IMMdStMM
Protection
Agwiey
OH to of
PwtteWM end Texfe SuMaiwn
WMtaingtonOC 20410
540/RS-90-082
Guidance for the , _; „
(nfi! •,, idtiim rtssources Center
Reregistration of ««hSSSw
_ . . . _ , . Washington,DC 20460
Pesticide Products
Containing ORYZALIN
as the Active Ingredient
HEADQUARTER UMMff
ENVtROKMENIUffiOTECn
WASHINGTON, DH 204«
-------
GUIDANCE FOR THE
REREOISTRATION OP PESTICIDE PRODUCTS
(REGISTRATION STANDARD)
CONTAINING
AS THE ACTIVE INGREDIENT
ORYZALIN
Case number: GS-0186
ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF PESTICIDE PROGRAMS
WASHINGTON, D.C. 20160
June 1987
<*»
i
-------
TABLE OF CONTENTS
Page
INTRODUCTION 1
• *"
PART I. REGULATORY ASSESSMENT 3
A. Description of Chemical
B. Summary of Assessment
C. Agency Assessment
D. Regulatory Position and Rationale
PART II. REQUIREMENTS FOR REGISTRATION 21
A. Criteria for Registration
B. Acceptable Ranges and Limits
C. Required Labeling
D. Submission of Generic Data
E. Instructions for Submission
APPENDICES
A - EPA Index to Pesticide Chemicals - Oryzalin . . 59
B - Labeling Requirements 135
1. Submission of Revised Labeling
2. 40 CPR 162.10 Labeling Requirements
3. Table of Labeling Requirements
4. Physical/Chemical Hazards
Labeling Statement
C - Container Disposal Instructions 157
D - Farmworker Safety Label Requirements 159
E - PIPRA S3(c)(2)(B) Summary Sheet
(EPA Form 8580-1) 16?
F - Certification of Attempt to Enter Into
an Agreement with Other Registrants for
Development of Data (EPA Form 8580-6) 169
G - Formulator's Exemption Statement 171.
BIBLIOGRAPHY 173
-------
INTRODUCTION
The Federal insecticide, Fungicide, and RodentIcide Act (PIFRA), •
Section 3(g), directs the Environmental Protection Agency (EPA)
to reregister all pesticides as expeditlously as possible.
To carry out this task, EPA has established the Registration
Standards program, which reviews all pesticide products contain-
ing active Ingredients first registered before January 1, 1977.
Pesticides are reviewed In use clusters which have been ranked to
give earliest review to pesticides used on food and feed crops.
The Registration Standards program•involves a thorough review of
the scientific data base underlying pesticide registrations and
•an Identification of essential but missing studies which may not
have been required when the product was Initially registered or
studies that are now considered insufficient. EPA's reassessment
results in the development of a regulatory position, contained
in a Registration Standard, on each pesticide and its uses. The
Agency may require the registrant to modify product labels to
provide additional precautionary statements, restrict the use of
the pesticide to certified applicators, provide reentry Intervals,
modify uses or formulation types, specify certain packaging
limitations, or other requirements to assure that proper use of
the pesticide will not result In unreasonable adverse effects on
the environment.
The scientific review, which is not contained In the Registration
Standard, but is available from the Freedom of Information Office,
EPA, concentrates on the technical grade of the active Ingredient
and identifies missing generic data. However, during the review
of these data, the Agency Is also looking for potential hazards
that may be associated with the end-use (formulated) products
that contain the active ingredient. If the Agency has serious
concerns, the end-use products will be addressed as part of
the Registration Standards program and regulatory actions, to
the extent necessary to protect the public, will be proposed.
This Registration Standard contains the results of the Agency's
review of all registered manufacturing-use products (NPs) contain-
ing oryzalin as the sole active ingredient. During this review,
the Agency evaluated all MPs and Section 3 and 24(c) uses
registered for oryzalin.
Part I, Regulatory Assessment, of this Standard contains a
description of oryzalin and a summary of the Agency's assessment
-------
of the chemical. This is followed by a more thorough
discussion of the data base and the resulting regulatory
position.
Part II, Requirements for Registration, of the Registration
Standard addresses the necessary requirements for maintain-
ing registrations of products containing oryzal-ln, along with
the instructions for submission of the data and information
to the Agency.
- 2 -
-------
FAHT I. REGULATORY ASSESSMENT
The Agency has conducted a thorough review of the scientific
data base on orzyalln. This Part of the Standard seta forth
the results of that review beginning with a description of
the chemical and its uses, followed by a discussion of the
data base and the resultant regulatory.position. A summary
of the Agency's review and position precedes the discussion.
- 3 -
-------
A. DESCRIPTION OP CHEMICAL
1. Description
Common Name
Chemical Name
Empirical Formula
Trade Names
Chemical Abstracts
Service (CAS) No.
OPP (Shaughnessy) No.
2. Use Profile
Type of Pesticide
pest Controlled
Registered Uses
Predominant Use
Method of Application
Mode of Activity
Formulations -
Technical
End Use
Orzyalln
3 , 5-dlnl tro-N1* , N*-dlpropyl-
s ul fan 11 amide
Ryzelan, SURPLAN, EL-119
19044-88-3
104201
Preemergence Herbicide
Annual Grasses; Broadleaf Weeds
Croplands; Noncroplands; Forestry
Soybeans (86.1 percent)
Broadcast; Banded Around; Aerial;
Irrigation Systems
Inhibition of root and shoot
growth of germinating weed
seedlings
95 percent active ingredient
Emulsifiable Concentrate;
Wettable Powder; Flowable
Liquid
3. History. Oryzalln was patented by Ell Lilly Company
TUTS. Patent No. 3,367,949) In 1969 and was first
registered for use in 1974. Technical oryzalln is
being produced in the United States by Elanco Products
Company of Indianapolis, Indiana, and at the present
time, Elanco Is the sole registrant of products
containing oryzalln.
-------
B. SUMMARY OF ASSESSMENT
The Agency has reviewed all data submitted to support the
registration of oryzalln. Based on 'the review of these data,
the Agency has reached the following conclusions. See Section
C of this Part for a discussion of this review.
1. Oryzalin poses a limited oncogenic risk front dietary
exposure. In accordance with the EPA Proposed Guide-
lines for Carcinogen Risk Assessment (November 23* 1984,
49 PR 46294), oryzalln has been classified as a Group C
carcinogen (Possible Human Carcinogen).
2. Applicator risk can be reduced to acceptable limits
through the use of protective clothing and gloves.
3. Oryzalin has significant benefits that are not outweighed
by the identified risks.
As a result of this review, the Agency has identified missing
data to evaluate the environmental and human risks associated
with the use of oryzalin. These data must be developed in
order to maintain registrations of products or register new
products containing oryzalin. The table in this section
summarizes the data gaps, in addition to product chemistry
information. Please note that this is only a summary and
more details can be obtained by referring to Table A, Section
D of Part II.
The Agency has also determined that label revisions must be
made in the following areas:
o Grazing Restrictions
o Use Patterns
o Environmental Hazards
o Protective Clothing
o Chemlgatlon Instructions
o Posting Requirement
Section D contains a discussion of the Agency's review which
resulted in these determinations and Section C of Part II
contains the required wording for the labeling revisions.
5 -
-------
SUMMARY OF DATA GAPS - ORYZALIN
(Refer to Table A, Section D, Part II,
for details regarding specific requirements)
Residue Chemistry: Nature of Residue (Metabolism)
Toxicology:
Chronic Toxicity (Non-rodent)*
Nutagenicity Testing
Environmental Fate; Degradation Studies
Metabolism Studies
Mobility Studies
Dissipation Studies
Accumulation Studies
* Chronic toxicity study design must include evaluation of
thyroid gland chemistry and pathology to more fully assess
thyroid function. (Chronic toxlcity study submitted 12/86.)
- 6 -
-------
AGENCY ASSESSMENT
The Agency has conducted a thorough review of the scientific
data base for oryzalln. The conclusions and requirements to
be Imposed as a result of this review are summarized in the
preceding section. The following is a discussion of the
results of the review.
1. Tolerance Reassessment. Tolerances have been estab-
lished for residues of oryzalln on a wide range of raw
agricultural products listed la 40 C7R 180.304. The
toxicity data considered In support of these tolerances
include:
a. A two-year mouse feeding study with a no-observed-
effect level (NOEL) of 500 ppra (75 mg/kg/day) and no
oncogenic effects observed up to 3650 ppm (547.5
mg/kg/day);
b. A two-year rat chronic feeding study with a NOEL of
300 ppm: positive oncogenic effects were noted;
c. A one year mouse chronic feeding study with a NOEL
of 500 ppra;
d. A three-month rat subchronlc feeding study with a
NOEL of 1600 ppm (BO mg/kg/day);
e. A three-month mouse subchronlc feeding study with a
NOEL of 3650 ppm (5^7.5 mg/kg/day);
A three-month dog subchronic feeding study with a
NOEL of 750 ppm
)g su
(18.
75 »g/lcg/day):
6
A three-generation rat reproduction study-with a
NOEL of 250 ppm (12.5 mg/kg/ day);
h. Rat teratology .studies jrith NQELa of -225 «g/kg/day
and 2250 ppm; and
1. Rabbit teratology Atudlea with -NOELs -of 125 mg/kg/day.
The Agency has .concluded that the three-generation rat
reproduction study provides the most'conservative estimate
for the acceptable dally Intake (ADI) for humans. A NOEL
of 12.50 rag/kg bw/day and 1000-fold uncertainty factor was
used to estimate the provisional ADI (PADI) or reference
- 7 -
-------
dose of 0.013 mg/kg/day. An uncertainty factor of 1000
was used to account for the Intra- and Inter-species
difference In extrapolation from the rat to the human,
and to account for the fact that the NOEL In the repro-
duction .study Is"not fully supported by chronic studies.
A long-term dog feeding study Is Identified as a data gap.
The maximum permitted Intake (MPI) for a 66 kg human has
been calculated to be 0.78 rag/day. To date the tolerances
granted have accounted for 1.7% of the acceptable dally
Intake (ADI) with a theoretical maximum residue contri-
bution (TMRC) to the dally diet of 0.0132 mg/day (for an
average 1.5 kg dally diet).
Because the Agency considers oryzalln to be a rat oncogen,
all existing tolerances and any proposed tolerance(s) have
been or will be, by necessity, considered on that basis.
However, the potential impact of each new use on the PADI
is also essential and provides an additional check on
estimating the safety or hazard of each request. Because
the PADI is currently a value which Is based on non-oncogenlc
effects, the long-term dog study Is considered an important
data gap in the toxicology profile of oryzalin.
No tolerances have been established for residues of oryzalin
in meat, milk, eggs, or poultry because the parent compound
was thought to be the only residue of concern, and it was
not present at detectable levels In feed. The Agency has
requested additional metabolism studies in ruminants,
chickens and plants in order to more fully define the
terminal residue and Identify if there are any metabolites
which may be of concern.
Tolerances for meat, milk, eggs, and poultry may be
necessary if it is determined that residues are found in
animal feed. At present, available toxlclty data support
the existing crop tolerances as they have been established
at or near the limit of detection. The Agency is requiring
the submission of residue studies in crops, plants and
animals to verify that this is the case.
Pending receipt of the additional studies requested, the
Agency will evaluate new uses and new tolerances on a
case-by-case basis and, if the incremental risks are
not slgnflcantly Increased, will continue to establish
new tolerances. However, food additive tolerances under
section 1J09 of the Federal Pood, Drug and Cosmetic Act
will not be established.
- 8 -
-------
2. Preliminary Riskand Benefit Analysis
a. Risks. To assess the risks associated with oryzalin,
the Agency reviewed the existing data base. This
included the review of studies conducted for oncogeni-
city, mutagenlclty, teratogenlclty and ^metabolism.
Based on these studies, dietary risk and applicator
exposure and risk have been calculated. The following
is a discussion of the results of the risk assessment.
(1) Oncogenielty Studies
Rat Study. Results in the Fischer 344 rat study
showed that oryzalin, when administered In the
diet, was associated with significantly elevated
Incidences of:
(a) Thyroid gland folllcular cell adenomas and
carcinomas (combined) in high dose males and
females (primarily adenomas):
(b) Three different groups of skin tumors—fibromas
and fibrosarcomas (combined) in mid- and high-
dose males: due primarily to an Increase in
fibromas): papllloraas, keratoacanthoraas and
squamous cell carcinomas (combined; due
primarily to an Increase in paplllomas and
keratoacanthomas) In high-dose males and
females; and basal cell adenomas and skin
adnexal tumors (combined) In mid- and high-
dose males and females: and
(c) Mammary gland adenomas, flbroadenomas and adeno-
carcinomas (combined) in low-, mid-, and high-
dose females (primarily flbroadenomas). In
addition, a significant positive trend for liver
adenomas was observed but the elevated Incidence
of this tumor type In high-dose males was only
of borderline statistical significance.
Most of the tumors (except for liver adenomas)
occurred at Incidences higher than historical
control incidences for the same respective tumor
type in F34U rats. (Recent NTP data: See Handbook
of Carcinogen Testing, H. A. Milman and E. K.
Weisberger, eds. pg. 282-325, In Press; Toxlcol.
Pathol. 12:126, 1984).
- 9 -
-------
The elevated Incidence of thyroid tumors observed
.In high dose male and female rats was accompanied
'by focal follicular hyperplasia of the thyroid
gland In males (control, 2/59; low dose 2/59; mid-
dose, 4/57; high dose, 15/56} and'females (control,
0/55; low dose, 1/59; mid dose, 5/57; high dose,
1V55). These responses are typical of compounds
producing an anti-thyroid response.
In the chronic rat bloaasay, the following were
observed at the three test levels:
(a) The highest dose tested (2700 ppm In the diet)
appeared to exceed a "maximum tolerated dose"
(MTD) level. The Agency noted that some of
the tumors that occurred In rats at the 2700
ppm dose which exceeded the MTD (I.e., tumors
of the thyroid gland, akin, and mammary gland)
also occurred at doses that did not exceed the
MTD level (I.e., skin and mammary gland tumors
at 900 ppm, and mammary gland tumors at 300
ppra). The effects seen at this dose Included:
o Reduced survival (p < 0.05) In males and
females;
o Weight loss (p < 0.05) in males and females
at the end of the studies;
o Depressed red blood cell, hemoglobin and
hematocrlt levels In males and females;
o Increased SOFT and BUN levels In females and
Increased creatlnlne levels In females; and
o Elevated .organ weights (liver, kidney,
thyroid gland, and heart) In males and
females.
(b) The mid-dose level (900 ppm) In rats did not
exceed the MTD. The only effects seen at this
dose were depressed red blood cell, hemoglobin
and hematocrlt levels In females, and elevated
organ weights In males (liver and kidney) and
females (kidney).
(c) The lowest dose tested (300 ppm) resulted In
no observed adverse effects.
- 10 -
-------
There Is presumptive evidence that the thyroid
gland tumors produced by oryzalln in male and
female rats were due to an anti-thyroid effect
.of the compound. Although no -biochemical tests
"were performed to evaluate an effect of oryzalin
on thyroid function in the data available for
review, several morphological changes were observed
in the thyroid gland In the chronic rat bioassays
. in addition to the tumors. These Included:
(a) Increased thyroid gland weights In high-dose
<2700 ppm) males.
. (b) A dose-related .Increase, in .cystic follicles of
the thyroid in males (controls, 3/59; low-dose,
5/59: mid-dose, 12/57; high-dose, 19/56) and
females (controls, 2/55: low-dose,8/59; mid-dose,
13/57; high-dose, 15/55); and
(c) Focal folllcular hyperplasia particularly at
the high-dose level, in males and females.
Mouse Study. Oryzalln was not oncogenic when adminis-
tered in the diet to B6C3F1 mice.
In the chronic mouse bloassays, the highest dose
tested In males (3650 ppm in the diet) did not exceed
a MTD. The only effect seen at this dose In males
was a reduction in body weight gain (approximately
-5*) at the end of the study. In female mice, the
3650 ppm dose did appear to exceed a MTD. This dose
In females did not affect mortality'but did produce
reductions In body weight gain at.12 months (-12$), 18
months (-15S), and 24 months (-19%) after the start of
the studies. In addition, reductions in blood glucose
•levels and uterus weights were also noted.
Other Data. Information:is 'available to suggest a
structural relationship between oryzalln and other
substances that have been demonstrated to be oncogenic
in rodents. Oryzalin is a para-substituted aniline
derivative and also a sulfonsmlde compound. The Agency
•considered flata .indicating that ^dietary Administration
of another-para-substituted aniline derivative,
2,4-dlaminoanlsole, to rats increased the incidences
of malignant tumors of the thyroid gland and the skin
In both sexes. (NCI Technical Report No. 84, 1978).
In addition, data on two sulfonamldes, sulfamethoxazole
and sulphlsoxazole, were considered. Orally administered
sulfamethoxazole produced thyroid gland hyperplasia and
- 11 -
-------
neoplasla (nodules and adenomas) In rats (IARC 2ft;285,
1980) whereas sulphlsoxazole was negative for oncogen!-
city in rats and mice (IARC 2^:275, 1980). Both of •.
these studies appeared to be adequately performed.
Furthermore, anti-thyroid effects have previously
been reported for para-substituted aniline derivatives
(of which the sulfonanldes make up the greatest
number) in rats, mice, and dogs (Endocrinology 32:l85»
1943; Goodman and Oilman, 2nd ed., pg. 1301, 1970)
and even in humans (Br. Med. J. 28jL:646, 1980;
Goodman and Oilman, 5th ed., pg. mil, 1975). On
the basis of this information the Agency considered
that oryzalin might act to cause thyroid tumors by
inhibiting the formation of thyroxin, resulting in
positive feedback stimulation of the pituitary gland
to release thyroid stimulating hormone (TSR),
thereby causing thyroid gland hypertrophy (goiter)
and the ensuing hyperplasia and tumor formation.
Along this line, the study design for the chronic
(1-year) toxiclty study in dogs being required to
fulfill EPA's requirements must include evaluation
of thyroid gland chemistry and pathology to more
fully assess thyroid function. The studies appeared
to be adequately performed.
(2) Mutagenlc Studies. No mutagenlc effect of oryzalin was
detected in several tests to assess gene mutations and
chromosomal aberrations. The compound did exert a
positive mutagenlc effect In one test (sister chromatid
exchange in Chinese hamster bone marrow cells) to assess
primary DNA damage/repair, but only when the intra-
perltoneal route of administration was employed; no
positive effect was observed when the oral route of
administration was employed. The compound was also not
mutagenic in another in vitro test for primary DNA
damage/repair. The Agency is requiring that an in
vitro cell transformation test be performed by the
registrant using oryzalin (other compounds demonstrated
to evoke thyroid gland tumors are positive in this
test).
(3) Teratology and Reproduction Studies. Five studies were
considered, as follows: ."
(a) In a teratology study in rats, oryzalin was not
terotogenic at the highest dose level tested (2250
ppm in the diet).
- 12 -
-------
(b) In a second! teratology study In rats, oryzalin was
not teratogenic, embryo/fetotoxic or maternally
toxic at the highest dose level tested (225 rag/kg/day
via gavage).
(c) In a teratology study in rabbits, oryzalin was
maternally toxic (reduced food Intake and weight loss)
and erabryo/fetotoxic (reduced mean litter sizes and
increased mean resorption rates) at doses of 55 and
125 mg/kg/day by gavage (highest dose tested), but no
teratogenic effects were observed at 125 mg/kg/day.
(d) In a repeat rabbit teratology study (oral doses of
10, 25, 55, and 125 mg/kg/day), no erabryo/fetotoxic,
maternal toxic, or teratogenic effects were observed.
(e) In a three-generation study in rats, administration
of oryzalin in the diet did not influence reproductive
performance at the highest dose tested, 112.5 mg/kg/day
(2250 ppra). Petotoxic effects (depressed growth) were
observed at 37.5 mg/kg/day (750 ppm). The fetotoxic
NOEL is set at the lowest dose tested, 12.5 mg/kg/day
(250 ppm).
CO Metabolism Studies. Limited metabolism data are available
from studies in rats, rabbits, and monkeys.
(a) In two studies in rats, orally administered radio-
active (Cli4) oryzalin resulted in peak plasma
levels of Cl4 of 20 to 30 ug/ml which remained
in this range for 24 hours. About 80 to 97 percent
was eliminated over 3 days, about half of which
was in urine and half in feces.
(b) In a single study in rabbits, orally administered
Cl4-iabeled oryzalin was excreted primarily in
the urine (67 percent within 24 hours).
(c) In a percutaneous absorption study in monkeys,
similar doses of radioactive oryzalin were adminis-
tered dermally (8.6 uCi) and i.v. (9 uCl) to deter-
mine the rate and extent of dermal absorption.
o With the i.v. route of administration, radio-
activity disappeared rapidly from blood (T 1/2
= 1.6 hours) and 74 percent was excreted in 96
hours (35 percent In feces and 23 percent in
urine in 24 hours).
- 13 -
-------
o With the dermal route of administration, levels
of radioactivity in blood remained constant
from 4 to 96 hours, and 9.7 percent was excreted
in 96 hours (4.6 percent in feces and 5.1 percent
in urine in 96 hours). 'Approximately 13 percent
of the dermally applied radioactivity was absorbed.
(d) No metabolites of oryzalin were determined in the in
vivo studies. Eight metabolites have been identified
in in vitro studies. No toxicity information was
avaTTable for any of these metabolites, which are as
follows:
Oryzalin -
Metabolite *1 -
Metabolite 12 -
Metabolite f3 -
Metabolite 44 -
Metabolite 45 -
Metabolite #6 -
3,5-Dinitro-N4, N4-dipropylsulfanilamide
3,5-Di nitro-N4~propy1su1fani1amide
3-Amino-5-nitro-4-propylaminobenzene-
sulfonamide
3,5-Dinitrosulfanilamide
3,4-Diamino-5-nitrobenzenesulfonamide
3-Amino-4-dipropylamino-5-nitrobenzene-
sulfonamide
3,5-Diamino-4-dipropylaminobenzene-
sulfonamide
Metabolite 47 - 2-Ethyl-4-nitro-C-benzimadazole-
sulfonanu.de
Metabolite 48 -
3,5-Dinitro-N4-propanolyl-N4-
propyls u If ani land, de
(5) Risk Assessment. The Agency has reviewed oncogenicity
studies for oryzalin, and concludes that these data provide
limited evidence of oncogenicity for the chemical in male
and female rats. According to EPA Guidelines for Carcinogen
Risk Assessment (September 26, 1986, 51 PR 33992), oryzalin
has been classified as a Group C oncogen, that is, a possible
human oncogen.
Oryzalin caused benign tumors at multiple organ sites in
both sexes of the rat, and is structurally similar to other
sulfonamides causing similar types of tumors. It did not
produce tumors in multiple species or strains, nor did it
produce tumors in multiple experiments. Oryzalin did not
- 14 -
-------
produce tumors to ati unusual degree with regard to incidence,
tumor site or type, or age of animal at onset, in addition,
short-tern tests .for mutagenicity, as well as teratogenicity
assays, were negative.
** . *
Because these data do not provide sufficient evidence of
carcinogenicity as determined through application of the
criteria set forth in Che Guidelines, oryzalin .is not.classi-
fied as a Group B2 carcinogen (Probable Hunan Carcinogen).
Although SAR information demonstrated positive tumorigenic
responses in the thyroid with other rpara-substituted aniline
derivatives, these were considered to be due primarily to a
demonstrated anti-thyroid effect, particularly in the absence
of any positive data from other short-term tests.
However, there is limited evidence of carcinogenicity, and
in accordance with the Guidelines, the Agency has classified
oryzalin as a Group C carcinogen.
The FIFRA Scientific Advisory Panel (SAP) reviewed the data
base supporting the EPA's decision to classify oryzalin as
a Group C carcinogen. The SAP concluded that the carcinogenic
data are compatible with the Group C classification.
(6) Dietary Risk. The oncogenic evidence is discussed above.
The dietary^risk associated with oryzalin is 10-5-10-6
(Group C carcinogen) using a TMRC of 0.0132 mg/day and a
Q* of 3x10-2 (ng/kg/day)"'. Dietary exposure to oryzalin
was calculated based on assumptions that 100% of crops are
treated, and that exposed individuals consume only crops
containing residues at the tolerance level. In addition,
established tolerances have been based on no detectable
residue levels or levels at the sensitivity of the analytical
method (0.01 ppm).
Dietary exposure to oryzalin per .se appears to be minimal,
and EPA expects that, because of tiKe assumptions made,
actual exposure is less than the calculated exposure.
Additional uses of oryzalin will be considered on a
case-by-case basis giving particular concern-for detectable
levels of .oryzalin per se. -which way be pree-ent, -»s
well as clarification of the texainal residue in terms
of measurable ..metabolites.
(7) Applicator Exposure and Risk. The toxicology data strongly
indicate no toxic effects associated with dermal contact and
inhalation exposure to oryzalin. However, 'the Agency is
concerned about.applicator exposure and risk because of the
- 15 -
-------
oncogenic response In the rat atudy. Exposure, as discussed
below, has been estimated using the toxicology data which
Indicate:
(a) Acute toxlclty by the dermal route Is low (>2 g/kg).
Orjualln Is not a dermal sensltlzer; 2 separate
subchronlc dermal studies using SurfIan 75W and
Surflan 4AS demonstrated no adverse effects to rabbits
when applied to Intact or abraded skth at concentrations
of 4.8J for 6 hrs* per day.
(b) Dermal absorption is poor. A percutaneous absorption
study using monkeys demonstrated a dermal absorption rate
of 9 1.6* of the applied dose. Moreover, the rate of
excretion Is high compared to the rate of absorption.
(c) Compound-related effecta associated with worker or
applicator situations have not been identified In.
the epidemiology data.
Evaluation of mixer/loader/applicator exposure via the
dermal and inhalation routes have been estimated using
surrogate data for ground application of oryealln in
almond orchards at 4 Ibs. a.1./acre and for both private
and commercial applicators to soybeans at 1 Ib. a.i./acre.
For almond orchards and private soybean applicators,
oryzalln is assumed to be used one day a year. Commercial
soybean applicators are assumed to apply oryzalin 15
days a year. Applicators were assumed to weigh 70 kg
and to work 35 years out of a 70-year lifetime.
For use in almond orchards by workers in normal work
clothes, excluding gloves, dermal exposure is 7 mg/year
(Incorporating the dermal absorption factor of 1.62)
and inhalation exposure is 1 mg/year. This gives a
lifetime average daily dose (LADD) of 2xlO~* mg/kg
day. For private soybean applicators, clothed as above,
corrected dermal absorption is 5 mg/year and inhalation
exposure is 1 mg/year with an LADD of IxlO"1* mg/kg/day.
For commercial applicators, clothed as above, the corrected
dermal absorption is 106 mg/year and the Inhalation
exposure Is 21 mg/year with an LADD of 2x10-3 mg/kg/day.
Using Q* - 3x10*2 (mg/kg/day)-1 (Group C carcinogen), the
upper 95% confidence limits on risks are
almonds « 10-5 - 10"6
soybeans (private) • 10-5 - 10**6
soybeans (commercial) » 10-1 - 10~5
- 16 -
-------
It Is estimated that exposure to mixers/loaders/applicators
could be reduced by as much as 90J by use of Impermeable
gloves and other protective clothing. Using these
protective measures, the upper 95* confidence limits on
risks a a,-a Group C carcinogen are:
almonds « 10-6 - 10-7
soybeans (private) . « 10'6 -' IQ-?
soybeans (commercial) - 10-5 - 10-6
b. Benefits* An assessment of the benefits of oryzalin was made
based on the use patterns of the chemical and the alternatives
available. The following Is a result of that.assessment.
Oryzalin controls a wide spectrum of annual grasses and broad-
leaf weeds (46 different weeds) in 32 fruits, nuts, vineyards,
forestry, noncrop areas, and certain agricultural crops.
Oryzalin, unlike other dlnitroanillne herbicides, can be
applied preemergence and can remain on the soil surface for
as long as 3 weeks before rainfall moves it into the weeds
germinating zones, whereas other herbicides require rainfall
within 7-10 days for activation or need to be soil incorporated,
Oryzalin fits well into a no-till weed control situation in
soybeans, because It affords the grower flexible timing and
can be applied either in the fall, early spring or over-the-top
which reduces the need for "burndown" herbicides. It can also
be applied aerially, by ground equipment, with liquid ferti-
lizers, over-the-top in tank mixes, or through chemigatlon
systems. Oryzalin is also widely tank mixed with various
herbicides in several crops to provide a wider weed control
spectrum and provides a low risk of carryover or subsequent
damage to the next crop.
Oryzalin is the only preemergence herbicide that can be
applied over-the-top of standing wheat or barley to control
spring germinating annual weeds. This use helps make relay
Intercropping (planting soybeans in standing wheat or
barley before harvest) a more viable cropping option.
In fruit, nut and vineyard crops, oryzalin gives the growers
the flexibility they need to control weeds from 2-12 months
without phytotoxlclty depending upon the application rate
selected. In ornamentals, the growers can also vary their
length of weed control from 2-8 months depending upon the
application rate selected.
- 17 -
-------
D. REGULATORY POSITION AND HATIONAIE
Based on review and evaluation of all available data and other
relevant information on oryzalin, the Agency has made the follow-
ing determinations:
1. If any of the risk criteria listed in Section 154.7 of
Title 40 of the U.S. Code of Federal Regulations have
been met or exceeded, a special review of the chemical
is conducted. Although oryzalin has met one of the
criteria, that of an oncogen In the rat, with potential
for oncogencity In humans, Ht Is not being placed Into
the special review process at this time.
Rationale; After considering both dietary and applicator
exposure to oryzalin, the Agency has concluded that the
risks posed by oryzalin are minimal and hence initiation
of a special review is not necessary at this tine.
2. Registrants -must place protective clothing statements on
the labels of manufacturing-use and end-use products con-
taining oryzalin. The specific language of these state-
ments is provided in Part II.
Rationale; Because of potential oncogenlc risk from
oryzalin, the Agency is requiring protective clothing
•statements on labels for oryzalin products. Applicator
exposure and risks are discussed beginning on page 13'
These risks can be reduced to an acceptable level by
requiring persons who may come in contact with the
chemical to wear protective clothing.
3. The Agency .has concluded that no change In present toler-
ances is indicated at this tine. New tolerances will be
evaluated on a .case-by-case .basis and.new tolerances estab-
lished if the incremental riiko are not algnifleantly
increased. The Agency will require additional residue'and
metabolism studies on soybeans, potatoes,-naalTmnts and
chickens, In order to determine .the natitre «f toe ^residue
In plants and animals.
Rationale; Current tolerances -are expressed In terns of
parent compound only; however, the Agency has determined
that the metabolism In plants and animals Is not adequately
defined. Most tolerances for oryzalin have been established
at or near the limit of detection of the analytical method.
Available information Indicates a need to further clarify
the composition of the terminal residue of oryzalin in
plants and animals.
- 18 -
-------
The Agency will assess the potential for contamination
of groundwater by oryzalin after the environmental fate
data required! by this Stanjarj are received.
Rationale; The Agency has no acceptable data on which
to base an evaluation of oryzalin 's potential for
groundwater contamination. This assessment will be done
after environmental fate data, as identified in Table A,
are received.
The Agency Is not requiring a reentry interval for currently
registered uses of oryzalin.
Rationale : The acute toxicity for oryzalin is low (Category
5.
Additionally, exposure and the resultant risks to
field workers are expected to be much lower than to
applicators handling the chemical. Therefore, no reentry
Interval is required.
6. The Agency Is requiring grazing restrictions for the labels
of all end-use products.
Rationale; There are currently no tolerances established
for residues of oryzalin in animals or animal byproducts.
7. The Agency Is Imposing label requirements for end-use
products Intended for use with center pivot irrigation
systems (chemigatlon) . See Section C of Part II for
the specific language.
Rationale; Because of the oncogenic risk associated with
the exposure of oryzalin, the Agency is requiring that
labels of end-use products contain precautionary statements
to reduce the chance of incidental exposure to field workers,
8. While the data gaps are being filled, currently registered
manufacturing-use products (MPs) and end-use products (EPs)
. containing oryzalin as the sole active ingredient may be
sold, distributed, formulated and used In the United States,
subject to the terms and conditions specified In this
Standard. Registrants must provide or agree to develop
additional data, as specified In Table A of Section D,
Part II, In order to maintain existing registrations.
The Agency will Issue registrations for substantially
similar products. Substantially similar products are those
that, when compared to a currently registered product: (1)
contains the same active Ingredient (s); (2) contains percent-
ages of the active ingredient(s) and the Intentionally added
- 19 -
-------
inerts and their percentages, or the impurities and their
percentages, which vary only to the extent that It can be
reasonably established! that the hazards are not different
from those associated with the registered product; and (3)
bears Identical or substantially similar uses.
New uses will be evaluated on a case-by-case basis. These
evaluations will consider the effects on the theoretical
maximum residue concentration (TNRC) and the maximum
permitted Intake (MPI), and the oncogenlc risks., and new
uses will be approved only If incremental risks are not
significantly increased.
Rationale; Section € of PIFRA authorizes the Administrator
to cancel a pesticide registration If he determines that
the pesticide will cause unreasonable adverse effects on
the environment. Based on available data, the Administrator
has not made such a determination as to oryzalin. The
Administrator has authority under PIFRA sections 3(c)(2)(B)
and (3)(c}(7) to require registrants and applicants for
registration to provide data needed to support new or
continuing registrations.
Issuance of this Standard provides a mechanism for identify-
ing data needs. These data will be reviewed and evaluated
and the Agency will determine if the data will affect the
registration of oryzalin.
- 20 -
-------
PART II. REQUIREMENTS FOR REGISTRATION
This Part of the Registration Standard discusses what data
and information are required to maintain existing registra-
tions or register new products containing oryzalln. It also
contains the instructions for submitting the necessary data
and information to the Agency.
- 21 -
-------
A. CRITERIA FOR REGISTRATION UNDER THIS STANDARD
To be covered by this Standard, MPs must contain oryzalln as
the sole active ingredient, bear required labelling and conform
to the product composition, acute toxicltjr limit a and use
pattern requirements listed in Section B.
The applicant for registration or reregiatratlon of..products
subject to this Standard must comply with mil •> terns and
conditions described in it. This Includes making a commit-
ment to fill data gaps on a schedule specified by ^he Agency.
Applicants for registration under this Standard must follow
the Instructions contained herein and complete and submit
the appropriate forms within the time specified.
- 22 -
-------
fi. 'ACCEPTABLE RANGES AND LIMITS
1. Product Composition Standard* Technical grade products
must contain at least 95.0 percent oryzaliw as the sole
active Ingredient. Each NP formulation proposed for
registration must be fully described with appropriate
certification of.limits. In addition, the active
ingredient must be substantially similar to that in
currently.registered technical products. Any .MPs not
Beeting these requirements will be considered a new
....• product, and.wil^ not be registered under this Standard.
2. Acute Toxlclty Limits. The Agency will consider registra-
tion of technical grade MPs containing oryzalln when the
appropriate acute toxlcity categories are no higher than
Category III. The labeling of any registered products
must bear the appropriate precautionary statements.
3. Use Patterns. To be registered under this Standard, MPs
containing oryzalin must be labeled for formulation into
end-use products that are to be used for control of
germinating annual grasses and broadleaf weeds In fruit,
nuts, vineyards (nonbearlng and bearing), soybeans, cotton
(Texas only), peas (English or green), tobacco (air- and
flue-cured), potatoes (white), small grains (wheat and
barley), forestry and Christmas tree plantations,
established ornamentals and noncropland (rights-of-way)
areas. Appendix A, EPA Index to Pesticide Chemicals -
Oryzalin, lists all registered uses, as well as approved
maximum application .rates and frequencies of application.
- 23 -
-------
REQUIRED LABELING
The required label statements must appear on the labels of
all products In channels of trade within two years of issuance
of this Standard. After review of data to be submitted
under this Standard, the Agency may impose additional label
requirements.
1. All Products. All products must bear appropriate labeling
as specified in 10 CPR 162.10. Specific information
regarding label requirements is Included in Appendix B.
Oryzalin is not designated as an acute or toxic hazardous
waste under the Resource Conservation and Recovery Act
(RCRA). The label must bear the following pesticide
disposal statement:
"Wastes resulting from the use of this product may be .
disposed of on site or at an approved waste disposal
facility"
The labels of all products must bear the appropriate
container disposal statement (see Appendix C).
Manufacturing Use Products.
the statements:
Labels of all MPs must bear
"For formulation Into end-use herbicide products
intended only for use on fruit, nuts, vineyards
(bearing and nonbearlng), soybeans, cotton (Texas
only), peas (English and green), Tobacco (air- and
flue-cured), potatoes (white), small grains (wheat
and barley), forestry and Christmas tree plantations,
established ornamentals and noncropland areas."
"Do not discharge effluent containing this product
into lakes, streams, ponds, estuaries, oceans, or
public waters unless this product Is specifically
identified and addressed in an NPDES permit. Do not
discharge effluent containing this product to aewer
systems without previously notifying the sewage treat-
ment plant authority. For guidance contact your
State Water Board or Regional Office of the EPA."
"Protective clothing (coveralls, a long-sleeved shirt,
shoes and Impermeable gloves) must be worn when
handling this chemical."
-------
3. End-Use Products
a. Labels of all formulated end-use products (EPs) must
bear the following statements:
"Do not graze or feed forage from treated fields
or orchards to livestock."
"Mixer/loader/applicators must wear protective cloth-
Ing, consisting of coveralls, a long-sleeved shirt,
shoes, and Impermeable gloves when handling this
product."
b. The labels of non-granular EPs Intended for outdoor use
must bear the following statement:
"Do not apply directly to water or wetlands. Do
not contaminate water by cleaning of equipment or
disposal of wastes."
c. The labels of all EPs applied by center pivot Irrigation
systems must bear the following posting requirements
statement and the appropriate chemigation instructions.
Posting Requirements
"Posting Requirements: Areas being treated with
pesticides applied through irrigation systems must
be posted at the usual entrances to the area, at
bulletin boards where workers assemble and where
the treated area lies adjacent to roads, residential
areas, or any other areas such as schools, parks, or
other public facilities. Posted signs must be
legible from 25 feet away and be printed in English
and any other appropriate language such as Spanish.
Signs must be posted prior to application, but may
remain in place indefinitely. The sign must indi-
cate the following:
NOTICE
Pesticides are applied In Irrigation water in
this field. Do not enter this field when the
irrigation system Is operating. Do not drink,
bathe in or play in water or in furrows, puddles,
ponds, canals or ditches associated with this
irrigation system."
- 25 -
-------
Chemigatlon Instructions
(1) Apply only through properly maintained Irrigation
systems having continuously moving laterals and
providing uniform distribution of water. Where
a system does not provide uniform water distri-
bution such as at the extreme ends of the lateral,
around supports, where treated discharge water
is released from water-powered motors, or where
extreme changes In elevation occur, unacceptable
weed control or crop Injury may occur.
(2) Apply the product only through irrigation systems
containing anti-siphon and check valves, to prevent
water source contamination and overflow -and siphon-
ing of slurry tank, and interlocking controls
between the metering device and the water pump, to
Insure simultaneous shut-off.
(3) Inject the product with a positive displacement
pump into the main line ahead of a right angle
turn to Insure adequate mixing.
(4) Application of more than label recommended quantities
of irrigation water per acre may result in decreased
product performance by removing the pesticide
from the zone of effectiveness.
(5) Do not apply when wind speed Tavors drift, when
connections or fittings leak, when nozzles do not
provide uniform distribution or when lines contain-
ing the product should be dismantled ,and drained.
Use of low trajectory angle sprinkler or drop
nozzles will decrease the likelihood of drift.
(6) Greater accuracy in pesticide calibration and
distribution will be achieved by injecting a
larger volume of more dilute slurry per hour.
(7) Constant agitation should be maintained in the
slurry tank during .the entire period of pesticide
application.
The labels of all products with Trtttfloor Agricultural
uses and which are applied to crop* utilizing band
labor tasks must bear general precautionary language
about farmworker safety. See Appendix D for the
required language.
- 26 -
-------
D. SUBMISSION OP GENERIC DATA
Generic data pertain to the properties or effects of a parti-
cular ingredienty and thus are relevant to an evaluation of
the rlaks of*mll products containing that ingredient, regard-
less of the product's unique composition or specific use.
EPA has the authority under FIFRA sec. 3(c)(2)(fi) to require
registrants to submit data that will answer the Agency's
questions regarding the hazard that may result from the
intended use of a pesticide.
Although sec. 3(c)(2)(B) provides that all registrants are
.responsible for these data, the Agency generally imposes
generic data requirements only on the registrants of the
manufacturing-use products (basic suppliers of the active
Ingredient) and other producers who do not. qualify for the
formulator's exemption. The formulator's exemption applies
to a registrant of a product if the source of its active
Ingredient(s): (1) Is a registered product, and (2) is
purchased from a source which does not have ownership in
common with the registrant's firm.
A producer who currently does not qualify for the forsulator's
exemption may qualify by changing its source of supply to a
registered source, provided the source does not share owner-
ship In common with the registrant's firm. A registrant may
do so by submitting a new Confidential Statement of Formula,
EPA Form 8570-4, identifying the registered source of the
active Ingredient, to the Product Manager listed in Section E
of this Part within 90 days of receipt of the Registration
Standard. The chart on the following page shows what is
•generally required of those who do and do not qualify for the
f emulator's, exempt ion in the Registration Standards program.
Registrants are reminded that PIFRA sec. 6(a)(2) requires that
factual information raising concerns of possible unreasonable
adverse effects of a pesticide must be promptly submitted.
If.interim results of studies In progress show possible
adverse effects, the Agency is to be notified of those interim
results. Eiis portion of the Registration Standard la issued
under the authority of PIFRA sec. 3(e)(2)(B). Table A, follow-
ing this section, lists the data required for maintaining the
reglstcatlon .of .each product.
EPA has determined that additional generic data described in
Table A must be submitted to EPA for evaluation in order to
maintain in effect the product registratlon(s). As required
by PIFRA sec. 3(c)(2)(B), registrants are required to take
appropriate steps to comply with this Standard.
- 27 -
-------
REGISTRATION STANDARD
I. Products 2hat Do Not Qualify
For The flormulator's Exemption
A. Single Active Ingredient
Products*
B. Multiple Active Ingredient
Products
II. Products That Do Qualify For
The flonaulator's Exemption
MAINTAIN REGISTRATION
These products must be reregis-
tered. To obtain rereglstratlon,
labeling, packaging and data
requirements must be satisfied
In accordance with the Regis-
tration Standard. '
These products trill not be
reregistered at this time.
However, generic data required
to continue the registration of
the active Ingredient under
review, as described in the
Registration Standard, will be
required and some labeling
precautions may also be
required.
Only when additional restric-
tions or labeling are needed to
protect humans or ttie environ-
ment will these products be
subject to the Registration
Standard requirements. Affected
products will be dealt with In a
variety of ways, Including but
not limited to the label
Improvement Program and special
Intent to cancel notices.
* End-use products of registrants who also produce a manufacturing
use product will not be required to be reregistered provided that
registrant fulfills the requirements specified In the Registration
Standard for manufacturing-use product(s). Such end-use products
will be subject to the labeling changes required for products In "II1*
above. If there are no manufacturing-use products registered by any
company, end-use products will be required to be reregistered.
NOTE: If all registrants in "I" above fall to meet the requirements In
I-A and B above, the registrants In "IP lose their right to qualify
for the formulator's exemption and became subject to the requirements
in I-A and B.
- 28 -
-------
EPA may suspend the registration of products unless, within the
specified time, the registrant informs EPA how it will satisfy
the requirements of this Standard. Any such suspension will
remain in effect until the registrant has complied with the
terms of this .Standard.
1. What GenericData MustbeSubmitted. Registrants nay deter-
mine which generic data must be submitted by consulting Table
A. That table lists the generic data needed to evaluate the
continued reglstrablllty of all products, and the dates by
which the data must be submitted. The required studies must
be conducted in accordance with EPA approved protocols (such
as those contained in the Pesticide Assessment Guidelines.!/)
or data collected under the approved protocols'of the Organ-
ization for Economic Cooperation and Development (OECD). If
registrants do hot wish to develop data In support of certain
uses appearing in their labeling, they may delete those uses
at the time they submit revised labeling.
For certain kinds of testing (generally ecological effects),
EPA requires the test substance to be a "typical formulation,"
and in those cases EPA needs data of that type for each major
formulation category (e.g., emulsifiable concentrates, wettable
powders, granulars, etc.) 'These are classified as generic data
and when needed are specified in Table A. EPA may possess data
on certain "typical formulations" but not others.
2. Options Available for Complying With Requirements to Submit
Data.Within 90 days of receipt of this Standard, registrants
must submit to EPA a completed copy of the form entitled "FIFRA
Section 3(c)(2)(B) Summary Sheet," EPA Form 8580-1 (Appendix E),
for each of their products. On that form, registrants must
state which of the following methods they will use to comply
with the requirements of this Standard:
a. Notify EPA that they will submit the data, and either
submit the existing data they believe will satisfy the
requirement, or state that they will generate the data
by conducting testing. If the test procedures they will
use deviate from (or are not specified in) the Pesticide
Assessment Guidelines or protocols contained In the
Reports of Expert Groups to the Chemicals Group, Organi-
zation for Economic Cooperation and Development (OECD)
Chemicals Testing Programme, they oust enclose the proto-
cols they will use.
I/ The Pesticide Assessment Guidelines are available in hard
copy or microfiche from the National Technical Information
Service, 5285 Port Royal Road, Springfield, VA 22161.
- 29 -
-------
OR
b. Notify EPA that they have entered Into an agreement
with one or more other registrants to Jointly develop
(or share In the cost of developing) the data. If
they elect .this option, they oust notify EPA which
registrant(s) are parties to.the agreement.
m +
OH
c. File with EPA a completed 'Certification of Attempt
to Enter Into an Agreement With Other Registrants
for Development of Date** EPA Form 8560-6 (Appendix F)l/.
OR
d. Request that EPA amend their registrations by deleting
the uses for which the data are needed. (This option Is
not available to applicants for new products.)
OR
e. Request voluntary cancellation of the registrations) of
the products for which the data are needed. (This option
Is not available to applicants for new products.)
FIFHA sec. 3(c)(2)(B) authorizes joint development of data by
two or more registrants, and provides a mechanism by which
parties can obtain an arbitrator's decision If they agree to
Jointly develop data but fall to agree on all the terms of the
agreement. The statute does not compel any registrant to agree
to develop data Jointly. In EPA's opinion, Joint data develop-
ment by all registrants subject to a data requirement or a
cost-sharing agreement among all such registrants is clearly
In the public Interest. Duplication of testing could Increase
costs, tie up testing facilities, and subject an unnecessarily
large number of animals to testing. As noted earlier, EPA has
discretion to suspend the registration of a product when a
registrant Tails to .submit data required under.FIFRA Section
3(c)(2)(BK EPA has concluded that It should encourage Joint
testing rather than dupllcatlve testing, and that suspension
should be withheld in certain cases to further this goal.
Accordingly, if (1) a registrant has informed EPA of Its intent
to develop and submit data required by this Notice; and (2) a
second registrant informs EPA that it has made a bona fide offer
to the first registrant to share in the expenses of the testing
[on terms to be agreed upon or determined by arbitration under
PIPRA Section 3(c)(2) (B)(111)3; and (3) the first registrant has
declined to agree to enter into a cost-sharing agreement, EPA
will not suspend the second firm*8 registration.
- 30 -
-------
3. Procedures for Requesting Changes In Testing Methodology and
Extensions or ¥lme.EPA recognizes that registrants may
disagree with the Agency's conclusions regarding the appro-
priate ways to develop the required data or how quickly the
data must be submitted. If the test procedures a registrant
plans to 4ise deviate from (or are not specified In) the
registration guidelines or protocols contained In the reports
of the Expert Groups to the Chemical Groups, Organization
for Economic Cooperation and Development (OECD) Chemicals
Testing Programme, the registrant must submit the protocol
for Agency review prior to the Initiation of the test.
-If a registrant believes it .will need more time to generate
the required data than Is allowed by EPA'a schedule, the
registrant may submit a request for an extension of time.
-' The extension -request -must be submitted In writing to the
Product Manager. The extension request should state the
reasons why the registrant believes that an extension is
appropriate. While EPA considers the request, the registrant
must strive to meet the deadline for submitting the required
data.
- 31 -
-------
Table A - Generic DataRequirements fop Oryzalin
Table A contains generic data requirements that apply to the
pesticide In .all products, Including data requirements for
which a "typical formulation" Is the test substance.
The data requirements are listed In the order In which they
appear In 40 CFR 158. The reference numbers accompanying
each test refer to the test protocols set out In the Pesticide
Assessment Guidelines, which are available from the National
Technical Information Service, 5285 Port Royal Road, Spring-
field, VA 22161. The following abbreviations are used in the
table:
Test Substance -
TGAI - Technical Grade of the Active Ingredient
PAI « Pure Active Ingredient
PAIRA= Pure Active Ingredient, Radlolabelled
TEP * Typical End-Use Product
MP - Manufacturing-Use Product
EP = End-Use Product
Use Patterns -
A
B
C
D
E
F
G
H
I
Terrestrial, Food Crop
Terrestrial, Non-Food
Aquatic, Food Crop
Aquatic, Non-Food
Greenhouse, Food Crop
Greenhouse, Non-Food
Forestry
Domestic Outdoor
Indoor
- 32 -
-------
16
u
(B x o c
n w 1 n
I
II
i
r-l 43
**.!
a ft o
11
»<
+>
e
w
8
iT< O
O "O
«- a e
o JB9
I I I
•~i <\i m
t-4 i"* «""!
vo vo vo
|
I
B Q n
fi- fl
eu esj cv
n n n
57i 5
-------
I
c
£
i
6
ce
Test
bstan
i
§
*-i
i
—* 4J
O 0
If
«°
Si
si
3
B
"
\D VD
VO -to
w
£
vo
in
in 'in
E1 E1 S1 E1 D D E1 C1 D E1 D
n n n n KI RI n g?i RI n R(
*—I ••—J I—I 4_J 4_J l_l 4_» i_J LJ «--• ?_J
in a: jr oc
e ac
g
I 5 S-S -8
as cc
i 1
d
s
1
6
e
••* **
•I 'S
5
»
5'
a a & ^ s
S • 2» SP S 3 *
I fe S S I 3 a
£ 5 £ 48 -eo fi ;^
ent
!•!.
*> I «r5
,5 >J3
8£
ty
« *5
S S
< I I I I I I I
O «-i
«o vo .vo ..vo .vo .vo to vo
£
I
nj
i
m
vo
-------
c
jc
W «•*
s *
«
B
i
C
»
'I
g
ro
&
*i
a.
§
CD
in
n
6
£
eo
i
so
M C w «0 O ^ ^
o ^ n o «-t TH o
t- o o> r1 •*•» >-i o.
£"5t
*«"
- 35 -
-------
i
S
»
«•*
0) a
5*H
t. O
^ • >>
n
5
oc
1-1
l
£
I
*H
i
6
I
in
03
in
i
i
I
iH
a.
i
n
£
CO
tH
i
3
I
M CO Q
s*.s s
S5 1s
•rH O SO
< CU £ £
E^S S3
£Si ^£
I
1
g
09
a
g
1 ^-i ^^
8 §
1
£
I
o>
!
- 36 -
-------
* BW4§
& ISfflB
•H .fiX *•
CM Jp
>— £
E
B
g
u
O CO
4j iifcrfr a; c
•H +» m g c
a
>> >»
"N
*-t 0)
05
<£ j> •
»
£3
«*-t
|a>
3 0)
a
o
foa
i
s a
I 4J
r-» T3
!S
O
CM
a o
I I
a
§
i I
o
t-4
«-»
V
- 37 -
-------
&
TO
43
CO
C- 43
!5s
o eo
-------
a tf
4* tw 43
flj ti <""» 03
a ajffl c
~~£
o co
SJ^feg
—1 » O 83
4J 4J>- ' QJ C
v< *» ra E c
£->*>>
2 09 •>—• i—(
4J
££
£ W I
-' 5 L t.
it
CO
4J
i
ca
4J
a
so o\
VO\D
mo
§fi
o
o
3
£
CM
?
(0
C co
CU «H 0)
34-5 —I
T C Q.
CV CO
W 4J
in
eg
CO
in
CM
V
JQ a
: : a
CO
(U
4-S
•D
CO
«^
Jl
C
^
09 CO
4» 0)
O C
c P
o-' 63
Ǥ
ss:
0
i
in
a
CO
o
o
CO
t
OB i
5
i
mo
§
43
CM
I
CO
^D 55
Is
eT co"
jf "t
J3
«^i
g5
£E
4-5
- 39 -
-------
«^
>? *^'>»
3 03 *—' >—<
ifi
!5
S
fe
E*i t, t.
- ^s
£4 ft) CD Q
v» B o w
'a^°
03
a
I
QOl
sss
^^ ^^ ^-^
8§S
flD?B Si
rn rn 1^1
r^co<
'8!
>VO'
S8§
1
o;
7 ^^ S
3 ' * "S
•§ 3— o
| 1
S
•D
i
ft
t»
^
!?
«
5
t
rt
03
11
r i
01
?
vo
\£>
r-tvD
O
O
I
V
I
-------
!B
i
.
o w
'-'DC
m E O
*3
. 03
s
d n
I *'
IQ to-—-i
££ fe
< 03 g e-
S -P t. t,
j*^0
10) O* *
H^Is
§
I
ts
5
I
«*4
_ 4->
as
CQ O
.5
3 -P
i o;
i*
s
{C
Kl
00,
»A
8
3 ' 3
*- *• *-«i •?
00 iH «-
-D 03 3
S v p
*» «-( I.
•H'O O
QAJ O,
IM 8
o
2
0)
s
"B
S
8
(0
&
i n
ai 1
s
•i
1
•O
3
V
'
t,
o
-------
g
«H >» t.
•3 S £
I SllaSS
-------
ji
en
I
&
Q. t,
Q. O *
JD t- n I* 4)
o
00
"8
C £ •• Q, «~3
sl.s^la §
*-t 3-D aj £ „ _
& 8 °-S5
3 1*3
«* s| c
t.
00
iii^is * «
C Q, •" W
w( O
CO O
* QL
<•— > 5r
•
<5 «
4^ «H
s« 2 * a?1-1 «1 c«uc:_
£09 «J « £ 3 r-t XS -H O c-l M t.
**^ *"sl5sn a.« = *
c C "S S *n B^ «*)U
re 9 ^ *H A ^3 * w o
CO ft) O
t.
«
•O
o
tt-t-onn t- E««J
O 3 • 5> La
.. • SJ S E c-nwea^!
•cT S cPt? *a
• 33 c -H -* 83 a
W L. irt -----
US-Sfe
09 CD
-------
4) CE
§
-------
* OJ
fi flj CQ JO
5?jj t
Q %^ dk
SJS
CD
»££
fg
1
fu
3
|
f-
CU
J
Rr
"8
1
§
T2
5
«
0)
^* -^^ *-^
Ck «H «H
IT . 4» *>
« "8 «
£
VO
I
m
vo
'••*
S
i
i
*> '
S
SP
- 7
..«•
VD
t
S
I
9
VD
I
.*r
vc
-------
1^^ ^^ mf "" 1^
«a 4j C to i—
X Ot *4 9) r-
03 3X «
t.
O
«-< • >i
*j t. cp •-
*«
'^H
«
05 a oo
CO
0)
*J
w<
on
i
C7
col
T>
s
O
u
^
5
Is S
•we *» oj So
|cS |£ ti
5^ <8~ A
»
in
so
i i
rvi m
in in
vo ^
60 0)
JC £
I I
CO (0
I
•g
btf
t
*
X)
a
§1 03
«H »•(
*•»
CO
o
r-
.Q
« Ju
0) 0
3«~c o
V o ** «
8~£ 1
•SO C ri
5*fi?8
CO fj$
- ^ -: 4> 0>
-1-6
g«« _
O ••« ._ - .
t* B S i-4*O.^> C
W *> t *J CX iH
I O «3 0) O
I rH S iS tj
i *•• .. ** «e} *<
- U6 -
-------
JB
ir
I
» t -«.
^ ** V *>*
a 4* t. m r-t
SC q) «H Q> IH
W 3 >• «
L O w
E E- cc
CD
*J c-
& 0)2
CD «
1— ' Q
«8 5
>\OVO -H.
'i «M «r i
sooo
f-OJ
vpi
go go o'
O O O O O '
1
I
oo
I
I
a
o
1
I
i i
c
M
g
5
1 *zr» r^ ^^
18 8 .8
S
S'
S;:
ii
§!
jr i
i
i
|
: 1
|?
i
I
too
Of
S
s
o. of o
£
S
-------
jj *5 «_• aj j
«^5°
i<&ii
2
3
!S
I
*3
a a>
t>- tO
S a
BJSrvj fc
S-nXC
•• -*^
3s
S8
a
BO ,-(
I
jj
^
O
^^
5
o
CT\
1 1
.a
1
T V
^
Ibx
ent
- J»8 -
-------
6
i
-
«j L.--O
O 0) S3
CD |