United Slates Prevention, Pesticides EPA-738-F-97-010
Environmental Protection And Toxic Substances April 1998
Agency (7508W) ,
3EPAI R.E.D. FACTS
Diphenylamine
Pesticide All pesticides sold or distributed in the United States must be
Reregistration registered by EPA, based on scientific studies showing that they can be
used without posing unreasonable risks to people or the environment.
Because of advances in scientific knowledge, the law requires that
pesticides which were first registered before November 1,1984, be
reregistered to ensure that they meet today's more stringent standards.
In evaluating pesticides for reregistration, EPA obtains and reviews a
complete set of studies from pesticide producers, describing the human
health and environmental effects of each pesticide. To implement
provisions of the Food Quality Protection Act of 1996, EPA considers the
special sensitivity of infants and children to pesticides, as well as aggregate
exposure of the public to pesticide residues from all sources, and the
cumulative effects of pesticides and other compounds with common
mechanisms of toxicity. The Agency develops any mitigation measures or
regulatory controls needed to effectively reduce each pesticide's risks. EPA
then reregisters pesticides that meet the safety standard of the FQPA and
can be used without posing unreasonable risks to human health or the
environment.
When a pesticide is eligible for reregistration, EPA explains the basis
for its decision in a Reregistration Eligibility Decision (RED) document.
This fact sheet summarizes the information in the RED document for
reregistration case 2210, diphenylamine.
Use Profile Diphenylamine (DPA) is a plant growth regulator used post-harvest
to control storage scald on apples. This end use pattern for the current
formulations has been classified as an indoor food use.
Formulations include an emulsifiable concentrate, a wettable powder,
a soluble concentrate/liquid and a ready-to-use liquid.
DP A is applied by is applied by dipping, drenching or spraying.
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Regulatory DPA was first registered as a pesticide in the U.S. in 1947. A January
History 1991 Data Call-In (DCI) required additional product chemistry, ecological,
residue chemistry and exposure data. Currently, three products are
registered. On August 3,1996, the Food Quality Protection Act of 1996
(FQPA) was signed into law. FQPA amends both the Federal Food, Drug,
and Cosmetic (FFDCA), and the Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA). The FQPA amendments were considered during
this reregistration decision.
Human Health Toxicity
Assessment In studies using laboratory animals, DPA generally has been shown to
be slightly toxic by the oral, dermal, and inhalation routes and has been
placed in Toxicity Category III (second lowest of four categories) for these
effects.
In a chronic feeding study using beagle dogs, diphenylamine caused
alterations in clinical chemistry. For chronic toxiciry, a No Observed
Effect Level was not achieved, however, a Lowest Observed Effect Level
was based on the alterations in clinical chemistry parameters.
DPA has been evaluated for potential carcinogenic activity in mice
and rats. It is classified as "Not Likely" in reference to carcinogenicity
based lack of evidence. However, diphenylnitrosamine (an impurity of
technical grade diphenylamine), is classified as a probable human
carcinogen based on increased incidence of bladder tumors in male and
female rats, reticulum cell sarcomas in mice, and for structural relationship
to carcinogenic nitrosamines. The dietary intake cancer risk for
diphenylnitrosamine is 2.8 x 10'" mg/kg/day, well below the Agency's
level of concern for nitrosamine.
There was no developmental toxicity observed in either the rat or
rabbit developmental studies at any dose tested.
Dietary Exposure
People may be exposed to residues of DPA through the diet.
Tolerances or maximum residue limits have been established for post-
harvest application on apples at 10.0 ppm and in meat and milk at 0 ppm
(please see 40 CFR 180.190). EPA has reassessed the DPA tolerances and
found that tolerances for residues in meat and milk, both currently 0 ppm,
should be increased. Separate tolerances of 0.01 ppm should be established
for residues in milk and meat, fat, and meat by-products (excluding liver) of
cattle, goats, horses, and sheep. Separate tolerances of 0.1 ppm should be
established for residues in liver of cattle, goats, horses, and sheep. Available
data also indicate that a tolerance of 30 ppm should be established for DPA
residues in wet apple pomace.
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The Codex Alimentarius Commission has established a maximum
residue limit (MRL) for DPA residues in apples (see Guide to Codex
Maximum Limits For Pesticides Residues, Part A. 1-58,1995). The Codex
residue definition and the U.S. tolerance expression for DPA are currently
compatible, since each includes only the parent, DPA. However, the Codex
MRL (CXL) for DPA on apples is 5 mg/kg compared to the 10 ppm U.S.
tolerance for apples. Since available residue data, based on the current U.S.
use pattern, indicate that the 10 ppm tolerance is appropriate, harmonization
of the Codex MRL and U.S. tolerance is not possible at the present time.
EPA has assessed the dietary risk posed by DPA. The Anticipated
Residue Concentration (ARC) for the overall U.S. population represents
2.27 % of Hie Reference Dose (RfD), or amount believed not to cause
adverse effects if consumed daily over a 70-year lifetime. The most
sensitive subpopulation, non-nursing infants less than one year old, has an
ARC which represents 20.8 % of the RfD. This low fraction of the
allowable RfD is considered to be an acceptable dietary exposure risk.
Occupational and Residential Exposure
Based on current use patterns, handlers (mixers, loaders, and
applicators) may be exposed to DPA during and after normal use in
agricultural and other settings. Specifically, pesticide handlers may be
exposed to DPA from using it as a drench on apples following harvest.
Exposure data for this use pattern are not available; consequently, the
Agency had to rely on surrogate data and adjust it .to fit the exposure
scenario. Margins of Exposure (MOEs) were calculated for minimum and
maximum label rates. MOEs were adequate when applicators were
assumed to wear a single layer of clothing (long sleeved shirt and long
pants) and mixer/loaders were assumed to wear chemical resistant gloves
and a single layer of clothing.
Human Risk Assessment
DPA generally is of low acute toxicity and has been classified as "Not
Likely " as a human carcinogen. An impurity of DPA,
diphenylnitrosamine, is classified as a "probable human carcinogen",
however the cancer risks for dietary intake and worker exposure fall below
the Agency's level of concern. Food crop use consist of post-harvest use
on apples. Dietary exposure to DPA residues in foods is within acceptable
limits.
Of greater potential concern is the risk posed to DPA handlers,
particularly mixers/loaders/applicatdrs, and workers who come into contact
with treated applescrop following application of this pesticide. Exposure
and risk to workers will be mitigated by the use of personal protective
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equipment (PPE) required by the Worker Protection Standard,
supplemented by engineering controls as required by this RED.
Applicators must wear a single layer of clothing (long sleeved shirt and
long pants) and mixer/loaders must wear chemical resistant gloves and a
single layer of clothing. Persons, who during the application remain inside
the truck cab with the windows and doors closed need not wear the required
PPE. If, however, drivers exit the truck cab in or immediately adjacent to
the treatment area during the application, they must wear the required PPE.
Post-application reentry workers will not be required to observe a Restricted
Entry Interval, however, persons manually handling treated apples or apple
containers that are still wet with DPA drench, must wear the same PPE
required for applicators/handlers.
EPA conducted additional risk analyses using available data in
response to the new FQPA requirements. Nothing in the available toxicity
database suggests special sensitivity of infants and children to DPA.
Therefore, the Agency concludes that an additional uncertainty factor is not
warranted. Based on the limited use pattern for DPA as a post-harvest
drench on apples and the absence of detections in the Agency's surface
water and groundwater databases, dietary exposure from drinking water is
expected to be negligible. Since there are no residential or non-
occupational DPA uses and dietary exposure from drinking water is
expected to be negligible, the only aggregate concern is dietary. All
chronic dietary exposures fall below 100 % of the RfD, and there is no
aggregate chronic dietary risk concern for DPA.
EPA does not have, at this time, available data to determine whether
DPA has a common mechanism of toxicity with other substances or how to
include this pesticide in a cumulative risk assessment. For the purposes of
this reregistration decision, EPA has not assumed that DPA has a common
mechanism of toxicity with other substances.
Environmental
Assessment Environmental Fate
Since this is considered an indoor food end-use chemical, only
hydrolysis data are required. Available data indicate that DPA is stable
towards hydrolysis at pH's 5,7, and 9. DPA has a moderate solubility in
water (39.4 ppm), a relatively high octanol/water partition coefficient
0^=3,860), and a high vapor pressure (6.39 x lO^torr). The high rate of
aqueous photolysis and the susceptibility of the chemical in aerobic
environments indicate that if DPA were to reach surface waters, it would be
short lived.
Ecological Effects
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Risk Mitigation
DPA is moderately toxic to fish and aquatic invertebrates. It is
practically non-toxic to avian species on an acute and subacute basis.
Ecological Effects Risk Assessment
This is an indoor food use chemical and Ihe Agency does not conduct
risk assessments for indoor use chemicals. However, given the the limited
volume and the pattern of diphenylamine use, the likelihood of adverse
effects on ecological systems is considered to be minimal. Discharge of
effluent containing DPA for manufacturing use is regulated by National
Pollutant Discharge Elimination System (NPDES) permits.
To lessen the worker risks posed by diphenylamine, EPA is requiring
the following risk mitigation measures.
• For mixer/loaders: chemical resistant gloves and single layer body
covering (long sleeved shirt and long pants).
• For applicators/drenchers: single layer body covering (long sleeved
shirt and long pants).
• Labeling changes to increase user safety (see Product Labeling
Changes Required section below)
Additional Data EPA is requiring the following additional generic studies for
Required diphenylamine to confirm its regulatory assessments and conclusions:
• in vivo/in vitro Rat Hepatocyte Unscheduled DNA Synthesis Assay
Guideline 84-4.
• Subchronic Dog study Guideline 82-1
• Deposition Study
• UV/Visible Absorption Study Guideline 830 7050
• Registrant must either certify that the beginning materials and
manufacturing process for the technical grade active ingredient have
not changed, or must submit an updated product chemistry package.
• An independent laboratory validation study if the data collection
method for meat and milk is to be used as an enforcement method.
The Agency also is requiring product-specific data including product
chemistry and acute toxicity studies, revised Confidential Statements of
Formula (CSFs), and revised labeling for reregistration.
Product Labeling
All diphenylamine end-use products must comply with EPA's current
pesticide product labeling requirements and with the following:
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Changes Environmental Hazards
Required "This pesticide is toxic to fish and aquatic invertebrates. Do not
contaminate water by cleaning of equipment or disposing of equipment
washwater or rinsate."
Application Restrictions
"Do not apply this product in a way that will contact workers or other
persons, either directly or through drift. Only protected handlers may be in
the area during application."
User Safety Requirements
"Discard clothing or other absorbent materials tiiat may have been drenched
or heavily contaminated with this product's concentrate. Do not reuse
them."
"Follow manufacturer's instructions for cleaning/maintaining PPE. If no
such instructions for washables, use detergent and hot water. Keep and
wash PPE separately from other laundry."
User Safety Recommendations
• "Users should wash hands before eating, drinking, chewing gum,
using tobacco, or using the toilet."
• "Users should remove clothing immediately if pesticide gets inside.
Then wash thoroughly and put on clean clothing."
• "Users should remove PPE immediately after handling mis product.
Wash the outside of gloves before removing. As soon as possible,
Wash thoroughly and change into clean clothing."
The use of currently registered products containing diphenylamine in
accordance with approved labeling will not pose unreasonable risks or
adverse effects to humans or the environment. Therefore, all uses of these
products are eligible for reregistration.
Diphenylamine products will be reregistered once the required
product-specific data, revised Confidential Statements of Formula, and
revised labeling are received and accepted by EPA.
For More EPA is requesting public comments on the Reregistration Eligibility
Information Decision (RED) document for diphenylamine during a 60-day time period,
as announced in a Notice of Availability published in the Federal Register.
To obtain a copy of the RED document or to submit written comments,
Regulatory
Conclusion
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please contact the Pesticide Docket, Public Information and Records
Integrity Branch, Information Resources and Services Division (7502C),
Office of Pesticide Programs (OPP), US EPA, Washington, DC 20460,
telephone 703-305-5805.
Electronic copies of the RED and this fact sheet are available on the
Internet. See http://www.epa.gov/REDs.
Printed copies of the RED and fact sheet can be obtained from EPA's
National Center for Environmental Publications and Information
(EPA/NCEPI), PO Box 42419, Cincinnati, OH 45242-2419, telephone
1-800-490-9198; fax 513-489-8695.
Following the comment period, 1he diphenylamine RED document
also will be available from the National Technical Information Service
(NTIS), 5285 Port Royal Road, Springfield, VA 22161, telephone 703-487-
4650.
For more information about EPA's pesticide reregistration program,
the diphenylamine RED, or reregistration of individual products containing
diphenylamine,, please contact the Special Review and Reregistration
Division (7508W), OPP, US EPA, Washington, DC 20460, telephone 703-
308-8000.
For information about the health effects of pesticides, or for assistance
in recognizing and managing pesticide poisoning symptoms, please contact
the National Pesticides Telecommunications Network (NPTN). Call toll-
free 1-800-858-7378, from 6:30 am to 4:30 pm Pacific Time, or 9:30 am to
7:30 pm Eastern Standard Time, seven days a week.
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