Document ID: EPA-HQ-OPP-2006-0731-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-12-06T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM     

	Date:	8/8/2005		

	Subject:	PP# 0E6107: Human Health Risk Assessment for the Proposed
Section 3 Use of Diphenylamine on Pear and for the Registration of a New
Product and Method for the Application of Diphenylamine to Apples.

DP Barcode: D314006

Decision Number: 354605

PC Code: 038501

40 CFR:  180.190

Trade Name:	

Xedamine A (Apples)

No Scald DPA ED-283 (Pears)	

Class: Plant Growth Regulator

	From:	Douglas Dotson, Chemist

		Karlyn Bailey, Toxicologist

		Margarita Collantes, Biologist

Registration Action Branch 2

		Health Effects Division (7509C)

	Through:	William Drew, Chemist

		Alan Levy, Toxicologist

		Zaida Figueroa, Industrial Hygienist

Richard Loranger, Branch Senior Scientist

		Registration Action Branch 2

		Health Effects Division (7509C)

	To:	Shaja Brothers/Barbara Madden, MUIERB

John Bazuin/Cynthia Giles-Parker, PM Team 22, Fungicide Branch

		Registration Division (7505C)

HED has conducted a human health risk assessment for the plant growth
regulator diphenylamine.  Pace International, L.P. is requesting
registration of a new 10% EC formulation of diphenylamine for use as a
post-harvest application to apples using a novel application technique
(thermal fogging), which reduces the total amount of diphenylamine used
and eliminates several problems associated with the current application
methods.  The end use product being proposed is Xedamine A (also
referred to as Xedamine Aerosol 88).  In addition, the Interregional
Research Project #4 (IR-4), has proposed a tolerance of 5 ppm for pear. 
The end use product proposed for use on pears is No Scald DPA ED-283.

1.0     EXECUTIVE SUMMARY

Toxicology and Endpoint Selection

The toxicology database is adequate to assess the hazards associated
with diphenylamine, including potential developmental, reproductive and
neurotoxic effects.  Acute toxicity data indicate that diphenylamine has
moderate toxicity (Category III) via oral and dermal routes of exposure.
 It is slightly  irritating to the skin (Category III) and is severely
irritating to the eye (Category I).  A data waiver was granted for the
acute inhalation study with the technical material, an acute inhalation
study with a formulation (EC-283; 31.0%) resulted in moderate toxicity
(Category III).  Diphenylamine was not a sensitizer in a guinea pig skin
sensitization study.  The liver, spleen and kidneys are targets for this
chemical.  Toxic effects involving these organs were observed throughout
the toxicology database at doses > 40mg/kg/day.  Toxic effects in the
liver and spleen were manifested as discoloration, increased organ
weights, extramedullary hematopoeisis, hemosiderosis (liver), and
congestion (spleen).  The toxic effects seen in the kidney included
discoloration, brown pigment deposits, increased kidney weights and dark
urine.  Developmental and reproduction studies show that there is no
evidence of increased quantitative or qualitative susceptibility of
fetuses to diphenylamine.  In a dermal study (rabbits) there was
systemic toxicity in the form of dark red foci in the stomach of both
sexes; there is no evidence of dermal toxicity.  Diphenylamine has been
classified as “not likely” to be carcinogenic to humans, and there
is no evidence that it is an endocrine disruptor.  Diphenylamine was
negative in all mutagenicity studies, except for an in vitro mammalian
cell gene mutation assay.  It was considered to be weakly mutagenic in
the presence of metabolic activation.  In a metabolism study in rats,
absorption of diphenylamine appeared rapid and complete for all dose
groups as judged from 24-hour excretion profiles.  Urine was the major
route of excretion of diphenylamine-derived radioactivity at both the
low and high dose, with between 68 and 81% being recovered for both
sexes at the single and repeated low dose, and 73 to 74% being recovered
at the single high dose.  Metabolites identified in urine included
dihydroxylated and monohydroxylated sulfate conjugates as well as
monohydroxylated glucuronide conjugates of diphenylamine.  Fecal
metabolites consisted of parent chemical and 4-hydroxydiphenylamine. 
Based on the available data, there is no appropriate endpoint identified
for acute exposures to diphenylamine; therefore an acute dietary risk
assessment is not required.  The chronic dietary endpoint was based on a
chronic feeding study in dogs (chronic PAD=  0.1 mg/kg/day).  Short- and
intermediate-term dermal/inhalation endpoints were based on results of
dermal (NOAEL=500 mg/kg/day) and developmental toxicity studies.  The
NOAELs in these studies were 500 mg/kg/day and 50 mg/kg/day,
respectively.

Residue Profile

Tolerances for diphenylamine are listed in 40CFR §180.190.  The residue
of concern in plants and livestock is parent diphenylamine only for both
tolerance enforcement and risk assessment.  Tolerances are established
for diphenylamine residues in/on apple at 10.0 ppm and in apple, wet
pomace at 30.0 ppm resulting from the direct application of
diphenylamine (EC or SC/L) to apples (pre- or post-harvest) as a spray,
dip, or drench application. Tolerances are also established for
diphenylamine residues at 0.01 ppm in milk, meat, fat, and meat
byproducts (except liver) of cattle, goat, horse, and sheep, and at 0.1
ppm in liver of these animals.  Interregional Research Project 4 (IR-4)
has proposed a tolerance of 5 ppm for the residues of diphenylamine
resulting from post-harvest (dip, spray, or drench) application to
pears.

Nature of the Residue in Plants and Animals

The qualitative nature of the residue in plants and livestock is
adequately understood based on acceptable apple, ruminant, and poultry
metabolism studies.  The HED Metabolism Committee has concluded that the
residue of concern in plants and livestock is diphenylamine, per se for
both tolerance enforcement and risk assessment.  As apples and pears are
members of the same crop group, pome fruit, a metabolism study in pears
will not be required.  As the diphenylamine uses are post harvest, the
nature of the residue in drinking water is not relevant to this risk
assessment. 

Crop Residue Levels

The level of confidence in the data being used to determine tolerances
is high.  For both apples and pears adequate numbers of trials were
performed in order to determine the highest residues likely to be found
in these commodities.

Analytical Enforcement Methodology and Multiresidue Methods

An adequate GC/MSD method (Hazelton Method #HWI 6524-100) is available
for enforcing tolerances on apple commodities, and this method was used
for data collection in the current post-harvest study.  The method was
adequately validated in conjunction with the sample analyses.  A
modification of this method was used in the pear analyses.  The FDA
PESTDATA database dated 1/94 (Pam Vol. I, Appendix I) indicates that
diphenylamine is completely recovered using FDA Multiresidue Protocol D
(PAM I Section 232.4) and that recovery of diphenylamine through FDA
Multiresidue Protocol E (fatty and nonfatty, PAM I Sections 211.1 and
212.1) is low (<50%).

Acute, Chronic, and Cancer Dietary Exposure

An acute dietary exposure analysis was not performed because no acute
endpoint was identified for diphenylamine.  A cancer dietary exposure
analysis was not performed because diphenylamine was classified as "not
likely to be a human carcinogen.”  A chronic dietary risk assessment
was conducted using the Dietary Exposure Evaluation Model (DEEM-FCID,
Version 2.03), which uses food consumption data from the USDA’s
Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996
and 1998.  The chronic dietary exposure analysis was based on tolerance
level residues, DEEM (Version 7.81) default processing factors, an
empirical processing factor for apple juice, and 100% crop treated
assumptions.  As the general U.S. population and all population
subgroups had risk estimates which were below HED’s level of concern
(i.e., 100% of the chronic population adjusted dose (cPAD)) it was not
necessary to make further refinements to the analysis.  As such, this
analysis is a very conservative one.  The cPAD value for the most highly
exposed population subgroup (Children 1-2 years) is 90%, and that for
the general U.S. population is 12%.  An assessment was also conducted
using the Lifeline( Model (Version 3.0).  The results from Lifeline(
were comparable to those from DEEM(.  The cPAD value for the most highly
exposed population subgroup (Children 1-2 years) is 87%, and that for
the general U.S. population is 9%.

Water Exposure/Risk Pathway

As the diphenylamine uses are post harvest, residues in drinking water
are not relevant to this risk assessment. 

Residential Exposure/Risk Pathway

There are no current registered non-occupational/residential uses for
fenpropathrin.  Therefore, an assessment for
non-occupational/residential exposures is not required.

Aggregate Risk Assessments

As residues are not expected in drinking water and there are no
residential uses for diphenylamine, there are no aggregate risk
assessments.  As a result, the total non-occupational risk from exposure
to diphenylamine is from food only.  The exposure and risk estimates are
equivalent to those from the dietary analysis.  The general U.S.
population and all population subgroups have risk estimates that are
below HED’s level of concern.  The cPAD value for the most highly
exposed population subgroup (Children 1-2 years) is 90%, and that for
the general U.S. population is 12%.   

Cumulative Risk

EPA has not made a common mechanism of toxicity finding as to
diphenylamine and any other substances, and diphenylamine does not
appear to produce a toxic metabolite produced by other substances.  For
the purposes of this tolerance action, therefore, EPA has not assumed
that diphenylamine has a common mechanism of toxicity with other
substances.

Occupational Exposure

A Section 3 registration is being requested for two end-use products:
Xedamine A and No Scald DPA EC-283 containing the plant growth regulator
diphenylamine as the sole active ingredient. This assessment will
address risks resulting from occupational exposure only, as there are no
residential uses associated with diphenylamine.  Diphenylamine is used
in post-harvest treatment of fruit to prevent the appearance of the skin
discoloration known as storage scald.  Xedamine A is applied to apples
kept in cold storage by an electric thermofogger.  No Scald DPA EC 283
is applied to pears by drive-through drenching.  Based on the number of
seasonal applications indicated on the product labels and additional
information provided by the registrant, non-dietary exposure is expected
to be short- and intermediate-term in duration.  There will be no
long-term exposure.

Handlers

The mixer/loader dermal and inhalation exposure scenarios resulting from
the thermal fogging and the drive through drench treatment processes for
apples and pears, respectively were assessed using PHED Version 1.1. 
All dermal and inhalation MOEs were greater than the LOC of 100, and
therefore were not of concern.  

As the application of diphenylamine is mechanically automated for the
thermal fogger, HED concluded that dermal exposure to the applicator
will be negligible. However, an operator/monitor stays directly outside
of the storage room with the fogger to ensure all pieces of apparatus
and instrumentation are functioning properly.  Although the operator has
no potential for dermal contact with product in the open pail because it
is automatically suctioned into the fogger, there is potential for
inhalation exposure.  However, as diphenylamine has a relatively low
vapor pressure (6.39 x 10-4 mm Hg), the evaporation of diphenylamine and
potential for inhalation exposure would be negligible.  Furthermore,
according to the proposed label, fogging applicators must wear a
full-face respirator with organic vapor filter which would further
reduce the risk of potential inhalation exposure.  Therefore risk of
inhalation exposure to fogging applicators is not of concern.  Exposure
to applicators from dipping, drenching and spraying of pears is also
expected to be minimal because these types of equipment are operated
remotely, and there is minimal contact with the equipment.  Furthermore,
it is HED’s understanding that packing plants now incorporate a
current drenching process where the driver vacates the cab.  Therefore,
HED concludes that there is negligible exposure to drench applicators
and an exposure assessment is not required.

Postapplication

Early Re-Entry Exposure for Thermal Fogger

Early re-entry into a treated area typically refers to entering a
treated area before the specified re-entry interval (REI).  In such
conditions, scouts or workers may be required to use PPE to limit dermal
and inhalation exposure.  For purposes of this assessment, “early
re-entry” will refer to the situation where an individual enters the
storage room to collect residue samples 4 days after application of the
product.  HED evaluated the potential for dermal and inhalation exposure
for early re-entry into a storage room to collect apples for residue
samples 4-days after treatment with diphenylamine.  No chemical specific
data were submitted in support of this registration.  The registrant has
indicated that because of the atmospheric conditions under which the
storage rooms are maintained (low levels of oxygen of 1 to 3% and
temperature ranging from 32 to 36(F), anyone who enters the storage
rooms must do so wearing full self-contained breathing apparatus (SCBA)
gear.   However, there is no mention of  PPE requirements for reentry on
the proposed label.  Based on the atmospheric conditions within the
storage rooms, the more acute danger to early re-entry workers is lack
of oxygen.  Use of SCBA gear will mitigate these concerns and provide
adequate protection from diphenylamine inhalation exposure.  Therefore,
HED recommends that the proposed Xedamine A label require the use of
SCBA for early entry into storage rooms for the purpose of collecting
residue samples.  With this label statement, a quantitative inhalation
risk assessment is not needed for early re-entry workers.  Furthermore,
as early re-entry workers are in the storage room for such a very short
period of time to collect residue samples in apples, dermal exposure is
expected to be negligible.  Therefore, a dermal exposure assessment for
early re-entry is not required.

Re-entry Exposure for Thermal Fogger

For purposes of this assessment, the term “re-entry” refers to
situations where workers enter the storage rooms 3 to 4 months after
initial fogging treatment to remove fruit for packing, shipping and
distribution.  As no chemical specific data were submitted, HED assumes
that most particles of diphenylamine will dissipate by the time fruit
removal is expected to take place.  This assumption is based on
diphenylamine’s relatively low vapor pressure (6.39 x 10-4 mm Hg) and
the dissipation properties of foggers (aerosols).  The risk of
inhalation exposure will be reduced to the point where it is negligible,
and a quantitative assessment for inhalation exposure to re-entry
workers is not required.

Dermal exposure to re-entry workers was evaluated using surrogate
dislodgeable residue data to determine a transfer coefficient and
chemical specific residue data for apples.  The short- and
intermediate-term dermal MOEs were all greater than 100  and therefore
did not exceed HED’s level of concern.  

Re-entry Exposure for Pear Packing Plants

For purposes of this assessment, the term “re-entry” will refer to
situations where workers sort, cull and pack pears for shipping and
distribution.  HED evaluated risk of inhalation and dermal exposure to
re-entry workers in pear packing plants.  HED assumes that most
particles of diphenylamine will dissipate by the time the driver returns
to the truck or by the time fruit removal is expected to take place. 
This assumption is based on diphenylamine’s relatively low vapor
pressure (6.39 x 10-4 mm Hg), the dissipation properties of particles
from the drench solution, and the typical ten-minute draining period for
the truck.  The risk of inhalation exposure will be reduced to the point
where it is negligible, and a quantitative assessment for inhalation
exposure to re-entry workers is not required.  No postharvesting data
for pears were submitted in support of this use.  Therefore, dermal
exposure for re-entry workers in packing plants was assessed using: (1)
the same surrogate DFR study (H.N. Niggs et al., 1984) as was used to
determine a transfer coefficient for apples, and (2) chemical-specific
residue data for pears.  The short- and intermediate-term dermal MOEs
were all greater than 100, and therefore did not exceed HED’s level of
concern.

Entry Restrictions

The proposed postharvest uses do not fall under the scope of the Worker
Protection Standards.  Nevertheless, based on the acute toxicity
category I for eye irritation for technical diphenylamine, HED
recommends that the Xedamine A label advise use of protective eye wear
for entry into apple storage rooms within 48 hours of treatment. 
Similarly, the No Scald label should advise protective eye wear for
workers handling treated pears within 48 hours of drenching.

RECOMMENDATIONS

HED does not object to the registration of Xedamine A for use on apples
in conjunction with the new thermal fogging technique.  HED also does
not object to the establishment of a tolerance of 5.0 ppm for residues
of diphenylamine on pear.  

HED recommends that the Xedamine A label require the use of SCBA for
early entry into apple storage rooms for the purpose of collecting
residue samples.  In addition, the Xedamine A label should recommend use
of protective eye wear for entry into apple storage rooms within 48
hours of treatment.  Similarly, the No Scald label should advise
protective eye wear for workers handling treated pears within 48 hours
of drenching.

HED advises that the petitioner/registrant be requested to submit an
analytical reference standard of diphenylamine to the EPA National
Pesticide Standards Repository.

International Harmonization

Codex MRLs have been established for the post harvest use of
diphenylamine on both apples and pears.  The apple MRL is 10 ppm and the
pear MRL is 5 ppm.  The apple MRL is the same as the U.S. tolerance, and
the pear MRL is the same as the recommended pear tolerance.  Canada has
an apple MRL of 5 ppm for postharvest treatment.  The residue data used
to establish the U.S. tolerance are based on the current U.S. use
pattern, and indicate that the 10 ppm tolerance is appropriate.  As a
result, the U.S. will continue to harmonize with Codex at 10 ppm, and
will not reduce the current tolerance to the Canadian MRL of 5 ppm.  The
International Residue Limit Status sheet is attached.

2.0 PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION

	Diphenylamine

Diphenylamine is a plant growth regulator.  Parent diphenylamine is the
residue of concern in plants and animals for both risk assessment and
tolerance expression.

TABLE 1.  Physicochemical Properties of the Technical Grade Test
Compound

Parameter	

Value	

Reference

Melting point/range	

52.7-54.7 (C	

42716501

pH	

5.9	

42716501

Density	

absolute density = 1.18 g/cm3 at 25 (C 	

42716501

Water solubility	

 (25(C) 0.038-0.042 mg/mL	

Solvent solubility	

 (at 25(C) acetonitrile at 808-897 mg/mL, methanol at 454-492 mg/mL,
octanol at 204-237 mg/mL, and hexane at 53-66 mg/mL	

42898801

Vapor pressure	

Pascal	torr

25 (C                 8.52 X 10-2  6.39 X 10-4

35 (C                 3.09 X 10-1  2.32 X 10-3 

45 (C                 9.46 X 10-1  7.09 X 10-3	

42876201

Dissociation constant, pKa	

pKa = 1.03 at 20(C in 4.75% EtOH 	

42716401

Octanol/water partition coefficient, Log(KOW)	

3.6	

42826601

UV/visible absorption spectrum	

not available	

3.0 HAZARD CHARACTERIZATION

3.1  Hazard Profile

The toxicology database for diphenylamine includes acceptable acute
(dermal, inhalation, eye/ skin irritation and skin sensitization
studies), subchronic/chronic (rat, mouse and dog), reproduction (rat)
and developmental (rat and rabbit) toxicity studies.  Twenty-one day
dermal (rabbit), rat metabolism, and mutagenicity studies were also
submitted.  The mutagenicity studies submitted for diphenylamine satisfy
the mutagenicity battery requirements for the previous registration of
diphenylamine.  The new guideline (40 CFR 158.340, 2004) requires a
structural chromosome aberration assay that was not included in the
toxicology database.  The HED RfD/QA Peer Review Committee (RED
document, August 1997) required that an in vivo/in vitro rat hepatocyte
unscheduled DNA synthesis (UDS) assay be performed based on the liver
effects seen throughout the toxicology database.  This assay was
requested to determine if a potentially genotoxic concentration can be
achieved in the liver.  The outcome of this study will determine if any
additional mutagenicity studies are required for diphenylamine.  This
requested study was not included in the toxicology database.

The acute toxicity data indicate that diphenylamine has moderate
toxicity (Category III) via oral and dermal routes of exposure.  It is
slightly irritating to the skin (Category III) and is severely
irritating to the eye (Category I).  An acute eye irritation study in
rabbits demonstrated corneal opacity (1/3) that was unresolved through
day 7.  For acute inhalation, a data waiver for the inhalation study
with the technical material was granted.  The investigators attempted to
produce small particle size by a milling process; however, the process
resulted in lumps of a large size or a melted mass.  An acute inhalation
study with a formulation (EC-283; 31.0%) resulted in moderate toxicity
(Category III).  Diphenylamine was not a sensitizer in a guinea pig skin
sensitization study.

The diphenylamine database indicates that the liver, spleen, and kidneys
are targets for this chemical.  Toxic effects involving these organs
were observed throughout the toxicology database, and there were several
studies in which multiple organs were affected.  Both liver and spleen
toxicity were observed in all of the following studies:  the subchronic
studies in both the rat and mouse, the chronic study in the dog, the rat
carcinogenicity study, and a 2-generation reproduction study in rats. 
Toxic effects were manifested as discoloration, increased organ weights,
extramedullary hematopoeisis, hemosiderosis (liver), and congestion
(spleen).  In addition, spleen toxicity was observed in a developmental
rat study (discoloration and increased spleen weights) and in a mouse
carcinogenicity study (hemosiderosis and congestion).  Evidence of
kidney toxicity was observed in the subchronic rat study, the rat
2-generation reproduction study, the chronic dog study, and the rat
carcinogenicity study.  The effects seen included discoloration, brown
pigment deposits, increased kidney weights, and dark urine.  Alterations
in hematology were seen in the subchronic and rat carcinogenicity
studies, and clinical chemistry alterations were observed in the
subchronic rat and chronic dog studies.  A greenish tint to the fur was
observed across the database in rats, mice, and dogs after exposure to
diphenylamine.  The author stated this effect was due to an “oxidative
product of the interaction of the test article or a metabolite with
urine or feces.” 

In a developmental toxicity study in rats with diphenylamine, maternal
toxicity was observed in the high-dose group (100 mg/kg/day) in the form
of increased spleen weights and discoloration of the spleen.  In a
developmental toxicity study in rabbits, there was a decrease in body
weight gains and food consumption at the highest dose tested (300
mg/kg/day).  No evidence of developmental toxicity was observed in the
rat or rabbit developmental toxicity studies.  A 2-generation
reproduction study in rats demonstrated maternal toxicity in the form of
gross pathological findings in the spleen and microscopic findings in
the kidney, liver, and spleen.  Reproductive toxicity (decreased litter
size) and offspring toxicity (decreased body weight of F2 pups) were
also seen in the study.  There is no indication of increased sensitivity
of rats or rabbits to in utero and postnatal exposure to diphenylamine. 
Based on the results of the submitted developmental and reproduction
studies, there is no concern for pre- and postnatal susceptibility
resulting from exposure to diphenylamine.

Systemic toxicity was observed in a 21-day dermal toxicity study in
rabbits as dark red foci in the stomach of both sexes (1000 mg/kg/day). 
No evidence of dermal toxicity was seen in the study.

Diphenylamine has been classified as “not likely” to be carcinogenic
to humans.  There was no increase in any tumors found in carcinogenicity
studies in rats and mice.

Acute and subchronic neurotoxicity studies are not available for
diphenylamine.  However, effects commonly observed with neurotoxicity
were not observed in the available studies.  These studies include
developmental toxicity studies in the rat and rabbit and a reproduction
study in the rat.  

There is no evidence that diphenylamine is an endocrine disruptor. 

Diphenylamine was negative in all mutagenicity studies, except for an in
vitro mammalian cell gene mutation assay.  It was considered to be
weakly mutagenic in the presence of metabolic activation.

In a metabolism study in rats, absorption of diphenylamine appeared
rapid and complete for all dose groups as judged from 24-hour excretion
profiles.  Terminal distribution data showed no significant residual
radioactivity in tissues 168 hours post-dose for both the low and high
oral dose groups.  Urine was the major route of excretion of
diphenylamine-derived radioactivity at both the low and high dose, with
between 68 and 81% being recovered for both sexes at the single and
repeated low dose, and between 73 and 74% being recovered at the single
high dose.  Male rats appeared to excrete a greater percentage of
diphenylamine-derived radioactivity in urine at the low dose level,
while female rats showed greater excretion in feces at this dose.  At
the high dose, the percentage eliminated in urine was equivalent in male
and female rats.  Metabolites identified in urine in this study included
dihydroxylated conjugates of diphenylamine, monohydroxylated sulfate
conjugates of diphenylamine, and monohydroxylated glucuronide conjugates
of diphenylamine.  Male rats appeared to show a much greater percentage
of dihydroxylated conjugates of diphenylamine in urine than female rats
at both the single and repeated low oral dose, but not at the single
high dose.  In contrast, females showed higher urinary percentages of
4-hydroxydiphenylamine-O-sulfonic acid than males at all dose levels. 
Fecal metabolites consisted of parent chemical and
4-hydroxydiphenylamine (0.5-3% of the administered dose in both sexes). 
Results of the toxicity studies conducted with diphenylamine are
summarized in Tables 2 and 3.



Table 2. Acute Toxicity Profile - Diphenylamine Technical 

Guideline No.	

Study Type	

MRID(s)	

Results	

Toxicity Category

870.1100	

Acute oral-rat	

00148523	

LD50=2720mg (2490-2980) mg/kg	

III

870.1200	

Acute dermal-rabbit	

00148524	

LD50 > 2000 mg/kg	

III

870.1300	

Acute inhalation-rat	

43794201	

LC50 = 1.46 mg/L	

III

870.2400	

Acute eye irritation-rabbit	

00148525	

Slight eye irritation	

III

870.2400	

*Acute eye irritation-rabbit	

41899404	

Corrosive: Corneal Opacity	

I

870.2500	

Acute dermal irritation -rabbit	

00148526	

Slight skin irritation	

III

870.2600	

Skin sensitization-guinea pig	

43540801	

Not a dermal sensitizer	

N/A

* As required by the Pesticide Assessment Guidelines (Subdivision F,
81-4) the eye irritation study failed to include an  observation period
(21 days) which was sufficient to evaluate fully the reversibility or
irreversibility of the effects observed.  The observation period in the
study only lasted 7 days.

Table 3.  Subchronic, Chronic and Other Toxicity Profile

GDLN 	

Study Type 	

Dose Levels	

MRID	

Results

870.3100	

1992-13 WEEK FEEDING-RAT	

ppm = 0, 150, 1500, 7500, 15000

mg/kg/day =

0, 7.5, 75, 375, 750

Acceptable/Guideline	

42339701	

NOAEL (mg/kg/day): 

 75

LOAEL (mg/kg/day): 375 based on decreased body weight and body weight
gain, dark urine, increased absolute spleen and liver weights,
congestion in spleen, kidney, and liver, discoloration and alterations
in hematological and clinical chemistry parameters.

870.3100	

1992-13 WEEK FEEDING-MOUSE

	

ppm = 0, 10, 525, 2625, 5250

mg/kg/day =

M:0, 2, 94, 444, 926

F: 0, 2, 107, 556, 1101

Acceptable/Guideline	

42542801	

NOAEL (mg/kg/day): 2

LOAEL (mg/kg/day): 

M/F: 94/107 

based on liver/spleen alterations (extramedullary hematopoiesis in the
liver, discoloration and hemosiderosis of the liver, congestion and
extramedullary hematopoiesis in the spleen).

870.3150	

1992-13 WEEK FEEDING-DOG

	

ppm = not given

mg/kg/day =

0, 5, 25, 50

Acceptable/Nonguideline	

42339801	

NOAEL (mg/kg/day): 

M/F= 50

LOAEL  (mg/kg/day): not determined

870.3200

	

1992-21 DAY DERMAL-RABBITS

	

mg/kg/day =

0, 100, 500, 1000

Acceptable/Nonguideline	

42304901	

Systemic: NOAEL (mg/kg/day):500

LOAEL: (mg/kg/day): 1000 

based on effects in the stomach (dark foci-red foci in both sexes-6/10)

Dermal: NOAEL (mg/kg/day):1000

LOAEL (mg/kg/day):

not determined

870.3700	

1992-DEVELOPMENTAL TOX-RAT

	

mg/kg/day =

0, 10, 50, 100

Acceptable/Guideline

	

42292001	

Maternal: NOAEL (mg/kg/day): 50

LOAEL (mg/kg/day):100

based on increased spleen weights and discoloration of the spleen.

Developmental: NOAEL (mg/kg/day): 100 

LOAEL (mg/kg/day): not determined

870.3700

	

1983-DEVELOPMENTAL TOX-RABBIT 

	

mg/kg/day =

0, 33, 100, 300

Acceptable/Nonguideline	

00148521	

Maternal: NOAEL (mg/kg/day): 100

LOAEL (mg/kg/day): 300

based on decreased body weight gains and food consumption.

Developmental: NOAEL (mg/kg/day): 300

LOAEL (mg/kg/day): not determined

870.3800	

1993-2-GENERATION REPRODUCTION-RAT 

	

ppm= 0, 500, 1500, 5000

mg/kg/day =

M: 0, 40, 115, 399

F: 0, 46, 131, 448 

Acceptable/Guideline

 

	

42638101	

Parental: 

NOAEL (mg/kg/day): not determined 

LOAEL (mg/kg/day):

M/F: 40/46 

based on gross pathological findings in the spleen and microscopic
findings in the kidney, liver, and spleen.

Reproductive:

NOAEL (mg/kg/day):

M/F: 115/131

LOAEL (mg/kg/day):

M/F: 399/448

decreased litter size in both generations

Offspring:  

NOAEL (mg/kg/day):

M/F: 40/46

LOAEL (mg/kg/day):

M/F: 115/131

based on decreased body weight of F2 pups in late lactation

870.4100

	

1993-1 YEAR FEEDING-DOGS

	

ppm = not given

mg/kg/day =

0, 10, 50, 100

Acceptable/Guideline	

43000601

	

NOAEL (mg/kg/day): 

10

LOAEL (mg/kg/day): 50

based on alterations in clinical chemistry parameters (increased BUN,
cholesterol, total bilirubin) and increased absolute/relative kidney,
liver and spleen weights.

870.4200	

1994-18 MONTH

CARCINOGENICITY-MICE 	

ppm = 0, 525, 2625, 5250

mg/kg/day =

M: 0, 73, 368, 756

F: 0, 91, 455, 937

Acceptable/Guideline	

43369501	

NOAEL (mg/kg/day):

not determined

LOAEL (mg/kg/day):

M/F: 73/91

based on histopathological lesions in the spleen

No evidence of carcinogenicity 

870.4300	

1994-2 YEAR TOXICITY/

CARCINOGENICITY-RAT

	

ppm = 0, 200, 750, 3750, 7500

mg/kg/day =

M: 0, 8, 29, 147, 302

ppm = 0, 150, 500, 2500, 5000

mg/kg/day =

F: 8, 25, 138, 286

Acceptable/Guideline	

43401401	

NOAEL  (mg/kg/day):

M/F: 29/25

LOAEL (mg/kg/day): 

M/F: 147/138 

based on reduced body weight and body weight gains, changes in
hematological parameters, spleen and kidney lesions and increased
clinical signs of toxicity.

μg/plate (Salmonella typhimurium) in the absence of metabolic
activation (S9);

10.0, 33.3, 66.7, 100, and 333 mg/plate in the presence of metabolic
activation.

Acceptable/Guideline	

42312101	

Negative

870.5300	

1992-IN VITRO MAMMALIAN CELL GENE MUTATION TEST	

5-80 µg/mL in DMSO  both in the presence and absence of rat liver
metabolic activation (+ S9).

Acceptable/Guideline	

42332101	

Weakly mutagenic in the presence of metabolic activation

870.5395	

1992-MAMMALIAN ERYTHROCYTE MICRONUCLEUS TEST 	

 mg/kg/day =  250, 500, or 1000 (males) or 375, 750, or 1500 (females)
single oral gavage

Acceptable/Guideline	

42312001	

Negative

870.7485	

1993-METABOLISM AND PHARMACOKINETICS-RAT 

	

mg/kg/day =

Low dose: 5

Repeated low dose: 

5 for 14 days,

Single high dose: 750 

Acceptable/Guideline

	

42994801	

Terminal distribution data showed no significant residual activity in
tissues 168 hrs post-dose for both the low and high oral dose groups:
urine was the major route for excretion.

Recovery after 168 hrs: 

single/repeated low dose= urine 68-81% (both sexes)

single high dose=73-74%

Male rats excreted a greater percentage of diphenylamine derived
activity at the low dose, while female rats showed greater excretion in
feces at this dose.  At the high dose, the percentage eliminated in
urine was equivalent in both males and females.

Metabolites-urine: dihydroxylated conjugates of diphenylamine,
mono-hydroxylated sulfate conjugates of diphenylamine, monohydroxylated
glucuronide conjugates of diphenylamine.

Metabolites-feces:

Parent chemical and 4-hydroxydiphenylamine, which comprised 0.5-3%
administered dose in both sexes.

3.2  FQPA Considerations

3.2.1.  Adequacy of the Toxicity Database

The toxicology database for diphenylamine is adequate for the evaluation
of risk to infants and children.  Relevant studies include acceptable
developmental toxicity studies in the rat and rabbit and a 2-generation
reproduction toxicity study in the rat.

3.2.2.  Evidence of Neurotoxicity

Acute and subchronic neurotoxicity studies are not available.  However,
effects commonly observed with neurotoxicity were not observed in the
available studies.  These studies include developmental toxicity studies
in the rat and rabbit and a reproduction study in the rat.  

3.2.3.  Developmental Toxicity Studies

Developmental Toxicity Study-Rat; OPPTS 870.3700a

Executive Summary:  In a developmental toxicity study  (MRID 42292001),
pregnant female Sprague-Dawley rats (25/group) received diphenylamine
(99.9%) in corn oil by oral gavage at dose levels of  0, 10, 50, or 100
mg/kg/day from gestation day six through gestation day 15, inclusive. 
Dams were sacrificed on gestation day 20.  None of the rats died during
the study.  Maternal toxicity was evidenced by increased spleen weights,
enlarged spleens and blackish-purple colored spleens in the dams at 100
mg/kg/day.  There was no evidence of developmental toxicity.

The maternal toxicity NOAEL is 50 mg/kg/day and the LOAEL is 100
mg/kg/day based on increased spleen weights and discoloration of the
spleen.  The developmental toxicity NOAEL is 100 and the LOAEL was not
determined.

The developmental toxicity study in the rat is acceptable and satisfies
the guideline requirement for a developmental toxicity study (OPPTS
870.3700) in the rat.

Developmental Toxicity Study-Rabbit; OPPTS 870.3700b

Executive Summary: In a developmental toxicity study  (MRID 00148521),
pregnant New Zealand White rabbits (16-18/group) received either 0, 33,
100, or 300 mg/kg/day diphenylamine (99.9%) suspended in 1%
methylcellulose by oral gavage from gestation day 7 through 19,
inclusive.  Animals were obtained from three different vendors.  The
author stated that the selection “reduced the risk of temporal
variations inherent in protracted studies.”  Maternal toxicity was
noted at 300 mg/kg/day as decreases in food consumption and associated
initial reductions in body weight gain.  There was no evidence of
developmental toxicity. 

The maternal toxicity NOAEL is 100 mg/kg/day and the LOAEL is 300
mg/kg/day based on decreased body weight gains and food consumption
early during the treatment period.  The developmental toxicity NOAEL is
300 mg/kg/day and the LOAEL was not determined.

The developmental toxicity study in the rabbit is acceptable, but does
not satisfy the guideline requirement for a developmental toxicity study
(OPPTS 870.3700) in the rabbit.   There were deficiencies in the conduct
and reporting of the study, poor animal health, and unacceptable methods
for fetal sacrifice and intracranial examinations.

 

3.2.4.  Reproduction Toxicity Studies

2-Generation Reproduction-Rat; OPPTS 870.3800

Executive Summary:  In a two-generation reproductive toxicity study
(MRID 42638101), Sprague-Dawley rats (28 per sex/group) received
diphenylamine (99.8%) in the diet at dose levels of 0, 500, 1500, or
5000 ppm.  F0 males received 0, 40, 115, or 399 mg/kg/day and F0 females
received 0, 46, 131, or 448 mg/kg/day during premating.  F1 males
received 0, 49, 145, or 546 mg/kg/day and F1 females 0, 54, 160, or 580
mg/kg/day.  Compound-related systemic toxicity was observed in a dose
related manner among both sexes and generations at all dose levels.  In
general, females were more affected than males and F1 animals were more
affected than F0 animals.  Clinical signs were evident at 5000 ppm. 
These signs included bluish colored fluid in the cage and bluish colored
staining of the coat in both sexes, and swelling of mammary gland(s) or
palpable lateral-ventral masses, primarily in females.  Body weight was
decreased at 1500 and 5000 ppm.  At 5000 ppm, there was a 6-9% decrease
in body weight values, as compared to control for F0  males, 5-8% for F0
females, 22-28% for F1 males, and 11-23% for F1 females.  At 1500 ppm
there was a 5-8% decrease in body weight values from controls for F0
females, a 7-9% decrease for F1 males, and a 5% decrease for F1 females.
 Food consumption (g/animal/day) was also decreased at 1500 and 5000
ppm.  Kidney, spleen, and liver appeared to be the target organs as
evidenced by weight differences from control at 5000 ppm in males and at
1500 and 5000 ppm in females.  Gross and microscopic findings at all
dose levels in both sexes provided further evidence that the kidney,
liver, and spleen are the target organs.  Gross findings included
enlarged and blackish-purple spleens.  Microscopic findings included
brown pigment in the proximal convoluted tubules of the kidney,
hepatocytic hypertrophy and brown pigments in the Kupffer cells of the
liver, and congestion and hemosiderosis of the spleen.  

Reproductive toxicity was noted as smaller litter sizes at birth
(significant for the F2 litters) in both generations at 5000 ppm.

Developmental toxicity was observed at 1500 and 5000 ppm, as evidenced
by significantly decreased body weight for F1 pups at 5000 ppm
throughout lactation (11-25 % less than control), for F2 pups at 5000
ppm from LD 4 through LD 21 (10%-29% less than control), and for F2 pups
at 1500 ppm on LD 14 (10%) and LD 21 (12%). 

The systemic toxicity NOAEL was not determined.  The LOAEL is 500 ppm
(40 mg/kg/day in males and 46 mg/kg/day in females) based on gross
pathological findings in the spleen (enlarged, discolored), and on
microscopic findings in the kidney (brown pigment in the proximal
convoluted tubule), liver (hepatic hypertrophy and brown pigment in the
Kupffer cells), and spleen (congestion and hemosiderosis). 

The reproductive toxicity NOAEL is 1500 ppm (131 mg/kg/day for maternal
animals) and the LOAEL is 5000 ppm (448 mg/kg/day for maternal animals),
based upon decreased litter size in both generations.

The offspring toxicity NOAEL is  500 ppm (46 mg/kg/day for maternal
animals) and the LOAEL is 1500 ppm (131 mg/kg/day for maternal animals)
based on decreased F2 pup body weight in late lactation.  

The multi-generation study in the rat is classified acceptable and
satisfies the guideline requirement for a reproduction and fertility
study (OPPTS 870.3800) in the rat.

3.2.5.  Additional Information from Literature Sources

A literature search did not reveal studies with diphenylamine that would
impact this risk assessment.

3.2.6.  Pre-and/ or Postnatal Susceptibility

Based on the results of the submitted developmental and reproduction
studies, there is no concern for pre- and postnatal susceptibility
resulting from exposure to diphenylamine.

3.2.6.1.  Determination of Susceptibility

There is no indication of increased sensitivity of rats or rabbits to in
utero and postnatal  exposure to diphenylamine.  In prenatal
developmental toxicity studies in rats and rabbits, no evidence of
developmental toxicity was observed.  In a 2-generation reproduction
study offspring toxicity (decreased body weight) was seen only in the
presence of maternal toxicity. 

3.2.7.  Degree of Concern Analysis and Residual Uncertainties for
Pre-and/or Postnatal Susceptibility

The toxicology database is complete with respect to pre and postnatal
toxicity.  No quantitative or qualitative susceptibility was observed in
the rat and rabbit developmental toxicity studies or in a  2-generation
reproduction study (rat) after exposure to diphenylamine.  Therefore,
HED has no degree of concern or residual uncertainties for pre-and/or
postnatal toxicity.

3.3  Recommendation for a Developmental Neurotoxicity Study 

3.3.1.  Evidence that supports requiring a Developmental Neurotoxicity
Study

 

A developmental neurotoxicity study is not recommended at this time.

3.3.2.  Evidence that supports not requiring a Developmental
Neurotoxicity Study

There were no neurotoxic effects observed in the available database for
diphenylamine.  The submitted studies include developmental toxicity
studies in the rat and rabbit and a reproduction study in the rat. 
There was no increase in susceptibility observed in the developmental or
reproduction studies after exposure to diphenylamine.

3.4  Hazard Identification and Toxicity Endpoint Selection

Table 4.4 provides a summary of the toxicological endpoints.

3.4.1.  Acute Reference Dose (aRfD) Females age 13-49

An acute reference dose for females aged 13-49 has not been established.
 Developmental toxicity studies in rats and rabbits and a 2-generation
reproduction study in rats did not demonstrate evidence of toxicity
attributable to a single dose.

3.4.2.  Acute Reference Dose (aRfD)-General Population

An endpoint attributable to a single dose was not identified from the
available database. 

3.4.3.  Chronic Reference Dose (cRfD)

Study:		Chronic - Dog 

NOAEL:	10 mg/kg/day

LOAEL:	50 mg/kg/day

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x
intraspecies variability)

Comments: A chronic dog toxicity study was used to select the dose and
endpoint for establishing the cRfD of 0.1 mg/kg/day.  The NOAEL of 10
mg/kg/day and the LOAEL of 50 mg/kg/day were based on alterations in
clinical chemistry parameters (increased BUN, cholesterol, total
bilirubin) and increased absolute/relative kidney, liver and spleen
weights.  The 2-generation reproduction study in the rat and the 13 week
feeding study in the mouse were also considered for the chronic
reference dose.  However, the 2 generation reproduction (rat) study
lacked a NOAEL, and the LOAEL of 40 mg/kg/day was based on kidney,
liver, and spleen alterations.  Similar toxic effects were observed in a
2-year carcinogenicity study in the rat (longer exposure period), which
resulted in a  NOAEL of 25mg/kg/day.  Therefore, it is unlikely that the
NOAEL for the 2-generation reproduction study is lower than the NOAEL
for the chronic dog study (10 mg/kg/day).  A 13 week study in the mouse
resulted in a NOAEL of 2 mg/kg/day and a LOAEL of 94 mg/kg/day. 
However, taking into account the incidence and severity of effects seen
at 94 mg/kg/day, the NOAEL is likely to be higher than 2 mg/kg/day.  As
a result, the low NOAEL observed in the mouse study is attributed to
dose spacing.  In all three studies considered for endpoint selection,
there were similar toxic effects (kidney, liver, and spleen alterations)
observed after exposure to diphenylamine.  The chronic dog was selected
and  considered protective of the primary toxic effects of concern.  The
duration of exposure is appropriate for this endpoint.

Chronic Toxicity Study-Dog; OPPTS 870.4100

Executive Summary: In a chronic toxicity study (MRID 43000601), beagle
dogs received by capsule either 0, 10, 50, or 100 mg/kg/day of
diphenylamine sodium salt (>99%) for 12 months.  Systemic toxicity was
noted at the 10 mg/kg/day dose group, lowest dose tested (LDT), and
above as alterations in clinical chemistry.  There was a dose-related
increase in total bilirubin levels in both sexes for the 10 mg/kg/day
group (up to 75%).  For the 50 mg/kg/day group bilirubin levels
increased up to 167%, p < 0.01, and for the 100 mg/kg/day groups,
bilirubin levels increased up to 150%, p < 0.01.  These increases showed
statistical significance in both sexes in the 10 mg/kg/day group at week
26 and in females only at week 39.  Also there was a decrease in blood
urea nitrogen (BUN) levels in females of the 50 mg/kg/day dose group
(16%), and in those of the 100 mg/kg/day dose group (20%) at week 52. 
Cholesterol was increased at 50 mg/kg/day and 100 mg/kg/day at all time
points (4 to 68%; occasionally p < 0.05), and albumin showed occasional
increases, although no differences were noted at the end of the study. 
Alterations seen in the hematological parameters included: a treatment
related decrease in red blood cells at 100 mg/kg/day (11%; p < 0.05 in
males at 52 weeks).  Also, hemoglobin was slightly reduced in both sexes
at 100 mg/kg/day (males, 7-9%; females, 4-7%), hematocrit was slightly
reduced at 100 mg/kg/day males (5-9%), mean corpuscular volume was
slightly increased in both sexes at 100 mg/kg/day (males, 2-4%; females,
6%), and platelets were increased in all treated males (3-35%; p < 0.05
to 0.01 at various time points).  The absolute and relative kidney
weights were increased in males at 50 mg/kg/day (40/36%) and 100
mg/kg/day (18/10%) and in females at both 50 mg/kg/day (24/13%) and 100
mg/kg/day (13/9%).  The absolute and relative liver weights were
increased at 50 mg/kg/day (males, 17/13%; females, 22/11%) and 100
mg/kg/day (males, 29/20%; females, 14/10%).  The absolute and relative
spleen weights were increased in all treated females (9 to 38%/11 to
32%) and the thyroid absolute and relative weights were decreased in 100
mg/kg/day females (23/25%), and there was  a greenish tint to the hair
of the feet in one animal at 50 mg/kg/day and two at 100 mg/kg/day.
Methemoglobin was not measured in this study.  

The NOAEL is 10 mg/kg/day and the LOAEL is 50 mg/kg/day based on
alterations in clinical chemistry parameters (increased BUN,
cholesterol, total bilirubin) and increased absolute/relative kidney,
liver, and spleen weights.

This study is acceptable and satisfies the guideline requirement for a
1-year oral toxicity study  (OPPTS 870.4100) in the dog.

3.4.4.  Incidental Oral Exposure (Short- and Intermediate-Term)

This risk assessment is not required.

3.4.5.  Dermal Absorption

There are no dermal absorption data available; therefore, a default of
100% dermal absorption is assumed.

3.4.6.  Dermal Exposure  (Short- and Intermediate-Term)

Short-Term Dermal Exposure (1-30 days)	

Study:	 21 Day Dermal-Rabbit	

NOAEL: 500	

LOAEL: 1000	

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x
intraspecies variability)

Comments: A 21-day dermal study was used to select a dose and endpoint
for evaluating short-term dermal exposure.  The systemic NOAEL of 500
mg/kg/day and the systemic LOAEL of 1000 mg/kg/day were based on dark
foci in the stomach in both sexes.  The dermal NOAEL and LOAEL were not
determined.  The primary toxic effects of concern were evaluated in this
study and the duration of exposure is appropriate for this endpoint. 

21 Day Dermal Rabbit; OPPTS 870.3200

Executive Summary:  In a 21-day dermal toxicity study (MRID 42304901),
New Zealand White rabbits (5/sex/group) received repeated dermal
applications (under occlusion) of diphenylamine technical (100%)
dissolved in distilled water at dose levels of 100, 500, or 1000 mg/kg
for six hours a day for 21 consecutive days with terminal sacrifice on
day 22.  Two additional groups of rabbits (5/sex) served as the vehicle
(distilled water) controls.  No mortality was noted in the study.  Gross
pathology was noted as dark-red foci in the stomachs of both sexes at
the 500 (20%) and 1000 mg/kg/day (60%) groups.   

The systemic toxicity NOAEL is 100 mg/kg/day and the LOAEL is 500
mg/kg/day based on effects in the stomach (dark red foci in both sexes).
 The dermal toxicity NOAEL was not determined.

This study is acceptable but does not satisfy the guideline requirement
for a dermal toxicity study (OPPTS 870.3250) in the rabbit.  Stability
data that reflect the experimental conditions of the study were not
submitted.  However, the study author stated that stability data are on
file with the registrant.

Intermediate-Term Dermal Exposure (1-6 months)	

Study:	 21 Day Dermal-Rabbit	

NOAEL: 500	

LOAEL: 1000	

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x
intraspecies variability)

Comments: A 21-day dermal study was used to select a dose and endpoint
for evaluating intermediate-term dermal exposure.  The systemic NOAEL of
500 mg/kg/day and the systemic LOAEL of 1000 mg/kg/day were based on
dark foci in the stomach in both sexes.  The dermal NOAEL and LOAEL were
not determined.  The primary toxic effects of concern were evaluated in
this study and the duration of exposure is appropriate for this
endpoint. 

21-Day Dermal Rabbit; OPPTS 870.3200

Executive Summary:  See section 4.4.6 

Long-Term Dermal Exposure (> 6 months)	

This risk assessment is not required

3.4.7.  Inhalation Exposure  (Short- and Intermediate-Term)

Short-Term Inhalation Exposure (1-30 days)	

Study: 	Developmental Toxicity-Rat	

NOAEL:	50	

LOAEL:	100	

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x
intraspecies variability)

Comments: A developmental rat study was used to select a dose and
endpoint for evaluating short-term inhalation exposure.  The maternal
NOAEL of 50 mg/kg/day and the maternal LOAEL of 100 mg/kg/day were based
on increased spleen weights and discoloration of the spleen.  The
duration of exposure is appropriate for this endpoint. 

Developmental Toxicity Study-Rat; OPPTS 870.3700a

Executive Summary:  See section 4.2.3

Intermediate-Term Inhalation Exposure (1-6 months)	

Study: 	Developmental Toxicity-Rat	

NOAEL:	50	

LOAEL:	100	

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x
intraspecies variability)

Comments: A developmental rat study was used to select a dose and
endpoint for evaluating intermediate-term inhalation exposure.  The
maternal NOAEL of 50 mg/kg/day and the maternal LOAEL of 100 mg/kg/day
were based on increased spleen weights and discoloration of the spleen. 
The duration of exposure is appropriate for this endpoint. 

Developmental Toxicity Study-Rat; OPPTS 870.3700a

Executive Summary:  See section 4.2.3

Long-Term Inhalation Exposure (> 6 months)

This risk assessment is not required

3.4.8.  Margins of Exposure

Table 4.  Summary of the Levels of Concern (LOC) for Occupational and
Residential

Exposure Risk Assessments for Diphenylamine

Route/Duration	

Short-Term 

(1 - 30 days)	

Intermediate-Term

(1 - 6 months)	

Long-Term

(> 6 months)

Occupational (Worker) Exposure

Dermal 	

100	

100	

N/A

Inhalation	

100	

100	

N/A

Residential (Non-Dietary Exposure)

Oral	

100	

100	

N/A

Dermal	

100	

100	

N/A

Inhalation	

100	

100	

N/A

3.4.9.  Recommendation for Aggregate Exposure Risk assessments

There are no registered or proposed residential uses for diphenylamine. 
Therefore, an aggregate exposure risk assessment is not required.

3.4.10.  Classification of Carcinogenic Potential

There were no treatment-related increases in tumors in rat and mouse
carcinogenicity studies.  Diphenylamine is classified as “not likely"
to be carcinogenic to humans.

Combined Chronic Toxicity/Carcinogenicity-Rat; OPPTS 870.4300

Executive Summary:  In a combined chronic feeding/carcinogenicity study
(MRID 43401401), Sprague-Dawley rats received diphenylamine (>99.0%) at
dose levels of 0, 200, 750, 3750 or 7500 ppm in males (equal to 8.1,
28.8, 146.7, or 302.1 mg/kg/day) and 0, 150, 500, 2500, or 5000 ppm in
females (equal to 7.5, 24.9, 137.8, or 286.1 mg/kg/day) in the diet for
2 years.  There was a 1-year interim sacrifice of 10 animals per sex per
dose group.  No treatment-related mortality was noted; however, the
study was terminated early because of increased mortality in the control
and low dose animals.  No effects were noted in ophthalmic examinations.
 The only treatment related clinical observation was a greenish tint to
the hair coat in the urogenital or ventral cervical area which the
author stated was due to an “oxidative product of the interaction of
the test article or a metabolite with urine or feces” in the high-mid
and high- dose groups.  Systemic toxicity was noted at the high-mid and
high-dose groups in both sexes as decreased mean body weights and body
weight gains (statistically significant).  Food consumption was
increased in the same dose groups; however, because of food spillage,
when food consumption values exceeded two standard deviations from the
mean, they were not included in calculation of the group mean food
consumption.  Treatment related effects were noted in hematology
involving red cell elements mainly in the high-mid and high-dose groups.
 Increases in albumin levels, decreases in globulin levels, and
increased albumin/globulin ratios were noted, but the biological
relevance to these changes is unknown as there was no related pathology.
 Some slight transient effects were also noted in alkaline phosphatase
and total bilirubin as well as in serum glutamic oxaloacetic
transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT). 
Urinalysis did not reveal any specific treatment-related effects except
a slight increase in ketones in the high dose group because incomplete
or partial interference of the test article caused a false positive
reading.  There was an increase in spleen weights in both sexes in the
high-mid and high-dose groups at the interim sacrifice and terminal
sacrifice.  Gross necropsy observations revealed a roughened surface to
the kidneys in the high dose groups.  Treatment related non-neoplastic
observations were: splenic congestion, increased hemosiderosis and
hematopoiesis in the spleen, pigment deposits in the kidneys, and
increased hematopoiesis in the liver in the high- mid and high-dose
groups.  No treatment related increase in any tumor type or site was
seen in either sex at any dose level.  Methemoglobin was not measured in
this study. 

The NOAEL is 28.8 mg/kg/day in males and 24.9 mg/kg/day in females and
the LOAEL is 146.7 mg/kg/day in males and 137.8 mg/kg/day in females
based on reduced mean body weight and body weight gains, changes in
hematological parameters, spleen and kidney lesions and increased
clinical signs of toxicity.  There was no evidence of carcinogenicity 

This study is acceptable and satisfies the guideline requirement for a
combined chronic/carcinogenicity study (OPPTS 870.4300) in the rat.

Carcinogenicity-Mouse; OPPTS 870.4200	

Executive Summary:  In a carcinogenicity study (MRID 43369501), CD-1
mice (60/ sex/group) were administered diphenylamine (>99%) in the diet
at levels of 0, 525, 2625 or 5250 ppm (males: 73.2, 368.0 and 755.7
mg/kg/day; females: 90.5, 455.2 or 936.6 mg/kg/day) for 18 months. 
There was a significant treatment-related increase in overall mortality
in the 2625 and 5250 ppm group males and females. The increased
mortality was due to cystitis in males and amyloidosis in females.  A
greenish staining of the hair was the most frequently observed clinical
sign with some of the 525 ppm group and essentially all of the 2625 and
5250 ppm groups being affected by the end of the study.  Mean body
weight gain was significantly decreased in the 5250 ppm group males at
the majority of the time points in the study; decreases were also
occasionally recorded for the 2625 ppm group males.  Changes in the
hematology parameters indicated that the chemical produced a
regenerative anemia in the 2625 and 5250 ppm group males and females. On
gross examination at the interim and terminal necropsies, the liver and
spleen of the 2625 and 5250 ppm group animals were dark and enlarged. 
The absolute and relative weights of the liver and spleen were also
increased in these animals.  On histopathology at the interim and
terminal necropsies, the 525 ppm group and above had increased
incidences of hemosiderosis and congestion in the spleen; also, the 2625
and 5250 ppm groups had increased incidences and/or severity of
hematopoiesis in the spleen and liver, and pigment in the
reticuloendothelial cells of the liver.  Pigment was also observed in
the convoluted epithelial cells of the kidney of these groups at the
terminal necropsy.  The incidence of pyelonephritis in the 5250 ppm
group males was marginally increased.  There were increased incidences
of cystitis and dilatation of the urinary bladder and balanoposthitis in
the penis and preputial area of the 2625 and 5250 ppm groups at both of
the necropsies.  For the 5250 ppm group females, the incidence of
amyloidosis was increased in the thyroid, adrenals, kidneys (also in the
2625 ppm group), stomach, small intestines, ovaries and uterus. 

For chronic toxicity the NOAEL was not determined and the LOAEL is  525
ppm (73.2 mg/kg/day for males and 90.5 mg/kg/day for females) based on
histopathological lesions in the spleen.  There was no evidence of
carcinogenicity.

This study is acceptable and satisfies the guideline requirement for a
carcinogenicity study (OPPTS 870.4200) in the mouse.

Table 5 provides a summary of the toxicological doses and endpoints
relevant to diphenylamine.



Table 5.  Summary of Toxicological Doses and Endpoints for Diphenylamine

for Use in Human Risk Assessments

Exposure

Scenario	

Dose Used in Risk Assessment, UF 	

Special FQPA SF  and Level of Concern for Risk Assessment	

Study and Toxicological Effects

Acute Dietary

(general population)	

N/A	

N/A	

No acute endpoint identified for this group. 

Acute Dietary

(females 13-49)	

N/A	

N/A	

No acute endpoint identified for this group. 

Chronic Dietary

(all populations)	

NOAEL= 10 mg/kg/day

UF=100

chronic RfD=0.1 mg/kg/day	

cPAD= cRfD/FQPA SF

cPAD=0.1 mg/kg/day	

Chronic Toxicity- dog

LOAEL (mg/kg/day): 50

based on alterations in clinical chemistry parameters (increased BUN,
cholesterol, total bilirubin) and increased absolute/relative kidney,
liver, and spleen weights.

Dermal 

Short-Term

(1 - 30 days)	

NOAEL=500 mg/kg/day	

Residential LOC for MOE = 100

Occupational LOC for MOE = 100	

21 Day Dermal-Rabbit

LOAEL: (mg/kg/day) 1000

based on effects in the stomach (dark red foci in both sexes)

Dermal 

Intermediate-Term

(1 - 6 months)	

NOAEL=500 mg/kg/day

	

Residential LOC for MOE = 100

Occupational LOC for MOE = 100	

21 Day Dermal-Rabbit

LOAEL: (mg/kg/day) 1000

based on effects in the stomach (dark red foci in both sexes)

Dermal 

Long-Term

(> 6 months)	

N/A	

N/A	

This risk assessment is not required.  

Inhalation 

Short-Term

(1 - 30 days)	

NOAEL (oral study)=50

mg/kg/day

(Inhalation absorption rate=100%)	

Residential LOC for MOE = 100

Occupational LOC for MOE = 100	

Developmental Toxicity-Rat

LOAEL=100 mg/kg/day

based on increased spleen weights and discoloration of the spleen

Inhalation 

Intermediate-Term

(1 - 6 months)	

NOAEL (oral study)=50

mg/kg/day

(Inhalation absorption rate=100%)	

Residential LOC for MOE = 100

Occupational LOC for MOE = 100	

Developmental Toxicity- Rat

LOAEL=100 mg/kg/day

based on increased spleen weights and discoloration of the spleen

Inhalation 

Long-Term

(> 6 months)	

N/A	

N/A	

This risk assessment is not required.  

Cancer (oral, dermal, inhalation)	

Classification: This chemical is “not likely” to be a human
carcinogen.

UF = uncertainty factor, FQPA SF = Special FQPA safety factor, NOAEL =
no observed adverse effect  level, LOAEL = lowest observed adverse
effect level, PAD = population adjusted dose (a = acute, c = chronic)
RfD = reference dose, MOE = margin of exposure, LOC = level of concern,
N/A = Not Applicable

3.5  Special FQPA Safety Factor

Based on the hazard database, HED recommended that the special FQPA
safety factor be reduced to 1x because there were no/low concerns and no
residual uncertainties with regard to pre- and/or post-natal toxicity. 
After evaluating the toxicological and exposure data, the diphenylamine
team recommends that the safety factor be reduced to 1x because of the
following:

The toxicity database showed no increase in susceptibility in fetuses
and pups with in utero and post-natal exposure.

The dietary food exposure assessment is based on HED-recommended
tolerance-level residues (except those processed commodities for which
processing factors were used) and assumes 100% crop treated for all
commodities, which results in very high-end estimates of dietary
exposure.

3.6  Endocrine Disruption

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) “may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other such endocrine effects as the Administrator may designate.” 
Following recommendations of its Endocrine Disruptor and Testing
Advisory Committee (EDSTAC), EPA determined that there was a scientific
basis for including, as part of the program, the androgen and thyroid
hormone systems, in addition to the estrogen hormone system.  EPA also
adopted EDSTAC’s recommendation that the Program include evaluations
of potential effects in wildlife.  For pesticide chemicals, EPA will use
FIFRA and, to the extent that effects in wildlife may help determine
whether a substance may have an effect in humans, FFDCA authority to
require the wildlife evaluations.  As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP).

In the available toxicity studies on diphenylamine, there was no
evidence of estrogen, androgen, and/or thyroid mediated toxicity.

4.0  EXPOSURE ASSESSMENT and CHARACTERIZATION

4.1  Summary of Registered Uses

Tolerances for diphenylamine are listed in 40CFR §180.190.  The
residue of concern in plants and livestock is parent diphenylamine only
for both tolerance enforcement and risk assessment.  Tolerances are
established for diphenylamine residues in/on apple at 10 ppm and in
apple, wet pomace at 30.0 ppm [40 CFR §180.190(a)] resulting from the
direct application of diphenylamine (EC or SC/L) to apples (pre- or
post-harvest) as a spray, dip or drench application. Tolerances are also
established for diphenylamine residues at 0.01 ppm in milk, meat, fat,
and meat byproducts (except liver) of cattle, goat, horse, and sheep,
and at 0.1 ppm in liver of these animals.

4.2  Dietary Exposure/Risk Pathway

4.2.1.  Residue Profile

4.2.1.1.  Tolerance Expression and Established Tolerances

Tolerances for diphenylamine are listed in 40CFR §180.190.  The residue
of concern in plants and livestock is parent diphenylamine only for both
tolerance enforcement and risk assessment.

4.2.1.2.  Proposed Tolerances

HED is recommending in favor of a tolerance of 5 ppm for the residues of
diphenylamine resulting from post-harvest (dip, spray, or drench)
application to pears.

4.2.1.3.  Nature of the Residue in Plants and Animals

The qualitative nature of the residue in plants and livestock is
adequately understood based on acceptable apple, ruminant, and poultry
metabolism studies.  The HED Metabolism Committee (C. Swartz, 2/2/95)
concluded that the residue of concern in plants and livestock is
diphenylamine, per se.  As apples and pears are members of the same crop
group, pome fruit, a metabolism study in pears will not be required.

4.2.1.4.  Crop Field Trial Residue Levels

The submitted apple trial adequately simulated commercial, post-harvest
application of diphenylamine (EC) to apples in controlled atmospheric
storage using thermal fogging.  Although only one test was conducted,
sufficient numbers of samples of each variety were collected over time
to adequately characterize residue levels resulting from the proposed
use.  Samples were analyzed using adequate analytical methods, and the
sample storage intervals are supported by the available storage
stability data.  The dip treatment of the pears simulated commercial
practice.  Sufficient numbers of samples were collected, treated, and
analyzed to determine maximum residue levels expected in pears. 

Following each application, there was little or no effect on residue
levels in apples from the position of samples within each bin (top or
bottom) or within the storage room, indicating that the thermal fogging
application evenly dispersed diphenylamine throughout the room.  Residue
levels were also generally similar between the two apple varieties,
although Red Delicious apples had slightly higher residues than Granny
Smith apples.  Both varieties showed the same pattern of residue decline
over time.  Following each application, residues initially increased
from Day 1 to Day 7 and then showed a steady decline from Day 7 to Day
90.  At 7 days after treatment (DAT), residues were 0.80-2.37 ppm in/on
16 samples following the first application and 1.37-4.10 ppm in/on 16
samples following the second application.  Including both varieties (16
samples/interval), average residues at 1, 7, 47, and 90 days following
the first application were 1.16, 1.41, 0.89, and 0.45 ppm, respectively,
and residues at 1, 7, 45, and 90 days following the second  application
were 1.76, 2.46, 1.32, and 1.04 ppm, respectively.  The maximum residues
were 4.10 ppm, indicating that residues resulting from the proposed use
pattern will not exceed the current tolerance of 10.0 ppm in/on apples.

In pears, the results from the two trials are consistent with each
other.  In the Washington pears, residues ranged from 2.05 to 2.85 ppm,
with the average being 2.38 ppm.  In the Idaho pears, residues ranged
from 1.80 to 2.41 ppm, with the average being 2.12 ppm.  The highest
residue value in any of the samples was 2.85 ppm.

The dietary exposure of livestock to diphenylamine will not be increased
as the proposed use pattern resulted in lower residue levels on apples
than did the current uses.  Therefore, current tolerances for livestock
commodities are adequate.  There are no significant livestock feed items
associated with pears.

4.2.1.6.  Analytical Enforcement Methodology

Plant commodities.  An adequate GC/MSD method (Hazelton Method #HWI
6524-100) is available for enforcing tolerances on apple commodities,
and this method was used for data collection in the current post-harvest
study.  The method was adequately validated in conjunction with the
sample analyses.  A modification of this method was used in the pear
analyses.

Animal commodities.  Tolerances are not being established for animal
commodities; therefore, a discussion of analytical methods for the
determination of diphenylamine in animal commodities is not germane to
this risk assessment. 

Multiresidue Method.  The FDA PESTDATA database dated 1/94 (Pam Vol. I,
Appendix I) indicates that diphenylamine is completely recovered using
FDA Multiresidue Protocol D (PAM I Section 232.4) and that recovery of
diphenylamine through FDA Multiresidue Protocol E (fatty and nonfatty,
PAM I Sections 211.1 and 212.1) is low (<50%). 

4.2.2.  Dietary Exposure Analysis

A chronic dietary risk assessment was conducted using the Dietary
Exposure Evaluation Model (DEEM-FCID, Version 2.03), which uses food
consumption data from the USDA’s Continuing Surveys of Food Intakes by
Individuals (CSFII) from 1994-1996 and 1998 (Memo, D319225, D. Dotson,
8/8/2005).

4.2.2.1. Chronic Dietary Exposure Analysis

The chronic dietary exposure analysis was based on tolerance level
residues, DEEM (Version 7.81) default processing factors, an empirical
processing factor for apple juice, and 100% crop treated assumptions. 
As the general U.S. population and all population subgroups had risk
estimates that were below HED’s level of concern (i.e., 100% of the
chronic population adjusted dose (cPAD)) it was not necessary to make
further refinements to the analysis.  As such, this analysis is a very
conservative one.  The cPAD value for the most highly exposed population
subgroup (Children 1-2 years) is 90%, and that for the general U.S.
population is 12%.

4.2.2.3. Cancer Dietary

A cancer dietary exposure analysis was not performed because
diphenylamine was classified as “not likely to be a human
carcinogen.”

Table 6 provides a summary of the dietary exposure analyses performed
for diphenylamine.

Table 6.  Summary of Dietary Exposure and Risk for Diphenylamine

Population Subgroup*	

Acute Dietary	

Chronic Dietary	

Cancer

	

Dietary Exposure (mg/kg/day)	

% aPAD	

Dietary Exposure

(mg/kg/day)	

% cPAD	

Dietary Exposure

(mg/kg/day)	

Risk

General U.S. Population	

N/A	

N/A	

0.012037	

12	

N/A	

N/A

All Infants (< 1 year old)

	

0.069376	

69

Children 1-2 years old*

	

0.089757	

90

Children 3-5 years old

	

0.054053	

54

Children 6-12 years old

	

0.018257	

18

Youth 13-19 years old

	

0.0063	

6.3

Adults 20-49 years old

	

0.004174	

4.2

Adults 50+ years old

	

0.00498	

5

Females 13-49 years old

	

0.004951	

5

*The most highly exposed population subgroup is in bold type.

4.3  Water Exposure/Risk Pathway

As the diphenylamine uses are post harvest, residues in drinking water
are not relevant to this risk assessment. 

4.4  Non-Occupational/Residential and Recreational Exposure and Risk

There are no current or proposed non-occupational/residential uses for
diphenylamine.  Therefore, an assessment for
non-occupational/residential exposures is not required.

5.0  AGGREGATE RISK ASSESSMENTS and RISK CHARACTERIZATION

5.1  Acute Aggregate Risk

As no acute dietary endpoint was identified, and acute aggregate risk
assessment is not required.

5.2  Short-Term Aggregate Risk (Food + Drinking Water + Residential)

There are no residential uses for diphenylamine and residues are not
expected to occur in drinking water.  As a result, a short-term
aggregate risk assessment is not required.

5.3  Intermediate-Term Aggregate Risk  (Food + Drinking Water +
Residential)

There are no residential uses for diphenylamine and residues are not
expected to occur in drinking water.  As a result, an intermediate-term
aggregate risk assessment is not required.

5.4  Chronic Aggregate Risk

Chronic aggregate risk assessments take into account risks from exposure
to diphenylamine through dietary exposure (i.e., food), drinking water
exposure, and exposure resulting from residential uses.  As exposures
through drinking water and residential uses are not expected, chronic
aggregate risk is equivalent to the food only exposures.  See Section
4.2.2.1, above for a discussion of the chronic dietary risks and Table 6
for a listing of the exposures and risks for the various regulated
population subgroups.  Aggregate chronic exposure to diphenylamine is
below HED’s level of concern for the general U.S. population and all
population subgroups.

5.5  Cancer Aggregate Risk

As diphenylamine is not likely to be carcinogenic to humans, a cancer
aggregate risk assessment was not performed.

6.0  CUMULATIVE RISK

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to diphenylamine and any other
substances, and diphenylamine does not appear to produce a toxic
metabolite produced by other substances. For the purposes of this
tolerance action, therefore, EPA has not assumed that diphenylamine has
a common mechanism of toxicity with other substances.  For information
regarding EPA’s efforts to determine which chemicals have a common
mechanism of toxicity and to evaluate the cumulative effects of such
chemicals, see the policy statements released by EPA’s Office of
Pesticide Programs concerning common mechanism determinations and
procedures for cumulating effects from substances found to have a common
mechanism on EPA’s website at
http://www.epa.gov/pesticides/cumulative/.

7.0  OCCUPATIONAL EXPOSURE and RISK

Xedamine A and No Scald DPA EC-283 contain the plant growth regulator
diphenylamine as the sole active ingredient.  Diphenylamine is used in
post-harvest treatment of fruit to prevent the appearance of the skin
discoloration known as storage scald.  Xedamine A contains 10% of the
active ingredient diphenylamine and is applied to apples kept in cold
storage by an electric thermofogger.   It is applied by a thermal
electrofogger at an application rate of 0.00001375 to 0.0000143 lb ai 
per lb of apples per day.  No Scald DPA EC 283 is formulated as a liquid
and contains 31% of the active ingredient diphenylamine.  It is applied
to pears by drive thru drenching at an application rate of 0.0166 lb
ai/gallon.  Occupational exposure is expected to be short- and
intermediate-term in duration

7.1  Handlers tc \l2 "7.1  Handlers 

7.1.1.  Thermal Fogger tc \l3 "7.1.1.  Thermal Fogger 

Xedamine A is sold in 5-gallon pails.  A wand attached to tygon tubing
suctions the product directly from the bung or spout of an open pail to
the XEDA electrofogger machine, which is placed outside of the storage
room.  Therefore, there is no mixing/loading of the product and no
transfer into other containers or equipment.  The electrofogger flash
heats the liquid to 165 - 170(C in a fast flow of air which is dispersed
as a fog of extremely small particles.   A rigid pipe and nozzle
extending from fogger intended for blowing the diphenylamine fog into
the room enters the storage room through an access hatch or porthole. 
Plastic sheeting and duct tape are put around the nozzle to cover the
hatch opening and keep fog from escaping from the room.  Prior to
treatment, a layer of plastic sheeting is also placed in front of the
apples closest to the hatch opening to prevent those apples from
becoming over saturated with fog.  

The treatment facility consists of a central hallway (60,000 to 250,000
cubic feet), with individual cold storage rooms opening to the hallway. 
The electrofogger is placed in the hallway during treatment.   The
entrance to the hallway is open and is covered by large strips of
plastic sheets to maintain proper temperatures within the storage rooms.
 A cold storage room of 128,000 cubic feet (average size for a storage
room), has a capacity to store 2500 bins.  One bin typically holds about
800 pounds of apples.  A packing facility may have several storage rooms
in operation at the same time; however, a worker will not treat more
than 2 rooms in a day.  Diphenylamine applications are seasonal.  There
is one application in the fall, immediately following harvest and a
second application, if necessary, in the winter, three to four months
later for long-term storage. 

If fruit is to be stored for prolonged periods (more than 4 months), a
second treatment of diphenylamine is advised 60 to 90 days after the
initial treatment.  The second treatment may be applied at a rate of 50
to 100% of the initial dosage, depending on susceptibility of the fruit
to scald and the projected length of the further storage (dosages higher
than 50% of the initial dose are rarely advised).

Twelve-hours prior to and during treatment, room cooling systems, and
humidifiers are turned off.  Circulation fans are turned off immediately
prior to and during treatment.  Once the fogger is operational, an
operator/monitor stays with the fogger to keep an eye on it and make
sure it is working properly.  According to the registrant, the fogging
process takes about 1 hour to treat 125 tons and  approximately 3 hours
to treat 400 tons of fruit.  An operator will not treat more than two
rooms a day.  The requirement for a full face respirator to be worn by
the operator appears on the Xedamine A label.

5.1.2.	Dipping, Drenching, and Spraying tc \l3 "5.1.2.	Dipping,
Drenching, and Spraying 

Packing house operations for pears include three post-harvest
treatments: 1) dipping (immerse fruit completely in diphenylamine
emulsion, then remove to drain and place in storage), 2) drenching, and
3) spraying.  Application equipment varies depending on the packing
facility; however, most equipment is automated and consists of dipping
vats, roller/conveyer belts which carry the fruit, spray bars, and
curtains which cover the entire system to prevent or limit spray drift. 

The number of gallons used to treat pears is the same no matter what
method of application is used.  For purposes of this assessment, HED
used the drive through automated bin drench scenario to assess handler
exposure. 

Diphenylamine is applied to pears mainly by a drive-through and an
automated bin drencher.  The registrant submitted a study on the two
drenching process techniques for diphenylamine.  The two techniques were
observed by an assessor.  The registrant asserts that the drive-through
drenching sites represent typical drenching operations.  A typical
description of the drive-through drenching process for diphenylamine
(Occupational and Residential Exposure Assessment and Recommendations
for RED for Diphenylamine; Bar Code D231693: April 23, 1997) is as
follows:

"The drive-through drencher process involved a truck loaded with bins of
apples, which is pulled through the drencher which is enclosed on the
sides.  The drencher is large enough for a flat bed truck with apple
bins stacked up to 3 layers high to pull through.  The truck cab is
pulled beyond the application area before spraying begins.  The driver
stays in the cab during the process.  Once the truck is inside the
drencher, the operator turns on the spray nozzles from inside the
drenching area and steps away from the application area.  The truck
driver pulls through slowly as the diphenylamine material is applied to
the apples using high-flow flood nozzles."

HED assumes essentially the same process is used to treat a truck load
of pears.  The assessor at the site observed that potential exposure
could occur to handlers when diphenylamine is loaded into the tank.  The
highest potential exposure may occur from drift and over-spray from the
drencher equipment onto the persons present during application and also
from routine cleaning of the system.

Since this time, the truck drencher process was assessed for imazalil
(Occupational and Residential Exposure Assessment and Recommendations
for RED for Imazalil; D270918: December 25, 2000).  In this more recent
review of the drenching process, the truck driver vacates the cab and
manually activates the drenching process.  A gate blocks the path of the
truck until the 10 minute draining period is satisfied.  It is HED’s
understanding that packing plants now incorporate this more current
drenching process where the driver vacates the cab.  

7.1.3.  Handler Exposure and Risk tc \l3 "7.1.3.  Handler Exposure and
Risk 

The mixer/loader dermal and inhalation exposure scenarios resulting from
the thermal fogging and the drive through drench treatment processes for
pears and apples are summarized in Table 7.  All dermal and inhalation
MOEs were greater than the target MOE of 100 and therefore were not of
concern.  	

As the application of diphenylamine is mechanically automated for the
thermal fogger, HED has concluded that dermal exposure to the applicator
will be negligible.  However, an operator/monitor stays directly outside
of the storage room with the fogger to insure all pieces of apparatus
and instrumentation are functioning properly.  Although the operator has
no potential for dermal contact with product in the open pail because it
is automatically suctioned into the fogger, there is potential for
inhalation exposure.  However, as diphenylamine has a relatively low
vapor pressure (6.39 x 10-4 mm Hg), the evaporation of diphenylamine and
potential for inhalation exposure would be negligible.   Furthermore,
according to the proposed label, fogging applicators must wear a
full-face respirator with organic vapor filter which would further
reduce the risk of inhalation exposure. 

Exposure to applicators from dipping, drenching, and spraying of pears
is also expected to be minimal as these types of equipment are operated
remotely and there is minimal contact with the equipment.  Furthermore,
it is HED’s understanding that packing plants now incorporate a
current drenching process where the driver vacates the cab.  Therefore,
HED concludes that there is negligible exposure to drench applicators
and an exposure assessment is not required. 

 

Table 7.  Occupational  Handler Short- and Intermediate-Term Exposure
Data and Assumptions

Scenario	

Use Site	

Mitiga-tion	

Dermal Unit Exposure 1 (mg/lb ai)	

Inhala-tion Unit Exposure 1 (mg/lb ai)	

Applica-tion Rate 2

	

Amount Treated 3

	

Daily Gallons Treated 4	

Dermal Dose 5

(mg/kg/day)	

Dermal MOE 6	

Inhalation Dose 7 (mg/kg/day)	

Inhalation MOE 8

 Open Mixer/loader

Xedamine A 

Liquid (10% a.i.) Reg # 64864-WA-1

Thermal Fogger	

apples	

single layer & gloves	

0.023	

0.0012	

 0.0000143 lb ai/ lb apple	

2,000,000 lbs apples/

day	

NA	

0.0094	

53000	

0.0005	

100000

No Scald DPA EC 283

Liquid (31% a.i.)

Reg # 2792-45

dripping, drenching and spraying	

pears	

 single layer & gloves	

0.023	

0.0012	

*0.0166 lb ai/gal

	

500,000 lb pears/day 	

550	

0.003	

170000	

0.000156	

320000

1.  Unit exposures were derived from PHED Version 1.1

2.  Application Rate based on proposed labels.  The liquid formulation
for Xedamine A resulted in the maximum application rate for Granny Smith
apples

2*  8.6 lbs product  x (0.31a.i.)   =   2.67 lb ai/gal;	2000 ppm DPA = 
1 gal. con.  	

1 gallon							        160 gal. emulsion

2* continued	      1 gal. con.	    X 	2.67 lb ai     =     0.0166 lb
ai/gal

160 gal. emulsion	   1 gal.

3.  Amount treated per day provided by Registrant and IR-4 Science
Experts

4.  500,000 apples ( 900 lbs of fruit treated by 1 gallon of drench =
550 gallons treated per day

5.  Dermal Daily Dose = Unit Exposure x application rate x Amount
treated 

Body Weight (70 kg)

6.  Short- and Intermediate-term Dermal MOE = NOAEL (500 mg/kg/day)

      Dermal Dose (mg/kg/day)

7.  Inhalation Daily Dose = Unit Exposure x application rate x Amount
treated 

Body Weight (70 kg)

8.  Short- and Intermediate-term Inhalation MOE =  NOAEL (50 mg/kg/day)

         Inhalation Dose (mg/kg/day)

7.2  Postapplication Exposure tc \l2 "7.2  Postapplication Exposure 		

HED has determined that there are potential exposures to persons
entering treated sites (e.g. packing plant workers and operators) after
application of pesticide is complete.  Diphenylamine applications are
seasonal.  No data regarding the number of exposure days per year were
provided.  Therefore, it is assumed that postharvest workers in packing
plants can be exposed for several months during peak seasons for various
fruits (Report prepared by Agricultural Reentry Task Force: Hours per
day spent performing reentry activities, 1997).  Thus, exposures are
expected to be short to intermediate in duration.  Long-term exposures
are not expected.

7.2.1.  Thermal Fogger tc \l3 "7.2.1.  Thermal Fogger 

As indicated on the label, 12-hours prior to and during treatment,
storage room cooling systems and humidifiers are turned off. 
Circulation fans are turned off immediately prior to and during
treatment.  Fog is allowed to stay overnight or until the fog has
totally disappeared (about 5-hours post treatment) before the fans and
cooling systems are restarted.  After that point, the apples are kept
stored under controlled atmosphere conditions (typically 1 to 3% oxygen
(with carbon dioxide controlled to about half the percent of the oxygen)
and 32 to 36(F) until they are removed for processing and/or
distribution.  According to the registrant, the earliest point that
anyone would enter the treated room would be 4-days, and that would only
be to collect samples for residue analysis.  Because of the low oxygen
content in the room, these workers do not enter storage rooms without
the use of full SCBA gear.  However, the label does not mention or
require the use of respirators or special equipment to reenter storage
rooms.  The time interval between diphenylamine treatment and removal of
apples from storage for processing and distribution can vary from 2
weeks to 4 months.  Any apples that are expected to be pulled from
storage in less than 2 weeks (i.e. apples that are harvested and
immediately cleaned, sorted and distributed) are not treated with
diphenylamine as the risk of storage scald in such a short period of
time is low. 

If fruit is to be stored for prolonged periods (more than 4 months), a
second treatment of diphenylamine is advised 60 to 90 days after the
initial treatment.  The second treatment may be applied at a rate of 50
to 100% of the initial dosage, depending on susceptibility of the fruit
to scald and the projected length of the further storage.  Dosages
higher than 50% of the initial dose are rarely advised.

Postapplication activities will consist of the following:

worker entering storage room 4 days after treatment to collect sample
for residues (early re-entry)

worker transporting crates of treated apples out of storage room for
processing and distribution (re-entry)

7.2.1.1.  Early Re-entry Exposure and Risk tc \l4 "7.2.1.1.  Early
Re-entry Exposure and Risk 

HED evaluated potential inhalation and dermal exposure estimated for
early re-entry into a storage room to collect apples for residue samples
immediately after treatment with diphenylamine.  The registrant has
indicated that because of the atmospheric conditions under which the
storage rooms are maintained (low levels of oxygen ranging from 1 to 3 %
and temperature ranging from 32 to 36(F), anyone who enters the storage
rooms must do so wearing full SCBA gear.   However, there is no mention
of  PPE requirements for reentry on the proposed label. 

Based on the atmospheric conditions within the storage rooms, the more
acute danger to early re-entry workers is lack of oxygen.  Use of SCBA
gear will mitigate these concerns and provide adequate protection from
diphenylamine inhalation exposure.  Therefore, HED recommends that the
proposed Xedamine A label require the use of SCBA for early entry into
storage rooms for the purpose of collecting residue samples.  With this
label statement, a quantitative inhalation risk assessment is not needed
for early re-entry workers.  Furthermore, as the early re-entry worker
is in the storage room for such a very short period of time to collect a
few apples for residue samples, dermal exposure is expected to be
negligible.  Therefore, a dermal exposure assessment was not required.

7.2.1.2.  Re-entry to Cold Storage Exposure and Risk

HED assumes that most particles of diphenylamine will dissipate by the
time fruit removal is expected to take place.  This assumption is based
on diphenylamine’s relatively low vapor pressure (6.39 x 10-4 mm Hg)
and the dissipation properties of foggers (aerosols).  The risk of
inhalation exposure will be reduced to the point where it is negligible,
and a quantitative assessment for inhalation exposure to re-entry
workers is not required.

Table 8 summarizes the dermal margins of exposure for re-entry workers. 
The short- and intermediate-term dermal MOEs were all greater than 100,
and therefore did not exceed HED’s level of concern.					

Table 8.  Re-entry Dermal Exposure for Diphenylamine on Apples

Scenario	

Transfer Coefficient (cm2/hr) 1	

Dislodgeable Foliar Residue (ug/cm2) 2	

Dermal Dose (mg/kg/day) 3	

Short- and Intermediate-term MOE 4

sorting/culling and packing	

1500 	

2.6	

0.46	

1100

1. Transfer Coefficient (cm2/hr) = Tc = 185 ug/hr (unit exposure from
surrogate study) ( 0.12 ug/cm2 (average DFR for two days  from surrogate
study Nigg, H.N., J.H. Stamper, and R.M. Queen (1984) The Development
and Use of a Universal Model to Predict Tree Crop Harvester Pesticide
Exposure.  Am. Ind. Hygiene. Association Journal 45:182-186.) = 1500

2.  Dislodgeable Foliar Residue = DFR = 2.6 ug/cm2

A “standard” apple has a diameter of 2.75 inches (~7 cm) and weighs
138 grams

the diphenylamine residue level in an apple is 3.0 ppm.  This was
obtained from residue trials from diphenylamine residue study on whole
apples following post-harvest fogging (Lab Project Number: 02022)

All of the diphenylamine in an apple is located on its surface

Amount of diphenylamine in an apple = 3.0 ug/g x 138 g/pear = 414 ug

Surface area of a sphere = 4πR2 =   4 x 3.14 x (7/2 cm)2 = 154 cm2

Residue value for diphenylamine = 414 ug ( 154 cm2 = 2.6 ug/cm2

3. Dermal Dose= [DFR (µg/cm2) x Tc (cm2/hr) x 0.001 mg/µg x dermal
absorption x 8 hrs/day] ( body weight (kg). 

4.  MOE = NOAEL (500 mg/kg/day)/Daily Dermal Dose

7.2.2.  Dipping, Drenching, and Spray

The main postharvest activities within the packing house consist of
sorting/culling and packing of pome fruits following post harvest
application.  For purposes of this assessment, “re-entry” will refer
to the situations where workers sort, cull, and pack pears for shipping
and distribution.  HED evaluated the risk of dermal and inhalation
exposure for re-entry workers in pear packing plants.  No postharvesting
data for pears were submitted in support of this use.  As a result,
dermal exposure for re-entry workers in packing plants was assessed
using: (1) the same surrogate DFR study (H.N. Niggs et al., 1984) as was
used to determine a transfer coefficient for apples, and (2)
chemical-specific residue data for pears.

7.2.2.1.  Packing Plant Postharvest Exposure and Risk tc \l4 "7.2.2.1. 
Packing Plant Postharvest Exposure and Risk 

HED assumes that most particles of diphenylamine will dissipate by the
time fruit removal is expected to take place.  This assumption is based
on diphenylamine’s relatively low vapor pressure (6.39 x 10-4 mm Hg)
and the dissipation properties of particles from the drench solution. 
The risk of inhalation exposure will be reduced to the point where it is
negligible, and a quantitative assessment for inhalation exposure to
re-entry workers is not required.  Table 9 summarizes the dermal margins
of exposure for re-entry workers to pear packing plants.  The short- and
intermediate-term dermal MOEs were all greater than 100, and therefore
did not exceed HED’s level of concern.  

Table 9.  Re-entry Dermal Exposure for Diphenylamine on Pears

Scenario	

Transfer Coefficient (cm2/hr) 1	

Dislodgeable Foliar Residue (ug/cm2) 2	

Dermal Dose (mg/kg/day) 3	

Short- and Intermediate-term MOE 4

sorting/culling and packing	

1500 	

2.15	

0.368	

1400

1. Transfer Coefficient (cm2/hr) = Tc = 185 ug/hr (unit exposure from
surrogate study) ( 0.12 ug/cm2 (average DFR for two days      from
surrogate study) = 1500

2.  Dislodgeable Foliar Residue = DFR = 2.15 ug/cm2

A “standard” pear has a diameter of 2.75 inches (~7 cm) and weighs
138 grams

The diphenylamine residue level in a pear is 2.4 ppm.  This was obtained
from the Interregional Research Project No 4 (petition EO6879) field
trials for pears

All of the diphenylamine in a pear is located on its surface

Amount of diphenylamine in a pear = 2.4 ug/g x 138 g/pear = 331.2 ug

Surface area of a sphere = 4πR2   (although a pear is not a sphere the
area which is handled has a similar area)   4 x 3.14 x (7/2 cm)2 = 154
cm2

Residue value for diphenylamine = 331.2 ug ( 154 cm2 = 2.15 ug/cm2

3. Dermal Dose= [DFR (µg/cm2) x Tc (cm2/hr) x 0.001 mg/µg x dermal
absorption x 8 hrs/day] ( body weight (kg). 

4.  MOE = NOAEL (500 mg/kg/day)/Daily Dermal Dose

7.3  Entry Restrictions

The proposed postharvest uses do not fall under the scope of the Worker
Protection Standards.  Nevertheless, based on the acute toxicity
category I for eye irritation for technical diphenylamine, HED
recommends that the Xedamine A label advise use of protective eye wear
for entry into apple storage rooms within 48 hours of treatment. 
Similarly, the No Scald label should advise protective eye wear for
workers handling treated pears within 48 hours of drenching.	

8.0  DATA NEEDS/LABEL REQUIREMENTS

HED recommends that the Xedamine A label require the use of SCBA for
early entry into storage rooms for the purpose of collecting residue
samples.  In addition, the Xedamine A label should recommend use of
protective eye wear for entry into apple storage rooms within 48 hours
of treatment.  Similarly, the No Scald label should advise protective
eye wear for workers handling treated pears within 48 hours of
drenching.

HED advises that the petitioner/registrant be requested to submit an
analytical reference standard of diphenylamine to the EPA National
Pesticide Standards Repository.

REFERENCES

Dietary Exposure Analysis: Diphenylamine Chronic Dietary Exposure
Assessment for the Section 3 Registration Action on Pears, D319225, D.
Dotson, 8/8/2005.

Residue Chemistry Summary Document:  Diphenylamine.  Request for
Tolerance on Pear and Registration of a New Formulation and Application
Technique on Apples in Storage.  Summary of Analytical Chemistry and
Residue Data, D303526, D. Dotson, 8/8/2005.

Occupational Exposure Analysis:  Diphenylamine: Occupational and
Residential Exposure Assessment for Proposed Section 3 Registration for
Post-harvest Use on Apples and Pears (Petition No. 06987). D305183, M.
Collantes, 8/8/2005.

cc: D. Dotson, K Bailey, M. Collantes, RAB2 Reading File



INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name: Diphenylamine

	

Common Name: Diphenylamine

	

( Proposed tolerance

( Reevaluated tolerance

( Other	

Date: 7/13/2005

Codex Status (Maximum Residue Limits)	

U. S. Tolerances

( No Codex proposal step 6 or above

( No Codex proposal step 6 or above for the crops requested	

Petition Number: 0E6107

DP Barcode: D316739

Other Identifier:

Residue definition (step 8/CXL):diphenylamine	

Reviewer/Branch: Doug Dotson/RAB2

	

Residue definition: Parent Diphenylamine

Crop (s)	

MRL (mg/kg)	

Crop(s) 	

Tolerance (ppm)

apple*	

10	

Apple	

10 ppm

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pear*	

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Pear	

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*postharvest use	

	

	

	

	

	

Limits for Canada	

Limits for Mexico

( No Limits

( No Limits for the crops requested	

X No Limits

( No Limits for the crops requested

Residue definition: diphenylamine

	

Residue definition:

Crop(s)	

MRL (mg/kg)	

Crop(s)	

MRL (mg/kg)

apple*	

5	

	

*Registrations 13471.00 and 18983.00, both for postharvest treatment	

	

	

Notes/Special Instructions:

S.Funk, 07/14/05.

Rev. 1998

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