Page 3 of 23

Residential 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 norflurazon risk assessment is 

prepared.

Under registration review, occupational handler and post-application exposure assessments may 

be required to reflect the current maximum single application rates for norflurazon uses.

Additionally, occupational exposures and risk assessments may need to be updated to reflect 

revised policies and procedures (including updated unit exposures for occupational/commercial 

handlers). Furthermore, if toxicology endpoints or points of departure are revised those will be

applied, as appropriate, to the occupational assessment. 

Introduction

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 registration review. HED has considered the most recent risk assessments for 

norflurazon, updates to its toxicity, exposure and usage databases, 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, grapes, alfalfa, asparagus, 

peanuts, soybeans, hops, cotton, nursery stock, and non-crop areas such as outdoor 

industrial/construction areas, and non agricultural rights-of-way, fence rows, hedgerows and 

uncultivated areas/soils. Norflurazon is not registered for any homeowner uses; 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/soil 

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 permitted 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 formulation 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 physical/chemical properties of norflurazon are 

presented in Appendix 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 accumulation 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 accordance 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 that 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. Norflurazon 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 developing 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 the 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 hepatic 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 Dose 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 are 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 were 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, the 

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 prenatal 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 inhalation exposures (10X for interspecies extrapolation, 10X for intraspecies variation). An 

uncertainty factor of 300X 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 Assessment Review Committee (HED Document No. 014286, dated 

August 10, 2000). This 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 occupational 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. Therefore, 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 been received and reviewed, the Norflurazon 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

In the December 2000, HED norflurazon risk assessment for bermudagrass and caneberry, 

several residue chemistry data requirements were identified as conditions of registration: 

additional rotational crop field trial data, confirmatory data for phenyl-labeled plant metabolism 
Page 6 of 23

studies, and a revised method for enforcement of livestock tolerances. Additionally, the safety 

finding for the 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 tolerance levels in bermudagrass and caneberry. 

Additional 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 safety 

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, requests were made for confirmatory 

data for the phenyl-labeled and pyridazinyl-labeled norflurazon studies (S. Funk, CBRS 13887, 

9/22/94; S. Funk,CBRS No. 13061, 5/5/94). Adequate 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 available (CBRS 15476, D.J. Miller, 5/25/95), HED 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 was identified as needing revision, particularly 

with regards to analysis of milk (D216019, D.J. Miller, 6/8/95). The registrant has submitted a 

new nature of the residue (NOR) study on lactating goats (MRID 45262801) and a 

radiovalidation study of the livestock method in animal tissues and milk (MRID 45262805); 

neither study has been reviewed. 

Conclusions: A lactating goat NOR study (2000; MRID 45262801) was submitted in support of 

the established and proposed uses of norflurazon. In addition, a radiovalidation study (2000; 

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 regulatory recommendations will 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 Appendix D attached 

to this document. Neither Codex nor Canada have established norflurazon Maximum Residue 

Limits (MRLs) in/on any commodity. Mexico generally adopts US tolerances and/or Codex 

MRLs for export purposes. Therefore, there are no harmonization issues.
Page 7 of 23

Tolerances are currently established 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 in 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 degradates, 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-(2H)-

pyridazinone) and its desmethyl metabolite (4-chloro-5-amino-2-[3-

(trifluoromethyl)phenyl]-3-(2H)-pyridazinone), calculated as the stoichiometric 

equivalent of norflurazon, in or on the commodity.”

Dietary Exposure

The most recent acute and chronic dietary (food) exposure assessments were conducted for the 

December 2000 norflurazon risk assessment and included plant-based foods 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 level 

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 requiring acute dietary exposure assessment, 

Females 13-50 years old, occupied 10% of the aPAD. The most highly exposed population 

subgroup for chronic exposures was Children (1-6 years), which occupied 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. Also, 

current percent crop-treated information (November 4, 2011) is available from BEAD and could 

be used to refine the dietary assessments, if an updated dietary risk assessment is conducted. 

EFED (Environmental Fate and Effects Division) provided estimated environmental

concentrations (EECs) for norflurazon and norflurazon desmethyl in ground water and surface 

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

prospective ground water studies done in Georgia and Florida. Surface water EECs were 

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

area factor of 0.87. These EECs 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 for 
Page 8 of 23

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

exceeds the risk cup. EFED may update the drinking water assessment under registration 

review;, and these results may then be directly incorporated into the dietary analysis, should a 

new dietary exposure analysis be warranted.

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

registration review. If a revised dietary assessment is required, estimated drinking water

concentrations (EDWCs) provided by EFED should be incorporated directly into the DEEM 

analysis. If there are revisions to the toxicological points of departure or FQPA/uncertainty 

factors, these should also be applied in the dietary assessment. Additionally, consideration 

should be given to the possibility of using PDP monitoring data and/or BEAD percent crop 

treated data if refined analyses are needed.

Residential Exposure

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 uses 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 spraying 

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 Regional 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 Force, 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 inhalation 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 evaluates the combined risk from dietary exposure (food and 

water) and any non-occupational (residential) uses. Since there are no registered residential 

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

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

water EECs were not directly added to the DEEM analysis with food residues. Instead, those 

EECs were compared to calculated DWLOCs for acute and chronic exposure. All scenarios 

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 risk assessment may be 

required.

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

norflurazon under registration review for the reasons cited in the above section “Dietary

Exposure.”

Occupational Exposure

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 treated 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 based 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 POD will be updated as appropriate.

Occupational Handlers

Based upon the current 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 applicators (enclosed cockpit) of sprays and granules.

4. Applicator using open-cab groundboom spray equipment.

5. Applicator 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 fertilizer in commercial 
Page 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 Reregistration 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 Handlers 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 values1. Consequently, occupational handler

scenarios may need to be revised during registration review.

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 noncrop 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 labels 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 specific exposure data for impregnated dry bulk 

fertilizer. Assessments 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 assessed.

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), and 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.html
Page 11 of 23

Occupational Post-Application

Post-application dermal and inhalation assessments 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. Dermal 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 necessary. Similarly, inhalation postapplication 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 inhalation 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 updated 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

The evaluation of the OPP Incident Data System (IDS) [Main IDS module] indicated one

incident 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, 2007 to February 22, 

2012, there was 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 chemical 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 information for this report. Based on the low frequency and severity of incident 

cases reported for norflurazon, there does not appear to be a concern at this time that would 

warrant further investigation. The Agency will continue to monitor the incident information 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 to 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 

prevailing 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.

Endocrine 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, neurotoxicity, 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 maturation, 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), 

norflurazon 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 wildlife 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 battery 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 with 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 caused 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 data 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 list 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 studies are required to support the registration 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. Summary 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, D237815. 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 Eligibility 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 the requirement of a subchronic 

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

Appendix A: Chemical Identity and Physicochemical Properties

Table A1. Chemical Identity 

Common Name Norflurazon

Other Names 

CAS Name: 4-chloro-5-(methylamino)-2-[3-(trifluoromethyl)phenyl]-

3(2H)-pyridazinone

IUPAC Name: 4-chloro-5-methylamino-2-(α,α,α-trifluoro-mtolyl)pyridazin-3(2H)-one

PC Code 105801

CAS no. 27314-13-2

Chemical Structure 

Norflurazon Physicochemical Properties

Empirical Formula: C12H9ClF3N3O

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

Appendix 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

Technical

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

YesA

yes

yes

no

yesB

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

noB

noB

CR

-

-

--

--

No

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: Summary of Toxicological Endpoints 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/daya, 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/daya, 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 value) 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 = chronic) 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 Mexico1 Codex

40 CFR 180.356:

Plants & 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 Mexico1 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 0.1
Page 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; 04/11/2012
Page 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

44168901B

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

40776705C

44424801C

acceptable study unavailable N/A

 

A

1-hour exposure; Bnew study submitted; Cnew study available
Page 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:375 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 nonrodents (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 caudal vertebrae, unossified first 

metacarpal (litter basis also), middle phalanx of the 5th digit of 

the forelimb, proximal epiphysis of the tibia on a fetal] observed.

At 60 mg/kg/day, decrease of 12% mean fetal body weight 
Page 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 Fo

males; 12.1, 62.0, and 129.7 

mg/kg/day for Fo females; 13.2, 

67.8, and 138.6 mg/kg/day for F1

males; 17.1, 81.7, and 173.0 

mg/kg/day for F1 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 Fo parental generation, 

and for both litters of the F1 parental generation. 

Offspring toxicity: 750 ppm based on decreased weight gain in 

F2b litter pups (18%) vs control for days 4-21 post-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 (19715)

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 

increase 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 

microscopic 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

14C-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, 

and 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.