Page 3 of 23

R esidential bystander exposures may potentially occur as a result of spray drift from norflurazon agricultural applications , volatilization, and/or other transport from treated areas. HED will evaluate the need for a bystander assessment when the next norf lurazon risk assessment is prepared

.

Under r egistration r eview, occupational handler and post

- application exposure assessments may be required to reflect the current maximum single application rates for norflurazon uses

. Addi tionally, occupational exposures and risk assessments may need to be updated to reflect revised policies and procedures (including updated unit exposures for oc cupational/commercial handlers)

. Furthermore, i f toxicology endpoints or points of departure are revised those will be applied, as appropriate, to the occupational assessment.

I ntroduction

HED has evaluated the existing human health risk assessments for norflurazon to determine

whether sufficient data are available and whether a new human health risk assessment is needed

to support r egistration r eview. HED has considered the most recent risk assessments for

norflurazon

, updates to its toxicity, exposure and usage datab ases, and current Agency science policies and risk assessment methods.

Use Profile

Norflurazon is a pre

- emergence herbicide currently registered on various agricultural crops including citrus , pome and stone fruits, nuts, cranberries, caneberries, gra pes, alfalfa, asparagus,

peanuts, soybeans, hops, cotton, nursery stock, and non

- crop areas such as outdoor industrial/construction areas, and n on agricultural rights

- of

- way, fence rows, hedgerows and uncultivated areas/soils. Norflurazon is not registered for any homeowner use s; exposures via the residential pathway are considered negligible.

Norflurazon end

- use products include: granular, and dry flowable (DF) formulations

. Norflurazon can be applied via aerial equipment, chemigation equipment (drip and/or sprinkler), groundboom equipment (soil broadcast and incorporation)

, spot treatments and ground/soi l directed applications (ring drench treatments), or impregnated onto dry bulk fertilizer.

Aerial applications are permitted on some agricultural crops, and non

- agricultural areas (e.g., rights

- of

- way, fence rows, hedgerows and uncultivated areas/soils). Ground/soil directed spot treatments ( ring drench treatments) are per mitted on citrus crops. Chemigation applications are permitted on alfalfa and citrus crops only.

Application rates of currently registered products range from 0.79 lb a

. i ./A (pre

- emergence broadcast aerial and ground applications of dry flowable formula tion on cotton) up to 8 lb a

. i ./A (post

- harvest broadcast and aerial applications of granular formulation on cranberries).

The chemical structure

, nomenclature

, and the physic al/ chemical properties of norflurazon are presented in A ppendix A

.Page 4 of 23

Hazard Identification/Toxicology

Norflurazon is a pyridazinone herbicide that is effective through disruption of carotenoid synthesis. It also causes a progressive deterioration of the lamellae in chloroplasts and an almost complete prevention of the accumulati on of the green chlorophyll pigment.

The toxicity database for norflurazon is incomplete but sufficient for characterization of potential carcinogenetic, mutagenic, developmental, and reproductive effects. An immunotoxicity study,

which is required in acc ordance with new data requirements for conventional pesticide registration (40 CFR Part 158), and a subchronic inhalation toxicity study, which is conditionally required, have not been submitted and are considered to be data gaps . The

HASPOC determined th at a 28

- day inhalation toxicity study is required for norflurazon to refine the risk estimate for occupational inhalation exposure

Norflurazon is not acutely toxic by the oral, dermal, and inhalation routes of exposure based on lethality studies. Norflu razon is not irritating to the skin or eyes and is negative for dermal

sensitization.

The major target organs for norflurazon

- induced toxicity are the liver, thyroid, parathyroid, and kidney. Toxicity is manifested as increased organ weights, increased incidence of non

- neoplastic pathology in the liver (hepatocellular hypertrophy), parathyroid hyperplasia and hypertrophic changes in the thyroids, and nephritis/pyelonmephritis in the kidney. The effects are consistent across time and species, and they do not appear to progress over time, except in the mouse liver. The male appears to be more sensitive than the female since effects occurred at lower doses

and/or were more severe in males.

Norflurazon shows no evidence of increased susceptibility in deve loping young following in

utero exposure in rats or pre

- and/or postnatal exposure in rats. However, increased susceptibility in the rabbit developmental toxicity study was observed, as evidenced by an

increase in the incidence of skeletal variations in t he fetuses at a lower dose than the dose that

caused maternal toxicity that manifested as abortions, clinical signs, and decreased body weight gain

. Reproductive toxicity was observed, as evidenced by the decrease in pre

- coital time in both generations ; however, the concern is low for the observed effects since reproductive

function was not affected in either generation

.

Norflurazon is classified as a “possible human carcinogen” based on the statistically significant increase in the incidence of hepati c adenoma/carcinoma only in male mice. No treatment

- related increase was observed in any tumors in female mice or in rats of either sex, and there is no concern for mutagenicity. Quantification of cancer risk is not required since the chronic

Reference Do se will adequately account for all chronic toxicity, including carcinogenicity that could result from exposure to norflurazon

.

In rats, norflurazon was rapidly absorbed orally and eliminated mainly in the urine (18

- 28%) and feces (65

- 80%). There ar e four pathways for norflurazon metabolism: N

- demethylation;Page 5 of 23

displacement of the chlorine atom by glutathione; glutathione attack on the aromatic ring; and replacement of the chlorine atom by hydrogen. No tissue accumulation was observed.

Toxicity endpoints we re selected for oral, dermal, and inhalation exposure pathways for the risk assessment conducted for the 2001 Tolerance Reassessment Eligibility Decision (TRED)

. Although there was increased susceptibility of rabbits to in utero exposure to norflurazon, th e FQPA Safety Factor was reduced to 3X because the toxicology data base was complete and the available data provide no indication of quantitative or qualitative increased susceptibility following in utero or postnatal exposure to norflurazon in the prenata l developmental toxicity study in rats or the multigeneration reproduction study in rats, and a developmental neurotoxicity study (DNT) was not required.

An uncertainty factor of 100X was applied to endpoints selected for chronic dietary and dermal

and i nhalation exposures (10X for interspecies extrapolation, 10X for intraspecies variation). An uncertainty factor of 300 X was applied to acute dietary endpoints for females 13+ only (conventional uncertainty factor of 100X plus an additional 3X FQPA safety factor). The FQPA safety factor will be re

- evaluated during registration review based on the results of all available

data.

Data Requirements: A subchronic (28

- day) inhalation toxicity study was identified as a data gap by the Hazard Identification Asse ssment Review Committee (HED Document No. 014286, dated August 10, 2000)

. Th is requirement was re

- evaluated by the HED HASPOC , and it was

determined that a 28

- day inhalation toxicity study is required for norflurazon to refine the risk estimate for occupa tional inhalation exposure (TXR No. 0056398, K. Rury, xx

- AUG

- 2012). An immunotoxicity study is required to fulfill revised 40 CFR Part 158 Toxicology Data Requirements.

Conclusions: The toxicity database is adequate to support the existing registrations. The acute dietary dose and endpoint may need to be revised in registration review. As the NOAELs and LOAELs in the rabbit developmental toxicity study are well characterized and are used as endpoints for risk assessment for the appropriate population subgroups (females 13+), retaining a 3X FQPA safety factor may not be justified

. Therefor e, reconsideration of the acute dietary dose and endpoint is recommended during registration review. Reconsideration of the points of departure for the inhalation exposure assessments is recommended following receipt and review of the required inhalation toxicity study. Any new assessments should also incorporate updates to exposure duration definitions. Once all of the newly required and outstanding toxicology data

have b een received and reviewed, the N orflurazon Registration Review Team recommends that the points of departure and safety factors be re

- evaluated during registration review to reflect updated data and policies . This process may trigger the need for a new norflurazon risk

assessment

.

Residue Chemistry

I n t he December 2000

, HED norflurazon risk assessment for bermudagrass and caneberry,

several residue chemistry data requirement s were identified as conditions of registration : additional rotational crop field trial data, confirmatory data for phenyl

- labeled plant metabolismPage 6 of 23

studies, and a revised method for enforcement of livestock tolerances. Additionally, t he safety finding for th e proposed new uses was contingent on satisfactory resolution of uncertainties regarding the drinking water EEC for desmethyl norflurazon. While these uncertainties were subsequently resolved, the resulting updated EECs for the sum of norflurazon and desmethyl

norflurazon exceeded the risk cup for chronic dietary exposure to infants and children, and precluded establishment of the recommended tole rance levels in bermudagrass and caneberry.

Additiona l considerations regarding the residue chemistry data gaps identified in the December

2000 HED norflurazon risk assessment follow.

The rotational crop field trial data were considered adequate for all Regions except for 5, 7, and

13. The risk assessment concluded that if, in the future

, the petitioner establishes a registration for application to a crop in the north or central portions of Region 5 or in Regions 7 or 13, then

additional rotational field trial data will be necessary. However, no current data gap exists for rotational crops. Further, the rotational crop data support establishment of the following rotational crop tolerances following a 365

- day plant back interval in the event that a safet y finding is eventually made for the bermudagrass and caneberry uses (for inclusion in 40 CFR 180.356(d)): 0.20 ppm for radish and carrot roots, leafy greens subgroup 4A, and leafy Brassica greens subgroup 5B; 0.25 ppm for turnip tops and roots; and 0.60 ppm for radish tops.

Based on initial review of the plant metabolism studies, request s were made for confirmatory data for the phenyl

- labeled and pyridazinyl

- labeled norflur a zon studies ( S. Funk, CBRS 13887, 9/22/94; S. Funk,CBRS N o . 13061, 5/5/94). Ad equate data were submitted and reviewed for the pyridazinyl

- labeled studies (D208749, D.J. Miller, 5/30/95). Because norflurazon and desmethyl norflurazon are the only residues of concern and adequate analytical enforcement

methods for plants are availabl e (CBRS 15476, D.J. Miller, 5/25/95), H ED will no longer consider the confirmatory data for the phenyl

- labeled plant metabolism studies to be a condition of registration ; these data are no longer required

.

The analytical enforcement method for livestock w as identified as needing revision, particularly with regards to analysis of milk (D216019, D.J. Miller, 6/8/95). T he registrant has submitted a

new nature of the residue ( NOR ) study on lact a ting goats (MRID 45262801) and a radiovalidation study of the liv estock method in animal tissues and milk (MRID 45262805); neither study has been reviewed.

Conclusions: A lactating goat NOR st udy (200 0 ; MRID 45262801 ) was submitted in support of

the established and proposed uses of norflurazon

. In addition, a radiovalidation study (200 0;

MRID 45262805 ) was submitted in support of the analytical enforcement method for livestock commodities. Both studies will be reviewed as part of the registration review process, and the appropriate r egulatory recommendations w ill then be issued. At this time, there are no residue chemistry data gaps remaining.

Tolerance Assessment and International Harmonization

A summary of US tolerances for residues of norflurazon may be found in A ppendix D attached

to this document. Neither Codex nor Canada ha ve established norflurazon M aximum R esidue

L imits (MRLs) in/on any commodity

. Mexico generally adopts US tolerances and/or Code x MRLs for export purposes. Therefore, there are n o harmonization issues

.Page 7 of 23

Tolerances are currently es tablished under 40 CFR §180.356 for the combined residues of

norflurazon and its desmethyl metabolite in/on a variety of crops and livestock commodities

. HED recommends that the residue definition for the current tolerance expression for

norflurazon be modified i n accordance with current policy on tolerance definitions (S. Knizner, 5/27/09), to read :

“ Tolerances are established for residues of the herbicide norflurazon

, including its metabolites and degradate s , in or on the commodities in the table below. Compliance

with the tolerance levels specified below is to be determined by measuring only the sum of norflurazon ( 4

- chloro

- 5

- (methylamino)

- 2

- [3

- (trifluoromethyl)phenyl]

- 3

- (2 H )

- pyridazinone ) and its desmethyl metabolite ( 4

- chloro

- 5

- amino

- 2

- [3

- (trifl uoromethyl)phenyl]

- 3

- (2 H )

- pyridazinone ) , calculated as the stoichiometric equivalent of norflurazon, in or on the commodity

. ”

Dietary Exposure

The most recent acute and chronic d ietary (food) exposure assessment s w ere conducted for the

December 2000 norflurazon risk assessment and included plant

- based food s as well as meat, fat, and meat byproducts (cattle, goat, hog, horse, and sheep) (D267639, T. Bloem, 4/18/00)

. The Dietary Exposure Evaluation Model (DEEM) analysis was performed using tolerance le vel residues and assuming either 100% crop treated (acute analysis) or average percent crop treated values, where available (chronic analysis)

. The acute and chronic dietary (food) risk estimates

were not of concern. The only population subgroup requirin g acute dietary exposure assessment

, Fema les 13

- 50 years old, occupied 10 % of the aPAD. The most highly exposed population subgroup for chronic exposures was Children (1

- 6 years) , which occupie d 11 % of the cPAD

.

Although not used in the dietary risk assessments, extensive monitoring data from the USDA’s Pesticide Data Program (PDP) for the six most recent years (2004

- 2009 ), indicate no detections

of norflurazon or norflurazon desmethyl in/ on any sample analyzed except for one sample of celery (0.008 ppm norflurazon) and one sample of collard greens (0.012 ppm norflurazon desmethyl), both from the 2007 report. At least 5,000 food samples were analyzed each year for

both norflurazon and its desmethyl metabolite. The reported method limit of quantitation varied with sample type but generally was 0.05 ppm or less for both analytes. These data may be used

to refine the norflurazon dietary risk assessment if refinement is warranted in the future. Al so
,

c urrent perce nt crop

- treated information ( November 4, 2011 ) is available from BEAD and c ould be used to refine the dietary assessments, if an updated dietary risk assessment is conducted.

EFED (Environmental Fate and Effects Division) provided estimated environment al concentrations (E E Cs) for norflurazon and norflurazon desmethyl in ground water and surface

water ( E. Behl, L. Libelo, and R.D. Jones, 5/3/02 ). Ground w ater EECs were determined from

p rospective ground water studie s done in Georgia and Florida. Surfac e water EECs were calculated using PRZM

- EXAMS and the Index Reservoir Scenario, corrected for a percent crop

area factor of 0.87. These E E Cs were not incorporated directly into the DEEM analysis but compared to HED ’s back

- calculated drinking water levels of comparison ( DWLOCs ) for acute and chronic exposure

. The surface water EEC for chronic dietary risk exceeds the DWLOC forPage 8 of 23

infant and children population subgroups; for these populations, exposure from water alone

e xceeds the risk cup. EFED may update the drinking water assessment under r egistration

r eview ;
, and these results may then be directly incorporated into the dietary analysis, should a new dietary exposure analysis be warranted

.

Conclusions: A revised diet ary risk assessment may be required for norflurazon under

r egistration r eview. If a revised dietary assessment is required, estimated d rinking water

concentrations ( E DW Cs ) provided by EFED should be incorporated directly into the DEEM analysis. I f there are revisions to the toxicological points of departure or FQPA/uncertainty

factors , these should also be applied in the dietary a ssessment

. Additionally, consideration should be given to the possibility of using PDP monitoring data and/or BEAD per cent crop

treate d data if refined analyses are needed

.

Residential E xpos ure

At this time, there are no registered products containing norflurazon that are intended for homeowner use. A single application (i.e., one application per year) on nursery stock is permitted prior to emergence on weeds. Thus, exposure from registered use s via the residential pathway is considered negligible.

Spray Drift

Although there are currently no uses for norflurazon that would result in direct residential

exposure
, spray drift is always a potential source of exposure to residents nearby to spray ing operations. Residential bystander inhalation exposures resulting from off

- site transport (e.g., spray drift or volatilization) may occur as a result of applications of norflurazon. The Agency has been working with the Spray Drift Task Force, EPA Regi onal Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Forc e, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods.

After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off

- target drift from specific products with significant risks

associated with drift.

Although a quantitative residential post

- application inhalat ion exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers (D220530, C. Lang, 08/05/99) . This exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post

- application inhalation exposure

scenarios ; flagger risks were not of concern

.Page 9 of 23

Aggregate Exposure

The aggregate risk assessment eva luates the combined risk from dietary exposure (food and water) and any non

- occupational (residential) uses. Since t here are no registered residential

uses of norflurazon , the aggregate assessment currently consist s of food plus drinking water.

In the mo st recent norflurazon risk assessment ( D282851, M.S. Metzger, 5/6/2002 )

, drinking

water E E Cs were not directly added to the DEEM analysis with food residues

. Instead , those

E E C s were compared to calculated DWLOCs for acute and chronic exposure

. All scena rios were below HED’s level of concern except for the infants and children population subgroups, where the chronic surface water EEC exceeded the DWLOC. Should EFED provide refined drinking water estimates for norflurazon, a revised aggregate exposure ris k assessment may be required.

Conclusions: A revised aggregate (food plus water) risk assessment may be required for

norflurazon under r egistration r eview for the reasons cited in the above section “Dietary Exposure

. ”

Occupational E xpos ure

Norflurazon is registered for many agricultural uses and for use in non

- crop areas. There is potential for short

- and intermediate

- term occupational exposure to norflurazon during handling (mixing, loading, and applying), or re

- entry into previously treat ed area. Based on the activity use pattern, the duration of exposure is expected to be short

- term (ST; 1 to 30 days) and

intermediate

- term (IT; 1 to 6 months) for occupational scenarios; long

- term exposures (greater than 6 months) are not anticipated bas ed on the proposed use pattern. For the dermal and inhalation routes of exposure, the same points of departure (PODs) were chosen for ST and IT exposures; therefore, risk estimates are protective for both durations of exposure

. The level of concern (LOC) for risk estimates is a margin of exposure (MOE) of less than 100 for short

- and

intermediate

- term exposure

. Upon review of the requested 28

- day inhalation study, the

inhalation P OD will be updated as appropriate.

Occupational Handlers

Based upon the c urrent use patterns, potential occupational exposure scenarios include:

1. Mixer/loader using open

- pour loading of dry flowable (solid soluble concentrate and water dispersible granules) for aerial application, chemigation, and ground applications.

2. Mixing/loading granules for ground and aerial application.

3. Aerial appl icators (enclosed cockpit) of sprays and granules

. 4. Appli cator using open

- cab groundboom spray equipment.

5. Appli cator using soil incorporating equipment.

6. Mixer/Loader/Applicator (MLA) for backpack and mechanically pressurized handgun sprayer applications for ground and soil directed (drench treatments)

. 7. Flaggers supporting aerial application (sprays and granules) operations.

8. Impregnating dry flowable herbicide formulation onto dry bulk fert ilizer in commercialPage 10 of 23

settings and on

- farm for cotton applications.

9. Applying impregnated dry bulk fertilizer with commercial equipment and grower

- owned equipment.

The following occupational exposure scenarios have not been assessed: mechanically pressurized handgun sprayer applications , soil drench treatments, and dry bulk fertilizer operations.

Occupational handler exposure and risk assessments were conducted for most of the agricultural crop use sites as part of the HED Chapter of the Reregist ration Eligibility Decision Document (RED) for Norflurazon (Odiott, O ., 09/10/95). Occupational handler scenarios previously assessed resulted in risk estimates that did not exceed HED’s level of concern (i.e., MOEs > 100) at some level of risk mitigation (e.g., chemical resistant gloves).

For norflurazon , no chemical

- specific data are available for exposure assessment to pesticide handlers; therefore, occupational handler assessments are based primarily on surrogate unit exposures from the Pesticide Hand lers Exposure Database (PHED). Previous risk calculations were typically based on the maximum application rates and assuming maximum area treated per day or gallons handled. However, HED policies have since changed yielding updated acreage assumptions as well as updated unit exposure values 1

. Consequently , occupational handler scenarios may need to be revis ed during r egistration r eview.

Exposure and risk assessments have not been conducted for some of the registered non

- crop areas (i.e., rights

- of

- way, fence rows, hedgerows and uncultivated areas/soils). The only non

crop area site previously assessed was for rights

- of

- way applications at a maximum application rate of 4.0 lb ai/A (D220530 , C. Lang, 08/05/99). However, the highest registered application

rate for non

- crop area is 7.9 lb a

. i

. /A (based on label EPA Reg. No. 100

- 849), therefore, these uses may have to be assessed for occupational handler exposure.

Additional potential occupational exposure scenarios including: spot treatments and ground/soil directed applications ( ring drench treatments ) utilizing soil incorporating equipment, backpack, and mechanically pressurized handgun sprayer applications may need to be conducted during registration review. Also, recently some norflurazon lab els include dry bulk fertilizer/norflurazon blends impregnation scenarios for use on cotton

. HED does not have data regarding the mixing/loading or the application of norflurazon impregnated dry bulk fertilizer. Additionally, HED does not have scenario sp ecific exposure data for impregnated dry bulk

fertilizer. A ssessments of these scenarios may be required because these scenarios involve different application techniques and/or greater amount of material handled than scenarios that have been previously as sessed.

Conclusions : Occupational handler scenarios may need to be reassessed during Registration Review to account for scenarios that have not been covered previously, current ORE policies (e.g., updated acreage assumptions and updated exposure data), a nd changes to the toxicological

PODs. Except for the impregnated dry bulk fertilizer scenario, there is sufficient information available to assess occupational handler exposure and risk for all norflurazon registered uses.

1 http://www.epa.gov/pesticides/science/handler

- exposure

- data.htmlPage 11 of 23

Occupational Post

- Application

P ost

- application dermal and inhalation assessment s were not conducted for norflurazon due to the low exposure potential

. Minimal exposure during harvesting or any other late season activities is expected since the chemical is applied pre

- emergent. D ermal post

- application exposure is expected to be minimal and less than exposure to mixer/loaders and applicators

, for whom risk estimates were below HED’s level of concern; thus, a separate post

- application

dermal exposure assessment was not considered ne cessary. Similarly, inhalation post

application exposure is expected to be minimal and less than potential exposures to occupational/commercial handlers, for whom risk estimates were below HED’s level of concern; thus, a separate post

- application inhalati on exposure assessment was not considered necessary.

Restricted Entry Interval (REI): The REI is 12 hours based on norflurazon’s acute toxicity classification IV for acute dermal and eye irritation routes of exposure.

Conclusions : An occupational post

- application assessment may be required in registration

review to address possible exposure to workers doing activities in previously treated areas. The existing policy on occupational post

- application activities was recently revised and includes

either u pdated values for quantitatively evaluating these exposures or it will provide more definitive qualitative rationale for not conducting a quantitative assessment (ExpoSAC Policy 3, released on June 2011).

Public Health and Pesticide Epidemiology Data

T he evaluation of the OPP Incident Data System (IDS) [Main IDS module] indicated one i ncident classified as moderate severity in the United States from January 1, 2007 through February 22, 2012 for norflurazon

. In the Aggregate IDS, from January 1, 200 7 to February 22,

2012 , there w as one case reported for norflurazon

. Because it falls within the categories reported as counts (which includes minor, unknown or no effects), there is no unique report that provides details about the incident and single chem ical incidents are not distinguished from multiple

chemical incidents. For norflurazon there appears to be a low potential for exposure.

Norflurazon is not included in the Agricultural Health Study (AHS), and therefore, the AHS does not provide informati on for this report. Based on the low frequency and severity of incident cases reported for norflurazon, t here does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to monitor the incident informat ion and if a concern is triggered, additional analysis will be included in the risk assessment.

Human Studies

Past norflurazon risk assessments rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide t o determine their dermal and inhalation exposure.Page 12 of 23

Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as the PHED and the Agricultural Reentry Task Force (ARTF)

Database. EPA has reviewed all the studies supporting these multi

- pesticide generic exposure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relative to the ethical standards

pre vailing at the time the research was conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued reliance on these studies.

En docrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxici ty, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturat ion, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of the norflurazon 2001 risk assessment decision (TRED), EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p),

norflu razon is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wi ldlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required

determinations. Tier 1 consists of a ba ttery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to

interact wi th E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects ca used by the substance, and

establish a dose

- response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Norflurazon was included on that list and has been issued an order to conduct the Tier 1 testing. Once all required Tier 1

and Tier 2 da ta have been received and reviewed, the endpoints and safety factors used for risk assessment purposes will be examined and a new risk assessment performed if necessary. For further information on the status of the EDSP, the policies and procedures, the l ist of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our

website: http://www.epa.gov/endo/

.Page 13 of 23

Data Requirements

The following stud ies are required to support the regi stration review of norflurazon

.

Toxicity studies ( HASPOC Decision, 7/12/12 )

870.3465: 28

- Day Inhalation Toxicity. 870.7800: Immunotoxicity.

Appendices

A. Chemical Identity and Physicochemical Properties

. B. Toxicology Data Requirements.

C. S ummary of Toxicological Endpoints.

D. Summary of US and International Tolerances and Maximum Residue Limits.

E. Updated Norflurazon Acute Toxicity.

F. Updated Norflurazon Toxicity Profile.

References

Metzger, M. S., 5/6/02

, D282851. Norflurazon Tolerance Reassessment Eligibility Decision (TRED): Update of TRED Considering New Drinking Water Assessment.

Hazel, W. J., 12/20/01

, D279777. Norflurazon. HED Risk Assessment for Tolerance Reassessment Eligibility Decision (TRED).

Bloem, T.; Ottley, M.; and Swackhammer, T

. , 12/5/00 , D2 37815

. Norflurazon in/ on Bermudagrass and Caneberries

. HED Risk Assessment.

Christian, M., 9/19/00, D267638. Norflurazon in/on Bermudagrass and Caneberries. Occupational Exposure and Risk Assessment.

Bloem, T., 8/28/00, D268337. HED Metabolism Assessment Review Committee (MARC) Decision Document for Determination of Residues of Concern in Drinking Water for

Norflurazon.

Bloem, T., 4/18/00, D267639. Norflurazon Acute and Chronic Dietary Exposure Analyses

.

Odiott , O., 9/10/95. HED Chapter of the Reregistration Eligibility Decision Document (RED)

for Norflurazon Case No. 0229 Chemical No. 105801

.

Lang, C., 8/05/99

. Comments on the Occupational and Residential Exposure Assessment and Recommendations for the Reregistration Eli gibility Decision Document for Norflurazon.

Recore, S., 5 / 3 /12 , D400785

. Norflurazon : Review of Human Incidents.Page 14 of 23

Rury, K., 8/15 /12, TXR No. 0056398. Summary of Hazard and Science Policy Council Meeting (HASPOC) Meeting of July 12, 2012. Recommendations on t he requirement of a subchronic

i nhalation study and the neurotoxicity screening battery for norflurazon.Page 15 of 23

Appendix A : Chemical Identity and Physi c ochemical Properties

Table A1. Chemical Identity

Common Name Norflurazon

Other Names CAS Name : 4

- chloro

- 5

- (methylamino)

- 2

- [3

- (trifluoromethyl)phenyl]

- 3(2 H )

- pyridazinone

IUPAC Name: 4

- chloro

- 5

- methylamino

- 2

- (α,α,α

- trifluoro

- m

tolyl)pyridazin

- 3(2 H

)

- one
PC Code 105801

CAS no. 27314

- 13

- 2

Chemical Structure

Norflurazon P hysi c ochemical Properties Empirical Formula: C 1 2 H 9 Cl F 3 N 3 O

Molecular Wt: 303.7 Appearance: Odorless, white crystalline solid Melting Point: 177 °C Vapor Pressure: < 1 x 10
- 5 Torr (at 25 °C)

Partition Coefficient: Kow = 2.3

Water Solubility: <40 mg/l

.Page 16 of 23

A ppendix B : Toxicology Data Requirements

The toxicology data requirements (40 CFR 158.340) for the food uses of norflurazon are presented below. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Study Techn ical

Required Satisfied

870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ .................. 870.1300 Acute Inhalation Toxicity

................................ .............. 870.2400 Primary Eye Irritation

................................ .................... 870.2500 Primary Dermal Irritation

................................ .............. 870.2600 Dermal Sensitization

................................ ...................... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

................................ ............... 870.3150 Oral Subchronic (nonrodent)

................................ ......... 870.3200 21

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 90

- Day Inhalation

................................ .......................... yes

yes

yes

no

yes Y es A

yes

yes

no

yes B

870.3700a Developmental Toxicity (rodent)

................................ ... 870.3700b Developmental Toxicity (nonrodent)

............................. 870.3800 Reproduction

................................ ................................ . yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

................................ .............. 870.4100b Chronic Toxicity (nonrodent)

................................ ........ 870.4200a Oncogenicity (rat)

................................ .......................... 870.4200b Oncogenicity (mouse)

................................ .................... 870.4300 Chronic/Oncogenicity

................................ .................... yes

yes

yes

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation

– bacterial

.................... 870.5375 Mutagenicity

— Structural Chromosomal Aberrations

... 870.5550 Mutagenicity

— Other Genotoxic Effects

....................... yes

yes

yes yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)

............................... 870.6100b 90

- Day Neurotoxicity (hen)

................................ ........... 870.6200a Acute Neurotoxicity Screening Battery (rat)

................. 870.6200b 90

- Day Neurotoxicity Screening Battery (rat)

............... 870.6300 Develop. Neurotoxicity

................................ ................. no

no

no B

no B

CR -

-

--

-- N o

870.7485 General Metabolism

................................ ...................... 870.7600 Dermal Penetration

................................ ........................ 870.7800 Immunotoxicity

................................ ............................. yes

no

yes yes

no

no

Special Studies

A unacceptable, but requirement satisfied by chronic study.

B HASPOC decision, 7/12/12 (28

- day study).Page 17 of 23

Appendix C : S ummary of T oxicological E ndpoints for use in Human Risk Assessment ( Norflurazon TRED [ D279777, W.J. Hazel, 12/20/2001])

.

Exposure Scenario Dose Used in

Risk Assessment, UF FQPA Safety Factor and

LOC for Risk

Assessment Study and Toxicological Endpoints

Acute Dietary (Females 13

- 50) NOAEL = 10 mg/kg/day

UF = 100 FQPA SF = 3x

aPAD = 0.03 mg/kg/day Developmental Toxicity Study in Rabbits

LOAEL = 30 mg/kg/day, based on increased

incidence in skeletal variations observed.

Acute Dietary (General population) n/a n/a No endpoint established.

Chronic Dietary (all populations) NOAEL = 1.5 mg/kg/day

UF = 100 FQPA SF = 1x

cPAD = 0.015 mg/kg/day 6

- Month Feeding Study in Dogs

LOAEL = 4.77 mg/kg/day, based on increased absolute and relative liver weight and increased

cholesterol in both sexes.

Incidental Oral,

Short

- Term Maternal

NOAEL= 30 mg/kg/day LOC for MOE < 100

(occupational) Developmental Toxicity Study in Rabbits

LOAEL = 60 mg/kg/day, Based on reduced body weight gain during gestation days 7

- 19.

Incidental Oral,

Intermediate

- Term Oral

NOAEL = 1.5 mg/kg/day LOC for MOE < 100

(occupational) 6

- Month Feeding Study in Dogs

LOAEL = 4.77 mg/kg/day

Based on increased absolute and relative liver weight in both sexes.

Short

- Term

Dermal a

and Inhalation b Developmental

NOAEL = 10 mg/kg/day a, b LOC for MOE < 100

(occupational) Developmental Toxicity Study in Rabbits

LOAEL = 30 mg/kg/day, based on increased

incidence in skeletal variations observed.

Intermediate

- and Long

- Term

Dermal a

and Inhalation b Oral

NOAEL = 1.5 mg/kg/day a, b LOC for MOE < 100

(occupational) 6

- Month Feeding Study in Dogs

LOAEL = 4.77 mg/kg/day

Based on increased absolute and relative liver weight in both sexes.

a Since an oral NOAEL was selected, a dermal absorption factor of 6% should be used in route

- to

- route extrapolation.

b Since an oral NOAEL was selected, an inhalation absorption factor of 100% (default va lue) should be used

in route

- to

- route extrapolation. legend: UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chron ic) RfD = reference dose; LOC = level of concern; MOE = margin of exposure; CARC = Cancer Assessment Review

Committee.Page 18 of 23

Appendix D: Summary of US and International Tolerances and MRLs

Summary of US and International Tolerances and Maximum Residue Limits : Norflurazon (PC Code 105801).
Residue Definition :

US Canada Mexico 1 Codex

40 CFR 180.356 : Plant s & livestock : combined residues of norflurazon (4

- chloro

- 5

- (methylamino)

- 2

- (alpha, alpha, alpha

- trifluoro

- m

- tolyl)

- 3

- (2 H )

- pyridazinone) and its desmethyl metabolite 4

- chloro

- 5

- (amino)

- 2

- alpha, alpha, alpha

- trifluoro

- m

- tolyl)

- 3(2 H )

- pyridazinone , expressed as

norflurazon None None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 1 Codex Alfalfa, forage 3.0 Alfalfa, hay 5.0
Alfalfa, seed 0.1
Almond, hulls 1.0

Almond 0.1 Apple 0.1 Apricot 0.1 Asparagus 0.05

Avocado 0.20 Blackberry 0.1 Blueberry 0.2
Cattle, fat 0.1
Cattle, liver 0.50
Cattle, meat 0.1 Cattle, meat byproducts, except liver 0.1 Cherry 0.1 Citrus, dried pulp 0.4
Citrus, molasses 1.0
Cotton, undelinted seed 0.1 Cranberry 0.1
Fruit, citrus 0.2
Goat, fat 0.1
Goat, liver 0.50
Goat, meat 0.1 Goat, meat byproducts, except liver 0.1 Grape 0.1

Hazelnut 0.1 Hog, fat 0.1 Hog, liver 0.50 Hog, meat 0.1Page 19 of 23 1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes. Hog, meat byproducts, except liver 0.1 Hop, dried cones 3.0 Hop, vines 1.0
Horse, fat 0.1
Horse, liver 0.50
Horse, meat 0.1 Horse, meat byproducts, except liver 0.1

Milk 0.1

Nectarine 0.1

Peach 0.1

Peanut 0.05 Peanut, hay 5.50 Peanut, hay 1.5

Pear 0.1

Pecan 0.1 Plum, prune, fresh 0.1 Poultry, fat 0.1 Poultry, meat 0.1 Poultry, meat byproducts 0.1 Raspberry 0.2 Sheep, fat 0.1 Sheep, liver 0.50 Sheep, meat 0.1 Sheep, meat byproducts, except

liver 0.1

Soybean 0.1 Soybean, forage 1.0 Soybean, hay 1.0

Walnut 0.1

Completed: M. Negussie; 04/11/2012Page 20 of 23

Appendix E : Updated Norflurazon Acute Toxicity (from 12/20/01 TRED).

Guideline No./Study Type MRID No. Results Toxicity Category

870.1100 Acute Oral Toxicity

- Rat 00111612 LD 50 = 9.3 g/kg (males) IV

870.1200 Acute Dermal Toxicity

- Rabbit 00090786 LD50 > 20 g/kg IV

870.1300 Acute Inhalation Toxicity

- Rat 00112980

44168901 B LC5 > 200 mg/L (1

- hour ) A

LC5 > 2.4 mg/L (4

- hour ) IV

IV

870.2400 Acute Eye Irritation

- Rabbit 00111612 No eye irritation IV

870.2500 Acute Dermal Irritation

- Rabbit 00111612 No dermal irritation IV

870.2600 Skin sensitization

- Guinea pig 00111615

40776705 C

44424801 C acceptable study unavailable N/A

A 1

- hour exposure; B new study submitted; C new study availablePage 21 of 23

Appendix F : Updated Norflurazon Toxicity Profile (from 12/20/01 TRED)

.

Guideline No. Study Type MRID No. (year)

Classification

Dose Levels Results

870.3100

Subchronic oral toxicity (rat) 00091055 (1971)

Unacceptable/guideline (guideline not satisfied; achieved doses not verified); not a data gap since there

are chronic data 9, 250, 500, 2500 ppm (0, 12.5, 25, 125 mg/kg/day) NOEL (females): 25 mg/kg/day LOEL (females): 125 mg/kg/day, based on increased liver weight (absolute and relative) NOEL (males): 12.5 mg/kg/day LOEL (males): 25 mg/kg/day, based on increased RBC, increased thyroid and liver weights, increased incidence of hypertrophic acinar epithelium and colloid deposition in the thyroid

870.3200b

21

- day Dermal Toxicity (rabbit) 00063617 (1972)

unacceptable/non

- Guideline (2 dose levels; 3 rabbits/dos/sex; no individual data) dermal doses of 150 mg 80% w.p./ml and 400 mg 80% w.p./ml, 5 days per week, 6

- 8 hours per day, for 21 days
≈375 and 1000 mg/kg/day, based

on 5 mL/rabbit dose volume and 2000 g BW Skin irritation NOAEL :37 5 mg/kd/day

Skin irritation LOAEL : 1000 mg/kg/day, based on slight erythema immediately after bandage removal

870.3700a Developmental Toxicity in rodents (rat) 00063621 (1972)

Acceptable/Guideline

0, 100, 200, or 400 mg/kg/day (20 rats/dose) by oral gavage on gestation days 6 through 15

inclusive. NOAEL:

Maternal: <100 mg/kg/day Developmental: > 400 mg/kg/day

LOAEL:

Maternal: < 100 mg/kg/day, based on decreased body weight gain. Developmental: >400 mg/kg/day.

870.3700b Developmental Toxicity in non

rodents (rabbit) 00131152 (1983)

Acceptable/Guideline

0, 10, 30, or 60 mg/kg/day norflurazon technical by oral gavage on gestation days 7 through

19 inclusive. NOAEL:

Maternal: 30 mg/kg/day Developmental: 10 mg/kg/day

LOAEL:

Maternal: 60 mg/kg/day, based on clinical toxicity (2 abortions on GD 24) and reduced body weight gain. Developmental: 30 mg/kg/day based on the statistical increase in skeletal variations [increase in fetal incidence of incompletely ossified frontal bones, 16 ca udal vertebrae, unossified first metacarpal (litter basis also), middle phalanx of the 5 th digit of the forelimb, proximal epiphysis of the tibia on a fetal] observed.

At 60 mg/kg/day, decrease of 12% mean fetal body weightPage 22 of 23

Guideline No. Study Type MRID No. (year)

Classification

Dose Levels Results

870.3800 Reproduction and fertility effects in rats (two generation) 43522301 (1991)

Acceptable/Guideline

dietary dose levels of 0, 150, 750, 1500 ppm over 2 generations (10.2, 50.8, and 102.5 mg/kg/day for F

o males; 12.1, 62.0, and 129.7 mg/kg/day for F

o females; 13.2,
67.8, an d 138.6 mg/kg/day for F 1 males; 17.1, 81.7, and 173.0 mg/kg/day for F 1 females). NOAELs: Parental toxicity: 150 ppm Reproductive toxicity: 750 ppm Offspring toxicity: 150 ppm

LOAELs Parental toxicity: 750 ppm based upon the significant increases in liver and kidney weights observed in both generations of parental rats and the increased incidence of hepatocellular hypertrophy in both generations of parental rats. Reproductive toxicity: 1500 ppm based on decreased mean

pre

- coital interval for the first litter of the F

o parental generation,

and for both litters of the F 1 parental generation. Offspring toxicity: 750 ppm based on decreased weight gain in

F 2 b litter pups (18%) vs control for days 4

- 21 po st

- partum and statistically significant increases in relative weight of the liver for male and female pups.

870.3800 Reproduction and fertility effects in

rats (three generation) 00080750 (197 1 5)

Unacceptable (Guideline)

Sprague

- Dawley rats (40 rats/dose)

received Norflurazon technical (98.8% a.i.) in the diet at nominal doses of 0, 125, 375, and 1025 ppm (0, 6.25, 18.75, and 51.25 mg/kg/day) NOAELs: Parental toxicity: > 51.25 mg/kg/day Reproductive toxicity: > 51.25 mg/kg/day Offspring toxicity: > 51.25 mg/kg/day

LOAELs: Parental toxicity: not established. Reproductive toxicity: not established. Offspring toxicity: not established.

870.4100 Chronic toxicity in dogs 00111618 (1973)

Acceptable/Guideline

0, 50, 150, and 450 ppm (1.53, 5.02, and 14.27 mg/kg for males; 1.58, 4.77, and 17.75 mg/kg for females) in the diet for 6 months NOAEL: 50 ppm (1.53 mg/kg/day males ; 1.58 mg/kg/day females )

LOAEL: 150 ppm (5.02 mg/kg/day males ; 4.77 mg/kg/day females ), based on increased absolute and relative liver weight, increased thyroid weight, and increased cholesterol in both

sexes.

870.4300 Chronic toxicity in rodents (rat) 00091056 (1971)

Acceptable/Non

- guideline

Sprague

- Dawley rats (80 rats/dose) 0ppm, 125ppm, 250ppm, and 500ppm (0, 6.25, 12.50, and 25.00 mg/kg/day) for 39 weeks in the diet NOAEL: 250 ppm (12.50 mg/kg/day)

LOAEL: 500 ppm (25.00 mg/kg/day) based on the dose

- related increase in liver weight in male and female rats at 39 weeks, the

increa se in gonad weight of females, and the microscopic changes observed in kidneys of both sexes (increased incidence of hyaline pigment deposition, medullary congestion and tubular degeneration).

870.4300 Chronic toxicity/ carcinogenicity in rodents (rat) 00082019 (1971)

Acceptable/Guideline

O, 125, 375, and 1025ppm (0, 6.25, 18.75, and 51.25 mg/kg/day) for

104 weeks in the diet. NOAEL: 375 ppm (18.75 mg/kg/day)

LOAEL: 1025 ppm (51.25 mg/kg/day) Based on increased kidney weight and accompanying microscopi c pathologic changes, as well as increased liver weight in male and female rats and the increase in thyroid weight in males. Treatment related increase in tumor

incidence was not found.Page 23 of 23

Guideline No. Study Type MRID No. (year)

Classification

Dose Levels Results

870.4200 Carcinogenicity study in mice 00111649 (1971)

Acceptable/Guideline 0, 85, 340, or 1360 ppm (0, 12.8, 58.7, or 218.8 mg/kg/day) for 100

- 104 weeks in the diet. NOAEL:

males: 85 ppm (12.8 mg/kg/day) females: 340 ppm (58.7 mg/kg/day)

LOAEL:

males: 340 ppm (58.7 mg/kg/day) based on the increased incidence of enlarged spleen, increased absolute and relative liver weight, and increased incidence of nephritis. females: 1360 ppm (218.8 mg/kg/day) based on the increased incidence of enlarged liver and cystic ovaries, the increased absolute and relative liver weight, and the increased incidence of pyelonephritis.

870.5100 Mutagenicity: gene mutation (bacterial) 00072974 (1977) Unacceptable/Guideline

0.1

- 500 μg/plate

44168903 (1986)

- 1000 μg/plate (confirmatory data) Acceptable No cytotoxicity at dose levels up to 500 μg/plate.

No evidence of gene mutation at 1000 μg/plate

870.5375 Mutagenicity: in

vitro chromosomal

aberration 00155734 (1985) Acceptable/Guideline

63

- 1000 μg/ml No evidence of a clastogenic response at any of the dose levels tested (with or without S9 activation)

870.5550 Mutagenicity:

Unscheduled DNA synthesis 00155375 (1985) Acceptable/Guideline

1

- 333 μg/ml No evidence of unscheduled DNA synthesis in rat hepatocytes at any of the dose levels tested.

870.7485

Metabolism 43081501 (1993)

Acceptable/Non Guideline

14 C

- Norflurazon was administered orally in ethanol : Emulphor

EL

- 620 (2:3.2, v/v) to groups (5 sex/dose) of rats at a single low oral dose (1 mg/kg; Group A) and a single high oral dose (100 mg/kg; Group B). In urine, the sulfone metabolite accounted for 0.03% of urinary radioactivity in Group A, and 0.2% in Group B. The sulfone metabolite accounted for 0.3% of fecal radioactivity in Group A,

a nd 0.1% of fecal radioactivity in Group B.

870.7485

Metabolism 260490 (1985)

Acceptable/Non Guideline

Single oral doses of 2 or 110 mg/kg; single i.v. dose of 2 mg/kg; single oral dose 2 mg/kg following administration of 2 ppm in animal

diet for 14 days. norflurazon is rapidly and almost completely absorbed into the systemic circulation and excreted in female rats within 4 days after dosing. The radioactivity recovered in the urine and feces

was 18.5

- 28.4% and 65.3

- 79.5% of the dose, respectively. There was no indication of bioaccumulation in any tissue or organ after administration of norflurazon.