No.
Special Pesticide Review
Division
Environmental Protection
Agency
u.
CorttractfC") or Grant(G) No.
Crystal Mall *2
(C)
Arlington, VA
(G)
12. Sponsoring Organization Name and ACdress
12.
Type of Report & Period Covered
Environmental Protection Agency
401 M St S.W.
Washington, D.C. 20460
14.
15. Supplementary Notfi
Preliminary Risk Assessment: Examination of possible unreasonable
risks associated with uses of pesticide and a gathering of all available
informatior, to deterttmre—whether or -rrot this—en" any other risk--does--
16. AOltricf tulrmt- TCO worc^5 . J
exist. Initiates literature search, and evaluates risk data,
information on exposure to forecast extent of risk.
Limited
Risk/benefit analysis: qualitative & quantitative risks of a pesiticde,
value of crop uses, availability of alternative pesticide, exposure to
man and environment. Identification of risk reducing regulatory options
and proposed Agency action.
17. Document Analysis a Descriptors
0703,0605,O17.-,
b ldentlfi«r»/Open-Ended Terms
0606
c. COSATI Field/Group
18. Availability Statement
Release Unlimited
19. Security Cl**i (This R«port)
Unclassified
20. Security Clatt (Thl» Pa«e)
IJnrlassi fieri
21. No. of Paces
22. Price
(See ANS1-Z39.18)
So* Instructions on Reverse
OPTIONAL FORM 272 (4-77)
(Formerly NTIS--3S)
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TABLE OF CONTENTS
PAGE
I. INTRODUCTION I
A. Regulatory History 1
5. Chemical Background 8
1. Nomenclature 8
2. Chemical and Physical
Characteristics. ........ 8
C. Uses and Production 10
1. Registrations and Use 10
2. Tolerances 12
3* Production 12
II. RISK ANALYSIS.... 1U
A. General Toxicology, Occurrence, and — - •
Formation of N-nitroso Compounds 14
B. Environmental Fate 20
1. Trifluralin 20
2. N-nitrosodipropylamlne (NDPA).... 22
C. Residues 25
D. Biological Fate 27
1. Trifluralin 2?
2. NDPA 29
E. Exposure Analysis 31
1. Exposure During Application 31
2. Exposure During Re-entry 45
3» Exposure to Other Workers 45
4. Potential Formation of N-nitroso
Compounds After Treflan Application... 46
5. Exposure From Products Used
Around the Home 47
6. Dietary Exposure 48
a. Background 48
b. Exposure Estimate 49
J >
i /V*
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PAGE
F. Cancer Risk Estimate... -52
1. Introduction 52
2. Evaluation of Cancer Data. 53
a. Irifluralin 53
(1) Rat Study R31-61 55
(2) Rat Study R0283 55
(3) NCI Bioassay . 56
(4) Summary of Trifluralln
Carcinogenesis Studies.......... 62
b. NPDA 62
(1) Method.... 62
(2) Druckery...... 64
(3) Reznik : — 64
(4) Pour.... 65
(5) Oickhaus.... 68
c. Comparison of Trifluralln and
NDPA Results. 70
3- Cancer Risk Estimate...- 74
a. Application Related Risk 74
b.. Post-Application Risk 77
c^ Dietary Risk 77
G. Mutagenesis and Spindle Effects 81
1. Introduction 81
2.. NDPA Mutagenicity Data 87
Z" Trifluralln Mutagenicity Data 87
a. Bacterial Tests.......... 88
b- Insect Studies 90
c- Studies with Fungi 91
d. Human Survey. 92.
e. Plant Studies 93
f. Salamander Study 95
4. Trifluralln Derivatives 96
5- Mutagenic Risk Assessment 97
a. DNAVGene Effects 98
b- Spindle Effects. 103
cr. Summary................. 106
H. Other Chronic Effects 106
1. Reproduction Studies 106
2. Teratology Studies.. 107
3» Other Studies 108
4-. Exposure and Related Risk Estimates.... Ill
a. Dietary Exposure.... Ill
b~ Acceptable Daily Intake CADI) 113
c- Worker Exposure 115
!• Environmental Risk 117
L. Aquatic Organisms.... 117
2- Terrestrial Organisms 117
ii
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PAGE
III. BENEFITS ANALYSIS 117
A. Introduction 117
5. Long-Run Economic Impact Analysis .... 122
1. Cotton 122
2. Soybeans 126
3* Fruits and Vegetables 127
4. Other Field Crops 128
IV. RISK-BENEFIT ANALYSIS OF ALTERNATIVE
COURSES OF ACTION : T". ; 130
A. Introduction 130
B. Options ' 130
V. PROPOSED REGULATORY ACTION.... 137
ill
f
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TABLES
PAGE
1. Tolerances for Trifluralin ..... 13
2. Occurrence of N-nitroso Compounds .. 15
3. Pesticides that Contain N-nitroso Compounds.... 16
4. Acute Toxicity of Several N-nitroso Compounds.- 18
5"~ Formation, of N-nitro3o Compounds .......... 19
6. Annual NDPA Exposure to Agricultural Workers
Involved in Trifluralin Application
Operations 36
7. Worker He-entry Exposure to NDPA in Bean3 39
8- Worker Re-entry Exposure to NDPA in Tomatoes... 40
9. Worker Re-entry Exposure to jNDPA in Tree and "
Vine Crops ...... . 41
10. Worker Re-entry Exposure to NDPA in Cole
Crops.. 42
11. NDPA Levels in Products Formulated from Old
Trifluralin 48
12. Potential Dietary Exposure to NDPA 51
13. Carcinogenic Risk to Agricultural Workers from
a. Two-Year Period of Exposure to NDPA. 54
14. Time-Weighted and Lifetime Average Doses of
Trifluralin. and NDPA.................. 59
15. Incidence of Significant Tumors in Female
Mice Fed Trifluralin 61
16. Incidence of Tumors in Sprague-Dawley Rats
from NDPA 66
IT. Incidence of Tumors in Syrian Golden Hamsters
from NDPA.. 67
18. Incidence of Tumors in Female NMRI" Mice from
NDPA. 68
iv
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PAGE
19. Estimated and Observed Tumor Incidence in the
NCI Trifluralin Test Due to NDPA
Contamination ' 72
20. Risk Estimates for Treflan Applicators 76
21. Post-Application Risk Associated with
Trifluralin........ 78
22. Estimate of Maximum Cancer Risk to the Geaeral
Population 79
23. Mutagenicity Tests of Trifluralin (Part I)
and NDPA (Part II) 83
24. Mutagenicity and Related Tests with
Formulated Treflan (Part I) Unspecified
Forms of Trifluralin (Part II) -.. 85
25. Short-Run Economic Impact from a Trifluralin
Suspension : 120
26. Long-Run Economic Impact from a Trifluralin
Cancellation ... 123
27. Risk/Benefit Comparison of Trifluralin Uses.... 131
~
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I. Introduction
A. Regulatory History
tf
On February 3, 1977, Congressman Andrew Maguire,
Congressman Henry Waxman, the Migrant Legal Action Program
(MLAP), the Maricopa County Legal Aid Society, and several
migrant farmworkers petitioned the Agency to suspend the
registrations of Treflan (EPA Reg. No.—3471-35), Trysben 200
(EPA Reg. No. 352-250), and Benzac 1281 (EPA Reg. No.
264-92), under Section 6(c) of the Federal Insecticide,
Fungicide, and Rodenticide Act (FIFRA)(7 U.S.C. 136 .et
seq.), because carcinogenic nitrosamines had been found to
contaminate them (Fine et al. , 1976).—^
The petitioners claimed:
The continued use of nitrosamine-containing
herbicides will have an unreasonable adverse
effect on the environment and constitutes an
imminent hazard to man during the time required
for cancellation. The risks involved in the
case of Trysben 200, Benzac, and Treflan far
outweigh the.ir benefits when viewed in light of
the fact that: (a) these three herbicides have
been found to contain significant quantities of
nitrosamines; (b) nitrosamines are known to be
potent carcinogens; and (c) there is a high
risk of human exposure to these herbicides in
agricultural and garden use (42 FR 10886,
February 24, 1977).
1/ The Agency subsequently agreed to the registrants'
requests to voluntarily cancel the Trysben 200 and
Benzac 1281 registrations. 43 FR 5567, February 9> 1978;
43 FR 35099, August 8, 1978.
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In preparing Its response to the petition, the
Agency sought Information at a hearing held pursuant to
FIFRA Section 21(b) in Phoenix, Arizona on March 7, 1977
and 1n Washington, D.C. on March 9, 1977 (42 FR 10886,
February 24, 1977). This hearing was attended by a
number of Congressmen, farmers* the MLAP» farm workers,
grower association representativesH the Trefla.n registrants
and university researchers who provided both .oral and
written 1 nformati on-rel evant to th-is issue. Hearing
transcripts and written comments made for the record at
this; hearing are available for inspection in the Office
of the Federal Register Section, Room E8-47, Ea^t.Tpwer,
401 M St. S.W., Washington D.C» 20460. Additional data
were- also obtained from the U.S. Department of Agriculture
(USCA), other Federal agencies, and. a number of individuals.
These data are also available for Inspection.
On the basis of this- information, the Agency decided
not to suspend the TrefTan registrat1ons (42 FR 40009,
August 8, 1977). The Agency determined that continued
Treflan use would not constitute an "imminent hazard" as
defined under 6(c)(1) of FIFRA since the risks associated
with that use during the period necessary to pursue cancella-
tion proceedings were substantially exceeded by the benefits.
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However, the Agency also concluded that the Treflan
nitrosamine contaminant (N-nitroso-di-n-propylamine ,
NDPA) met or exceeded the oncogenic risk criterion,—^
and that, therefore, an RPAR should be issued. The Agency
also indicated that it would investigate the possibility
that NDPA-contaminated Treflan met or exceeded other
additional risk criteria.
In September 1977, as part of its RPAR investiga-
tion and as required by the August 1977 Response to the
Suspension Petition, the Agency met with the Treflan
registrant and established test protocols to assess NDPA
exposure to applicators, incorporators, mixers,Jgaders,
and field workers. The registrant performed these
studies and submitted the results 1n March 1978 (Day et
al., 1978). These data, other information from the
literature, and Information on uses of Treflan and
general agricultural practices for Tref1an-treated
crops, provided at a meeting of the Agency, USDA, and
the registrant in Indianapolis, Indiana (June 20-23,
1978), were used to calculate worker exposure to NDPA
due to Treflan use.
21 40 CFR f162.11(a)(3){i1)(A) provides that if any ingredient
of a pesticide has been found to induce oncogenic effects
in experimental mammalian species or man from oral, inhalation,
or dermal exposure, an RPAR shall be issued against that
pesticide. Initially, the Agency decided not to proceed
against Treflan individually, but to initiate an RPAR action
against all pesticides which contained NDPA. Subsequently,
however, the Agency decided not to delay regulatory action
regarding Treflan until the entire class of NPDA-conta1ning
pesticides had been Identified and reviewed.
-3
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Because most of the trifluralin produced is
formulated as Treflan EC,—^ the RPAR review focused
primarily on the risks and benefits of Treflan use. The
Agency's proposed regulatory actions pertain, however, to
all tr1f1uralin-containing pesticides.
The Agency's consideration of the risks associated
with tri fl ural ijr use, has. been base
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of the pesticide's use. If one or more of the presumptions
of risk is not rebutted, the Agency must determine whether
the continued use of the pesticide would cause "unreasonable
adverse effects on the environment" (Section 6(b) FIFRA).
Section 2 (bb) of FIFRA defines "unreasonable adverse
effects on the environment" to mean "any unreasonable risk
to man or the environment, taking into account the economic,
social and environmental costs and benefits of use of any
pesticide." Therefore, if the risks of a pesticide's use
outweigh the benefits, the Administrator must issue a notice
of intent either to cancel or deny the pesticide's
registration without qualification or to cancel -or- deny the
pesticide's registration if the registrant fails to meet
Agency requirements which would reduce risks to a level
where they are exceeded by the benefits (Sections 6(b)
and 3(c)(6) of FIFRA). The United States Department of
Agriculture (Section 6(b) of FIFRA), the Scientific Advisory
Panel (Section 25(d) of FIFRA), and the public—7' review
the Administrator's proposed notice of Intent to cancel or
deny. The Administrator then considers all the comments
which were made in a timely manner before publishing a final
decision.
4/ Although not required by law, 1t has been Agency policy
to initiate a public comment period upon referral of the
Administrator's proposed notice of intent to cancel.
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In the case of trifluralin, two of the analytical
RPAR phases - the initial determination that the risk
criteria had been exceeded and the weighing of risks and
benefits to determine the appropriate regulatory action —
have, been combined, uni nterrupted by the rebuttal comment
period. The Agency believes that this modification is
justified by the unusual circumstances associated with the
trv^luralln review. Moreover, the approach used has not
denied the public, the opportunity to comment on any
determinations or Issues raised by this position document.
Regarding the special circumstances of this RPAR, a
hearing was held to obtain information concern i rt"9 'whether
or rot EPA should suspend the Treflan registrati on. Such
hearings are not usually part of the RPAR process. During
this hearing, the primary U.S. trifluralin registrant
presented its position concerning Treflan risk. It
conceded that the N-nitroso-contaminant was carcinogenic,
but it asserted that Treflan was still safe to use because,
due to low exposure, the risk was slight, and the substantial
benefits outweighed that slight risk.—7' To some extent,
therefore,, the primary trifluralin registrant has had an
opportunity to rebut the presumption that NDPA-contaminated
Treflan 1s an oncogen. Tn addition, the registrant and
othe-s have submitted detailed paper? regarding many of
5/ Transcript of Public Hearings on Petition to Suspend
"Certain Pesticide Products Section 6, FIFRA. March 7,
1 977., Phoenix, Arizona, p. 11-26 and March 9 , 1 977 ,
Washington, D.C- p. 2-13 through 2-23.
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the aspects of risks which have been considered by the
Agency in making its determination. Furthermore, the
Agency, with the aid of USDA and state agricultural
colleges, considered benefits data presented by the
registrant when its benefit determination was made.
Much of what the registrant would have submitted at
the usual RPAR rebuttal stage, therefore, has already been
submitted during the modified trifluralin RPAR. It seems
reasonable, therefore, to focus public discussion on the
risk/benefit analysis by presenting the Agency position in
a single document followed by a public comment period
during which time the registrant and anyone else^maj
submit comments-^ in response to the Agency's tentative
risk/benefit conclusions regarding trifluralin. The
Agency believes that neither the registrant nor any other
interested person has been prejudiced by this procedural
modification since they will not be deprived of their
opportunity to participate meaningfully in the administrative
decison-making process affecting the continued registration
of this pesticide.
6/ Under 40 CFR § 162.11(a) (1) (1), only a registrant has the
right to submit rebuttal evidence when its registered pesticide
has been presumed against. It is Agency policy, however to
allow anyone to submit timely evidence and to consider such
evidence before making regulatory decisions.
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B. Chemical Background
1. Nomenclature
Trifluralin (CAS 1582-09-8), a pre-emergence herbicide,
1s the common name for the d1n1troanl1ine compound alpha,
alpha, alpha-tr1f1uoro-2,6-din1tro-N,N-dipropyl-p-toluidine.
This compound, first described by Alder et a1. (I960), 1s
a.1so known as:
IT, H-di-rr-propyl -2,6-ctf ni.tro-4-ttri f 1 uoromethyl anl Tine;
4-(D1-n-propylam1no)-3,5-din1tro-l-tr1fluoromethylbenzene;
2,6-din1tro-N,N-di-n-propyl-a1pha-tr1fluoro-p-tolu1dine;
N,N-Dipropyl-4-trifluoromethyl-2,6-dinitroani1ine; and
2,6-di nitro-fo,N-dipropyl-4-(tri fluoromethyl)-benzenamine
Trade names- for formulated trlfluralin are Elancolan,
1-36352, Lilly 36,352, Su Seguro Carpidor, Trefanocide,
Treffcon, Treflan, Trifluoralin, Trifluraline* Triflarex,
and Trim (Tracor-Jitco,. 1977). The most commonly used trade
name is Treflan.
2- Chemical and Physical Characteristics
The molecular weight of trifluralin is 335.3; its
molecular formula Is C13H16F3 N^O^; and its chemical
structure is:
CF
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Trifluralin, a yellow-orange crystalline solid, melts
from 48.5° to 49.0°C, and boils from 96° to 97°C at
0.18 mm Hg. Its vapor pressure is 1.99 x 10"^ mm Hg at
29.5°C. Some of its solubilities in grams per 100
ml at 27°C are: acetone (40), ethanol (7), xylene (58),
and water (less than 1 ppm) (Hilton, 1974).
Technical trifluralln 1s reported to be more than 95%
pure (National Academy of Science, 1977). The impurity of
concern, N-n1troso-d1-n-propylam1ne (NDPA) 1s a symmetrical
dialkylnitrosamine; its molecular formula 1s CgH-^NgO,
and its chemical structure 1s:
ch2-ch2-ch3 '
0 => N-N
ch2-ch2-ch3
The molecular weight of NDPA is 130.19, its density is
0.9163 at 20°C, and its boiling point is 78°C at 8 mm
Hg. NDPA's vapor pressure is 0.104 mm Hg at 26°C (Probst,
1978). Nitrosamines are generally soluble in methanol,
ethanol, acetone, and ether (Bontoyan, 1978). NDPA
solubility in water 1s 7.6 mg/1 (Monitoring Data Support
Division, 1978).
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It was first brought to the Agency's attention that
Treflan, Trysben 200, and Benzac 1281 contained N-nitroso
contaminants at an annual meeting of the American Chemical
Society (Fine et al., 1976). At that meeting NDPA was
identified at a level of 154 ppm irr Treflan samples.
Subsequently the-.Treflan registrant fras decreased this:
level to less than 1.0 ppm by modifying the synthesis
process. NPOA can be produced in trifluralin from the
nitrosatlon of d1propyl amine by residual nitrogen oxides 1n
the reaction mixture during the latter part of product
synthesis (Severn, 1977). In addition, NDPA may be"a '
contaminant of the d1propyl amine feedstock (Des Rosiers,
1978) -
C. Uses and Production
1 ^ Registrations ana Use
Trifluralin has been registered for use on an increasing
number of crops and ornamental plants since it was first
registered in January, 1963. The 105 registered trifluralin
products (56 Federal, 39 State, and 10 special local needs
registrations) are formulated with trifluralin as the
sole pesticidal active ingredient,. in- combination with other
pesticidal active ingredients, with fertilizers, or with
both.
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These 105 registered products can be categorized
thus: technical material (7), professional use on ornamentals/
nursery use (7), domestic use (37), and agricultural use
(54). In addition to these, trifluralln is also registered
as a tank mix with Eptam, Diphenamid, and Sencor. Trifluralin
products formulated for use contain from 0.095S to 44.52
active ingredient.
The estimated use of trifluralin in 1972 by national
region in millions of pounds was: Northeast, 0.4; Southeast,
2.3; North Central, 6.5; South Central, 6.2; Northwest and
Southwest, 1.6. In addition, about four million pounds of
trifluralin were exported in that year (von Rumker .et
al ., 1974).
Section III of this document includes the estimated
agricultural use of trifluralin by crop category.
Trifluralin is used once a year for pre-emergent
control of annual grasses and some annual broadleaf weeds.
It is normally applied before planting to field and
vegetable crops such as soybeans and cotton. It is also
applied to ornamental trees and shrubs, roses, certain
established flowers, and fruit and nut trees after planting.
The emulslflable concentrate 1s the major formulation in
use, but granular formulations are also used in smaller
amounts-
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Tr1f1uralin is applied by low pressure surface sprays
(20-40 psi),- hand or machine broadcast, subs-urface layering,
and in a few instances, by air spraying. Soil 1ncorporation
within 24 hours 1s recommended for most trlfluralin uses.
For some products, surface application or surface appli-
cation followed by irrigation is recommended. At the
recommended application rates,, from 0.25 to 4.0 pounds of
acttve- ingredient" are- applied per-acre, of- sail surface^
2. To!erances
Table I gives tolerances for trifluralln. There are
no established- tolerances for the NDPA contaminant of
trifluralin in or on raw agricultural commodities, processed
food, or feed.
3- Producti on
Section 7(c) of FIFRA requires producers to inform
the Admi ni stra.tor of the types and amounts of pesticides
and, if applicable, active Ingredients used in producing
pesticides in their establishments.
Section 7(d) of FIFRA specifies that:
Any information submitted to the Administrator
pursuant to Subsection (c) other than the names
of the pesticides or active ingredients used in
producing pesticides produced, sold, or distributed
at art establishment shall be considered confidential
and shall be subject to the provisions of
Section 10.
12
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TABLE 1
TOLERANCES FOR TRIFLURALIN
Crop Tolerance (opm)
Mungbean sprouts
2.0
Carrots
1.0
Alfalfa hay
0.2
Citrus fruit
___ .
0.05
Cottonseed
0.05
Cucurbits
0.05
Field corn grain fodder and
forage
0.05
Forage legumes
0.05
Fruiting vegetables
0.05
Grapes
0.05
Hops
0.05
Leafy vegetables
0.05
Nuts
0.-O5
Peanuts
0.05
Peppermint hay
0.05
Root crop vegetables (except
carrots)
0.05
Safflower seed
0.05
Seed and pod vegetables
0.05
Spearmi nt hay
0.05
Stone fruits
0.05
Sugarcane
0.05
Sunflower seed
0.05
Wheat grain
0.05
Wheat straw
0.05
Asparagus
0.05
Peppermint oil
z.ol-'
Spearmint oil
z.oi/
1/ From CFR 21 193.440; all others from CFR 40 180.207
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Section 10 specifies the types of information that
may be disclosed and limitations on and conditions of
such disclosure. The Section also specifies penalties that
may be levied upon government employees for improper
disclosure of such information. This production information
is provided to the Administrator in a confidential attachment
to this report.
According'to public data,.5,184,000 pounds of*
trifluralin were produced in 1966 (Mrak 1974), 21 million
pounds in 1972 (von Rumker et al., 1974), more than 23
million pounds in 1974 (Xeil et al., 1977), and more than
24 million pounds in 1975 (Severn, 1977).
II~ Risk Analysis
A. General Toxicology, Occurrence, and Formation of
N-nltroso Compounds
The NDPA contaminant in trifluralin is one member
of the general chemical class known as N-nitroso compounds.
This class, Is subdivided into nitro3amines and nitrosamides,
which, are common constituents of many natural and man-made
components of the environment. This section discusses the
general toxicology, occurrence and formation of this class
or compounds. NDPA toxicology, occurrance, formation,
environmental chemistry, and biological chemistry is
discussed in sections II B, C, and D of this document.
Table 2 lists some common sources of N-nitroso compounds,
and. Table 3 summarizes information on additional pesticides
that contain N-nitroso compounds.
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TABLE 2
OCCURRENCE OF N-NITROSO COMPOUNDS
Source
N-nitroso
Compound Detected
Concentration
Reference
Meat curing mix
Bacon
Salami, dry sausages
Fried bacon
Spice-cure mixes
Sable, salmon, shad
Cooked Bacon
Marine salt fish
Water
Herbicides
Air
Tobacco
Tobacco
Cigarette smoke
Various cosmetics
Cutting fluids
N-ni trosopyrroli d1ne
N-nitrosopiperidine
N-ni trosodi methyl ami ne
N-nitrosopyrrolidine
N-nitrosodimethyl amine
N-nitrosodimethylami ne
N-nitrosopyrroli di ne
N-nitrosodimethylamine
N-n1trosopyrrol1di ne
N-n1trospiperi dine
N-nitros odi methyl ami ne
N- n i t rosopyrro 1 i di ne
N-nitrosodi methyl ami ne
N-nitrosodimethylamine
N-nitrosodi propyl ami ne
N-nitrosopropylbutyl ami ne
N-nitrosopyrrolidine
N-nitrosodipropyl amine
N-ni trosodimethylami ne
N-n1trosodimethylamine
N-nitrosodimethylamine
N-n1trosodiethanolamine
N- n i t ros od i methy 1 ami ne
N-n1trosoethylmethyl amine
N-nitrosodiethyl amine
N-n1trosodi propyl ami ne
N-n1trosopyrrol1di ne
N-n1trosopiperidine
N-ni trosodi butyl ami ne
N-ni trosodiethanolamine
N-ni trosodiethanolami ne
2.5-6.0 ppm
7.0-25.0 ppm
0.85 ppm
0.004-0.025 ppm
0.002-0.03 ppm
•0.01-0..08 ppm
7.0-139.0 ppb
50-200 ppb
0-26 ppb
10-108 ppb
0.05-0.30 ppm
0.05-1.0 ug/1
13.0 ug/1
3.2-8.2 ug/1
0.63 ug/1
154 ppm
187-640 ppm
40 ng/m^
0-140 microgram/
cigarette
0.1-173.0 ppb
Sen et al.t 1973
0
M
Sen et al., 1973a
Sen et al., 1973a
Sen, 1972
Havery et al., 1976
Havery et al., 1976
o
n
Fazio et al., 1971
Fazio et al., 1973
Fong and Chan, 1973
NEIC, 1977
»
0
U
Fine et al., 1976
NEIC, 1977
Rhodes & Johnson, 1972
Schmeltz et al., 1977
5-180 ng/cigarette McCormick et al., 1973
To 40 ng/c1garette
To 28 ng/cigarette
1.0 ng/cigarette
1-110 ng/c1garette
1-9 ng/cigarette
3 ng/cigarettte "
Trace-130 ppm Yates 4 Wenninger, 1978
0.02-3.OS Fan, 1976
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TABLE 3
PESTICIDES THAT CONTAIN N-NITROSO COMPOUNDS^
Pesticide
Contaminant Refere
Benzthlazuran
Nitroso Derivative
a
Carbaryl
Nitroso Derivative
a
Propoxur
Nitroso Derivative
a
Fenuron
OMN
a
Atrazine
Nitroso Derivative, NOELA (0.54 ppm)
a,
Simazine
Nitroso Derivative
a
Z1 ram
DMN
a
Thiram
• DMN —
a
Ferbam
DMN
a
Succinic acid 2,2-dimethylhydrazide
DMN
a
Oryzali n
NDPA (1 ppm) Unknown (1.5-42 ppm)
b,
Trifluralin
NDPA (6-202 ppm)
b,
Isopropalin
NDPA (9-87 ppm)
b,
Butralin
NBEA Unknown, (2.4-74 ppm)
b,
Benfluralln
NBEA 28-38.4 ppm) Unknown
c
(30-261 ppm)
Maleic hydrazinde (Salt of)
NDELA (< 1 ppm) Unknown (1.4 ppm)
c
Diphenamide
DMN (< 1 ppm)
c
2,4-0 (Salt of)
DMN (0.6 - 6 ppm)
b,
MCPA
DMN (0.24 - 2.0 ppm)
b,
MCPP
DMN 0.32 - 1.0 ppm)
b,
2,3,6-trichlorobenzoic acid
DMN (1-359 ppm)
b,
Profluralin
CMPNA (4 ppm)
b
Dinoseb
NDELA (217-233 ppm)
b
N-buty1-N-ethyl-2,6-dini tro-4-
tr1f1uoromethy1-ani1i ne
BENA (8-38 ppm)
b
N,N-diethyl-2,4-dinitro-6-trifluro-
methyl-1,3-phenylenediamine
DEN (100-153 ppm)
b
N-(1-ethyl propyl)-3,4-di methyl -
2,6-di ni tro-benzenami ne
Nitroso derivative (102-104 ppm)
b
4-(2,4-di chlorophenoxy)butyri c
acid (salt of)
DMN (2.5-6 ppm)
b
2,3,6-trichlorophenyI acetic
acid (salt of)
DMN (18-24 ppm)
b
_]_/ This list may not be complete since it contains only
those n-nitroso contaminated pesticides reported in the open
literature prior to preparation of this position document.
References are as follows: a) Mlrvlsh, 1973; b) Bontoyan
et al.t T979; c) Cohen et al., 1978.
-16-
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Magee, et al. (1978), EPA (1977), Alexander (1976),
and NAS (1978) have published general reviews of N-nitro30
toxicology, formation, occurrence, and chemistry.
Nitrosamines (including NDPA) are stable at
physiological pH and require metabolic transformation to
active intermediates to exert their effects; nitrosamides,
however, are unstable and decompose to active intermediates
without being metabolized (Shanki 1975T." Table 4 shows
the of several N-nitroso compounds.
A number of scientists have studied the acute
toxicity of N-nitroso compounds. Table 4 (Part II) lists
these studies and their results.
Druckery et al. (1967) and IARC (1973, 1974, 1978)
extensively reviewed the data on the carcinogenicity of
N-nitroso compounds, and Montesano and Bartsch (1976)
reviewed data on carcinogenicity versus mutagenicity of
N-nitroso compounds. Shank (1975) reported that
nitrosamines induce tumors in skin, nose, tongue, esophagus,
stomach, duodenum, colon, lungs, bronchi, liver, pancreas,
kidney, urinary bladder, brain, spinal cord, thymus,
lymph nodes, and blood vessels.
Table 5 summarized the results of tests showing
that N-nltroso compounds are formed in various
chemical mixtures.
-------
TABLE 4
ACUTE TOXICITY OF SEVERAL N-NITROSO COMPOUNDS
Compound
Part I:
Til S
50
Dimethylnltrosamine
Diethylnitrosami ne
Di-n-propylnitrosamine
Di-n-butylnitrasami ne
Di-n-aniylnitrosamine:
Methyl-n-butylnitrosamine-
Met hy1-1-b uty1n11 ro s am1ne
Ethyl-n-butyln1trosamine
Ethyl -t-butyln1trosamine
Ethyl-2-hydroxyethylnitrosami ne
Di-2-hydroxyethylnitrosami ne
Methyl phenylni trosami ne
Methyl benzylnitrosami ne
Nitrosomorphol ine
Methyl nitrosourea
Methylnitrosourethane
Nitrosohexamethyleneimi ne
Nitrosoheptamethyleneimine
Nitrosooctamethyleneimine
27-41
216
> 400='
1200
1750
130
700
380
1600
7500
5000
200
18
282
180
240
336
283
566
Part II
Comoound
Effect
Reference
DMN, DEN,
DMN
Unspecified
nitrosamines
DMN
DMN
Centrilobular
necrosis of liver
Hepatic vein damage
Interference with
protein synthesis
Necrosis of
seminiferous epithelium
Fetotoxicity
Shank, 1975
Koppang and
Rlmeslatton, 1976
Reuber, 1975
Kleihues et al. 1975
Reynolds, 1977
Plapp, 1975
Hard and Butler, 1970
Druckery, 1974
V Ltiso units mg/kg, single oral dose, adult male rats (Shank, 1975).
7/ MaTe and female Syrian golden hamsters.
-18-
-------
Table 5
Formation of N-nitroso Compounds
Nitroso Compound
Formed
Comments
Reference
N-nitrosodi ethanolami ne
Various N-nitroso
compounds
Various N-nitroso
compounds
DMN
DMN
DMN
DMN
Various N-nitroso
compounds
Various N-nitroso
compounds
Various N-nitroso
compounds
Zingmark and Rappe, 1976
lijinsky and Singer, 1975
Fiddler et al., 1972
Industrial grinding
fluid Incubated under
gastric conditions
Amines mixed with
nitrous acid
Quaternary amnonium'
compounds and related
tertiary amines incubated
in vitro with sodium
"nTtrite
Dimethyl amine and sodium Klubes et al., 1972
nitrite incubated with
rat intestinal bacteria
under anaerobic conditions "" ' '
In vitro mixing of
certain pesticides
with nitrite
In vitro and _i_n vivo
mixing of thiram, ziram,
ferbam, DSMA with sodium
nitrite
Egert and Greim, 1976
1976a
Sen et al., 1975
In vivo mixing of ziram Elsenbrand et al., 1975
and sodium nitrite
In vitro mixing of
atrazme, simazine,
propoxur, carbaryl,
benzthiazuron with
sodium nitrite
Injection of pi peri dine,
pyrrolidine with sodium
nitrite into infected rat
bladders
Eisenbrand et al., 1975
Hawksworth and Hill, 1974
Formation in pesticide Mittleman, 1977
treated soil (theoretical
analysis)
-19-
-------
The following sections discuss studies of the
errvironmental fate, routine environmental monitoring
for chemical residues,and the biological fate of
trifluralin and its specific N-nitroso contaminant,
NOPA.
B. Environmental Fate
1. Trf fl ural i n-
Several researchers have studied the degradation of
trifluralin in soil (Parka and Tepe, 1969; Savage, 1973; and
Golab and Amundson, undated). In general, these scientists
found that trifluralin did not accumulate in mos-t-soils
after repeated annual applications. However, very low
residues may persist in certain soils, both in the field
(West, and Day, 1977 ; Probst et a.1 ., 1967) and under laboratory
conditions (Kearney,. 1574-75)..
Many factors influence the persistence of trifluralin
and its degradation in soil- These factors include the
soil's organic matter content, its moisture and temperature,
and the methods by which trifluralin was incorporated into
it. According to Mosler and Saunders (1977), trifluralin is
highly resistant to leaching. Boyd (1978) reported that
trifluralin is strongly adsorbed to organic matter-
-20-
-------
According to the available data, trifluralin does not
readily run off from treated fields. Willis et al. (1975)
stud.ied the rate at which several herbicides, including
trifluralin, were lost from surface drainage waters in
Louisiana. Runoff volumes differed due to variations in
plant canopy, soil texture, and soil surface conditions, and
runoff volumes clearly influenced herbicide loss. Only
0.05% of the total trifluralin which was applied to cotton
or soybeans was lost through runoff in the three months
following application.
Trifluralin 1s also readily volatilized and photo-
degraded in the environment. Spencer and Cliath (1974) and
Parochetti and Hein (1973) indicated that trifluralin
volatilization rates increase significantly with increasing
temperature and soil moisture.
Soderquist et al. (1975) reported that trifluralin
vapor is stable in the dark but degrades rapidly to dealkylated
din1trotolu1dines, cyclic d1ol-benzlmldazole precursors
(benzimidazolines , benzimidazole-N-oxides), and benzimidazole
when exposed to light in a photoreactor. After 12 days
of Irradiation, the principal products were the benzimidazoles.
leitis and Crosby (1974) reported a photodecompos1tion
mechanism for trifluralin involving oxidative dealky1ation,
nitro reduction, and cyclizatlon.
-21-
-------
Parochetti and Hein (1973) reported no photochemical
degradation of trifluralin on the soil surface over a-
24-hour period, baaed upon residual herbicidal activity;
however, chemical analysis demonstrated that photode-
composition had, in fact, taken place in this 3tudy. In
addition, Parochetti and Hein (1973) found that trifluralin
adsorbed to soil in a petri dish photodegraded with a
half-life of" 2..2 hours.
Kearny et al. (1974-1975) reported tentative results
of studies which indicated that trifluralin is metabolized
in soil to the same dealkylated toluidines and benzimidazole
compounds (seven months after treatment) as from photo-
decomposition. They gave no quantitative results.
2. N-nitrosodlpropylamine (NDPA)
The Agency reviewed studies on the Environmental fate
of NDPA in order to assess the extent of human exposure to
NDPA from Treflan use. In general, NDPA photodegrades in
soil,, water, and as a vapor, but it doesn't readily hydrolyze
and- it volatilizes from soil only slightly.
Tate and Alexander (1975) reported that NDPA has a
half-life of about 40 days in silt loam soil. However, the
soil in thi3 experiment lost little of the compound over the
first seven to ten days of incubation; the authors noted
that this time lag might indicate microbial degradation of
NDPA.
-------
Gray and Saunders (1977, 1977a) determined that NDPA
degrades more slowly under anaerobic than under aerobic
condi ti ons.
In a field leaching study, Mosier and Saunders (1977)
incorporated NDPA into sandy and silty clay loam soil
columns. The assay indicated that NDPA was being lost by
degradation, volatilization, and some leaching. NDPA
also leached readily in a laboratory study using sandy and
silty clay loam soils; from 89% to 96% of added ^*C-NDPA
was found in the leachate (Saunders, 1977),
West and Day (1977) analyzed soil which had been
treated with NDPA contaminated Treflan for NDPA immediately
after treatment. They found no NDPA at a level of detection
of 0.05 to 0.20 ppb (50-200 ppt). This is not surprising
since at an application rate of 1.0 pound active Ingredient
(containing 6 ppm NDPA) per acre, the upper 6 inches of soil
would contain only 6 ppt (parts per trillion) NDPA, assuming
a soil density of 0.06 1b/1n ^(Mlttelman, 1978c).
NDPA does not readily hydrolyze. In experiments by
Saunders (1976), NDPA in solution maintained at 51°C and pH
3-9 had not hydrolyzed after 32 days.
When exposed to ultraviolet (UV) light, however, NDPA
in solution is readily photolyzed. Mosier and Saunders
(1977a) exposed an N0PA solution in lake water to sunlight
and found that the NDPA had a half-Tife of about 3 hours.
-23-
-------
Day and West (1977) analyzed pond water from a field treated
six months earlier with Treflan EC (emulsifiable concentrate)
and found no detectable NDPA residues. They also artificially
irradiated NDPA in distilled water (2.2 ppm) in the laboratory.
Under these conditions, the NDPA had a half-life of about 45
minutes.—
NDPA..also: photodegrades in the*, vapor phase. Gray
and Saunders (1977b) estimated the half-life of NPDA in
natural sunlight to be 20 minutes.
After surface application to soil, however, NDPA is
apparently less photodegradable. In dry soil field experi-
ments performed by Mo3ier and Saunders (1977b), about 90? of
the NDPA remained eight hours after application. Mosier
and Saunders also performed wet soil experiments in which
about 73? of the NDPA remained 0.25 hours after application,
and nearly U7J remained after eight hours. These experi-
ments indicate that NDPA volatilizes at a faster rate
from, moist soil than from dry soil.
Oliver (unpublished data, 1973 (JSDA) incorporated
radiolabeled NDPA into the top 7.5 cm of various diverse
soil types enclosed in glass chambers and passed air over
the soil surface. NDPA volatilized from the 30il at a
decreasing rate throughout the 192 hours during which the
system was monitored. The cumulative total of volatilized
NDPA at 24 hour3 was 2.35%; at 192 hours it was 3-77J.
-24-
-------
C. Residues
Trifluralin ha3 been detected in several routine
environmental monitoring programs. The data available .
from these programs were too limited to use in the Agency's
exposure or risk calculations, however. NDPA has not
been detected in any of the monitoring programs.
The National Soils Monitoring Rrogram (NSMP) (Kutz
1977) sampled agricultural sites between FY 1969 and
FY 1974. Trifluralin was applied to 72 of 1,684 sample
sites in 1969 and 88 of 1,165 sites in 1974; more than
855 of the applications during this time were either to
soybeans or to cotton. The number of trifluralin applications
increased steadily between FY 1969 and FY 1974. This
reflected the growing trend toward chemical, rather than
mechanical, weed control by farmers.
Trifluralin residues were detected in an increasing
number of agricultural soil samples in the National Soil
Monitoring Program (NSMP) between FY 1969 and FY 1973.
The arithmetic mean concentration of trifluralin in the soil
samples (less than 0.01 ppm), however, did not change
significantly during this period.
Trifluralin residues in crop samples collected from
NSMP monitoring sites from FY 1969 to FY 1973 were found in
three of 41 crop materials: cotton stalks, sorghum stalks,
and soybeans. These values ranged from 0.01 to 0.31 ppm;
most were less than 0.1 ppm. A total of 3,576 samples were
analyzed during this period.
-25-
-------
The Urban Monitoring Program has sampled 42 urban
areas since 1971. This program has detected trifluralin in
only two urban locations, San Francisco, California and
Springfield, Illinois, at an average level of 0.05
and 0.01 ppm, respectively (Kutz, 1977).
Air was. monitored for pest-icides- in 1970 and 1 972 in
predominantly agricultural areas of 16 States; trifluralin
war found in 11 of-" the States (Kutz, J977).. The maximum
values detected ranged from 1.1 to 30.3 nanograms (ng) per
cubic meter of air.
The Market Basket Survey of the Food and Drug Adminstra
tion (FDA) monitors, pesticide residues in a samp.le daily
diet of an average 16 to 19-year-old American male in
various regions of the country. To date, trifluralin has
nat. been detected 1n this survey (Cornel 1 ussen 1 978).
The FDA surveillance and compliance program's multi-
residue method can detect trifluralin at 0.01 ppm or greater
in commodities. In 1975 trifluralin was not detected in the
8,009 samples analyzed in that program. Ia 1976 trifluralin
was found at 0.10 ppm in one parsnip sample and at 0.03
and 0.04- ppm in two carrot samples out of a total of 8,416
samples. In 1977 trifluralin was detected at 0.02 ppm in one
potato sample, at 0.04 ppm 1n one parsnip sample, and in 16
carrot samples at levels ranging from 0.03 ppm to 0.19 ppm.
There were 6,674 samples analyzed in that program in 1977.
26
-------
Trifluralin has not been reported in the APHIS (USDA)
"Objective Phase Biological Residue Report (1 973-1 976)".
EPA's Storet System, which maintains data on water quality
parameters, has no data on trifluralin.
The National Soils Monitoring Program, FDA's Market
Basket Survey, and FDA's surveillance and compliance program
for food and feeds have not monitored for NDPA (Cornellussen,
1978), nor was NDPA reported on the APHIS (USDA) "Objective
Phase Biological Residue Report (1973-1976)". EPA's Storet
System of water quality parameters currently contains no
monitoring data for NDPA; however, NDPA is one of the
compounds on the List of Priority Pollutants whfch EPA will
monitor in water.
D. Biological Fate
The ability of living organisms to absorb, translocate,
and metabolize a compound is important in determining
whether various toxic effects occur. Since no studies of
I
the biological fate of trifluralin and NDPA in humans
exists, a number of studies with various animal species
were reviewed in order to determine the fate of these
compounds in living organisms. These and the biological
fate of trifluralin ad *NDPA in plants are discussed below.
1~ Tr1flurali n
Generally, trifluralin 1s not readily translocated to
the above-ground portions of most tolerant plants. However,
-27-
-------
certain root crops, such as carrots, onions, and garlic,
have been showrr to absorb and metabolize, the compound
(Probst et al., 1967). Peanut and sweet potato leaf extracts
also metabolize trifluralin. Even though some plants may
metabolize trifluralin, significant residues of trifluralin
or its degradation products reportedly do not accumulate in
edible portions of plants (Probst et al., 1975).
Marine- 1nvertebrates~metabol iz.e triflural in through
the pathways of oxidatfon, reduction, hydrolysis, and conjuga
tion (Garnas, 1976). Spacie (1975) found that trifluralin
accumulated in the fat of three species of fish exposed to
874 ppt trifluralin in an industrial effluent. Levels
decreased in two species by 40% to 835 after activated
carbon filtration of the industrial effluent started. The
fish exhibited no acute effects during this investigation.
Irr degradation studies with ruminant animals,
trifluralin- was fed to a- lactating cow and a goat; blood,
milk, feces, and urine from the treated animals were then
analyzed for trifluralin or its metabolites. No residues
were detected in milk or blood. Detectable residues were
found only in feces of a cow fed 1,000 ppm trifluralin for
16 days, and 1 rr the feces (81.25) and urine (17.81) of a
goat fed' 1 ppm trifluralin for 16 days. Little trifluralin
was metabolized; most passed through the animals unchanged
(ffolab et al., 1969). Williams and Feil (1971) found that
two of 12 species of rumen bacteria tested metabolized
triflural 1 n.
-28-
-------
Male Harlan-W1star rats excreted 80% of a single 100
mg/kg oral dose of trifluralin, in the feces (Emmerson and
Anderson, 1966). Female dogs also metabolized trifluralin.
Nelson et al. (1977) also studied the in vitro
metabolism of trifluralin and other dinitroani1ine herbicides
in rat liver microsome preparations. In addition to other
metabolites, Nelson detected minute amounts of a possible
benzimidazol e compound from tri f 1 ural.tn. metabol i soi for the
first time in a mammalian system..
2. NDPA
Nitrosamines are reportedly metabolized relatively
rapidly by animals (Office of Research and Development,
1977). In the absence of metabolic enzymes, they are
chemically stable under physiological conditions; metabolic
activation to a reactive intermediate is necessary for
adverse effects to occur (Montesano and Bartsch, 1976).
Metabolism by oxidative dealkylation beginning at the
alpha carbon of one chain ultimately lead'ing to a reaction
with cellular macroniolecu!es has been proposed by several
scientists (Druckery et al., 1969; Brusik and Mayer, 1973).
Krueger (1971, 1973, 1973a) found that NDPA undergoes beta
hydroxylat 1 on ultimately producing alkylating compounds that
react with nucleic acids in the rat liver. Blattman and
Preusman (1973) reported omega oxidation and" omega-1-oxida-
tion in a study of rat urinary metabolism of NDPA. The
oxidation scheme is but one potential mechanism Involved in
29
-------
dialky1 ni trosamine metabolism. Three other schemes involving
protolytic fragmentation have been suggested to explain
experimental observations which are inconsistent with the
oxidation model (Olah et al., 1975)•
Samples of soybeans, cotton, cauliflower, carrots,
and alfalfa, grown in soil treated with Treflan contaminated
w-ith from 78 to. 500. ppm NDPA had- no detectable levels, of
NDPA at a test sensitivity of 0.10-0.20 ppb (West and Day,
1977a). Wherr Berard (1977) grew soybean plants in a nutrient*
solution contal ni ng^C-1 abeled NDPA, about 255 of the
applied radioactivity translocated to the soybean plants;
however, only 1% of. the radioactivity was identified as NDPA
after seven days. Berard did not attempt to identify the
remaining radioactivity* Berard and Rainey (1977) performed
a fie-ld study irr which soybeans were grown in soil treated
with the equivalent of 5,000 ppm NDPA.. They detected less
14
than 0.3 ppb C expressed as NDPA equivalent at 21 and 49
days, and detected no residue in soybean seed after 119
days.
NDPA was readily absorbed and passed into goat's milk
after a single oral dose of 30 mg/kg body weight. The
detectable quantity of NDPA In milk peaked at 5.8 mg/kg
after 0.5 hours. After 24 hours only a trace remained,
and none was detected at 36 hours. NDPA levels in the blood
were 1.578 mg/kg after one hour and 0.0004 mg/kg after six
hours (Juszkiwicz and Kowalski, 1975).
-30-
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£. Exposure Analysis
This section discusses only the exposure to NDPA
which is associated with the use of formulated tri f1ural1n ,
not with exposure to tri f1ura1i n itself. This is because
the primary concern relative to the toxicity of this compound
(for RPAR purposes) 1s associated with Its NDPA contaminant.
Tri flurali n exposure is discussed briefly in the appropriate
sections of this document which-present evaluations of
specific toxic effects and in full in the Agency's exposure
report for trifluralin and NDPA (Mittelman, 1978).
1• Exposure During Application
Humans who use trifluralin and are therefore potentially
exposed to NDPA include agricultural and nursery workers who
mix, load, apply, and incorporate the compound into the
soil; fieldworkers; domestic users; and the population at
large. The Agency has estimated NDPA exposure from Treflan
use, and this provides the basis for the
estimates presented here (Mittelman, 1978).
Exposure estimates in this document are given for
workers on average size farms for each of the uses
assessed. The Agency estimated the number of workers who
apply Treflan from Agency information, Doane Agricul-
tural Statistics data, personal communications with USDA,
university and other experts, and the registrant. In
arriving at the estimate, the Agency assumed that there is
-31-
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only one private applicator per farm. Figures derived
/
1n such a fashion may underestimate exposure to applicators
on larger farms. However, large farms use more efficient
apparatus, larger spray booms, faster tractors with enclosed
cabs, larger spray tanks, and several applicators, all
of which tend to lessen any increase in exposure.
The. extent of exposure to applicators, incorporatcrsr
mixers, and loaders depends on their rate of respiration,
time exposed, climatic condition (wind speed, ambient
temperature, humidity), soil conditions (soil temperatures,
organic matter content of the soil, moisture content), rate
of trifluralin application, NDPA content of the_trif1ura1in,
and other variables. Of the factors affecting NDPA exposure,
total time exposed is the most important. This factor, in
turn,, depends upon the total acreage involved,, speed of
performing constituent operations, condition of the field,
and the apparatus used- Time is thus a highly variable
parameter.
Exposure estimates were based on studies reported 1n
the open literature and field monitoring studies performed
by the registrant. The Treflan EC used in field monitoring
studies contained from 3.5 to 6.4 ppm NDPA (Day et al.,
1978). In these studies sources of exposure, which
included vapor inhalation, particulate inhalation/ingestion,
and recovery from the soil surface, were effectively measured
for NDPA. Due to the volatility and photo!abi11ty of NDPA,
monitoring for dermal exposure was not successful and
resulted in extremely low NDPA recovery.
-32-
-------
Results of vapor phase sampling studies Indicate an
average concentration of 0.0047 ug NDPA/ m of air in the
breathing zone during application and simultaneous Incorpora-
tion plus about 0.0001 ug NDPA/nr adsorbed to particulate
matter that can be inhaled or ingested during soil treatment.
Ouring mixing and loading, the concentration of NDPA 1n the
air was determined to be 0.012 ug/m . The Agency calculated
vapor/particulate NDPA exposure via inhalation and ingestion
from the following:
ETI -
-------
The Agency calculated dermal exposure to applicators,
Incorporators, mixers, and loaders from, results obtained
in an experiment using an artificial adsorber. Such an
estimate is inexact, but it is likely to be closer to
actual levels than an estimate calculated on a worst-case
basis or using zero from the unsuccessful dermal monitoring
studies (Day et al.f 1978). Hourly dermal exposure was
calculated to be 0.083 ug/hr (Mittelman, 1978)^ The Agency
then calculated total dermal exposure for applicators,
incorporators, mixers, loaders, and private farmers
incorporating custom-applied Treflan as follows:
Etd « CHa)(£hd)
where:
Etd s Total exposure (dermal)
=¦ Hours applying- trifluralin/year
=. Hourly dermal exposure during application
= 0.083 mg/hr
The true dermal exposure is difficult to assess due
to the absence of an acceptable method of measuring this
factor. Dermal exposure is important since it is generally
much higher than inhalation exposure. These exposure
estimates concern only that amount of NDPA deposited upon
the skin. The risk estimates discussed later in this
document adjust the total NDPA dermal exposure estimate for
the proportion of NDPA that is thought to be absorbed.
9
-34-
-------
Table 6 summarizes the total NDPA exposure to persons
who apply Treflan (contaminated with 3.5 to 6.4 ppm.NDPA) to
various crops. Exposure to private and commercial applicators
is presented separately. Private applicators apply and incor-
porate the material whereas commercial applicators normally
only apply the material. The farmer must then incorporate
this commercially-applied material within 24 hours. Table 6
groups exposure to private applicators/. incorporators and
incorporators of commercially applied Treflan together
(Group I), and lists commercial applicators (Group II)
as a separate category. Differences in total NDPA exposure
estimates between private workers who perform all kinds of
application operations and those who only incorporate
commercially-applied Treflan are small. Incorporators
of commercially-applied material do not mix and load, but
these operations are of short duration. For example, in
soybeans, private applicators of Treflan receive a total
annual exposure of 1.45 ug NDPA, whereas private individuals
incorporating commercially-applied Treflan receive 1.42 ug
NDPA per year, a difference of only 0.03 ug.
2. Exposure During Re-entry
While primary NDPA exposure is likely to occur to
applicators, workers re-entering treated fields may also be
exposed to NDPA as a vapor or NDPA adsorbed to particles of
soil. Exposure from this source was evaluated by two
different methods.
-35-
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TABLE 6
ANNUAL NDPA EXPOSURE TO AGRICULTURAL WORKERS INVOLVEO
IN TRIFLURALIN APPLICATION OPERATIONS
Total Number of
Inhalation/
Application Site
Individuals
Inqestion
Dermal
Total
Group I—
Soybeans
193; 13?
0.1?
r.33"
1.45
Cotton
63,954
0.11
l.Off
1.19
Fruits and Vegetables
•
—
Tomatoes
13,490
0.04
0.42
0.46
Potatoes
1,800
0.05
0.50
0.55
Dry Peas
202
0.13
1.41
1.54
Engli sh Peas
2,776
0.04
0.42
0.46
Field Peas-/
Cole Crops=-
156
0.04
0.42
0.46
4,162
0.04
0.50
0.54
Carrots
657
0.07
0.83
0.90
Peppers
2,267
0.02
0.17
0.19
Celery
166
0.11
"1.33
1.44
Cucumbers
3,030
0.01
0.17
0.18
Watermelons
2,718
0.02
0.25
0.27
Cantaloupes
Mints*'
335
55
0.03
0.18
0.33
2.16
0.36
2.34
Okra ..
Beans^'
856
0.02
0.17
0.19
23,689
0.07
0.75
0.82
Other Field Crops
Peanuts
4,474
0.06
0.59
0.65
Sugar Beets
5,178
0.14
1.66
1.80
Sunflowers
5,523
0.13
1.50
1.63
Miscellaneous Crops,
Trees and Vines —
.6/
Hops
Greens^-'
Dill
Alfalfa
Spring Wheat
Mustard for seed
Saff1ower
Sugar Cane
3,985
0.07
0.75
0.32.
51
0.23
2.74
2.97
3,259
0.01
0.17
0.18
16
0.08
0.91
0.99
320
0.07
0.83
0.90
890
0.34
4.07
4.41
68
0.12
1.33
1.45
933
0.27
3.24
3.51
116
0.40
4.65
5.05
-------
Group II
All Crops
(Commercial Applicators) 3,800 0.14 1.74 1.88
TOTAL 342,064
^ These estimates apply to both fanners who mix, load,
apply, and incorporate the pesticide as well as those who
only incorporate commercially-applied Treflan.
2/ Cole Crops: brussel sprouts, cauliflower, cabbage,
broccol1.
3/ Mints: spearmint, peppermint.
7/ Beans: castor, snap, lima, southern peas, guar, mung, dry
?/ Tree and Vine: grape,-lemon, grapefruit, nectarine,
orange, tangelo, tangerine, almond, apricot, peach,
pecan, plum, prune, walnut.
y Greens: collards, kale, turnip,, mustard.
-37-
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In the first method, Mittelman (1978) calculated a
3:1 ratio of recoverable volatilized NDPA in the air between
a model system (Oliver, USDA,. unpublished data, 1978) and
•a field monitoring system (Day et al., 1978) (discussed
earlier 1n Section II. B.). From this ratio, the Agency
calculated the quantity of volatilized NDPA for 12, 24, 48,
96, and 192 hours* post-treatment", thusr
The concentration of NDPA in the air was then
evaluated for re-entry periods (the interval between the
time a pesticide Is applied and the time a worker re-enters
the field) in soybeans, cotton, beans, tomatoes, cole crops,
and tree and vine crops- Tables 7, 8, 9, and TO summarize
these findings. From this analysis the Agency determined that
there would not be quantifiable inhalation exposure to NDPA
from the air over treated soybean and cotton fields at the
average time of first re-entry (day 14 and day 30, respec-
tively)- Based, on this model, the total annual NDPA exposure
for a field worker performing all re-entry activities in the
remaining crops assessed would be:
Time
(hours)
NDPA In Air
nq/m3
6-12
12.-24
24-48
48-96
96-192
1.01
0.68
1.75*
0.56
0.39
Crop
Total Exposure
(Dermal^Inhalation;
ug/Year)
Beans
Tomatoes
Tree and Vine
Cole Crops
0.05
0.09
0.24
0.09
V Water was applied to soil at this point, increasing NDPA
volatilization from soil.
-38-
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TABLE 7
WORKER RE-ENTRY EXPOSURE TO NDPA IN BEANS
(ug/year)
Activity
Average Days Hours Spent Concentration
After Treatment In Activity
In Air - Inhalation Dermal—^ Total
(Range) Per Year (Hlcrograms/m ) Exposure Exposure Exposure
Second
Incorporation^-'
Planting
Tillage
Irrigation
Harvest
7
(0-14)
18
(0-35)
42
(28-56)
56
(28-84)
98
(49-147)
6
13
20
8
32
0.00039
0.003
0.042
0.05
TOTAL - 0.05
1/ 10% of total Is bedded cultured requiring no second Incorporation.
?/ This Is estimated to be 15 times Inhalation exposure.
-39-
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TABLE 8
WORKER RE-ENTRY EXPOSURE TO NDPA IN TOMATOES
fug/year)
Activity
Average Days Hours Spent Concentration ~7.
After Treatment In Activity In Air Inhalation Dermal-' Totql
Seeding^
3
8
(0-7)
Tillage
42
5
(One time)
(28-56)
Irrigation
45
8
(Four times)
(7-84)
Hand Hoeing
35
125
(28-42)
Harvest
105
16
(90-120)
0,00056
0.005 0,08) Q.09
TQTAL p 0.09
1/ Most tomatoes are directly seeded (90%) and do not require second Incorporation.
7/ This Is estimated to be 15 times Inhalation exposure.
-40-
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TABLE 9
WORKER RE-ENTRY EXPOSURE TO NDPA IN TREE AND VINE CROPS
("g/year)
Activity
Average Days Hours Spent Concentration ~Z.
After Treatment In Activity In Air - Inhalation Dermal—' Total
(Range) Per Year (Mlcrograms/m ) Exposure Exposure Exposure
Second
Incorporation
Planting^
Irrigation
(Eight times)
Tillage and
Spraying
Harvest
3
(0-7)
7
(0-14)
45
(7-210)
134
(28-240)
210
(150-270)
6
24
16
66
224
0.00056
0.00039
0.004
0.06
0.06
1/ Fifty percent of total acreage consists of new planting.
?/ This 1s estimated to be 15 times Inhalation exposure.
Q.OU
0.165 0.18
totAl « 0.09
-41-
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TABLE 10
WORKER RE-ENTRY TO NDPA IN COLE CORPS
(ug/year)
Average Pays
After Treatment
(Range)
Hours Spend Concentration ~ 1 ~
In Activity In Air Inhalation Dermar' Total
Per Year (ug/m3) Exposure Exposure Exposure
Activity
Second
Incorporation
Direct Seedling^
Tillage
(Two times)
Hand Hoeing
Irrigation
(Six times)
Harvest
0
(0-7)
3
(0-7)
45
(28-63)
42
(28-56)
45
(7-84)
105
(84-126)
16
12
44
(225-1100)
0.00056
0.00056
0,002
0.004
0.030
0.060
0,03
0.06
Total 0t09
1/ Sixty percent of total acreage 1s directly seeded; transplanting requires about 9f>
hours per worker.
2/ This Is estimated to be 15 times Inhalation exposure.
-42-
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In this model the Agency chose not to include a
factor for photodegradation of NDPA, a well-established
characteristic discussed in Section II (B) of this document.
Therefore, in the second model the Agency incorporated
factors for photodegradation into these calculations, which
resulted in an estimate of even lower levels of NDPA in the
air at times when workers are in'the field.
In order to estimate such NDPA exposure considering
photodegradation the Agency used the study by Oliver
previously discussed (USDA, 1978). In that study by Oliver
NDPA volatilization from soil which had been treated' with
trifluralin containing 18 ppm NDPA was monitored over an
eight-day period. In the first six hours 1.46% of the NDPA
had volatilized into the air above the soil, and after
eight days a total of 3.77$ of the applied NDPA had
volatilized. Very little additional NDPA volatilized after
two days.
-42a-
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An upper limit to the air concentration of NDPA
was calculated from an assumed application rate of 1.29
pounds of active ingredient per acre, 3.5 ug NDPA/g active
ingredient, a volatilization rate of 1.465 of this material
into a 2-meter layer of air above the field in the first six
hours, and no dilution from air convection. The concentration
was estimated to accumulate to 8.4 nanograms NDPA/m^ of
air in the absence of photodegradat1 on. However, with a
photodecomposition half-life of twenty minutes, the concentra-
|Q 3
tion would likely decrease to (1/2) x (8.4 nanograms/m ),
which is a negligible amount.
Dermal NDPA exposure from contact with the compound
in soil during re-entry to treated fields is theoretically
possible. This quantity is difficult to estimate because of
the extreme variability of the field activities performed, the
degree of physical contact with the soil by workers,
the amount of exposed body area, the length of time exposed,
and the partitioning co-efficient of trlfluralin between
soil particles and the part of the human body which comes
into contact with the soil. This exposure is expected to be
low, if it exists at all, since the level of NDPA in the
product 1s already low and application disperses it still
further. To quantify this, an upper limit to the level of
potential exposure to fleldworkers was calculated. West and
Day (1977) found up to 0.19 ug NDPA/kg soil 26 days after
application of 0.75 lb active 1ngredient/acre. The trifluralln
used contained from 78-252 ppm NDPA.
-43-
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If 1t Is assumed that a worker entering the field has
a total uncovered skin surface area of 2,900 cm (Mittelman,
1978), and that a uniform layer of soil forms a film on the
uncovered skin 1.0 mm thick,, the maximum quantity of NDPA
can be calculated thus:
S « (SAg)(T)(Q)
wher&:
S » Quantity of soil on exposed skin (grams)
SAg » Exposed body surface area
T * Soil layer thickness on skin area
Q * Quantity of soil in a cubic meter
(assuming a soil density of 3.0)
S-. » (Q.29m2) (0.001m) (3 ,000,000 g/m2) =- 870 g
Then the NDPA in the soil adhering to the exposed skin would
be calculated thus:
NDPA in soil orr skin » (S)(Rs)
where:
S * Quantity of soil on exposed skin (kilograms)
Rs ¦ NDPA soil residue (based on old trifluralin having
front 78-252 ppm NDPA contamination)
NDPA in soil on skin * (0.87 kg) (0.19 ug/kg in soil)
» 0.1653 ug
-44-
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By this model, 0.1653 ug NDPA would be in the soil
adhering to the skin. However, only an unknown fraction of
this amount is actually expected to translocate into
the body. This would depend upon the amount of NDPA that
moves from the soil to the skin surface, the amount that
penetrates into the skin (assumed to be about 22% by CAG),
the actual contamination level in the product (currently
less than 1 ppm as opposed to 78-252 ppm 1n the study
leading to the 0.19 ug NDPA residue), the photodegradation
of NDPA in the soil or on the skin, and other factors.
By applying the penetration factor of 22*, the level decreases
to about 0.036 ug during re-entry if all NDPA adsorbed onto the
soil particles is assumed to move from the soil -to- the skin
surface.
3. Exposure to Other Workers
In addition to these large groups, several smaller
groups use or are exposed to trifluralin products: nursery
workers, aerial applicators, flaggers, and landscape contrac-
tors. Exposure of aerial applicators and flaggers to NDPA
is unknown but negligible compared to that received by
ground applicators, because little trifluralin is applied
aerially (Mittelman, 1978).
A small but unknown number of individuals apply
Treflan EC to nurseries. This product 1s applied by proce-
dures similar to those used on agricultural sites. Exposure
to these nurserymen is not likely to differ from that to
applicators for other agricultural uses.
-45-
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In addition, a small number of nurserymen and landscape
contractors apply Treflan 5% granular product. There are no
data with which to quantify potential inhalation exposure
from- this use. Assuming normal care is used, it is unlikely
that significant dermal exposure would occur during applica-
tion of this formulation (due to lack of contact with the
granules by the applicator during application (Mi ttel man,
T978JV
4. Potential Formation of N-nitroso Compounds
After Treflan Application
01propyTamine is expected to be a carryover product
at levels to 10 pprrr during production of tri f 1 ur-a>i n. Day
et al. (1977) found that dipropyl amine, a material used in
the synthesis of Treflan, reacted slowly with the nitrite
present 1n liquid fertilizers to form low concentrations of
NOPA (0.002 ppm) over a 42-hour period. However, 48 hours
after mixing Treflarr with various liquid fertilizers, Day
detected no increase in the NOPA content of the Treflan.
One of tri f 1 ural i n1 s photodecompos1tion products 1s
2.,5-d.i nitro-N-n-propyl-tri fl uoro-p-tol uidi ne (Leitis and
Crosby, 1974; Soderquist et al., 1975 ). A potential N-nitroso
product 1n soil would be 2,6-dinitro-N-nitraso-N-n-propyl-
tr1fluoro-p-toluidine- Galab and Althaus (undated)
applied *^C-Tabeled trifluralln to field plots at the rate
of 1.5 lb active 1ngredlent/acre to soil fertilized with 500
lb/acre of 6-24-24 fertilizer. Analysis by Thin Layer
-46-
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Chromatography and Liquid Scintillation Counting four months
after application revealed a.potential concentration of
0.08 ppb of such a dealkylated N-nitroso compound in soil.
Since this level was lower than the reliable sensitivity of
the test method {0.1 to 0.5 ppb), it is not certain that the
compound is actually formed in the soil. Even assuming that
the compound is formed, the maximum level in soil would be
0.08 ppb; and, therefore, human exposure 1s likely to be
insignificant (Mittelman, 1978).
5. Exposure From Products Used Around the Home
A number of products containing trifluralin are
formulated for use around the home. The concent-ration of
trifluralin in these products is generally low; only a few
contain greater than 2.8* trifluralin. Because of the low
use of trifluralin 1n this group, low concentration, applica-
tion procedures which lead to little physical contact, and
the small size of treated areas involved, the Agency does
not expect that homeowners would be exposed to measurable
levels of NDPA from such uses.
NDPA levels reported to the Agency for a number of
home use products produced from old manufacturing use
trifluralin (having much higher NDPA levels than that
presently produced) are summarized in Table 11- Such
products should contain even less NDPA as the new trifluraliTi
which has Tess than 1.0 ppm NDPA 1s introduced into commerce
during 1979.
-47-
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TABLE 11
(Mlttelman, 1978b)
NDPA LEVELS IN PRODUCTS FORMULATED FROM OLD TRIFLURALIN
Trifluralin In Formulated
Products (S)
Concentration of
NDPA Reported (ppm)
1.47
1 -75
3-0-
5-Q
9.0
< 0.1
0.5 - 0.8
< 0»1
0.45
0.6
Note:v The-level of detection was 0*. V ppm in' these analyses.
Two of these analyses showed no detectable residues
of NDPA in the product. Those remaining contained an amount
that would be below the level of detection when applied to
the soil. —• -
This- discussion of potential dietary exposure is
confined to NDPA residues in treated crops since the cancer
risk (the only quantifiable risk in this assessment) is a
property of the NDPA. contaminant of trifluralin.
West and Day (1977a) could not detect NDPA at a test
sensitivity of 0.10 to 0.20 ppb in crops grown on agricultural
land treated for successive years with Treflan EC, which
contained as much as 450 ppm NDPA. Crops analyzed included
soybeans, mature cotton seed, mature cauliflower (fruit and
leaves), mature carrots (roots and tops), volunteer alfalfa,
and cotton seedlings.
6- Dietary Exposure
a- ' Background
-48
-------
Laboratory studies, however, have indicated that
nitrosamines can be taken up by plants, at least during the
short-term. In a study by Dean-Raymond and Alexander (1976)
during which relatively large amounts of dimethylnltrosamlne
(DMN)were added to soil in clay pots, lettuce and spinach
assimilated DMN during a 2-to 15-day interval 1n proportion
to the amount added to the pots in which they grew. Berard
(1977) grew soybean plants with their roots immersed in a
nutrient solution containing 0.17 ppm NDPA (6.72 ug/container)
The I0-day-o1d plants took up 0.3 to 0.8 ug equivalents
of radio-labeled NDPA over a seven-day treatment period.
Berard and Rainey (1977) planted soybean seeds in
soil treated with Treflan EC, to which radio-labeled NDPA
had been added at a concentration equivalent to 5,000 ppm.
These soybean plants contained 0.00025 ppm and 0.00012 ppm
NDPA equivalents after 21 and 49 days, respectively. In
this test, control plants contained background radioactivity
levels equivalent to 0.00010 ppm and 0.00006 ppm NDPA at the
same sampling time. In addition, seed from soybean plants
harvested 119 days after the Initial soil treatment with
Treflan contained no radioactive residue.
b. Exposure Estimate
To maintain consistency within the various exposure
estimates, the Agency estimated dietary residues based on an
NDPA contamination level of 5 ppm in the formulated product
(Treflan EC). At this level in the Treflan EC formulation,
-49-
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the ratio of trifTuralin to NDPA 1s 89,000 to 1. The Agency
used this ratio to calculate the exposure to NDPA from data
on trifluralin. To estimate exposure to Treflan containing
other levels of NDPA contamination, this ratio would be
changed as appropriate-
Trifluralin can be recovered 1n the market basket
survey procedures of the FDA,, but no such residues have been
reported. However^ there, are a few reports of' tri f 1 ural i n
found by the FDA 1n Its surveillance and compliance programs
for the period 1975-1977. No residues were found in sur-
veys by APHIS of USDA. Furthermore, there are no known
reports of residues of NDPA found in any of these surveys.
For these reasons other means were used to deveTop the
^probable case" exposure (summarized in Table 12 for
trifluraTin and. NDPA)_ This; method, uses information on the
percentage of crop acreage treated, published information on
trifluralin tolerances, data on food factors,, and an
established, trifluralin to NDPA ratio of 89 ,000 to 1 in
formulated TrefTan, The total probable dietary exposure to
NDPA fs about 1.92 x 10"^ mg/kg body weight/day (Beusch
and Johnson, 1978) ~
For comparison, available data on NDPA residue
analyses of the few crops listed above (West and Day, 1977a)
were used to calculate a residue level based on the sensitivity
of the analytical method used. In so doing, it was necessary
to assume NDPA was present in crops at the level of detection
-50-
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TABLE 12
POTENTIAL DIETARY EXPOSURE TO NDPA
Maximum Dally NDPA Intake.
Food Type ^ (x 10 ) mg/kg of Diet^
Asparagus 0.79
Carrots 21.7*1
Citrus Fruit 1.69
Corn, grain 5.62
Cottonseed 0.59
Curcurbits
Cantaloupe 0.21
Cucumber 1.19
Watermelon ... 2.41
Fruiting Vegetables
Peppers 0.26
Tanato 11.09
Grapes/Raisins 0.22
Hops 0.04
Leafy Vegetables
Broccoli 0.37
Brussel Sprouts 0.11
Cabbage 2.76_ „ ,
Cauliflower 0.22
Celery 0.64
Collards 0.43
Kale 0.16
Mustard Greens 0.29
Turnip Greens 0.16
Mung Beans 6.74
Nuts 0.04
Peanuts 0.40
Peppermint 0.52
Root Crop Vegetables
Potatoes 1.62
Safflower 0.17
Seed/Pod Vegetables
Beans 8.66
Soybeans 1.95
Peas 0.54
Qkra 0.39
Dill 0.09
Mustard Seed 0.17
SpeamLnt 0.52
Stone Fruits 0.70
Sugar, Cane & Beet 2.39
Sunflower 0.11
Wheat 0.64
All Foods 76.695^
1/ To estimate exposure to trifluralin containing-1 ppm NDPA
these figures would be divided by 5. ,
2/ Equivalent to 1.92 x 10~y mg/kg body weight/day:
[(76.695 ma/kg of diet) (1.5 kg diet/day)]
60 kg
-51-
-------
for this method (Q.I ppb). Using this method, the total
dietary exposure is 2.3 x 10"^ mg/kg body weight/day- This
estimate has not been used further in the Agency reviews
since it is two orders of magnitude greater than the previously-
stated level, which is the maximum leveT that could be present
if all of the NDPA in trifluralin (at 5 ppm contamination)
were taken up by plants growing on treated sites-
F_ Cancer Risk Assessment'
I- Introduction
The Agency's Interim Cancer Assessment Guidelines
(Cancer Guidelines) (41 FR 21402) state that when a chemical
1s judged to be a potential human carcinogen, the Agency
will estimate Its possible impact on public health at
current and anticipated levels of exposure. The Cancer
Guidelines also recognize that the available techniques for
assessing the magnitude of cancer risk to human populations
based on animal data are at best very crude; this is due to
uncertainties in the extrapolation of dose-response data to
very low dose Tevels and to differences in levels of
susceptibility of animals and humans- Accordingly, these
risk estimates are neither scientific certainties nor
absoTate upper Tirm'ts on the risk of cancer from use of
Treflan- Ratherr these estimates should be viewed as a
heaTth hazard index that incorporates the degree of carcino-
genic activity and humair exposure to the compound.
-52-
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The Agency estimated the risk of cancer to Treflan
users in 1977 when 1t responded to a petition to suspend
registrations for this herbicide (42 FR 40009, August 8,
1977). Due to inadequate NDPA field monitoring data,
additional assumptions to those normally made in risk
estimation were necessary in that analysis. The 1977
estimate is summarized in Table 13.
2. Evaluation of Cancer Data
The Agency's Carcinogen Assessment Group (CAG) has
prepared an update of the 1977 estimate of cancer risk from
trifluralin (Treflan)/NDPA use. This expanded evaluation
(CAG, 1978) was based upon a large volume of dat_a. from the
published literature, special field monitoring data provided
by the registrant, and contact with various experts knowledge-
able in relevant scientific disciplines. These studies are
discussed in the following sections.
a. Tri f1urali n
Three lifetime rodent feeding studies assessed the
carcinogenicity of trifluralin. Two were performed by the
registrant (Worth et al., 1966), and one was conducted by
Hazelton Laboratories America, Inc. under the sponsorship of
the National Cancer Institute (NCI, 1978)-
-53-
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TABLE 13
CARCINOGENIC RISK TO AGRICULTURAL WORKERS FROM A TWO-YEAR PERIOO
OF EXPOSURE TO NDPA-'
Risk
Category 1-Hit Model Log-Problt ModeT
Applicators 7 19
% Individual Risk 2,0 x 10"' 4.5 x 10"*^
Number of Cancer Cases 9.6 x 10"' 2,0 x 10"p
Field Workers a
Jndlvldual Risk 7,1 x 10"? 9.0 x 10"},
Number of Cancer Cases 2.7 x 10~J 3.0 x 10~U
1/ Treflan was assumed to contain 16 ppm NDPA for this
analysis,
-54-
-------
(1) Rat Study R31-61 (Worth et al., 1966)
In this study, male and female Harlan-Wistar rats
were fed trifluralin for two years. Out of the initial six
animals of each sex in each dose group, the proportion of
animals surviving was 1/12 of controls, and 6/12, 4/12,
2/12, and 0/12 in animals dosed with 20, 200, 2,000, and
4 __
20,000 ppm trifluralin, respectively. The animals in the
highest dose group were much smaller and died at a much
earlier age than the animals given other doses. According
to an FDA review (Schultz, 1967), the difference in ages at
death was statistically significant. A variety -o-f. pathological
conditions were observed, but too few of the animals
survived to draw meaningful conclusions. The CAG concluded
that this study showed no evidence of carcinogenicity,
but that the study was not an adequate basis for safety
evaluation because of the low number of animals in each
test group and the low number of animals surviving (CAG,
1978)*
(2) Rat Study R0283 (Worth et al., 1966)
Worth et al. (1966) fed male and female Cox rats
doses of 0, 200, 1,000, and 2,000 ppm trifluralin for two
years. He used 25 animals of each sex per dose group*
There were no significant differences between dose groups in
the number of survivors, food consumption, weight gain,
hematocrit, hemoglobin, red blood cell counts, glucose,
or serum glutamic pyruvic transaminase (SGPT) determinations.
-------
The number of survivors in each group ranged from 9 to 13 of
the Initial 25, except for the group of 1,000 ppm males,
from which only three survived. In the pathological
diagnosis, the only treatment-rel ated effects- observed were:
an increase in pheochromocytomas of the adrenal medulla in
males of the two high dose groups; an Increase In "light
cell" adenomas and carcinomas of the thyroid in the
ma-les of the two hlgjvest dose groups;, and. a higher rat-e of
progressive glomerulonephrosis in all treated males than in
controls. Since only the latter effect was statistically
significant, the CAG concluded that this study showed no
evidence of carcinogenic1ty and that the study was an ade-
quate basis for safety evaluation. Schultz (1967)--, in his
review of this study for FDA, concluded that thyroid and
kidney lesions indicated a possible chronic endocrine system
abnormali ty.
(2) Nd Bioassay (NCI, 1978)
In this- study, trlfluralin was fed to Osborne-Mendel
rats for 78 weeks; the animals were observed for an additional
33 weeks and then sacrificed- The same preparation was
administered to B6C3F1 mice for 78 weeks,, and the animals
were observed for 12. additional weeks and then sacrificed.
The technical grade trlfluralin used in this study
was characterired at the beginning of the bioassay by
melting point range determination and gas-liquid chromato-
graphy. The material had a wide melting-point spread (6°C),
-56-
-------
indicating that more impurities were present than company
specifications indicated. The chromatographs showed 13
minor peaks and indicated a purity of greater than 90S.
Results of a second analytical characterization done one
year later showed no significant sample decomposition. Three
years later (after the completion of the bioassay)^ NDPA was
found in the test material at a concentration of 84 to 88
ppm.
The rats initially received doses of 13,000 and 6,500
ppm trifluralin. In week 22 the doses were reduced to 6,500
and 3,250 ppm because of toxic signs. Then in week 63, high
dose females were fed no trifluralin for a week, then fed
6,500 ppm for four weeks. This cyclic pattern of one week
off and four weeks on was continued for the rest of the
treatment period. In the high-dose male rat.s the cyclic
feeding procedure was started at week 68 of the experiment.
The low dose males and females, however, received a constant
dose. Table 13 gives the time-weighted average doses of
trifluralin and NDPA fed to the rats-
The initial trifluralin concentrations for male mice
were 4,000 and 2,000 ppm; for female mice they were 9,000
and 4,500 ppm. In week 18 the female doses were reduced to
4,500 and 2,250 ppm, and in week 57 the compound was withdrawn
from the high dose group of both sexes. The cyclic pattern
described for the rats of one week off and four weeks on the
compound was continued for the mice until week 78.
-57-
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The time-weighted average doses of trifluralin and
NDPA fed to the mice are tabulated 1n Table 14, along
with the Ttfetime averages- The lifetime of the experiment
was the feeding plus observation time, which was 90
weeks for mice and 111 weeks for rats- During the course of
this bioassay several pathology protocols were irt effect*
each for different periods of time- In addition, the number
of animals for which particular organs, tissues, or lesions
were examined, microscopical ly varied and does not necessarily
represent the number of animals that were placed on experi-
ment in each group.—^
At the dose levels used in this experiment, the
results are inadequate to demonstrate that trifluralin 1s a
carcinogen in Osborne-Mendel rats (NCE,. 1978). The survival
of the rats was adequate, since over 46% of the rats survived
fn alT groups and treated groups did not differ signifi-
cantly from controls- The body weight was uniformly lower
in treated groups tharr controls, and clinical symptoms of
aging were observed, in all groups- The hi stopathol ogi cal
findings were typical of aging rats, with no significant
differences between treated and control groups-
However, 1n female B6C3F1 mice, trifluralin was
associated with" a statistically significant increase in
7/ The Agency's Carcinogen Assessment Group (CAG) considers
these variations to be inconsequential in the final
analysis, since they are adequately accounted for in
the tabulated data-
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TABLE 14
TIME-WEIGHTED AND LIFETIME AVERAGE DOSES OF TRIFLURALIN AND NDPA (ppm)
(NCI. 1975)
Dose Time-Weighted Average _ .-Lifetime Average^
Species Group Trifluralin NDP/ff TnfluraTtn SHE*
Male Rats
High
8,000
.688
5,622
.483
Low
4,125
.355
2,899
.249
Female Rats
High
7,917
.681
5,563
.479
Low
4,125
.355
2,899
.249
Male Mice
High
3,744
.322
3,245
.279
Low
2,000
.172
1,733
.149
Female Mice
High
5,192
.447
5,000
.387
Low
2,740
.236 •
2,375
.205
. _
1/ Average over the duration of dosing and observation. The conversion
factor for rats is 78/(78+83) and for mice 78/(78+12)*
2/ NDPA is assumed to be present at 86 ppm 1n the technical trlfluralin.
-59-
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hepatocellular carcinomas and alveolar/bronchiolar adenomas
under conditions of this experiment (NCI, 1978). Table 15
presents the data on which these conclusions were based.
Although the incidence of squamous- cell carcinomas of the
stomach was not statistically significant compared to either
matched or pooled controls, this tumor type is rarely seen
in this strain of mouse. In fact, in none of the 1,985
untreated female (B6C3F1) mice In the NCI bioassay program
has a> tumor of- th-1 s* type- been found, kith- such a low-
historical background rate (0/1985), NCI considered even one
squamous cell carcinoma of the stomach to be a biologically
significant finding. The NCI report concluded that the
occurrence of*" rel ated proliferative lesions of the stomach
in treated animals provided supplementary evidence that
these tumors were related to the trifluralin treatment. NCI
found no significant differences between treated male mice
and either pooled or matched controls.
The survival patterns were also different for males
and females. The males of both dose groups and the control
group- died earlier in the bioassay tharr did the females; the
male survival rate for all groups was about 40%. In females
the control and Tow dose survival rate stayed above 90S even
at 90 weeks, whereas in the high dose group the 60S survival
paint was at 86 weeks (compared to 63 weeks for high dose
maTes). Since in the last 10 weeks mortality in high-dose
females was accelerated more than in the other groups, fewer
were at risk from late-developing tumors; therefore* the
incidence of tumors in the females of the high dose group
might be underestimated. NCI did not estimate the magnitude
of this effect.
-60-'
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TABLE 15
INCIDENCE OF SIGNIFICANT TUMORS IN FEMALE MICE FED TRIFLURALIN
(NCI>1978)
Lifetime Average
Doses (ppm)
Trlfluralin NDPA
Stomach:
Squamous Cell
Carcinoma
Hepatocellular
Carcinomas
Lung:
A1 veolar/Bronchi ol ar
Adenoma
0 0 0/60 (pooled)
0 0 0/20 (matched)
2,375 0.205 12/47 (26%)
5,000 0.387 21/44 (48%)
0/59 (pooled)
0/19" (matched)
6/43 (14%)
3/30 (10%)
0/60 (pooled)
0/20 (matched)
4/45 (9%)
1/44 (2%)
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(4) Summary of Trifluralin Carcinogenesis Studies
The chronic rat studies submitted In 1966 by the
registrant contained no evidence of carcinogenesis at doses
up to 20,000 ppm. However, the NCL bioassay demonstrated a
significant Increase of hepatocellular carcinoma and alveolar/
bronchiolar adenomas 1n female mice fed trifluralin at 2,375
and 5,000 ppnw Trifluralin induced no detectable carcinogenic
response in male mice, or-fn. rats of erther- sex^ The irregu-
larity of the NCI dosing schedule and the variation 1n
pathology protocols do not invalidate the results of this
test, but the positive response in female mice could have
been caused by the high levels of NDPA found 1n the trifluralin
used in the study. This possibility is discussed further in
the following section.
b_ NDPA
(I) Method
Four rodent lifetime studies on the carcinogenic
effects of NDPA have been published: two concerning rats,
one hamsters, and one mice- NDPA induced a carcinogenic
response in all four studies. In order to evaluate
the possibility that the carcinogenic response observed in
the NCT bioassay was due to contamination by NDPA, the
Agency has reviewed the organs affected in each study and
quantified the potency of the compound in inducing the
effect.
-62-
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To quantify the potency, the Agency evaluated the
slope B of the one-hit dose-response model:
(1) 1=1- exp (-Bdtm)
where:
_I ¦ Tumor incidence after correction for the control
incidence with Abbott's correction factor—''',
t_ ¦ Time during the expe.riment_when the incidence I
was measured {expressed in fractions of a lifetime)
d_ -» Lifetime average dally dose (expressed as ppm
~
equivalent dietary concentration)
m a A constant to be determined from the data^
When the dose 6 1s expressed in these units, it can
be assumed that the potency factor _B is applicable to all
species. This 1s equivalent to assuming that the tumor
Induction time in days is proportional to the animal's life
span, and that the carcinogenic efficacy of administering
the compound at a certain dose rate (1n mg/day) is propor-
tional to the animal's rate of calorie, food, or oxygen
consumption.
87 The factor 1s I « (pt-pc)/(1-p ) where pt is the
proportion of treated antmaTs with tumors ana P is the
proportion of control animals with tumors.
9/ This value is assumed to be 3.0 when no data are available
Tn the experiment-
-63-
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(2) Druckery et al., 1967a
Qruckery et al - (1967a) administered NOPA in the
dally diet to B-D rats at dose levels of 4, 8, 15, and 30
mg/kg/day for the lifetime of the animals- No differences
were observed between males and females. At 30 mg/kg/day,
all 15 rats had liver cancer. At 15 mg/ kg/day, all 15 had
T1ver cancer, and one had esophageal cancer as well. At 8
mgVkg/day, 15 of the 15" had liver cancer, and four-also had
carcinomas of the esophagus and pharynx. At 4 mg/kg/day, 12
of 14 had liver cancer, six had carcinomas at the base of
the tongue, and an unspecified number of others had esophageal
cancer. The average induction time for the tumors (organ
not specified but probably liver tumors) was 120, 155, 202,
and 300 days for the dose groups of 30, 15, 8, and 4 mg/kg/day,
respectively. Using a series of equations described in
detail in the Agency's cancer risk assessment of trifluralin
(CAG,. 1978), the Agency calculated the potency of NDPA
to be- 0.0733 in Druckery's rat experiment-
(3) Rezrtik et al ., 1975
Reznik et al~ (1975) administered NDPA subcutaneously
to Sprague-Dawley rats once per week at doses of 024.36,
48.72, and 97-44- mg/kg/week for life. The surviving controls
were sacrificed 100 weeks after the start of the experiment;
aTT 10 rats 1n each treatment group died by week 71.
-64-
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All animals were autopsied and histologically examined. The
data, presented in Table 16, show that, with the exception
of lung tumors in females, both males and females had a
statistically significant higher incidence of tumors
of the nasal cavity, lung, esophagus, and liver than controls
(p < .05 with no correction for multiple comparisons). The
highest incidence occurred in the. nasal cavity and the
liver. The potency of NDPA in this experiment was 0.0763.
(4) Pour et al ., 1973 -.:jf.-
Pour et al. .(1973) demonstrated the marked, .card nogeni c
effect of NDPA in Syrian golden hamsters. In this study
Pour et al. administered NDPA subcutaneously once per week
to hamsters at doses of 3.75, 7.5, 15, 30, and 60 mg/kg/week.
A control group was used in these experiments, but no data
were given for it. Initially 40 animals (20 females and 20
males) were started in each group. The experiment was
terminated after the death of the last treated animal, and
complete necropsies were performed on all animals except
those lost through cannibalism. Table 17 shows the findings,
which are not broken down by sex, since both sexes responded
in the same way.
-ff 5-
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TABLE 16
INCIDENCE OF TUMORS IN SPRAGUE-DAWLEY RATS FROM NOPA
(Reznlk et al., 1975T
IT
Sex
1/ Average
Survival
(ppm) Time (wks)
Dose Survival 3/
TBA M.N.MS
Nasal Tumors
irar
Endoturblnals Lungs
Esophagus j.1ver
Male
278
24.8
139
26.9
70
39.8
0
78.0
Female
278
27.8
139
35,0
70
38.2
0
85.5
8
6
8
2
8
8
7
5
7/10 p=,00042
5/10 p=,0088
7/10 p=,00042
1/20
1/10 p=,33 4/10 p=,0077 1/10 pa,33 5/10 p?r0018
0/10 3/10 p-.030 5/10 pa,0018 0/10
0/10
3/10 p=.030
0/20
3/10
0/10
0/20
5/10 p w__
1/10 p=,33
0/20
4/10 p=,031 1/10 p=,33 2/10 p=,103
7/10 p=,00042 6/10 p=.00035 1/10 p=.33
5/8 p=.0030 2/8 p=,074 1/8 p=,29
J/20 0/20 0/20
0/10
0/20
1/10 p=,33 6/10 p* ,00035
0/10 2/10 pa,103
3/8 p=,017 0/8
0/20 0/20
1/ Doses are calculated as ppm dietary equivalent assuming
rats eat 5% of their body weight/day. For example, the
highest dose is 97.44 mg/kg/week x 1/7 x 1/.05 = 278 ppm.
2/ Average survival time was not given separately for ma1e$
and females,
3/ Number of tumor-bearing animals, 4/ M =
maxllloturblnals, N = nasoturblnals, MS 3 maxillary sinuses,
_5/ Results of Fisher's exact test for the significance of
the differences In proportions between treated and control
groups are designated as £ values.
-66-
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TABLE 17
INCIDENCE OF TUMORS IN SYRIAN GOLDEN HAMSTERS FROM NDPA
(Pour et al., 1973T
Effective Nasal and Paranasal Laryngobronchtal
1/ Number Average Tumors Tumors Lung Tumors
Dose Of Survival Latency/^ Latency/ Latency/
(ppm) Animals Time (wks) Incidence lifetime Incidence Lifetime Incidence Lifetime
6,7
32
54
22/32
= .69
38/85 -.45
21/32
-.66
38/85
-.45
5/32
-.16
42/85
-.49
13,4
40
49
22/40
-,55
26/85 -.31
32/40
-.80
28/85
-.33
8/40
-.20
46/85
-.54
26,8
36
40
30/36
¦•83
26/85 -.31
34/36
-.94
24/85
-,28
6/36
-.17
28/85
-.33
53,6
40
33
26/40
¦.65
16/85 -.19
39/40
-.98
16/85
-.19
12/40
-.30
28/85
-.33
107.1
37
29
34/37
-.92
24/85 -.28
37/37
-1.0
17/85
-.20
25/37
-.68
24/85
-.28
1/ Doses are calculated as ppm dietary equivalent assuming
Hamsters eat 8% of their body weight/day as follows
(1/7)(1/*08) (dose In mg/kg).
2/ Lifetime was assumed to be 85 weeks In the absence of
(fata on controls. This Is between the standard lifetime of
mice (78 weeks) and rats (104 weeks).
-67-
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Tn the nasal and paranasal cavities, Pour observed
benign tumors, squamous celt carcinomas, and adenocarcinomas.
The number of squamous ceTT carcinomas in all animals
increased slightly with dose, but the number of adenocarcinomas
was strongly dose-dependent- Tumors were also found in
the larynx, trachea, and sternal bronchi. The number of
tumors frr air three areas was dose-dependent, but the-
ratio-of carcinomas, to benign tumars was. not g.iven. Pour'
found adenomas (which were not dose-dependent) as well as
carcinomas (which were dose-dependent) 1n the lung. The
potency of NDPA in producing nasal, 1aryngobronchial, and
lung tumors was 0.354, 0.0722, and 0.0884, respectively,
in this experiment.- .
(5) Dickhaus et al., 1977
Dickhaus et aT- (1977) administered NOPA
subcutaneously once per week to female NMRI mice at dose
levels of 138, 69, and 34.5 mg/kg/week. A control group
was maintained, and the control animals were sacrificed
after the Tast treated animal had died. Table 18 shows the
histopathological findings. Dickhaus observed a high
incidence of tumors in the nasal cavity, respiratory
tract,. Tungs,. and upper gastrointestinal tract in this
experiment. Nasal cavity tumors were squamous cell
papillomas and cardrromas.
Significance at the Towest dose occurred both with
nasal tumors and a combined group consisting of pharynx,
esophagus, and stomach tumors. Although in both cases the
-68-
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TABLE 18
INCIDENCE OF TUMORS IN FEMALE NMRI MICE FROM NDPA
(Dlckhaus et al., 1977 7
Nasal Tumors
y Average Nasal & Endo- Larynx Pharynx
Dose Survival Maxlllo j?/ and Ecto- Trachea Esophagus
(ppm) Time (wks) Turblnals Turblnals Bronchi Stomach LIver Lung
152
29
5/12
PB.052
4/12
p=.033
6/12
p=.0040
7/12
pa.0074
4/12 pa.033
2/12
76
36
4/14
p=,16
7/14
pB ,0029
6/14
p« f0080
7/14
pa»016
1/14
7/14
38
44
9/14
pB,0022
3/14
p=.110
3/14
p-.ll
13/14
p-4.9xl0"6
0/14
11/14
0
79
1/14
0/14
0/14
1/14
i
>
0/14
10/14
1/ Doses are calculated as ppm dietary equivalent assuming
mice eat 13% of their body weight/day. For example, the
highest dose is 130 mg/kg/wk x 1/7 x 1/0.13 = 152 ppm*
2/ The p-values are results of Fisher's Exact Test for the
significance of the difference in proportions between
treated and control groups*
-69-
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tumor response was considerably less at the two higher
doses, this must still be considered an effect of treatment,
since the tumor site is known to shift with changes in dose
for several nitrosamines, including NDPA (Druckery et al.,
1967)- The Agency estimated the potency of NDPA in this
experiment to be 0.391.
c. Comparison of Trifluralin and NDPA Results
4 t
Female mice in the NCI experiment had hepatocellular
carcinomas, lung adenomas, and squamous cell carcinomas of
the forestomach; however, cancer was not induced in male
mice or in rats of either sex. In rats, mice, and hamsters,
NDPA caused benign and malignant nasal cavity tumors, upper
gastrointestinal tract tumors (tongue, pharynx, esophagus,
and forestomach), respiratory tract tumors, and lung tumors.
The organs in female mice in which trifluralin treatment
induced a carcinogenic response are, therefore, also
susceptible to tumor induction by NDPA.
The CAG (1978).evaluated the data, summarized above
to determine whether NDPA levels in trifluralin were
sufficient to cause the responses observed in the female
mice in the NCI experiments The NDPA potencies derived
earlier were used together with the estimated NDPA
concentrations 1rr the NCI test material to calculate the
expected incidence of tumors irr rats and mice. The
potency for mice was assumed to be the same as 1n the
-70-
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Dickhaus et al. (1977) mouse experiment, and the potency
for rats was taken to be the geometric mean of potencies
in the rat experiments of Druckery et al. (1967), Reznick
et al . (1975), and the hamster experiment of Pour et al.
(1973). Tfiese potencies are B = 0.391 for mice and B =
C(0.0733) (0.0763) (0.354) (0.0722) (0.0884)]1/5 - 0.105
for rats-^-^. Using these parameters, the Agency calculated
the theoretical tumor incidences in the NCI experiment.
These are shown in Table 19.
The observed tumor incidence for female mice in the
NCI bioassay was about three times higher than the incidence
estimated in Table 19. At face value this would indicate
that there was insufficient NDPA in trlfluralin to account
for the response of the NCI animals. However, several
factors indicate that the NDPA concentration in the
trlfluralin used by NCI may have been higher than that
measured three years after completion of the bioassay, and
which was the basis of the estimate. FDA analyzed
the test material in March 1976, three years after completion
of the bioassay, and found 88 ppm NDPA contamination. The
test material had been stored in a green glass container,
under fluorescent lights at a room temperature of 27°C
5° during the test and until the FDA analysis (Powers,
1979). Since NDPA is volatile and photolabile, it
is likely that the concentration of this impurity in the
I'd'/ For rats the potency from Pour et al. (1973) was calculated
separately for each of the tumor types {CAG, 1978). The
three separate estimates are used 1n lieu of the 0.641
potency shown earlier in this Section to calculate this mean
potency.
-------
TABLE 19
ESTIMATED AND OBSERVED TUMOR INCIDENCE IN THE NCI
—TRIFLUftALIN T£ST DUE TO NdPA CONTAMINATION
Sex NDPA NDPA Estimated Observed..
Species Level (ppm) Potency B Incidence Incidence^-'
Male Rats
.483
.105
.051
<
.08
.Z4ST
.105" -
.026
<
.08
Female Rats
.479
.105
.050
<
.08
.249
.105
.026
<
.08
Male Mice
.279
.391
.106
<
.30
.149
.391
.058
<
.30
Female Mice
.387
.391
.151
.48
.205 ..
.391
.080
_ . .
.26
T7 In experiments where response was insignificant, an
upper limit was calculated, via Fisher Exact Test, as the
incidence above which the treated group would be significant
at the .05 level.
-72-
9
-------
NCI trifluralin sample was higher than 88 ppo durifig the
period when it was administered to the test animals (CAG,
1978).
The Agency concluded that the NDPA contamination
of the trifluralin used by NCI explains their findings of
hepatocellular carcinoma in female mice. This conclusion
is based on three factors: 1) there is a close similarity
betwen the types of tumor known to be induced by NDPA and
those observed in the NCI trifluralin bioassay; 2) the
incidence of tumors in the NCI study was only slightly
lower than that predicted from data assuming an NDPA
contamination level of 88 ppm; and 3) that NDPA levels in
the material tested by NCI were probably higher than 88
ppm measured three years after the test and which was the
basis of the estimate.
The primary trifluralin registrant is now performing
tests to detect the carcinogenicity of trifluralin in
which NDPA contamination has been reduced to undetectable
levels. The Agency will evaluate results from this test
when it is completed. These results should be available
during the first-half of 1980....
10/ For rats the potency from Pour et al. (1973) was calculated
separately for each of the tumor types (CAG, 1978). The
three separate estimates are used in lieu of the 0.641
potency shown earlier in this Section to calculate this mean
potency.
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3. Cancer Risk Estimate
a. Application-Related Risk
The Agency based its estimate of human exposure to
trifluralin and its NDPA contaminant on field studies
using commercial Trefl'arr EC containing NDPA at a level of
3-5" to. 6.4 ppm (average of 5 P'pm). This estimate was
discussed for typical use patterns irr Section IT, E of
this report. The vapor and part-icul ate concentrations of
NDPA and trifluralin were measured during field applications
of Treflan EC under conditions similar to actual field
use. These measurements were used to estimate the average
yearly inhalation exposure.
The only information available for estimating the
amount of NDPA absorbed across the skin is from a rat
dermal absorption study submitted by the registrant
(Hanasono et al.y 1978). From this experiment, CAG
estimated that 22% of the NOPA deposited on the skin is
absorbed. The rest is either bound to the skin or escapes
Into the air. This is a crude approximation of the actual
situation because it assumes that steady-state conditions
are reached fn much less than one hour, and that no
Tong-term storage of NDPA would, occur in the skin.
Based upon the rationale discussed 1n the preceedlng
Section, the Agency calculated the lifetime risk of cancer
to individual farmers who use Treflan assuming that the
-74.
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individual lifetime risk, J*, from the NDPA equals J3x, where
£ is the likely value of the slope parameter for the compound
(0.4) and jc is the lifetime average daily NDPA intake
expressed as ppm in the diet.—^ Using this technique,
the number of cases which the Agency estimates to occur from
a lifetime exposure to this population is NBx» where 2i is
the number of people exposed (both private farmers spraying
* .
Treflan in the fields and farmers who assist commercial
spray applicators by incorporating Treflan).
Table 20 shows the individual lifetime risk to
applicators and the total number of expected cases. These
calculations assume a 40-year working lifetime, a 70-year
lifespan, and a diet of 1,94 kg/day; they also assume that
the amount of trifluralin absorbed from the skin is 22% of
the amount deposited on the skin J), and that the amount
absorbed via the lung is 100% of the respiratory intake I_.
The formulas used were:
Risk =• Bx
» 0.4 x 1/365 x 40/70 x 1/1.94 x 10"3 x
(I + 0.22 D)
- 3,23 x 10~7 x (I + 0.22 D)
Number of Cases » NR
11/ Since the value of B is expressed in units of ppm in
"tTfe diet, it is necessary to convert the NDPA Intake to
the same units. For this purpose the daily inhalation and
daily dermal intake in milligrams in divided by the daily
food consumption (1.94 kg) to obtain the equivalent ppm in
the diet.
-75-
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TABLE 20
RISK ESTIMATES FOR TREFLAN APPLICATORS^
Crop
Number of
People
Inhalation
Exposure, _I
(ug/year)
Dermal
Exposure, £
(us/year)
Lifetime
Individual, 1/
Risk x (10"')
Lifetim
Number
Cases
Soybeans
193,138
0.12
1.33
1.30
0.03
Cotton
63,954-
0.11
1.08
1.10
<0.01
Tomatoes
13,^90
0.04-
0.42
0.43
<0.01
Cole Crops
4,162
0.04
0.50
0.49
<0.01
Beans.
23,689
0.07
0.75
0.76
<0.01
Trees and.Vines.
3,985
0.07"
0»75
0.76
<0.01
Hops
51
0.23
2.74
2.70
<0.01
Potatoes
1,800
0.05
0.50
0.52
<0.01
Carrots
657
0.0T
0.83
0.82
<0.01
Okra
856
0.02
0.17
0.19
<0.01
Greens
3,259
0.01
0.17
0.15
<0.01
Spanish Peanuts
4,474
0.06
0.59
0.61
<0.01
Celery
166
0.11
1.33
1.30
<0.01
Peppers
2,267"
0.02
0.17
0.19
<0.01
Mint
55 ••
0-18
2.16
-2.-10-
<0.01
Dill
16
0.08
0.91
0.91
<0.01
Alfalfa
320
0.07
0.83
0.82
<0.01
Spring Wheat
890
0.34
4.07
4.00
<0.01
Mustard Seed
68
0.12
1.33
1.30
<0.01
Safflower
933
0.27'
3.24
3.20
<0.01
Sunflower
5,523
0.13
1.50
1.50
<0.01
Sugar Beets
5,178
0.14
1.66
1.60
<0.01
Sugar Cane
116
0.40
4.65
4.60
<0.01
Cucumbers
3,030
0.01
0.17
0.15
<0.01
Cantaloupes
335
0.03
0.33
0.33
<0.01
Watermelons
2,718
0.02
0.25
0.24
<0.01
Dry Peas
202
0.13
1.41
1.40
<0.01
English Peas
2^776
0.04
0.42
0.43
<0.01
Field Peas
156
0.04-
0.42
0.43
<0.01
Commercial
%
Applicators
3,800
'
(All Crops)
0.14-
1.74-
1.70
<0.01
Total
342,064
<0.04
V Column entry is multiplied by the factor in_the column
heading; i.e., for cotton the risk is 1.1 x 10 .
2/ These estimates were based upon exposure to Treflan containing
5 ppm NDPA. With all other factors being equal, NDPA exposure, and the
risk" therefrom would be directly proportional to the product contamination
level. Therefore, these risk estimates can be adjusted by a factor equal, to
that factor which describes the relation of the contamination level to 5 ppm
if one desires to estimate the risk fran Treflan contamination level other
than 5 ppm.
-76-
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b. Post-Application Risk
Exposure to workers entering the fields after
Treflan has been incorporated into the soil was discussed
in Section II,E,2 of this document. Using the method
reported by Mittelman (1978), the Agency estimated post-
application exposure to NDPA for several crops. The
cancer risk from these types of exposure is summarized in
Table 21. • —•
The expected number of cancer cases was calculated
per 100,000 exposed workers becase an estimate of the number
of field workers working in these crops was not available.
Since this model did not consider photodegradation
of NDPA, CAG (1978) made a second estimate in order to
arrive at a more probable risk estimate for field workers.
This estimate, which was discussed in Section II (E) of this
document, considered such exposure to be negligible; there-
fore, the risk would also be negligible.
c. D1et a ry Risk
Table 22 summarizes the risk of cancer from potential
dietary exposure to NDPA, calculated by using the one-hit
model for risk assessment* The formulas for calculating
the estimates 1n the table are as follows:
1) Maximum Daily NDPA Intake * £t.j x a- x b^ x
1/89,000
-77-
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TABLE 21
POST-APPLICATION RISK ASSOCIATED WITH TRIFLURALIN
(Mlttelman'3 Exposure Method)
Crop
NDPA Exposure/Tear
(Micrograms)
Lifetime Individual
Risk (x 10"')
Lifetime Cases/
100,000 Field Workers
Beans
0-.013
0.042
<0.01
Tanatoea
0.022:
0.069 —
<0.01.
Tree and Vine 0.064
0.210
<0.01
Cole Crops
0.026
• 0.083
<0.01
-78-
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TABLE 22
ESTIMATE OF MAXIMUM CANCER RISK TO THE GENERAL POPULATION^ -
Maximum Daily
Lifetime
Trifluralin
Fraction
Fraction
NDPA Intake,
Individual
Total Num.
Tolerance
of Food
of Crop
(x ICf5)
Risks
of Cases
Food Type (nw/kg of diet)
In Diet
Treated
mg/kff of Diet (x 10 )
Lifetim
Asparagus
0.05
.0014
1.000
0.79
0.315
0.07
Carrots
1.00
.0048
0.403
_21.74
8.690
1.91
Citrus Fruit
0.05
.0381
0.079
1.69
0.676
0.15
Corn, grain
0.05
.0100
1.000.
5.62
2.250
0.49
Cottonseed
0.05
.0015
0.695
0.59
0.234
0.52
Curcurbits
Cantaloupe
0.05
.0052
0.100
0.29
0.117
0.03
Cucumber ¦
0.05
.0073
0.291
1.19
0.477
0.11
Watermelon
0.05
.0143
0.300
2.41
0.964
0.21
Fruiting Vegetables
Peppers
0.05
. .0012
0.378
0.26
_ . Q.102
0.02
Tomato
0.05
.0287
0.688
11.09
. 4.440
0.98
Grapes/Raisins
0.05
.0049
0.079
0.22
0.087
0.02
Hops
0.05
.0003
0.251
0.04
0.017
<0.01
Leafy Vegetables
0.650
0.146
Broccoli
0.05
.0010
0.37
0.03
Brussel Sprouts
0.05
.0003
0.650
0.11
0.044
0.01
Cabbage
0.05
.0074
0.665
2.76
1.106
0.24
Cauliflower
0.05
.0007
0.546
0.22
0.086
0.02
Celery
0.05
.0029
0.394
0.64
0.257
0.06
Collards
0.05
.0008
0.960
0.43
0.173
0.04
• Kale
0.05
.0003
0.960
0.16
0.065
0.01
Mustard Greens
0.05
.0006
0.859
0.29
0.116
0.03
Turnip Greens
0.05
.0003
0.963
0.16
0.065
0.01
Mung Beans
2.00
.0003
1.000
6.74
2.697
0.59
Nuts
0.05
.0010
0.079
0.04
0.018
<0.01
Peanuts
0.05
.0036
0.196
0.40
0.159
0.03
Peppermint
2.00
.0003
0.077
0.52
0.208
0.05
Root Crop Vegetables
0.647
0.14
Potatoes
0.05
.0543
0.053
1.62
Safflower
0.05
.0003
1.000
0.17
0.067
0.01
Seed/Pod Vegetables
0.76
Beans
0.05
.0204
0.756
8.66
3.465
Soybeans
0J5
.0092
0.377
1.95
0.779
0.17
Peas
0.05
.0069
0.138
0.54
0.214
0.05
Okra
0.05
.0007
1.000
0.39
0.157
0.03
Dill
0.05
.0003
0.536
0.09
0.036
0.01
-79-
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Mustard Seed
0.05
.0003
t.000
•* 0.17
0.067
Spearmint
2.00
.0003
0.07T
0.52
0.208
Stone Fruits
0.05
.0125
1.000
0.70
2.809
Sugar, Cane 4 Beet
0.05
.0364
0.117
2.39
0.957
Sunflower
0.05
.0003
0.650
0.11
0.044
Wheat
0.05
.1036
0.011
0.64
0.256
All Foods
76.70
O.OT
0.05
0.62
0.21
0.01
0.06
<8.00
U This table represents a maximum, estimate based upon calculated NDPA residue
levels. NDPA residues have not been detected in the following crops which have
been grown in fields treated" for-successive yeara with Treflan: soybeans, mature-
cottonseed, mature cauliflower-(fruit and leaves), mature carrots (roots and tops),
volunteer alfalfa, and cotton seedlings test sensitivity 0.1 to 0.2 ppb).
2J These estimates were based upon exposure to Treflan containing
5 ppm NDPA. With all other factors being equal, NDPA exposure, and the
risk: therefrom would be directly proportional to the product contamination
level. Therefore, these risk estimates can be adjusted by a factor equal to
that factor which describes the relation of the contamination level to 5 ppm
if one desires to estimate the risk frcm Treflan contamination level other
than 5 Dcm.
-80-
9
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2) Lifetime Individual Risk = Maximum Daily NPDA
Intake x
3) Number of Cases in Lifetime = Lifetime Individual
Risk x 2.2 x 10®
for the i th food item, where,
t^ is the food tolerance for trifluralin
a^ is the fraction of the food in the standard diet
b^ is the fraction of the crop treated with Treflan
The values for t^, a^f and b^ were reported by Agency
health scientists (Beusch and Johnson, 1978).
The risk from dietary exposure is a maximum number
based on the assumption that NDPA residues are present*
These residues may be much lower. In fact, NDPA residues
have not yet been detected in harvestable crops which
have been grown in fields treated with Treflan EC.
12/ 0.4 is a constant calculated earlier for NDPA in this
Section of the document»
-81-
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G. Mutagenesis and Spindle Effects
1. Introduction
4Q. CFH I62.11(a0(3)(ii)(A) provides that-"a rebuttable-
presumption shall arise if a- pesticide*s ingredient^),
metabolite(s), or degradation product(s).... induces mutagenic
affects:, as determined by multitiest evidence~"
The Agency ha3 concluded that the NDPA contaminant of
trifluralin, and therefore products containing trifluralin
# r" * *
exceed the multitest criterion for mutagenicity— [40 CFR
162.11(a)(3)(ii)(A)1 and that a rebuttable presumption
against these registrations should be issued. The Agency's
evaluation of the data upon which this conclusion was based
and its evaluation of the risk from this hazard (Mauer 1978
and 1979) is discussed in the following paragraphs. These
data are summarized in Tables 23 and 24.
V The Agency has also compared the existing data on
trifluralin and its NDPA contaminant to the mutagenicity
testing guidelines contained in its proposed guidelines for
human hazard evaluations (43 FR 37336,- August 22, 1978).
The Agency has concluded that the criterion for mutagenicity
contained therein has also been exceeded by products
containing trifluralin.
-82-
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TABLE 23
MUTAGENICITY TESTS OF TRIFLURALIN (PART I) AND NDPA (Part H)
(Part I)
Test System
Technical Trifluralin
SDecies/Strain
Result
Reference
A. Gene Mutations
1. Bacterial
2. Insect
3. Other
B. Chromosomal Mutations
1. Insect
C. Primary DNA Damage
1. DNA Repair, Bacteria
2. least Mitotic Recombina-
tion and/or Gene Conver-
sion
Unscheduled DNA Synthesis
Salmonella typhimurium
(8 Strains) ?/
Salmonella typhimurium!
TA 100
TA 1535 .
TA 1537
TA 1538 ^
Escherichia coll—
WP2
Drosophila melanogaster
Escherichia coli with
Neg^'
I /
Andersen et al., 1
Tn bacteriophage
Drosophila melanogaster
Escherichia coli
W3110/p 3478
Bacillus subtilis
H17(Rec*)/MU5(Rec")
Saccharomyces cerevisiae
D3
Human Fibroblasts
WI-38 Cells
Neg
Simmon et al.,
197
Neg
Simmon et al.,
197
Neg
Simmon et al.,
197
Neg
Simmon et al.,
197
Neg
Simmon et al.,
197
Neg^
.Murnik, 1978a
2/,6/
Neg
Andersen et al.
, 1'
Negi7
Murnik, 1978
Sinsnon et al.,
19T
Ne^'2/
Simmon et al.,
197
Negl7'^
Simmon et al.,
197
Simmon et al.,
197
-83-
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TABLE 23
MUTAGENICITY TESTS OF TRIFLURALIN (PART I) AND NDPA (Part II)
iPartUl
NDPA
Result
Test System
Species/Strain
Reference
A. Gene Mutations
I*. Bacterial
2- Mammalian Somatic
Cells in Culture
B. Chromosomal Mutations
1- Mammalian cells in
culture
Salmonella typfrimuriumr
Unspecified
TA 98
TA 100 _.
TA 1530
TA 1535
Escherichia coll
Sd-B(TC)
Chinese Hamster
V79 Lung Cells
Chinese Hamster
CHL cells
PosK McCann et aU, 1975
Negft Yahagl et al., 1977
Posi' Yahagi" et al 1977
Pos^' Bartsch et al., 1976
Camus et al., 1976
Pos^ Olajos and Cornish, 1976
Pos—/ Nakajima et al., 1974
Pos^/ Kurokt et al., 1977
Pos^/ Matsuoka et al., 1979
C. Primary ONA Damage
1- Yeast Mitotic Recombination Saccharomyces cerevisiae
and/or Gene Conversion D3 Posi , Brusick and Mayer, 1973
1/ Strains tested with and without metabolic activation.
2/ Test material contained 87 ppm NDPA as a contaminant.
7/ No metabolic activation used.
T/ Preliminary data - sample of test material with NDPA
removed in the laboratory^
5/ Metabolic activation used-
%] Test for rll mutation.
-84-
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TABLE 24
MUTAGENICITY AND RELATED TESTS WITH FORMULATED TREFLAN (PART I)
UNSPECIFIED FORMS OF TRIFLURALIN (PART II)
(Part I)
Test System
Treflan Formulations
Species/Strain Result Reference
A- Gene Mutations
"U Bacterial
2- Insect
B. Chrcmosanal. Mutations
1. Insect
2. Other Studies
Salmonella typhimurium
(8 Strains)
Drosophlla melanogaster
Exposed Humans
Neurospora
Sbrdaria
Negi^ Andersen et al.f 1972
Neg^'-7 Murnik, 1978
Drosophlla melanogaster Pos=^
5/,6/
Po$
p°4;
Pos2/
Murnik, 1978
loder et al., 1973
Griffiths, 1978
* ' Bond, 1978
Test System
Unspecified Forms of Trifluralin
Species/Strain Result Reference
A- Gene Mutations
1. BacteriU
B- Chromoscmal Mutations
L. Plants
Salamanders
(Part II)
Salmonella typhimurium^
TA 1535
Neg
Shirasu
et
al.,
1975
TA 1536
Neg
Shirasu
et
al.,
1976
TA 1537
Neg
Shirasu
et
al.,
1976
TA 1538
Escherichia coli—
Neg
Shirasu
et
al.,
1976
B/r WP2 her*
Neg
Shirasu
et
al.,
1976
WP2 her"
Neg
Shirasu
et
al.,
1976
Haemanthus katheriniae
(Blood lilly)
Tradescantia paludosa
Vicla faba
Triturus helveticus
(salamander)
Pleurodeles waltlii
(salamander)
2/ Jackson and Stetler,
1973
3/ Sawamura and Jackson,
1968 ~
3/ Sawamura and Jackson,
1968
7/ Sentein, 1977
7/ Sentein, 1977
-85-
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TABLE 24
(Part II Continued)
Test System
Unspecified Form of Trifluralin
Species/Strain Result Reference
C- Primary DNA Damage
I. DNA Repair, Bacteria
BacilTus subtil is . ,
H17(Rec-)/M45{Rec") Ne^-'
Shirasu et al.
1976'
\J Metabolic activation not used.
Zf Decreased number of microtubules, accumulation of large
vessicles at the cell plate region.
3/ Disruption of mitotic process, temporarily impeded
chromosome movement.
£/ Chromatid lesions in lymphocytes of workers exposed to
many herbicides.
5/ Preliminary data.
IT/ Product sample used contained 177 ppm NDPA.
7/ Inhibition of mitosis as a consequence of spindle
abnormalities (microtubule and aster formation).
-86-
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2. NDPA Mutagenicity Data
The principal contaminant of trifluralin technical
preparations is NDPA, which is a demonstrated oncogen in
rodents (Montesano and Bartsch, 1976). NDPA has been
studied in ^in vitro mutagenicity assays with bacteria
and yeasts, and in mammalian cell culture, coupled with
appropriate mammalian metabolic activation systems (see
Table 23). In bacterial assays,- NDPA has caused reverse
mutations by base-pair substitution at concentrations up to
1.0 millimole (mM), but only in the presence of complete
liver enzyme preparations from rodents; when the cofactors
for the microsomal mixed function oxidase were omitted, the
mutagenic effect was absent. Positive results for gene
mutation as well as chromosomal aberrations were also
obtained in Chinese hamster lung cell cultures treated with
20 mM NDPA and a rat liver enzyme preparation (Kuroki
et al., 1977; Matsuoka et al., 1979).
Kruger (1973) alqo found direct evidence that
NDPA alters genetic material in vivo; he reported the
presence of alkylated guanine residues in DNA after
administering NDPA to rats.
3. Trifluralin Mutagenicity Data
Positive results have not been obtained in tests
with technical trifluralin containing known and undetermined
levels of NDPA contamination in a number of mutagenicity
systems.. Tests resulting in negative responses are discussed
below-
-87-
-------
a. Bacterial Test3
Simmon et al. (1977) tested 20 pesticides, including
technical trifluralin (90%) containing 87 ppm NDPA (as a
contaminant), in reversion-type mutagenic assays. Four
typhlmurium strains and the WP-2 strain of Escherichia
coll were used, both with and" without" mamnraiiair metabolic
activation systems- Activation was obtained-by using,
liver preparations from rats pre-treated with the
polychlorinated biphenyl (PCB), and Arochlor • 1254
Trifluralin was negative in this study.
Simmon et al. (1977) also tested the same trifluralin
sample for unscheduled DNA synthesis in human fibroblasts
(Wr—38 cells), mitotic recombination in the yeast Saccharomyces
cerevisiae strain D3, and preferential toxicity in repair-
deficient strains of Escherichia coll and Bacillus subtllls
as compared to strains which could repair DNA damage. Each
of these assays was performed both with and without mammalian
metabolic activation, and over a wide range of trifluralin
concentrations~ Trifluralin was negative in all of these
assays. The Agency considers the- experimental and data
reporting procedures used in this study to be adequate
(Sandhu, 1977)* .....
Andersen et al. (1972) evaluated 109 herbicides,
including both technical and formulated (44-..5?) trifluralin.
Specifically, they looked, for induction of point mutations
in a battery of standard bacterial and viral plate assays
-88-
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involving base-pair substitution and frameshift rever-
sions, as well as forward mutation. Results were compared
to positive results with known mutagens specific for each of
four assays; single doses of all test chemicals, including
formulated trifluralin (20 or 25 ug per plate) did- not
induce any changes significantly different from the spontaneous
rates of mutation in eight histidine-requiring mutants of
Salmonella typhimurlum t two rll mutants- of bacteriophage
T4, or Escherichia coll strain KB.
The Agency considers this study to be inconclusive
in demonstrating safety, because no exogenous metabolic
activation was provided to mimic possible conversion- of the
chemical to potentially active intermediates, and only one
dose was administered (Mauer, 1978; Sandhu, 1977).
Shirasu et al. (1976) studied the mutagenicity of an
unspecified form of trifluralin in four histidine-requiring
strains of Salmonella typhlmurium in a standard Ames assay,
as well as in differential toxicity assays with Bacillus
subtllis strains H17 (Rec+) and M45 (Rec~), and in
reversion assays using two strains of Escherichia coll which
require tryptophan. For each of these assays, bacterial
cultures were treated with a single saturated paper disc
containing* 0.02 ml solution of a standard sample made up at
a concentration of 1 mg trifluralin/ml dimethylsulfoxide.
-89-
-------
Trifluralin was negative for mutagenicity in this study,
but 3ince mammalian metabolic activation was not used, and
only one concentration was tested, the Agency regards these
results as inconclusive (Sandhu, 1977).
b- Insect Studies
Preliminary results front a study of both gene and
chromosomal effects In Drosophlla.. melanogaster, (Murnik,
1978 and 1978a) showed "no evidence ... that trifluralin
induces point mutations in Drosophlla," but some of the
results of these two separate studies are contradictory.
Ia one portion of the first study, larvae-were fed a
diet containing 0.01% formulated trifluralin (U4.5$ AI)
throughout their stages, and the number of sex-linked
lethal3 was recorded In the. (second) generation; in
replicate test3, no significant differences were found in
percent lethals between the treated (0.10? for the first
test) and combined control (untreated spontaneous, 0.12$)
groups. No positive controls were reported, and the
formulated, trifluralin tested, contained about 177 ppm NDPA
(Bontoyan, 1978)- In the second portion, feeding adult
males 0.02J of the formulated trifluralin for two days
likewise resulted in no increase in sex-linked lethal3.
A later repeat of this 3tudy with technical
trifluralin which contained no detectable NDPA was also
negative for sex-linked lethal3 (Murnik 1978a).
-90-
-------
Although preliminary results from the two studies
showed no evidence that trifluralin induces point mutations
in Drosophi 1 a, Murnilc reported an increase in chromosomal
nondisjunction. Her first study involved the chronic
feeding of 0.01% trifluralin (formulated) throughout the
larval stages. This resulted in a significant increase
(0.12%) of XXY males compared to those of a control
population (0.04%). However, the feeding of 0.02% trifluralin
(formulated) to adult male Drosophi1 a for two days resulted
in no increase in non-disjunction. XXY non-disjunction was
the only chromosomal effect reported in this test; there
were no increases over controls in chromosome loss (X0
progeny) or breakage. When the chromosomal portion'of the
first study was repeated using technical trifluralin with
no detectable NDPA, non-disjunction was not observed in
test animals at a level significantly different from that
of the control population. Thus these cytogenetic results
are inconclusive, as well as contradictory (Chaisson,
1978).
c» Studies with Fungi
Trifluralin has also been tested for non-disjunction
in Neurospora crassa (Griffiths, 1978), as well as in
Sordaria brevicollis (Bond, 1979). The Agency recently
received a tabulation of raw data from Griffiths which
indicated increased incidences of "aneuploid" ascospores in
treatment groups over a range of concentrations from 1 to
122 mg/1 as compared to controls (rate unspecified), but
-91-
-------
which showed no clear dose-response effect. The preparation
used was reported to be a "formulation" t bu.t no other
details, such as the NDPA level, were given- Hence these
results as well as, data from Bond are inconclusive because
inadequate information is available to indicate whether a
test protocol acceptable to the Agency was followed.
df. Susan Survey
4.
loder et al. (19T3) observed chromosome alterations
in lymphocyte cultures prepared from pesticide applicators.
Blood was drawn once during the mid-winter lull in spraying
operations and again during the peak summer spraying
period- Forty-two white male applicators with from 1 to 25
years (mean exposure, 8.5 years) of prior occupational
exposure to a variety of pesticides were matched as closely
as possible in age and physical characteristics to
a control group of 16 businessmen, students, and teachers
with no history of involvement with pesticides. The exposed
group was further divided into two subgroups. One consisted
of 16 people who had been exposed to a variety of IT
Insecticides, while the other consisted on 26 employees
of weed control agencies who had been exposed to a variety
of 14 herbicides (most frequently 2,4-D, aaitrole, and
atrarine, but also formulated trifluralin)- The incidence
or chromatid lesions per person in the applicator groups
increased significantly over that in the control group, but
only in blood samples taken in the summer- Although loder
et al~ observed no heteroploidy (which may be indicative of
-92
-------
non-disjunction) in any of the exposed or control cells,
they noted a small number of chromatid exchange figures
among the exposed groups. The Agency regards this study as
inconclusive in implicating trifluralin as a chromosome
breaker, since this substance was only one of many pesticides
used by the same workers (Mauer, 1978).
e. Plant Studies
The Agency reviewed a number of plant
studies in order to determine whether trifluralin has the
potential to disrupt the cellular spindle apparatus. These
studies were not performed specifically to assess the issue
. • —« m '
of mutagenicity. In an in vitro and ultrastructural study
in cellwall free endosperm cells of the African blood lily
(Haemanthus katherinae), Jackson and Stetler (1973) reported
that concentrations of trifluralin, ranging from 0.1
through 100 ppb, inhibited the rate at which cells progressed
through all stages of mitosis from prophase to cell plate
appearance. Jackson and Stetler observed these effects by
time-lapse phase microscopy during a two-hour period.
Since 0.1 ppb had a near-maximum inhibitory effect, the
data presented from all concentrations were pooled.
Electron microscopic studies showed a decreased number of
microtubules and an accumulation of large vesicles in the
cell plate region^
While the ultrastructural and mitotic index studies
appear to have been conducted according to established
protocols, the bioassay used to assess these effects is not
-93-
-------
well documented. Further, Jackson and Stetler established
no dose-response relationship included no positive control
1n the study, used no mammalian metabolic activation with
the bioassay, and provided no information on the amount of
NDPA which contaminated the study material. This study
does" indicate, however,. tha-tL tri fl ural i n interferes with
the formation and function of plant cell microtubules, and
it may have a potential, therefore, for disrupting the
mitotic spindle and thereby Inducing numerical chromosomal
aberrations (Sandhu,. 1977).
Sawamura and Jackson (1968) treated staminal hair
cells of the tetraploid, Tradescantia paludosa, and leaf
cells af Vicia faba with 0.2. to 1.6 ppb trifluralin. The
degree of NDPA contamination was not known for this material.
At the highest dose (1.6 ppb),. the authors reported the
appearance of "dicentric bridges" in late stages of mitosis
(anaphase and telophase) in both cell types and cell elonga-
tion' irr staminal hair cells only. This study demonstrates
that trifluralin can disrupt various stages of plant cell
mitosis; however,, it is of limited value since the system is
questionable,. the data are not quantitative, and the study
was not designed to assess mutagenicity (Sandhu, 1977).
-94-
-------
I • wiu I U IIIU l|UC I vwuu
Sentein (1977) reported that trifluralin inhibited
mitosis by interfering with the spindle apparatus in two
urodele salamanders, Triturus he!veticus and PIeurodeles
walt1ii. Eggs of these species were incubated in various
concentrations (1/8 through full saturation) of an unspecified
form of "trifluralin" for one to ten mitotic cycles prior
to the beginning of cleavage, or at tfie'2-, 4-, 8-, and
16-blastomere stages. Cytolog1cal' observations were made
during treatment and after various periods of incubation
following transfer of eggs to triflural1n-free culture
medium. At similar concentrations, the effects ^reported
were more severe in PIeurodeles than in Triturus eggs, but
multinucleate blastomeres and disorganized mitotic figures
occurred in both species. Sentein also reported disturbances
in chromosomal condensation, especially at chromosomal sites
associated with the mitotic spindle attachments, and gaps
(discontinuities) at prophase. According to the author, the
cytologlcal effects of trlfluralin resembled those induced
by classic anti-mitotic agents, but trifluralin was much
less potent. The author concluded that these effects
demonstrate trifluralin interferes with the formation
or function of cell ul ar microtubular elements.
This study is difficult to Interpret because some
details of protocol were not given. For example, the source
and composition of the trifluralin were not stated, nor were
-95-
-------
any control data (the solvent was reported to be polyethylene
glycol) included. The study, however, confirms in an animal
cytological test system the potential anti-mitotic action of
trifluralin previously found in plant cytological studies.
The cytological studies also support the genetic
studies in Neurospora and Drosophila which indicate possible
non-disjunctional activity of trifluralin (Mauer, 1978).
4-. Trifluralin Derivatives
The Agency has also considered the mutagenic potential
of degradation and/or metabolic products of trifluralin.
Section 162.3(e) defines a degradation product as "...a
substance resulting from the transformation of a pesticide
by physlcochemicaT or biochemical means." Evidence indicates
that tri f 1 ural i n mi ght be degraded to a series of products,
including substituted, benzimidazoles in a mammalian-derived
in vitro microsome system (Nelson et al., 1977). Such
conversion has been reported to occur under ultraviolet
photodecomposition conditions, especially in the vapor phase
above treated soil,, as well as in the soil. This is of
concern because some benzimidazoles have been shown to be
mutagenic (Seller, 1972) ~
A recent preliminary report presents some interim
results from bacterial mutagenicity assays performed with
nine trlfTuraTIrr metabolites^ including the benzimi dazol es
-96-
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previously identified (Nelson, 1977), by plate incorporation
at concentrations up to 200 ug per plate using a standard
battery of five Ames test strains of typhlmurium, both
with and without metabolic activation (Nelson, 1978a,
unpublished). In a summary of these results, Nelson
reported that he had found "no potent mutagens among these
trifluralin derivatives tested thus fan?, compared to the
expected response of positive controls appropriate to each
of the test strains. The Agency's inspection of Nelson's
tabulations revealed no significant differences between
experimental and control groups (Mauer, 1979).
5. Mutagenic Risk Assessment
Neither technical nor formulated trifluralin
(containing NDPA at levels up to 177 ppm) have
shown any mutagenic activity. The principle contaminant
of both (NDPA) has induced mutations in various test systems
at concentrations greater than 20 times those contained in
current formulations of trifluralin (< 1.0 ppm Mauer,
1978). NDPA is therefore considered to be a mutagen, and the
Agency has evaluated the potential for mutagenic risk
associated with NDPA contaminated trifluralin.
Two situations of potential mutagenic risk were
considered: The direct DNA/gene effects related to the NDPA
contaminant; and potential effects to the spindle apparatus
induced by trifluralin.
9
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a. DNA/Gene Effects
When testa were performed with metabolic activation,
technical-grade trifluralin (containing about 87 ppm
NDPA) was negative for gene mutations and primary DNA
damage~ Formulated trifluralin (a3 Treflan or unspecified)
was also negative in some of the same tests; however, the
Agency considered results: of these latter tests to. be
inconclusive since they were performed without metabolic
activation. Other preliminary studies indicate that
Treflan containing 177 ppm NDPA, as well as trifluralin
with no detectable NDPA, give negative results in the
Drosophila sex-linked recessive lethal test. On the other
hand, NDPA by itself has been 3hown to be mutagenic in
several _iri vitro microbial test systems by causing base-pair
substitution and primary DNA damage (Chaisson and Burkhalter,
1978)~ This seeming contradiction may be due to the fact
that the NDPA concentrations in the trifluralin preparations
tested, were too low to produce gene mutations or direct DNA
interaction, especially in the presence of trifluralin
(Chaissoil and Burkhalter, 1978) ~
Trifluralin/NDPA mutagenesis data are not
adequate to determine, much less quantify, any risk for
gene- or DNA interactions posed by Trifluralin~ For the
reasons developed belowr however,, the Agency considers that
such: a risk would be low, if in fact it exists.
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This assessment considers any potential DNA/gene
effects to be associated with the NDPA contaminant of
trifluralin formulations. To pose a potential, heritable
genetic risk to humans, a chemical must be a mutagen and
must be capable of reaching mammalian germ cells in a
metabolically active form. There is no evidence regarding
whether mutagenically active forms of trifluralin or NDPA do
or do not reach mammalian germinal tissue, or whether these
compounds are metabolized ^n situ to active forms if they do
reach these tissues. The NDPA data presented in Table 23
indicate the need for metabolic activation of this compound
before it can induce mutagenic responses in test organisms.
Although NDPA shows mutagenic activity in some in vitro test
systems, including mammalian cells in culture, no in vivo
tests have been performed. To bridge these data gap3, the
Agency used information on the structurally related aliphatic
nitrosamines, dimethylnitrosamine (DMN), and diethylnitrosamine
(DEN).
DMN and DEN are mutagenic in both the Ames and
Drosophila sex-linked lethal tests. Three mouse dominant
lethal' studies on these chemicals were also surveyed. A
single intraperitoneal dose of DEN (13.5 mg/kg body weight)
did not significantly increase mutations in the offspring of
treated males (Propping et al., 1972). DMN was also
negative when male mice were dosed by the same route with
8 or 9 mg/kg body weight (Epstein et al., 1972). DMN was
reported as producing a weak dominant lethal effect in a
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second study with male mice (Propping et al., 1972). It
is of interest that the second, study was positive at a
DMN dosage lower than that yielding a negative response
in the other study; however, the mouse strain and route
of administration differed in the two studies. There was
only a single drug-treatment group in the Propping et al.
staidy;. the laclc of varying, treatment. le.vels precluded- any
within-experiment repetition of the results or knowledge
of dose-response relationships. The authors did state
that the 4.4 mg/kg dose was the highest dosage of DMN
compatible with survival- Due to the great variation in
the responses of animals in the dominant lethal test'and
the finding of this positive at a level of significance just
meeting the authors' accepted critical level, one is not
absolutely certain about the outcome of the test. At face
value it suggests that DMN can reach the mammalian gonad.
A negative interpretation, however, is consistent with the
finding- that neither DMN nor DEN stimulated unscheduled DNA
synthesis in the mouse testis following intraperitoneal
dosing- of the test compounds and tritiated thymidine (Gary
Sega, 1979f personal communication). Also, DEN was negative
in a mouse specific locus test (Russel, 1977). NDPA itself
has not been tested for germinal or in vivo mammalian
mutations -
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Therefore, the Agency considers it unlikely that
Treflan containing NDPA would cause a significant risk with
respect to DNA and gene effects because;
1. NDPA appears to have point mutagenic activity in
some in vitro systems, but information is lacking
from in vivo tests. Some other short-chain
alkylnitrosamines have been reported to be positive
in the Drosophila sex-linked recessive lethal
test.
2. There is no direct evidence regarding whether
NDPA does or does not reach the mammalian gonad in a
genetically active form. As for other nitrosamines,
it has been reported, that neither DMN nor DEN
stimulates unscheduled DNA synthesis in the mouse
testis; and only one of three dominant lethal
studies with these chemicals in mice suggests a
positive effect, and that is a very weak positive
with DMN. Additionally, DEN was negative in an
inadequate mouse specific locus test.
3. Testing of trifluralin products containing 87 ppm
NDPA have been consistently negative for mutagenic
and DNA-damaging activity..
4. A preliminary study with Treflan containing 177 ppm
NDPA was negative in the Drosophila sex-linked
recessive lethal test.
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5- The- Agency expect3 human exposure to NDPA through
the use of trifluralin to be very low (See Table 5,
?. 36)-
At this time the Agency is not able to quantify
the mutagenic hazard which might be associated with the
use of NDPA contaminated trifluralin because information on
the presence of the active compound in the mammalian gonad
and-the results of germinal testing are lacking. The
occupational exposure to NDPA (<5.05 ug/year) and those
to the general population through consumption of treated
food (about 1-92. x 10~^ mg/kg body weight/day assuming
the presence of a residue and a 5 ppm level of N£P4 .
contamination in Treflan) is very low..
Since risks of adverse effects are Intimately
related to exposure and since the expected human exposures
to NDPA are low, it is expected that any risk from point
mutagenic effects would be low.
•
Since the- exposure estimate above assumed 5 ppm NDPA
contamination of trifluralin and since the manufacturer
ha3- already lowered the contamination to 1 ppm or less
any risk would be reduced further by a factor of about
five-
In order to be better able to evaluate point mutagenic
risks, other tests on NDPA would need to be conducted,
» including- studies assessing the ability of the chemical to
reach the mammalian gonad in a metabolically active form.
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Once more, the approach employed should not be interpreted
as setting Agency policy for future assessments; it is
simply a way to use the data at hand and specifically
refers only to Treflan, and/or other trifluralin/NDPA
formulations. Any more in-depth procedure must await
further results of experimentation.
b. Spindle Effects
The limited studies available appear to show
that high concentrations of trifluralin (with or without
stated levels of NDPA) have the capacity to disrupt formation
or function of the spindle apparatus in dividing cells,
thereby having the potential to cause abnormal segregation
of chromosomes (non-disjunction).
Inconclusive results from tests with formulated
trifluralin (containing about 177 ppm NDPA) in Drosophila
showed non-disjunction. However, when these tests were
repeated using technical trifluralin with no detectable
NDPA, negative results were obtained. Inconclusive positive
results showing effects to the spindle were also reported
when formulated trifluralin (NDPA content unknown) was
tested on Neurospora-
As a result of recent discussions at the National.
Institute of Environmental Health Sciences Workshop on
"Systems to Detect Induction of Aneuploidy by Environmental
Mutagens", four model chemicals including trifluralin
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(the others are para-fluorophenylalanine, colchicine, and
methyl-Z-benzimidazole carbamate) are now being- tested by
several laboratories to investigate their effects on the
mechanism of spindle function- Reports of these tests are
not yet available (Chaisson, December lUr 1978).
The positive chromosomal effects reported in plants
and salamanders indicate that trifluralin Cor trifluralin
plus NDPA) may affect spindle fibers by interfering with
microtubule formation or function. No comparable studies
in mammalian test systems, however, either in vitro or in
vivo, are available. Since the apparatus for cell division
does not differ significantly between plants and "animals,
similar spindle effects might be expected to occur in
mammals exposed to trifluralin.
Based, on the above information, the Agency scrutinized
mammalian and. fish studies for evidence of mitotic disturbances
or abnormalities in treated embryos, and for any other
chromosomal, spindle, or cellular effect of trifluralin on
developmental processes. Overt manifestations of such
effects- would include depressed cell formation and maturation,
decreased viability of embryosr high resorption rates, or
delayed tissue maturation such, as slow rates of ossification
in newborns- Na such effects were- noted in any of the
reproduction studies- with: rats, and dogs or in a teratogenicity
assay i» rabbits (these tests, hare been determined to be
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unacceptable under current registration procedures (see '
Section II- H. 1 and 2). Reports of vertebral hypertrophy
in treated fish (Couch et al., 1978 preprint) and variations
in skeletal development in mice (Beck, 19T7) are not
evidence of mitotic spindle effects, and do not support a
mutagenic effect of trifluralin in mammalian systems-
Evaluation of hematological values from chronic toxicity
studies also did not elicit any such evidence (Mauer,
1978).
In summary then, several lines of evidence from
both the plant and animal kingdoms suggest that trifluralin
products, containing known or unknown levels of NDPA,
possess the ability to interfere with the cell division
spindle. No studies have been carried out on mammalian
somatic or germinal cells, but it might be anticipated that
mammalian cells would respond in a manner similar to cells
of other organisms.
The Agency concluded that the existing data are not
adequate to indicate the existence of a significant risk
from effects to the cell division spindle at estimated,
trifluralin or NDPA exposure levels. In addition it is
not clear whether trifluralin itself, a metabolite, or a
contaminant in this pesticidal preparation is the active
component in this regard. Additional studies will be needed
to clarify these uncertainties.
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c. Summary
The Agency has evaluated the mutagenicity data on
trifluralin preparations (including the formulated
product) containing NDPA and considers that in the case
of direct DNA effects as well as for spindle effects,
there is an inadequate data base upon which to evaluate
these potential hazards- In regard, to the- ability of NDPA
fro induce mutagenic effects, the - expected, low exposures to
this chemical suggests that the degree of hazard, should
NDPA be a germinaL mutagen, could be low.
H. Other Chronic Effects
Various N-nitroso compounds have been shown to affect
the fetus (see Section IX, G of thi3 document). For this
reason the Agency reviewed a number of studies in which
trifluralin (NDPA. contamination level unknown) wa3 tested
for reproductive, teratogenic, and developmental effects
(Bennett, 1978),. These studies are discussed below.
1- Reproduction Studies
Worth et al~ ( 1966) reported the results of a. three-
generation reproduction study in rats treated with trifluralin.
In this study'weanling- rats of the Harlan strain were fed
oasb containing- either dr 200, or 2,000 ppo trifluralin.
The first litters were- discarded at weaning. Animals from
the second litters whose individual weights approximated the
average- weight of their- respective litters were used to
continue the study~
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No significant differences in the growth curves were
observed for any of the generations. The indices for
fertility, gestation, and viability were lower for the
second litter of the F2 generation in the 2,000 ppm group
than for controls. The values for these indices for the
2,000 ppm group in the F^ generation were comparable to
the controls; however, the 2,000 ppm group in the F^
generation consisted of only one animal- The statistical
significance of these results can not be determined since an
insufficient number of rats were used in this study. However,
the Agency concluded at that time that the no-effect level
was 200 ppm based upon the data presented.
Because an insufficient number of study animals were
used in this test and because the study animals were stressed
from severe temperature regulation problems which occurred
when the animals were moved to a new location during this
test, the Agency has determined that even though the study
did not indicate a trigger for reproductive effects, it does
not fulfill present regulatory requirements for an acceptable
reproduction study and as such constitutes a data gap
(Chitlik, 1979).
2. Teratology Studies
In a rabbit teratology study (Worth et al.,
1966), trifluralin was administered orally to four
groups (eight animals per- group) of New Zealand white
rabbits from days 8 through 16 of gestation. Dose
levels were 225, ^50, or 1,000 mg/kg/day. The animals
were sacrificed on the 25th day of gestation and the
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fetuses were delivered by Cesarean section. The
weights of both fetuses and mothers were slightly
reduced, and the number of stillborn animals increased
in all treatment groups. The number of resorption
sites also increased at the highest dose (1,000/mg/kg/day).
Neither the decrease in weight, the increase in resorptions,
nor the increase in still births was statistically
significant.
At the lowest dose (225 mg/kg/day) two animals
in one litter had underdeveloped hind limbs and hind-
quarters- Worth did not consider this effect to have
been caused by trifluralin since it was observed in
only two of six rabbits from one litter at the low.iiose
level (47 animals total) and was not statistically
significant. At 1,000 mg/kg/day, maternal weight gain
decreased. While this is not a teratogenic effect, the
Agency decided to U3e 450 mg/kg/day as the "no-effect"
level in order to obtain the most conservative estimate of
risk- The Agency has determined that even though this
study did not indicate a trigger for teratogenic effects,
it does not fulfill present regulatory requirements for an
acceptable teratology study 3ince an insufficient number
of rabbits were used, dosing was carried out for an
insufficient interval of time, and dams were sacrificed
prematurely (Chitlilc, 1979).
3- Other Studies
Couch et al. (1978 preprint) reported consistent
vertebral hyperplasia in sheepshead minnows exposed to
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various levels of trifluralin throughout their early
development (zygote to young adult). Histological
examinations of sections of 28-day-old fish revealed an
extreme semisymmetrical hypertrophy of vertebrae (3 to 20
times normal) in those minnows exposed to 5.5 to 31 ug/1
trifluralin. Fish exposed for 51 days to 16.6 ug/1 trifluralin
had a more pronounced dysplasia of their vertebrae.. Vertebral
dysplasia was the only bone effect noted.
Serum calcium concentrations significantly increased,
but this occurred only in a pooled serum sample from adult
?ish exposed for six days to trifluralin at 16.6 ug/1.
The noted hyperostosis was the result of the
direct effect of trifluralin on the hormonal control of
calcium metabolism of young developing fish rather than
an effect on the zygote or embryo since extending the
exposure time from 28 days to 51 days increased
the observed effect. Surviving fish which were examined
after 51 days exposure exhibited no further increase in
vertebral dysplasia. Apparently the ability of this
species of fish to bioaccumulate trifluralin contributes
to this syndrome.
Vertebral hyperplasia in fish is not considered to
indicate a human health hazard, since chronic feeding
studies performed in mammals (a more appropriate indicator
system for humans) did not show the effect (Bennett, 1978).
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Beck (1977) studied the effects of trifluralin on
normally-occuring variations in skeletal development (e.g.
extra knobs on the bones or variations in the number of
openings in the bone for nerves). Trifluralin was administered
to pregnant CD-I mice via stomach tube at 1.0 g/kg between
days 6 and 15 of gestation. Another group received only the
corn oil vehicle, and one group was untreated. The litters
were born in isolation and examined after birth and at
weaning. Beck sacrificed all offspring at 62 ^ 2 days and
examined them for more than 40 normally-occurring variations.
The results indicated that CD-I mice which had received
prenatal treatments of 1.0/kg/day of trifluralin could be
differentiated from the control group by the number, magnitude,
and spectrum of normally-occurring- skeletal variations.
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4. Exposure and Related Risk Estimates
a. Dietary Exposure
The Agency calculated safety factors between the NEL
and estimated human dietary exposure (Theoretical Maximal
Residue Concentration, TMRC) for the reproduction and
teratology studies as follows:
Based upon the rat reproduction study:
a. NEL = 200 ppm '
b. Equivalent to 10 mg/kg/day (conversion factor 0.05)
c. Human daily dose in 1.5 kg diet (TMRC) - 0,0429 mg/c
- Equivalent to 0.0429 mg/day 3 0.00072 nig/kg/day
6Q kg-
- NEL: Dietary Exposure = 10.0 mg/kg/da.y * 13 ,889:1
0.00072 mg/kg/day
- Safety Factor - 13,889
By adding a factor to this calculation which corrects
the estimate for the percent of the commodities actually
treated with tri flurali n, the modified Theoretical Maximal
Residue Concentration (TMRCMod) of tri flurali n in the
daily human diet is estimated to be 0.0102 mg/day. The
safety factor between the NEL in the dog chronic feeding
study and the TMRCMod is greater than 58,000. This was
calculated as follows:
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Human dally dose in 1.5 kg diet (TMRC^^) * 0.0102 mg/day
- Equivalent to • 0.0102 mg/day » 0.00017 mg/kg/day
60 kg
- NEL: Dietary Exposure,, . » 10 mg/kg/day ¦ 58,824:1
0.00017 mg/kg/day
- Safety F,actor ^ 58 ,824
Based upon the rabbit teratology study, the safety
factor for dietary exposure would be as follows:
a. Human Daily Dose in 1.5 kg diet (TMRC) 3 0.0429 mg/day
- Equivalent to - 0.0429 mg/day = 0.00072 mg/kg/day
60 kg
- NEL: Exposure Dietary =• 450 mg/kg/day = 625 ,000:1
0.00072 mg/kg/day
- Safety factor = 625,000
b. Human Daily Dose in T.5 kg diet { TMRCMqcj )—^ a 0.0102 mg/da,
- Eqiii val net to ® 0.0102 mq/day 3 0.00017 mg/kg/day
60 kg
- NEL: Exposure Dietary^., » 450 mg/kg/dav = 2,647,059:1
Mod 0.00017 mg/kg/day
- Safety Factor =¦ 2,64-7 ,059
13/ TMRC x percent of total crop receiving trifluralin
treatment.
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Based upon these figures, the current intake of
*
trifluralin on food crops does not pose a hazard to human
reproduction (Bennett, 1978),
b. Accept able Daily Intake (API)
In evaluating an application for a new tolerance,
the Agency calculates dietary exposure_ to the population.
For trifluralin the Agency has calculated an acceptable
daily intake (ADI) of 0.10 mg/kg body weight/day based
upon two- and three-year chronic feeding studies 1n
dogs.—'' The lowest no-effect level (NEL) in those tests
was 400 ppm. Converting this to mg/kg/day (400 ~ppm'x
0.025) gave a daily dose of 10 mg/kg/day in the dog.
The ADI was then calculated, using a safety
factor of 100, to be 0.10 mg/kg/day [(10 mg/kg/day)].
100
Assuming an average human body weight of 60 kg, the
maximum permissible intake (MPI) was calculated as:
60 kg x 0.10 mg/kg/day ¦ 6.0 mg/60 kg person/day.
14/ An ADI has not been established for trifluralin by the
?J0/WH0; however, the National Academy of Scienc (NAS) also
calculated an ADI of 0.1 mg/kg/day (NAS, 1977).
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Based upon existing tolerances, the theoretical
maximal residue concentration (TMRC) for trifluralin in the
daily human diet "is estimated to be 0 .0429 mg/day. This"
estimate assumes that trifluralin residues in treated
commodities exist at the level of the tolerance. Based upon
this, the TMRC in the daily diet would be about 0.72% of the
AD I (Coberly, 1978). The safety factor between the NEL in
the dog chronic feeding study and the TMRC is greater than
1 3 ,000 . This was calculated as. follows:
a. NEL = 400 ppm
b~ Equivalent to 10 mg/kg/day (conversion factor 0.025)
c. Human daily dose in 1.5 kg diet (TMRC) = 0.0429 mg/day
- Equivalent to 0.0429 mq/day = 0.00072 mg/kg/day
60 kg
- NEL: Oietary Exposure = 10 .0 mq/kq/day = 13,889:1
0.00072 mg/kg/day
- Safety Factor = 13,889
The safety factor between the NEL in the dog chronic
feeding study and the TMRC^Q(j 1 s greater than 58,000 :1
and was calculated as follows:
a. Humarr daily dose in 1.5 kg diet *
0.0102 mg/day
- Equivalent to » 0.0102 mq/day » 0.00017 mg/kg/day
60 kg
- NEL: Dietary Exposure,, . - 10.0 mg/kg/day = 58 ,824:1
0.000 17 mg/kg/day
- Safety Factor » 58,824
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c. Worker Exposure
Worker exposure to trifluralin occurs on onlj a
few days per year (ranging from 2.2 hours to 60.6 hours
for agricultural pesticide applicators and for less
than 162 hours per year for field workers).
Because exposure to workers is intermittent and the
only available test data on reproductive effects (Worth et
al., 1966) was obtained from a chronic feeding study,
the Agency concluded that it would be inappropriate to
calculate a reproductive safety factor between the 200
ppm NEL in the rat reproduction test and the level of
worker exposure estimated for trifluralin. — • -
However, teratogenic responses can theoretically
result from exposure on any one day during the critical
periods of gestation. Therefore, the Agency calculated
teratogenic safety factors between the NEL of 450
mg/kg/day in the rabbit test and worker exposure during
pesticide application and post-application.
Based upon the rabbit teratology study, these calcula-
tions are as follows:
a» NEL » 450 mg/kg/day
b- Applicator exposure, peppers (low of the range)
- 0-77 mg/yr of 2.2 hrs » 1 day of exposure!^./
to 0.77 mg
f
15/ Each eight-hour interval is considered to equal (1)
day for these calculations-
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- Equivalent to * 0.77 mq/day * 0.013 mg/kg/day
60 kg
- NEL: Exposure A p p 1 i.cator, .» 450 mq/kq/day *- 34,615:1
l0w 0.013 mg/kg/day
- Safety Factor » 34,615
c. Applicator exposure, sugar carte (high of the range)
- 21-49 mg/yr of 60.6 hrs ¦ 8 days of exposure to 21.49 mg
* 2.69 mg/day
- ELqui v-aJent to- « 2.69 mq/day - 0.045 mg/kg/day
5Fkg ~
- NEL:Exposure Applicator. . ,= 450 mq/kq/day =» 10,000:1
3 0 »04b mg/kg/day
- Safety Factor » 10,000
d. FieTdwarker exposure, cotton (low of the range)
- 32.49 ug/yr of 155 hrs » 20 days of exposure to 32.49 ug
» 1.53 ug/day exposure
» 0.00163 mg/day exposure
- Equivalent to = 0.00163 mg/day = 0.0000272 mg/kg/day
60 kg
- NEL:Exposure Fi el dworker, 450 mg/kg/day = 15,544,118
low0.0000272 mg/kg/day
- Safety Factor » 16,544,118
e- Fi el dwarker exposure, tomato (high of the range)
- 245.4 ug/yr of 162 hrs » 21 days of exposure to 245.4 ug
= 11.69 ug/day exposure
- 0-01169 mg/day exposure
- Equivalent ta * 0.01169 mq/day * 0.000195 mg/kg/day
- NEL:Exoosure FieTdworker,.. _u» 450 mq/kq/day = 2 ,307 ,692:1
hig0.000195 mg/kg/day •
- Safety Factor * 2,307,692
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I. Environmental Risk
1. Aquatic Organisms
The Agency has prepared an aquatic analysis for
trif1ural in*(Bushong, 1978). That analysis reported that
trifluralin 1s toxic to aquatic organisms at low levels.
Trifluralin is not applied directly to water; if it were
applied to water at normal field application rates, the
acute toxicity level for.sensitive aquatic organisms would
be exceeded. When trifluralin is applied and incorporated
into the soil as recommended, toxic quantities of the
compound do not move into the water (see Section II,B of
this document). The Agency has found that trifluralin
accumulates in various fish and a species of snail, but
toxic resonses to this accumulation have not been reported.
2. Terrestrial Organisms
The Agency's analysis of the risks to terrestrial
organisms indicates that the acute toxicity level for trifluralin
ranges from 2,000 mg/kg to greater than 10,000 mg/kg (Bushong,
1978). These levels are so high that the Agency does not
consider the compound to pose a hazard to terrestrial
wildlife..
Ill- Benefits Analysis
A. Introducti on
This section describes the benefits of using Treflan
on major crops and crop groups. Impacts are shown comparing
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the economic impact of not continuing product registrations
versus a situation in which the product is registered and
available for use.
The economic impact information in this section is
taken from the economic analyses for Treflan prepared by the
United States Department of Agriculture (USDA) and the
Agency (USDA/EPA; 1978 ,. 1.978a) and from data supplied by the
Natiorra.1 Herbicide Assessment Team for Trifluralin (USDA/
States, 1977). Appendix I lists the individuals who made
up the latter team. These analyses are an update of the
assessments prepared earlier for the petition response
published in the Federal Register (4-2 FR 40009, August 8,
1977) - '
Treflan is a pre-emergent herbicide used once a year
ta control annual grasses and some annual broadleaf weeds.
Generally* TrefTan is applied by low pressure spray
and is incorporated into the soil within 24 hours.
Its efficacy is not dependent on subsequent irrigation or
rainfall.
Since: its introduction into the marketplace in the
early 1960's, Treflan has gained acceptance by agricultural
producers of more than 50 cropsr including soybeans, cotton,
fruits,, and vegetables- Treflan use irr these crops ranges
from Z-l* of the totaT U.S.. cucumber acreage to more than 37%
of U.S- soybean acreage (over 19 million acres) and almost
70% of U.S. cotton acreage (over 8 million acres).
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In May 1977, a short-run analysis was completed on
the economic impact of a passible Treflan suspension (USDA/EPA,
1977). That analysis concluded that agricultural income would
decline by $521 million the first year after suspension.
In August 1977, the Agency decided not to suspend Treflan
because the benefits of its uses substantially outweighed
the risks during the two-year period estimated to be necessary
for completion of RPAR proceedings (42 FR 40009, August 8,
1977).
A revision of that short-run analysis completed in
August 1978 indicated that the economic impact of a
Treflan suspension would be a decline in agricultural
income of about $573 million. This information is summarized
in Table- 25. The short-run analysis will not be discussed
in this document since it is applicable only to a suspension
a ct i o n.
Instead, the Agency completed a long-run economic analysis
on the impact of a possible Treflan cancellation in August 1978,
as part of the pre-RPAR review of Treflan (USDA/EPA, 1978a).—^
4
Because analytical precision diminishes directly with the length
of time to be considered, the long-run estimates are applicable
16/ This report "Long-run Economic Analysis of Trif1uralin"
TITSDA/Land Grant Universities), and data supplied by the
National Herbicide Assessment Team for trifluralin (USDA/
States, 1977) provides the basis for the discussion of this
secti on.
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TABLE 25
SHORT-RUN ECONOMIC IMPACT FROM A TRIFIURALIN SUSPENSION
Crop
Tri fluralin
Treated Acres
U.S.
Acreage
for this
crop {%)
Output Change
Without
Triflural 1n
Change in
Weed Control
Cost (S)
Value of
Change in
Output (S)
Cotton^
8,314,000
69.5
-574 M
-959 M
lbs4/
IbsJ/
5,900,000 -392,400,000
Soybean
Fruits &
Vegetables
19,700,000
37.7
-95.5 M bushels
36,000,000 -538,700,000
•
Potatoes
72,000
5.3
+
472,000
~-
Tomatoes
337,250
68.8
+
7,505,000
•
Peas (all),.
Cole Crops—'
131,610
30.0
—
505,000
•
128,281
62.7
5,385,000
«
Carrots
31,526
40.3
+¦
1,185,000
*
Peppers
20,395
37.8
1,169,000
~
Celery
Cucurbits^/
13,510
39.4
¦f-
364,0"0'0
80,080
24.5
-t-
2,607,000
•
Mint
7,040
7.7
+-
141,000
•
Collards/Okra
Beans^'
9,450
90.0
+¦
1,069,000
311,192
75.6
+¦
8,324,000
- 10,852,000
Sub Total
1,142,334
27,716,000 - 10,852,000
Other Field
Crops
. Dry Beans 1,232,000
. Peanuts 301,000
. Sugar Beets 264,880
. Sunflowers 650,000
79.2
19.6"
19.3
65.0
Sub Total
2,477,880
+- 34,108,000
¦K 3",303,000
> 11,811,000
5,827,000
+- 55,049,000
- 28,468,000
- 11,840,000
- 6,142,000
• 46,450,000
TOTAL
31,634,214
+124,665,000 -988,402,000
-120-
-------
TABLE 25
(Continued)
Income Change From Income Change
Price Increase On Acres
or Acreage Normally Using
Diversion ($) Trifluralin ($)
Crop
Total Change
in Costs and
Value of Output
Income Change
On Acres Not
Normally Using
Trifluralin ($)
Net
Income
Change (S)
Cottor^/
Soybean
Fruits &
Vegetables
. Potatoes
. Tomatoes
. Peas (all).,
. Cole Crops^'
. Carrots
. Peppers
. Celery 5/
. Cucurbits^/
. Mint
. Collards/Okra
. Bean&H./
Sub Total
-398,300,000
-574,700,000
472,000
- 7,505,000
- 10,347,000
- 5,385,000
- 1,185,000
- 1,169,000
364,000
- 2,607,000
141,000
- 1,069,000
- 8,324,000
- 38,568,000
Other Field
Crops
. Dry Beans
. Peanuts
. Sugar Beets
. Sunflowers
Sub Total
total!/
- 62,576,000
- 15,143,000
- 11,811,000
- 11,969,000
-101,499,000
-1,113,067,000
+345,300,000
+376,500,000
+721,800,000
- 53,000,000
-198,200,000
472,000*
- 7,505,000*
- 10,347,000
- 5,385,000*
- 1,185,000*
- 1,169,000*
364,000*
- 2,607,000*
141,000*
- 1,069,000*
- 8,324,000*
- 38,568,000
- 62,576,000
- 15,143,000
- 11,811,000
- 11,969,000
-101,499,000
-391,267,000
+149,000,000 + 96,000,00i
-331,200,000 -529,400,00
- 38,568,0C
-101,499,0(
-182,200,000 -573,467,0(
1/ Midpoint estimate of data from price elasticities of demand of -0.3 and -1.0,
7/ Lint cotton
7/ Cottonseed
T/ Cabbage, broccoli, brussel sprouts, cauliflower only.
?/ Watermelons, cantaloupes, honeydews, cucumbers only.
?/ Snapbeans, lima-beans, southern peas only..
7/ These totals may not sum exactly due to rounding errors.
*/ This impact is based only upon increased production costs. Yield/quality
reductions were not expected for this crop.
-121 —
-------
only to a period of from three to five years after the time of a
possible cancellation.—
B- Long-Run Economic Impact Analysis
Lf Treflan were cancelled, it is estimated that
annual agricultural income would decline by $313 millionl^;
Treflan users would lose $564-2 million and non-users would
gain $250.9 million (Table 26). The $564.2 million loss to
users includes a loss of $"596 .1 mi 111 or* due to a decrease in
yield, plus an additional $262.9 million in increased weed
control costs- This gives a total reduction in revenues of
$859 million, which is partially offset by a gain of $294.8
million from shiftingto other crops and higher crap, prices.
Cancelling Treflan would also cost consumers of
agricultural products at least $328.5 million per year.
However, this long-run economic analysis used partial
budgeting techniques, and this total annual figure is the
only consumer impact which was estimated. The rest of the
analysis deals with changes in agricultural income-
I- Cotton
Based on the average number of acres planted in
cotton from 1971 to 1976,. Treflan is used on approximately
8-3 million acres of cotton per year (70% of the total U.S.
1// Impacts are generally expressed in terms of 1974-76
dollars- Both farm input and outut prices representative
for 1979 would be generally higher due to inflation
and the atypically large increases fir foreign demand.
18/ The numbers used in this section are taken from the
text of USOA/EPA (1'978a) which are rounded off. The supporting
figures which were based on estimates for the crop years
1973-1976 can be found in the tables of that document.
-122-
-------
TABLE 26
LONG-RUN ECONOMTC IMPACT FROM A TRIFLURALIN CANCELLATION
\J7T.
Acreage
for this
crop (%)
Crop
Triflural in
Treated Acres
Output Change
Without
Triflural in
Change in
Weed Control
Cost ($)
Value of
Change in
Output (5)
Cotton
Soybean
Fruits &
Vegetables
. Potatoes
. Tomatoes
. Peas (all)
Cole Crops^/
Carrots
Peppers
Celery ..
Cucurbits-^'
Mint
Collapds/Okra
Beans^'
8,314,000
19,700,000
72,000
337,250
131,610
128,281
31,526
20,395
13,510
80,080
7,040
9,450
311,192
69.5
37.7
5.3
68.8
30.0
62.7
40.3
37.8
39.4
24.5
7.7
90.0
75.6
-286 M lbs
1/
-479 M Ibs^
-61.5 M bushels
+ 32,700,000
+150,300,000
387,000
7,505,000
462,000
5,385,000
1,185,000
1,169,-000
364,000
2,607,000
141,000
897,000
6,729,000
+
+
+
-195,600,000
-346,800,000
- 10,398,000
Sub Total
1,142,334
+ 25,907,000 - 10,398,000
Other Field
Crops
. Dry Beans 1,232,000
. Peanuts 301,000
. Sugar Beets 264,880
. Sunflowers 650,000
Sub Total
2,477,880
79.2
19.6
19.3
65.0
+ 32,737,000
+ 4,031,000
+ 11,811,000
+ 5,369,000
+ 53,948,000
26,935,000
10,692,000
5,670,000
43,297,000
TOTAL
31,634,214
+262,855,000 -596,095,000
-123-
-------
TABLE 26
(Continued)
Income Change From Income Change Income Change
Total Change in Price Increase On Acres On Acres Not Net
Cost and Value or Acreage Normally Using Normally Using Income
Croo of Output ($) Olversion ($) Trlfluralin ($) Trifluralin ($) Change (!
Cotton -228,300,000 + 76,500,000
Soybean -49r,100,000 +218,300,000:
Fruits &
Vegetables
. Potatoes
. Tomatoes
. Peas (all)-.
. Cole Crops=-'
. Carrots
. Peppers
. Celery ..
- Cucurbits—'
. Mint
. Collards/Okra
. Beans^/
-151,800,000 + 36,000,000 -115,800,0(
-278^JB00,Q00 +214,900,000 -63,900,0(
387,000*
- 7,505,000*
- 9,936,000
- 5,385,000*
- 1,185,000* ...
- 1,169,000*
364,000*
- 2,607,000*"
141,000*
897,000*
- 6,729,000*
Sub Total - 36,305,000 - 36,305,000 - 3&,305,0(
Other Field
Crops
. Dry Beans - 59,672,000
~ Peanuts - 14,723,000
» Sugar Beets - 11,811,000
. Sunflowers - 11,039,000
Sub Total - 97,245,000 - 97,245,000 - 97,245,0(
858,950,000 +294,800,000 -564,150,000 +250,900,000 -313,250,0(
1/ Lint cotton
~£l Cottonseed
7/ Cabbage, broccoli, brussel sprouts, cauliflower only.
4/ Watermelons, cantaloupes, honeydews, cucumbers only.
7/ Snapbeans, lima beans, southern peas only,
7 This Impact 1s based only upon Increased production costs. Yield/quality
reductions were not expected for this crop.
-124-
-------
planted cotton acreage). If Treflan were cancelled, users
could expect their yields to decrease and weed control costs
to increase. The total value of this loss in yields is
estimated to be $195.6 million (based on an average yield
from 1971 to 1976, and a price for lint cotton of SO.60 per
pound and cottonseed of $0.05 per pound) .-12/ Assuming that
alternative herbicide prices would be unchanged, that
alternative herbicides would be available in sufficient
quantities, and that there would' be suTficient hand labor
and mechanical equipment available at current market prices,
the cost of controlling weeds would increase by $32.7
million.—/ it is expected that the price of cotton would
increase, partially offsetting the loss to Treflan users by
21 /
$76.5 million.—In making this determination, the Agency
assumed that some cotton previously going to the export
market would flow to the domestic market in response to the
cotton shortage caused by reduced yields. The net loss of
income to cotton producers using Treflan would be $151.8
million* This includes a $195.6 million loss due to reduced
cotton yield, a $32.7 million increase in weed control
costs, and a $76.5 million offsetting revenue gain from a
cotton price increase. Because the price for cotton would
increase, the income of farmers who do not use Treflan would
19/ Gaede, 1979. This is a projection based on 1973-1977 data.
TO"/ The herbicides selected as possible alternatives to Treflan
wTll vary according to region. Costs are estimated on one
application of either f1uchloralin, dinitramine, pendimethalin ,
profluralln, fluometuron, diuron, prometryn, norflurazon, DCPA,
bensulide, alachlor, other dinitroani1ines, various mixtures, or
cultivation and hoeing.
21/ A price elasticity of demand at - 1.5 was used for lint cotto
which increased price by 2.2 cents per pound. No change in
cottonseed price was assumed.
-1 25-
-------
increase by $36 million- The total income change for all
cotton growers would be a decrease of $115.8 million (-$151.8
million for Treflan users; +• $36.0 million for non-users).
2. Soybeans
Based on the average number of acres planted in
saybeans. from 1974 to L976 Tref 1 art is used on a^jpraxi mately-
19.7 million- acres of soybeans per year (38% of the total
acres planted in soybeans 1n the U.S.). As with cotton, if
Treflan were cancelled, users could expect yields to
decrease and weed control costs to increase. The value of
the yield reduction is estimated to be $346.8 million (based
on a soybean price .of $5.64 per bushel).—'' Assuming that
alternative herbicide prices would be unchanged, that
alternative herbicides would be available in sufficient
quantities, and that there would be sufficient hand labor
and mechanical equipment at current market prices, the
cost of controlling weeds would increase by $150.3 million.—^
Lt is expected that the price of soybeans would increase,
yielding an additional $209.1 million for Treflan users plus
$9.2 million i rr revenue from acres shifted to corn.—''
22/ The soybean base price is a weighted average from
1774-1976.
23/ The herbicides selected as possible alternatives to
Treflan will vary according to region. The analyzed alterna-
tives are- metribuzin, other d1 n1 troani 1 i nes, aTachlor alone,
alach-Tor and metribuzin or linuron or naptalam, vernolate,
chloramben, linuron and additional cultivations, and non-
chenrical controls: cult1 vatiorr^ rotation to corn, and
delayed planting.
24/ Price changes as a result of decreased soybean output
were estimated using revenue flexibilities from a simultaneous
equation ntadei and are an increase of $0.60 per bushel for
soybeans and a decrease of $0,069 per bushel for corn for
each 100 million bushel changes in production. The base
price for soybeans is $5.64 per bushel and for corn, $2.68
per bushel (1974-1976 average). It is estimated that
340,000 soybean acres would be shifted to corn.
-------
This would mean a total offsetting increase in revenues of
$218.3 million. Thus, the net income loss for soybean
producers using Tref1 an would be $278.8 million {- $346.8
million in the value of soybean yield; - $150.3 million in
increased weed control costs; + $209.1 million offsetting
revenue gain from increased soybean value; + S9.2 million
from acres shifted to corn). The income for non-users of
Tref1 an would increase by $214.9"mi 11 fcm (from a $337.2
million increase in the value of their soybeans as a result
of a price increase, and a $122.3 million loss from a
decrease in corn prices). The total income change for
soybean and corn growers would be a decrease of $63.9
million (- $278.8 million for Tref1 an users; + $214.9
million for non-users).
3. Fruits and Vegetables
Based on the average number of planted acres from
1974 to 1976, Treflan is used on approximately 1.1 million
acres of fruits and vegetables. If Treflan were cancelled,
weed control costs would Increase, but yields would decrease
only for peas. The value of this yield reduction is estimated
to be $10.4 million.—'' Assuming that alternative herbicide
prices would be unchanged, that alternative herbicides would
be available in sufficient quantities, and thSt there would
be sufficient hand labor and mechanical equipment available
25/ Assumes an average pea yield of 1.3 tons/acre in the
U.S. and a three year average price of $204/ton. Average
yields were estimated to decline by 5% on prof1urali n-treated
acres, 20X on dalapon-treated acres, and 405 on acres using
cultivation only.
-127-
-------
at current market prices, the cost of controlling weeds
would increase by $25.9 million ($16»0 million for hand
weeding, $5-9 million for alternative herbicides, $4.0
million for mechanical cultivation).—'' Price changes were
not estimated for fruits and vegetables due to a possible
Treflan cancellation- The income loss for vegetable
and fruit growers using Treflan is estimated to be $36.3
million (due. to a $T0.4- million rfeductron as a result o.f-
reduced pea yields, and $25.9 millron in increased weed
control costs)~
4. Other Field Crops
Based on the average number of planted acres from
1974 to 1976, Treflarr is used on approximately 2.5 million
acres of dry beans, peanuts, sugar beets, and sunflowers.
If Treflan were cancelled, current users could expect their
yields to decrease (except for sugar beets) and weed control
costs to increase- The value of yield reductions is estimated
to be $43.3 million (based on average yields and prices for
1974-19 76).—^ Assuming that alternative herbicide prices
26/ Alternative herbicides considered were diphenamid,
bensulide, napropamide, pebulate, dalapon, EPTC, profluralin,
nitrofen, dinitramine, oil, chlorpropham, linuron, DN8P,
alachlor, metribuzin, terbacil, chloramben, naptalam,
various chemical combinations, mechanical cultivation and
hand weeding were also considered where applicable.
27/ It is. estimated that yield losses will be 5-10% for
sunflower, 5—15%. for peanuts, 0-7% for dry beans (except in
Tdaho where an additional 0 to 20% yield loss could result
due to shattering), and no yield change for sugarbeets.
-128-
-------
would be unchanged, that alternative herbicides would be
available in sufficient quantities, and that there would be
sufficient hand labor and mechanical equipment available at
current market prices, the cost of controlling weeds would
increase by $53.9 million (an increase of $48.5 million for
hand weeding, $7.4 million for mechanij^l cultivation, and a
decrease of $1.9 million 1n the cost of alternative
'herbicides).—"^ No estimates were made for price changes
due to a possible Treflan cancellation. The income loss
to growers of dry beans, peanuts, sugarbeets, and sunflowers
is estimated to be $97.2 million (- 543.3 million reduction
in the value of yield; - $53.9 million in increased weed
control costs)-
757 It is estimated that there would be a decreased alterna-
tTve herbicide cost for dry beans of $6.9 million and an
increase cost for peanuts ($1.0 million), sunflowers ($3.6
million), and sugarbeets ($0.4 million. Alternatives that
were considered are: profluralin, dinitramine, EPTC,
alachlor,, chloramben, DN8P, and hand weeding for dry beans;
alachlor vernolate, dinitramine, mechanical and hand weeding
for peanuts; EPTC, mechanical mechanical cultivation and
hand weeding for sugarbeets; chloramben, profluralin,
EPTC, and mechanical cultivation for sunflowers.
-129-
-------
IV. Risk-Benefit Analysis of Alternative Courses of Action
A. Introduction
The Agency has determined that both technical and
formulated trifluralln is contaminated with low levels of
the N-nitroso contaminant NDPA, a demonstrated oncogen in
rats, mice, and hamsters, and a mutagen in bacteria, yeast,
and in an in vitro mammalian cell culture. Treflan (the
trade name- for trifluralln) Is, therefore, presumed to be. an
2Q /
oncogen and a mutagen.—
B. Options
The Agency has considered three regulatory
options: .. _ . .
(1) to cancel registrations of all products containing
trifluralln,
(2) to allow continued trifluralln use without further
regulation, or
(3) to allow continued trifluralln use only if Its NDPA
contamination does not exceed a certain level.
(1) Cancell Registrations of all Products
Containing Trifluralln
Table 27 summarizes information from the risks and
benefits analysis for the agricultural uses of the predominant
29/ Under W CFRf162.11(a)(3)(ii), "A rebuttable presumption
3hall arise if a pesticide's ingredient(s)... meet or exceed
any of the following criteria for risk,... Induces oncogenic
effects in experimental mammalian species or in man as
a result of oral, inhalation or dermal exposure; or induces
mutagenic effects, as determined by multitest evidence."
NDPA-contaminated Treflan would also be considered a mutagen
under the Proposed Mutagenicity Guidelines. 43 FR 37336,
S.I 11 1 HTQ . JiJVt
-------
TABLE 27
RISK/BENEFIT COMPARISON OF TRIFLURALIN USES"
1/
Number of
AG - Worker
Cancer
Use
Workers
Cancer Cases
Cases
Soybeans
193,000
0.03
0.17
Cotton
64,000
<0.01
0.52
Potatoes
1,800
<0.01
0.14
Tcmatoes l.,
Cole Crops-
13,500
<0.01
0.98
4,200
<0.01
0.30
Carrots
700
<0.01
1.91
Peppers
2,300
<0.01
0.02
Celery
Cucurbits^-
Mintsl^,
200
<0.01
• 0.06
6,000
<0.01
0.35
50
<0.01
0.10
3,500
<0.01
0.09
23,700
<0.01
1.36
3,100
<0.01
0.05
Peanuts
4,500
<0.01
0.03.,,
Sugar Beets
5,200
<0.01
0.2vH7
Sunflower
5,500
<0.01
0.01
Sugar Caneg./
Tree/Vine-^
100
<0.01
22/
4,000
<0.01
0.79
Hops
50
<0.01
<0.01
Dill
< 50
<0.01
0.01
Mustard Seed
50
<0.01
0.01
Safflower
1,000
<0.01
0.01
Spring Wheat
1,000
<0.01
0.06
Alfalfa
300
<0.01
16/
Corn Grain
0.49
Asparagus
1
0.07
Subtotal
337,800
<0.01
7.76
Commercial
3,800
<0.01
NA
J/ Long-Run Economic Analysis"
2/ Dietary Farm Income Losses
From a Trifluralin
Cancellation
5/
63,900,000
115,800,000
387,000
7,505,000
5,385,000
1,185,000
1,169,000
364,000
2,607,000
141,000
897,0002-;.
66,401,000^'
9,936->QOO
14,723,000
11,811,000
11,039,0001U/
PNA-—-
FNA
.PNA
PNA
PNA
PNA
PNA
PNA
PNA
PNA
313,250,000
NA
Applicators
Total
340,000
<0.04
<8.00
313,250,000
-131-
-------
TABLE 27
(Continued)
y This estimate is based upon a maximum theoretical
calculation which assumes that crop residues of NDPA exist
following Treflan treatment. Such residues have not been
detected in a number of species analyzed at a level of
sensitivity of 0.1 to 0.2 ppb. This estimate assumes an
NDPA level of 5 ppm in Treflan. To calculate the approximate-
risk at 1 ppm NDPA in Treflan divide these numbers by 5.
2/ Applicators, incorporators, mixars, loaders.
2/ For U.S.. population-of 2.2 x 10. from: J 0-y ear-exposure
period.
V Cole crops: cauliflower, broccoli, brussel sprouts,
cabbage.
5/ Numbers are negative unless otherwise indicated. They
reflect annual economic Impact estimates for the immediate
3-5 years following possible cancellation.
6/ Curcurbits: cantaloupes, watermelon, cucumbers.
7/ Mints: spearmint, peppermint.
¥/ Greens: kale, collards, turnips, mustard.
W Collards only.
10/ Beans: guar, mung, lima, snap, southern peas, dry beans.
11/ Snap beans, lima, southern peas and dry beans only.
12/ Peas: dry, English, field.
13/ Dietary parameters combine sugar cane and sugar beets.
W PNA: parameter not assessed.
15/ Tree/Vine: grapes, citrus, nut trees, stone fruits.
JE/ No human food use.
-132-
9
-------
form of trifluralin, Treflan EC. The risk estimates are
made for Treflan contaminated with 5 ppm NDPA.—/ The risk
shown is that for cancer to applicators through work-related
exposure and to the general public through dietary exposure.
Other uses, including nursery, landscape, and home uses,
involve application of the compound on smaller areas (each
applicator would use smaller amounts of trifluralin and
would have less exposure time than his agricultural
counterpart) or involve products 'with nrnch. less trifluralin
and therefore less NDPA in their composition. Use of such
products would confer only a fraction of the risk shown
for agricultural uses. In addition, because of the low
trifluralin and NDPA levels in many of these other products,
it is not possible to measure NDPA exposure from their
use*
There are more than 300,000 workers involved with
Treflan application operations to agricultural sites
(including mixing, loading, application, and incorporation).
The number of workers applying the herbicide to a particular
crop ranges from less than 50 for dill to almost 200,000
for soybeans. Exposure to NDPA from Treflan use ranges
from a low of 0.18 ug per year in greens to a high of
5.05 ug per year in sugarcane. Workers applying the
product have an estimated risk of developing cancer from
such exposure on the order of one in 10,000,000. The
Agency estimates this would result in less than one case
of cancer in the entire applicator population.
*J This level would be divided by 5 to derive an estimate of
approximate risk from Treflan contaminated at 1 ppm NDPA.
-133-
-------
The Agency estimated risk to field workers entering
Treflan-treated fields to be about 1 in 10,000,000 using a
worst-case model and to be negligible in another model.
Risk from contact- with contaminated 3oil would be of the
same magnitude or- less-
The.Agency has estimated the dietary exposure to
Q
NDPA from Treflan use to be about 8.0 x 10 mg/kg diet/day
from all crops treated with this herbicide. This would
_q
result in an approximate risk of less than 9 x 10 7 for
the U.S. population over a 70-year lifetime of ingesting
Treflan-treated crops which might contain NDPA. It must be
emphasized that this estimate is very imprecise and
conservative since analyses of Treflan-treated crops at
harvest have not succeeded in detecting NDPA residues, and
since measurable levels of such residues are not likely
because of the low product contamination.
Technical and formulated trifluralin preparations
have not shown mutagenic activity in numerous test systems,
however, the principle contaminant of both (NDPA) has
induced point mutations in bacterial and mammalian in
vitro tests and altered genetic processes in a yeast.
Limited studies appear to show, that high concentration of
trifluralin have the capacity to disrupt formation or
function of the spindle apparatus in dividing cells,
thereby having- the potentiaL to cause abnormal segregation
of chromosomes (noa-disjunction).
-------
Existing data are not adequate to determine or
to quantify any risk for gene or DNA interactions posed .
by NDPA contaminated trifluralin. However, since existing
data from studies with NDPA contaminated trifluralin
preparations seem to contradict positive results obtained
in mutagenicity assays with NDPA alone, and because human
exposure to NDPA from trifluralin use is extrmely low, the
Agency considers the potential for such_a hazard to be
low. In addition, data on transport of NDPA to germinal
tissue and its metabolism to active forms therein is
inconclusive.
With respect to spindle effects, the Agency is
not certain whether trifluralin itself, a metabolite or
a contaminant in this herbicide is the active component
in this regard. The existing data are not adequate
to demonstrate the existence of a significant risk
from effects to the cell division spindle at estimated
trifluralin or NDPA exposure levels.
The Agency assessed the long-run impact of cancelling
Treflan. The net loss of farm income was estimated to be
greater than $300 million per year for 3- to 5- year
period following a cancellation. This figure does not
include some of the minor use crops treated with this
herbicide-.
If all Treflan registrations were cancelled, therefore,
the carcinogenic and mutagenic risks which derive from
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Treflan use would be eliminated and farm income would
decrease by approximately $300 million per year for the
years immediately following cancellation.
(2) Allow Continued Trifluralln Use Without Further
Regulation
This option would, not reduce the carcinogenic and
mutagenic risks associated with Treflan-use, as described
in., the. previous section. Furthermore, NDPA contamination
of Treflan could increase above the current level, causing
an increase in risic without any increase in benefits.
Farm income, however, would not suffer any of the $300
million per year estimated loss due to cancellation.
(3) Allow Continued Trifluralln Use Only if Its NDPA
Contamination Does Not Exceed a Certain Level
The single U.S.. producer of Technical trifluralln has
informed the Agency that it now produces the technical and
end use product contaminated with 1 ppm NDPA or less.
If the Agency were to require that thi3 level, of purity be
maintained, risk would be reduced from that associated with
5 ppm NDPA contamination. There would be no impact on
benefits; farm income would be unchanged because all
Treflan uses would continue, and the single trifluralln
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30 /
producer would not experience any added expense— since
it has already made the necessary modifications to produce
trifluralin at 1 ppm NDPA or less.
V. Proposed Regulatory Action
The Agency proposes to adopt option 3 — to allow
continued trifluralin use only if its NDPA contamination
does not exceed a certain level. At the current low level
of NDPA contamination (1 ppm or less), and because of
low exposure and substantial benefits, the Agency has
determined that the benefits of Treflan use outweigh the
risks. Therefore, the Agency has decided not to unconditionally
cancel all trifluralin registrations (Option 1).~~ The
Agency has determined, however, that use of trifluralin
contaminated with greater than 1 ppm of NDPA would be
unreasonable, because the risks would be increased unnecessarily
with no offsetting increase in benefits (Option 2).
The only active producer has demonstrated, furthermore, that
it is technically feasible to produce trifluralin at this
level of contamination. Therefore, the Agency proposes to
issue a section 6(b)(1) notice of intent to cancel all
30/ this anal ysis pertains to the single Treflan registrant
wFich currently produces Treflan as well as other registrants
with the current capability of producing Treflan at 1 ppm
NDPA or less. With regard to potential registrant-producers
who would be unable to meet the NDPA contamination level
requirement without substantially Increased cost, a separate
risk/benefit analysis would be required which would examine
the risks and benefits of Treflan at the higher NDPA contamina-
tion. That analysis would also examine the cost of reduci ng
the NDPA contamination to 1 ppm and the reduction of risk
achieved by that limitation.
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-------
trifluralin registrations-^- unless registrants amend their
tera3 and conditions of registration to limit the NDPA
content in trifluralin to a level not to exceed 1 ppm.-2^/
In regard to those who are currently operating under State-
approved trifluralin registrations with Federal trifluralin
registration applications pending' final EPA. decision-23/
and. those who may have' submitted applications for new
trifluralin registrations, their 'applications will be denied
unless those applications are amended to satisfy the require-
ment that the NDPA content in trifluralin does not exceed 1
ppm. Once these applications are amended to comply with
these requirements, they will continue to be reviewed by the
Agency to assess whether all registration requirements have
been satisfied.
31/ Some registrants have received state registrations
for trifluralin to meet special local needs under the
authority of 24(c) of FIFRA. These registrations are
federal registrations governed by FIFRA. They are subject to
this proposed 6(b)(1) notice of intent to conditionally
cancel all trifluralin registrations.
32/ Once registrants have amended their- terms and conditions
of registration to comply with- the maximum NDPA contamination
requirement, it will be unlawful (under sections 12(a)(1)(c)
and (E) of FIFRA) to sell or distribute trifluralin products
whose registrations have been so amended if they are
contaminated with NDPA at levels greater than 1 ppm.
33/ Under 40 CFR 162.17, all State-registered pesticide
products, unless governed by sectioon 24(c) of FIFRA,
must be registered under FIFRA» Pending a final EPA
registration decision, however, State registrants nay
continue to sell or* distribute the pesticide product if
solely within: Intrastate commerce.
-138-
-------
The label amendment proposed by this notice shall
appear on the label under the inert ingredients section
of the ingredients statement and shall read as follows:
N-nitroso-di-n-propylamine (NDPA).. .».< 1 ppm.
The amendment to the confidential statement of
formula proposed by this notice shall appear in that
statement under the inert ingredients~section of the
ingredients statement and shall read as follows:
N-nitroso-di-n-propylamine (NDPA) < lppm.
The trifluralin registrants will be requi_red_to
certify that this level is an upper limit in accordance
with £163.61-6 of the Guidelines for Registration of
Pesticides in the United States, Subpart D, Chemistry
Requirements, as proposed on July 10, 1978 [43 FR 29709-29710].
A registrant who distributes a pesticide product, the
chemical composition of which differs from the amended
chemical composition statement, will be in violation
of FIFRA section 12(a)(1)(C) and subject to sanctions under
section 13 and 14 of FIFRA.
The registrants of trifluralin must also advise
the Agency as to quality control procedures they will
institute to assure the Agency that the level of NDPA as
stated on the label 1s not exceeded. In addition, registrants
must maintain accurate quality control records on these
products and make such records available to the Agency
on demand.
-139-
-------
Finally, the Agency considers the data on the
mutagenic potential (including ONA, gene and chromosomal
effects) of this compound (including it benzimidazole
metabolites) to be Inadequate for a precise determination
of risk. Additionally,, the Agency considers the data on
reproduction and teratology to be inadequate. FIFRA Section
3(c)(2)(B) states in part, that:
(i) If the Administrator determines that additional
data are required to maintain in effect an
existing regi stra.t.1 on of a pesticide, the
Admin1strator shall notify all existing registrants
of the pesticide to which the determination
relates and provide a list of such registrants
to any interested person.
The Agency, therefore, will require registrants
of products containing trifluralin to test trifluralin
and provide the Agency with data concerning the mutagenic
potential of this, compound and its benzi mi dazol e metabolites
see Section III (mutagenicity risk assessment). Additionally
the Agency will require the registrants to perform new
reproduction tests (see Section III. H. 1 of this PD)
»
and teratology tests (see Section III. H. 2 of this PO)
to satisfy data gaps existing for those criteria. The
Agency will specify requirement for filling these data
gaps consistent with the expeditious resolution of these
Issues*
-T 40-
W
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and health. Safe Drinking Water Committee, Part II, Chpt.
6-7.
National Academy of Science (NAS), 1978. Nitrates: An
environmental assessment. A report prepared by the panel
on nitrates of the coordinating committee for scientific
and technical assessments of environmental pollutants,
Nat. Res. Council, Wash. D.C.
National Cancer Institute- (NCI), 1978. Bioassay of tri-
fluralin for possible carcinogenicity. NCI Carcinogenesis
Technical Report Series No- 3^»-
National Enforcement Investigation Center (NEIC), 1977.
Reconnaissance of environmental levels of Na's in the South
East, NEIC, Office of Enforcement, EPA Denver, Col.,
330/1-77-009, 8/77.
Nelson, J.O., 1978a.. Unpublished data in letter to P.C.
Kearney, (JSDA. September 28, 1978.
Nel3on, J.O., P.C. Kearney, J.R. Plimmer and R.E.""M'erizer,
1977. Metabolism of trifluralin, profluralin, and fluchlo-
ralin by rat liver microsomes. Pest. Biochem. and Phy3io.
7:73-82.
Office of Research and Development, 1977. Scientific and
technical assessment report on nitrosamine3. EPA-600/
6-77-001. ERC, 0RD, EPA, Research Triangle Park, N.C.
Olah, G.A, D.J. Donovan, and L.K. Keefer, 1975. Carcino-
gen chemistry 1. Reactions of protonated dialknitrosamines
leading to alkylating and aminoalkylating agents of poten-
tial metabolic significance. J. Nat. Cane. Inst., 54:465-^72.
Olajos, E.J. and H.H. Cornish, 1976. Mutagenicity of
dialky— nitrosaminea, metabolites and derivatives. Tox.
Appl. Pharm., 37:109—110—
Oliver, J.E., 1978. USDA, unpublished data.
Parka, S.J. and J.B* Tepe, 1969. the disappearance of
trifluralin from field soil3. Weed Sci., 17(1):119-122.
Parochetti, J.7. and E- R. Hein, 1973. Volatility and
photo- decomposition of trifluralin, benefin and nitralin.
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150
-------
"Plapp, F.V., 1975. Polysome disaggregation by dimethyl-
nitrosamine. Dissertation Abstra. B36(2):65S—659-
Pour, P., F.W. Kruger, A. Cardesa, J. Althoff, U. Mohr,
1973- Carcinogenic effects of di-n-propylnitrosamine in
Syrian Golden Hamsters. J. Nat. Cane. Inst., 51:1019-1027.
Powers, M.B., 1979. Telephone Conversation with T. Miller,
2/14/79.
Probst, G.W., J. Golab, R.J. Herberg, F.J. Holzer, S.J.
Parka, C. Van der Schans, and J.B. Tepe, 1967. Fate of
trifluralin in soils and plants. J. Agric. Food. Chem.,
15(4):592-599•
Probst, G.W., J. Golab, W. L. Wright, 1975. Dintroanllioes
- in degradaton and mode of action. 2nd ed., Vol.1, Dekker,
n.y.
Probst, G.W., 1978. Letter to T. Miller, 3/1V78.
Propping, P., G. Rohrborn, and W. Buselinaier. 1972- -
Comparative investigations on the chemical induction of
point mutations and dominant lethal mutations in mice.
Molec. gen. Genet. 117:197-209.
Reuber, M.D., 1975. Hepatic vein thrombosis in Buffalo
strain female rats ingesting dimethylnitrosamine. Path.
Europ. 10:241-244.
Reynolds, E.S., 1977. Comparison of early injury to liver
endoplasmic reticulum by halomethanes, hexachloroethane,
benzene, toluene, bromobenzene, ethionine, thioacetamide ,
and dimethylnitrosamine. Biochem. Pharm., 21:2555-2561.
Reznik, G., U. Mohr, and F.W. Kruger, 1975. Carcinogenic
effects of di-n-propylnitrosamine, beta-hyroxyypropyl-n
-propylnitrosamine and methyl-n-propylnitroaamine on
Sprague-Dawley rats. J. Nat. Cane. Inst., 54:937-941.
Rhoades, J.W. and D.E. Johnson, 1972. N-dimethylnitrosa-
mine in tobacco smoke condensate. Nature, pp. 236-307.
Sandhu, Shabeg, 1977. The evaluation of trifluralin for
mutagenicity. Memo from S. Sandhu, to M.D. Waters, Bio-
chemistry Br. EPA, HERL, RTF, NC.
Saunders, D.G., 1976. A hydolysis study on nitrosodi-
propylamine. Elanco submission No. 9f December [Proprietary],
Russell, L. 3. Validation of the la vivo somatic mutation
method in the mouse as a prescraen for germinal point nuta*
tions. Arch. Toxicol. 38:75-85. 1977.
151
-------
Saunders, D.G., 1977. A laboratory soil leaching study
with nitrosodipropylanine. Elanco -submission No. 9,
December [Proprietary].
Savage, K.E, 1973- Nitralin and trifluralin persistence in
soil. WeedSci., 21(4):285-288.
Sawamura, S. and W.T. Jackson. 1968. Cytological studies
in vivo of picloram, pyraclor, trifluralin, 2,3,6-TBA,
2,3,5,6—TBA and nitralin. Cytologia, 33:545-554-
Schmeltz, I., S. Abidl, and D» Hoffman, 1977. Tumorigenic
agents: in* unburned. processed tobacco: N-nitrosodiethanola-
mine-and 7-1-dimethylhydrarine. Carreer—Ltrs., 2: 125-132.
Schultz, J.E., 1967. Untitled review of Eli Lilly tri-
fluralin- toxicology data, 8/24/67, (USPHS).
Sega, G. Letter to Dr. Richard Hill, April 19, 1979 with
attached tables.
Seller, J.P., 1972. Mutagenicity of benzimidazole and
benzimidazole derivatives. (1) Foreward and reverse muta-
tions in Salmonella typhimurium caused by benzimidazole and
some of its derivatives.. Mutation Res. 15:273-276.
Sen, N.P., B.A. Donaldson, T.C. Charbonneau, 1973- Forma-
tion of nltrosodimethylamine from the interaction of cer-
tain pesticides and nitrites. IARC Sci., Pub. No.9, pp.
75-79., P- Bogovsky and E.A. Walker.
Sen, N.P., B.A. Donaldson, J.P. Xyenger, T. Panalaks,
1973a- Nitrosopyrolidine and dimethyl-nitrosamine in bacon.
Nature, 241:473-474. Feb.
Sen, N.P-, W.E- Miles, B.A. Donaldson, T. Panalaks, and
J.R. Iyenger, 1973. Formation of nitrosamines in a meat
curing mixture. Nature, 245:104-105.
Sen, N.P., 1972. The evidence for the presence of di-
methylnitrosamine in meat products. Food Cosmet. Toxicol.,
10:219-223-
Sentein, P.r 1977- An inhibitor of the achromatic appara-
tus which alters chromosomes, trifluralin. Archives d*
Anatomic Microscopique, 66 (4): 263-277.
Severn, D. J., 1977. Estimates of human exposure to nitro-
samlnes from the use of trifluralin and trichlorobenzoic
acid, herbicides. CED, OPP, EPA.
152
-------
Shank, R.C.,^1975. Toxicology of N-nitroso compounds, Tox.
Appl. Pharm., 31:361—368.
Shirasu, Y., M. Moriya, K. Kato, A. Furuhashi, and T. Kada,
1976. Mutagenicity screening of pesticides in the micro-
bial system. Mut. Res., 40:19-30.
Simmon, V.E. , A.D. Mitchell and T.A. Jorgenson, 1977.
Evaluation of selected pesticides as chemical mutagens- in
vivo and _in vitro studies. Stanford Res. Inst., for EPA
5to7l-77-028.
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Seiber, and J.E. Woodrow, 1975* J. Agrre. Food Chem. 23
(2):304-309.
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manufacturing effluent by fish in the Wabash River.
Dissertation Abst. Int., B36:4367.
Spencer, W.F. and M.M. Cliath, 1974. Factors affecting
vapor loss of trifluralin from soil. J. Agr. Food Chem.,
22(6):987-991 . " ' '
Tate, R.L. and M. Alexander, 1975- Stability of nitro-
samines in samples of lake water, soil and sewage. J. Nat.
Cane. Inst.,. 54(2):327-330.
Tracor-Jitco, 1977. Pesticide chemical use profile for
trifluralin. Vol.s X, II, II, Tracor-Jitco, Inc. for EPA.
Transcript of Public Hearings on Petition to suspend
certain Pesticide Products Section- 6, FIFRA. March 7,
1977, Washington, D.C., p2—133 through 2-13 through 2/23.
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Rev., 8/78.
153
-------
USDA/EPA, 1978a. Long-run economic analysis of triflura-
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G.L. Kelso, F.Horay, D.C. Reese, J. Turim, and J". tempter,
1974. Production, distribution, use, and environmental
impact- potential-of selected-pesticides.- EPA.-5.40/1-74-00 1 ,
OPE.,. CEQ. , _
West, S.D. and E.W. Day Jr., 1977. Residues of N-nitro-
sodipropylamine and trifluralin in soil from fields treated
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sodipropylamine and trilfuralin in crops from fields treated
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prietary] _ . .
Williams, P. P. and V.J". Feil, 1971. Identification of
trifluralin metabolites from runen microbial cultures.
Effect of trifluralin on bacteria and protozoa. J. Agri.
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of diuron, linuron, fenac, and trifluralin in surface
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Worth, H.M.; R.M. Small, P.N. Harris, and R.C. Anderson,
1966- Chronic toxicity studies with trifluralin. Eli Lilly
Tox. Lab- [Proprietary].
lahagi, T., M. Nagao, Y. Seino, T. Matsushima, T. Sugimura,
and M. Okada, 1977. Mutagenicities of N-nitrosamines on
Salmonella. Hut. Res., 48:121-130.
Yates, R.L. and J.A. Wenninger, 1978. Progress report on
the analysis of cosmetic products and raw materials for
H-nitrosodiethanolamine. FDA, Wash.D.C.
loder, J. M. Watson, and W.W. Benson, 1973- Lymphocyte
chromosome analysis of agricultural workers during extensive
occupational exposure to workers.
Mut. Res., 21:335-340.
Zingmark, P. A. and C. Rappe; 1976. On the formation of
N-nitrosodiethanolamine from a grinding fluid under simu-
lated gastric conditions. AMBIO.
1 e a
-------
Acknowledgements
Writing Staff
Karen O'Stsen - Writer Editor, SPRD, OPP
Paul Parsons - Writer Editor, SPRD, OPP
Tom Miller, Project Manager, SPRD, OPP
EPA Technical Support Team
Laura Bennett - Physiologist, TB, HED, OPP
Dr. George Beusch - Chemist, RCB, HED, OPP
Dr. Thomas Burkhalter - Plant Physiologist, PSB, BFSD, OPP
Clayton Bushong - Biologist, EEB,' HED,~OPP
Dr. C. F. Chaisson - Biochemist, TB, HED, OPP
Laurence A. Cook - Attorney, OGC
Dr. David Coppage - Aquatic Biologist, EEB, HED, OPP
Dr. L.B. Dale - TB, HED, OPP
Dr. Roger Gardner, TB, HED, OPP
Dr. F. Hayashi - Biochemist, PSB, BFSD, OPP
David Johnson - Chemist, RCB, HED - • ¦
Dr. George Keitt - Plant Scientist, PSB, BFSD, OPP
Merle Markley - Wildlife Biologist, EEB, HED, OPP" '
Dr. Irving Mauer - TB, HED, OPP
Dr. Robert McGaughy - Toxicologist, CAG
Abraham Mittelman - Chemist, EFB, HED, OPP
Dr. S. Nesnow - HERL, Research Traingle Park, N.C., EPA
Gerald O'Mara - Economist, EA3, BFSD, OPP
Dr. S. Sandhu - HERL, Research Triangle Park, N. C., EPA
Dr. David Severn'- Chemist, EFB, HED, OPP
Dr. Bernard Smale - Plant Scientist, PSB, BFSD, OPP
Dr. Mike Waters, HERL, Research Triangle Park, N. C., EPA.
Pesticide Chemical Review Committee
Dr. Elizabeth Anderson - CAG, ORD
Dr. Richard Hill - OTS
Dr. Allen Jennings - SRD, 0PM
Dr. Donna Kuroda - OHEE, ORD
David Menotti - OGC
John J. Neylan - PTSED, OE
155
-------
Appendix I
NATIONAL HEHBICIDE ASSESSMENT TEAM
for Trifluralin (Treflan)
St.. Louis, Missouri,
March 9, 10, 11, 1977
Member
Bob Anderson
Gale Buchanan
Herman Delvo
Clyde Dowler
Stanford Fertig
Stan Heathaa
John Holstun
John Miller
Art Lange
Phil Kearney
Chester McWhorter-
(Co Chairman)
Arnie Paulsen
Roman Romanowski
Fred Slife (Chairman)
Loyd Wax
Allen Wiese
¦ Af flTatlor,
ARS - Minnesota
Auburn University
ERS - Washington, DC
ARS - Georgia
ARS - Washington, DC
University of Arizona
ARS - Missouri
ARS - California •
University of Californ
ARS - Beltsville
ARS - Mississippi
Iowa State University
Eurdue- University
University of Illinois
ARS - Illinois
Texas A&M
156
-------
*
P. S. Department of Agriculture and State Assessment Team
Bob Anderson - ARS, USDA, Minnesota
Dr. Gayle Buchanan - Auburn University
Dr. Herman Delvo - ERS, USDA, Washington, D.C.
Clyde Dowler - ARS, USDA, Georgia
Dr. Stanford Fertig, ARS, Washington, D.C.
Dr. Stan Heatham - University of Arizona
John Holstun - ARS, USDA, California
Dr. Phil Kearney - ARS, Washington, D.C.
Dr. Art Lange - University of California
Dr. Chester McWhorter (Co-Chalrman), ARS, Mississippi
John Miller - ARS, PSDA, California
Dr. Arnie Paulsen, Iowa State University
Dr. Roman Romanowslci - Purdue University
Dr. Fred Slife - (Chairman), University of Illinois
Loyd Wax - ARS, USDA, Illinois
Dr. Allen Wiese - Texas A&M
Other Contributors
Homer Hall - Chief Branch 1, SPRD, OPP _ _
157
-------
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159
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161
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11/13/79
**** PE0D7CT SEARCH LISTING **** PAGE
FEDERALLY REGISTERED FSCDQCTS CONTAINING TSIFL CJFILIN
* ##*## ********* **#*#***# ***** ** **** * * **#* **# *
~FEGISTEANT* *NA 31 AND ADDRESS*
* 0112'a TIE GIT CHEaiCAL C03EANY
177 10 STUDEBAKE2 RD
CEBEITOS CA 90701
**************** proC3CT NA3E ****************
**00019* tbiflobalin eholsifiable concentrate
*** » 4 4* #*#***# ** ********* ***#*#**#*41# *4*4* * #*#*** *##***#* * *#****#*#*:»***
•ESSTSTSAKT* *KA3E AND ADDRESS* — • '
* 011603 jam CHEM HPGHS.f LTD,
ASHCOD C/O SOICOOF. INC.
415 KADISOU AVENOE
N2H YORK, NY 10017
~a##********#*#* PRODUCT MAKE ****************
**00013- TRIFLOREX TECHNICAL
**0001'-* IRIFL0SE3 E30LSIFIAELE CCNCENT3ATE
****************************** ***##* ****** ********* £********** **********
*5*GIST2ANT* *NA3E AND ADDRESS* -
* 013e0i REGISTRATION CONSULTING ASSCC,
C/O CHA5LE5 C. YEA GEE
9 SEST KUOLL BO AD
ABDCVER, aA 01810
**#*#»»****«***» PSQEOCT NAHE ***»*******»***#
**0 0012* TR'riORAITN TECHNICAL
167
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163
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***~ PRODUCT SEARCE LISTING **** ?AGZ
APPLTCAHTS POR 3EGIST2ATTCU C7 PRODUCTS CONTAINI3G T2IFL0RA
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*EEGISTRAST* *HAHE AHD ADDBESS*
* 001H71 2LAUC0 PEODUCTS DIVISION Ell LILLY
ATTN: RALPH HILL 3 17.26 12
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~***• ?SOOUCT SEA2CH II3TISG **** PAGE
~
01/10/79 APPLICANTS* JOE 22GISTRATI0H OP PRODUCTS COHTAIUIHG T2IFLT3AIi:i
~SEGIST3A3T* ~HA3I AND ADDRESS*
005735* TXDI PHODOCTS' IUC.
ATTN? 3.3. MABSH 5122832901
aor 102-0
EDrHHD"HG,, TBZAS.. T853.9. _
**************** P30D0CT UA32 ****************
**04816*
TIDE
HEEC
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**0'-i81 8*
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FOR COTTCIJ-FALL APPLICATION
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POR SOYEEAHS
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**0 4844*
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**0553 0*
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**0 5531*
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**0 5535*
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****** ******************************* *** ************** ****** * ************* **m
~EEGISTRAST* *NAilI AilD ADDRESS*
« 008278 3ET50 BIOLOGICAL LA2
82-1 GAZ ST
CYPRESS CA 9063 9
»»***»***#***««* PSQEUCT ITAH2' ****************
**092*€* H2T20 (TESTED) CUES IT
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OVO/79
**** PRODUCT SEARCH LISTING **** PAGE
APPLICANTS FOE REGISTRATION CP PRODUCTS CONTAINING TRIFLURAJ
•REGISTRANT* *HAHI AND ADDRESS*
* 010163 G03AU COMPA2IT
P. C. BOX 5696
IOHA, ABIZOSA 8535^
»»*****»»**#***# PRODUCT JIAliE **»**~»*****«#~*
**06^01 =* PROKIL TFIFLOSALIN U EC (IFA PILE SYMBOL 10 163-T*)
~REGISTRANT* '
* 910583
*«*******«***<*** PRODUCT KAHE ****************
=**03260* C0RTS0L-2A?ir KIIIS1
**08553* CONTEOL-EAPIE Kill# 1
**09353* CONTE CL- RAPID KILL #1
*~***»~~#***#*~*#****»»**#~*»* »»***« #»»********»» «i
~EEjTSIBAST* *hahi aud address*
* 011093 3 AS IE? SUaSEHiaES'S ASSK C/O LEO DUFUICE
362 0 1/2 HT CIABIO ELVD
LAPATETTE CA 9'-i5*9
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**07125* U9'E2 GOLD STEIKE 3SA5D GEA3U1A3 G13DE3 HEEDEE
*HA2E AITC ADDRESS*
GENERAL COS?SOL COKEAKY INC
212 6 S ALVSENOI!
TUCSOH A2 85711
171
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PHCD1CT SEARCH LISTING **** PAGE '
01/10/79 APPLICANTS FOR R2GISTSATICN C? E30D UCTS CONTAINING T3IPL02ALIN
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* ************ a + **** ************************************ **»********»*>
*BEGISTR ANT* *NAaE AND ADEEESS*
¦j
*¦ 037800 EUSEETTE 2ILL 5 GIB, INC.
BOX 278
SASEINGT03, GL 30673.
**************** PBOCaCT NAME ****************
** 0 83 8 5 * EESTILIZER CONTAINING
**08387* FERTILIZES CONTUSING
*#** ** * ** * ** * * * * ** * * *** ***************-a ********* *:
*5IGI5T3A:T7* *NAJ!E AND ADDRESS*
*' 037820 KINIT2H CANAL CO~, ISC. • •
BOX 338
XI5EEH, LA 706U8
**************** P2OE0CT NAilE ****************
**08!i25* TSErLAN EC
**08^32* SENCOS-TEEELAN EC
**#***«»*##»»***:***************************************m***** **********s********
*FZGIST3ANT* *3AfiE AND ADDRESS*
* 037821 EAHSHA2T LIQCTID FZBT~ CC.
EOr 10-1
BSOr ah 72083
**************** PHOEUCT NA2E ****************
**180.29* LANES AST EHAHD 5-15-20 EE3TI1IZEE &TTH . «* TH5TL4N
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01/10/79
*»** PRODUCT SEARCH LISTING **** PAGE
APPLICANTS JOS REGISTRATION Cr PRODUCTS CONTAINIUG TSIFL05AL
*FE^TSTB AZIT* ~NAM! AHC ADDRESS*
* 0378«7 3ICELAHE SEED CO.
303 N. 3AIR BOX 32
STUTTGART/ AR 721 60 . • _ '
**************** pHOCCCT SAME ****************
*~03316* ETSCO-'-i- 12-2U WITH TREF1AH
*** *********************** ******** ******************** ***sr** * 3 *************
* REGISTRANT* *HAai AKD ADDRESS*
* 037863 BOG ASD GRAIN C SEED CO. , 171C,
BOX 720
STUTTGART, AP. 72160
**************** P20EUCT 3AUE ****************
**081?=* TREELAN
0
4*********ft*****?*********4**********************±*ft*
*FEGIST3ANT* *NAHI AKD ADDRESS*
* 037911 S2IIH-SBEPPA2D CONCRETE CC ItJC
BOX 755
SJHES3SVILLE, GA 31082
**************** PRODUCT HAKE ****************
»*09iC3* T22EXAN I.C.
173
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*»** PRCDaCT SEARCH LISTING **** ?AG£
»
i)i/tO/^g AP?L~CAM7S FOR HEG~ ST2.XITCM CF cHODHCTS CO NTS. TU IMG I?" ?L?2i t-;;
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*5rGIST3A:iT* *3AKI ISC AuDHESS*
* 038*5- U.T.S-. COLLEGE OF 1GSIC. AUC LIFE SCI- CCEIfELL 'JSI
ATTENTION: C2, DE^E* 6072561233
ITHACA, U2L? toBK" 14-852; _
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300if 318, PEDESAL EUILDIIIG
2ALEIGS, It, C. 27601
***************** PRODUCT 7A3E **********'******
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