UNITED STA TES ENVIRONMENT AL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

DATE: 20 May 20 15 

SUBJECT: Furfural. Human Health Scoping Document in Support of Registration 

Review. 

PC Code: 04330 I DP Barcode: 424668 

Decision No.: 498470 Ref!istration Nos.: 

Petition No.: NA Regulatory Action: Registration Review 

Case No.: Risk Assessment Type: NA 

TXRNo.: NA CAS No.: 

MRIDNo.: NA 40 CFR: 

FROM: Kelly O'Rourke, Biologist/Risk ~o~ ~ 1 · fYfl~lA...­ Thurston Morton, Chemist .-f-?~ 1-?f..J('J . . 

THROUGH: 

TO: 

Jessica Kidwell, Toxicologist ~ l 

Risk Assessment Branch 4 () 

Health Effects Division (7509P) 

E

Ri

li

s

ssa 

k Assessme

Reaves, Ph.D

nt Branch 

., Bra

4 

nch hi ef C~ 

Health Effects Division (7509P) 

Jolene Trujillo, Chemical Review Manager 

Risk Management and Implementation Branch 5 

Pesticide Re-Evaluation Division (7508P) 

Attached is HED's human health risk assessment scoping document for furfural to support 

Registration Review. 
Furfural Scoping Document 0424668 

Executive Summary 

This document summarizes the review of the Health Effects Division's (HED's) human 

health assessments to support the Registration Review of furfural. To determine the scope 

of work necessary to support Registration Review, HED has considered updates to agency 

science policy and risk assessment methodologies and to the toxicity, exposure, and usage 

databases. The most recent risk assessment for furfural, dated August 8, 2012, was 

conducted for the use on athletic fields and outdoor ornamentals (D389907, D395132). 

Furfural (2-furancarboxaldehyde), a heterocyclic aromatic aldehyde, is a non-systemic 

nematicide and fungicide. It is currently registered for use to control root infesting plant 

parasitic nematodes and suppress fungal plant diseases on turf and ornamentals. 

Furfural has a vapor pressure of 2.6 mm Hg and is considered volatile relative to typical 

insecticides/fungicides. Therefore, the inhalation route is expected to be a significant 

component of overall exposure. For the general public, inhalation exposure is expected to 

be the major route of exposure. Occupational workers have potential for both inhalation 

and dermal exposure. The currently registered use patterns (golf courses, sod farms, 

athletic fields, and ornamentals) are considered non-food uses. However, because of the 

high application rate of furfural, and the large amounts of water used during and after 

application, furfural may inadvertently be transported into drinking water sources. 

Therefore, to be health protective, the HED evaluated the potential dietary exposure 

associated with drinking water. 

The hazard database for furfural is complete. Several inhalation studies are available and 

include a special acute portal-of-entry study as well as repeat dosing inhalation studies. 

Respiratory effects, both at the portal of entry (the nose) and in the deep lung (pulmonary 

effects) were observed across the inhalation studies. The portal-of-entry effects (e.g. nasal 

inflammation as indicated by infiltration of inflammatory cells, hyperplasia, and 

degeneration) occur at lower concentrations than the pulmonary effects (breathing 

abnormalities that can progress to mortality at high doses), and so protecting for portal-ofentry effects protects for pulmonary effects. Importantly, portal-of-entry effects of low 

severity (e.g., slight nasal inflammation) that occur after a single exposure are completely 

reversible within two weeks. Acute or repeated oral exposures of rats to concentrations of 

furfural higher than those that cause portal-of-entry effects results in pulmonary effects 

(e.g., breathing abnormalities) and mortality that likely resulted from respiratory distress. 

For the oral route only, liver toxicity is also observed, but at lower doses than those that 

cause pulmonary toxicity; therefore, protecting for liver effects also protects for pulmonary 

effects and mortality. Clinical signs of toxicity that could be neurotoxic and/or agonal are 

also observed at concentrations/dose levels of furfural that cause pulmonary toxicity and 

mortality by the oral and dermal routes. There was no evidence of qualitative or 

quantitative susceptibility seen in the developmental rat and rabbit studies or in the 2-

generation reproduction study in rats. In 2013, the Cancer Assessment Review Committee 

(CARC) re-classified furfural and furfuryl alcohol (soil degradate of furfural) each as 

"Likely to Be Carcinogenic to Humans". The CARC recommended the low dose 

extrapolation method (Q 1 *) for quantification of human cancer risk. 

Page 2 of20 
Furfural Scoping Document 0 424668 

Acute and chronic dietary risk assessments for water only were previously conducted for 

furfural used on non-food sites (i.e., turf and ornamentals). No dietary risks of concern 

were identified. The cancer dietary risk was not evaluated, because furfural and furfuryl 

alcohol had not been classified at the time of the 2012 risk assessment. Updated dietary 

exposure and risk assessments will be necessary to reflect changes to the acute dietary 

endpoint and point of departure (POD) as well as the cancer re-classification. 

The residential and occupational exposure databases for furfural are adequate for 

Registration Review. Although no residential risks of concern were identified in previous 

risk assessments, updated residential bystander risk estimates resulting from off-site 

transport (i.e., volatilization) associated with occupational applications are likely to be 

necessary given the cancer re-classification. 

Although no occupational risks of concern were identified in previous risk assessments, 

updated occupational exposure and risk assessments are likely to be necessary given the 

cancer re-classification, and any changes to PODs and uncertainty factors. 

Use Profile 

Furfural is currently registered for use on golf courses (i.e., tees and greens, and as a spot 

treatment on fairways and roughs), athletic fields and sod farms at application rates ranging 

from 47.7 lb ai/A to 69.5 lb ai/A, up to 6 times per season, at 14- to 28-day intervals. 

Application equipment/methods for these existing uses include groundboom sprayer, 

chemigation, mechanically-pressurized handgun, manually-pressurized handwand and 

backpack sprayer. It is also registered for ornamentals; post-plant application rates range 

from 19.5 lb ai/A to 47.7 lb ai/A, up to 8 times per crop, at 14- to 28-day intervals, by 

chemigation only (drip tubes/tapes). Drench application rates range from 0.174 lb ai/ 100 

gal to 0.339 lb ai/ l 00 gal, at 7- to 28-day intervals. 

There is a proposed new use that is currently undergoing evaluation for registration. 

Hazard ldentificationff oxicology 

The hazard database for furfural is complete. The toxicity database consists of single- and 

repeated-dose animal toxicity studies from the open literature that use various species and 

various routes of exposure as well as several studies conducted according to agency 

guidelines (See Attachment 2). The previously required studies, whjch included acute 

neurotoxicity (MRID 48998502), 2-generation reproduction toxicity (MRID 49139201 ), 

and immunotoxicity (MRID 48999301) studies, have been submitted, reviewed, and found 

to be acceptable. The requirement of a subchroruc neurotoxicity study has been waived by 

the HASPOC (TXR No. 0056939). This approach considered all of the available hazard 

and exposure information for furfural including: 1) The oral acute neurotoxicity (ACN) 

resulted in systemic effects at high doses (200 mg/kg); 2) the inhalation studies suggest 

portal-of-entry effects are more sensitive than systemic effects; 3) the PODs for risk 

assessment are protective of neurotoxicity when considering the shorter duration of 

exposure associated with relatively rapid dissipation due to volatilization and degradation 

Page 3 of 20 
Furfural Scoping Document D424668 

and 4) a subchronic neurotoxicity study, either oral or inhalation, will not likely provide a 

lower POD or a more sensitive endpoint for the risk assessment. 

Inhalation exposure to furfural vapor in rats results in respiratory effects, both at the portal 

of entry (the nose) and in the deep lung (pulmonary effects) following both acute and 

repeated exposures. The portal-of-entry effects (e.g. nasal inflammation as indicated by 

infiltration of inflammatory cells, hyperplasia, and degeneration) occur at lower 

concentrations than the pulmonary effects (breathing abnormalities that can progress to 

mortality at high doses), and so protecting for portal-of-entry effects protects for 

pulmonary effects. Importantly, portal-of-entry effects of low severity (e.g. slight nasal 

inflammation) that occur after a single exposure are completely reversible within 2 weeks. 

Exposure to furfural via the oral and dermal routes also results in pulmonary toxicity 

indicative of respiratory distress, which likely mediates the mortality observed at high dose 

levels of furfural. For the oral route only, liver toxicity is also observed, but at lower doses 

than those that cause pulmonary toxicity, and so protecting for liver effects protects for 

pulmonary effects and mortality. Liver effects were observed in both rats and mice and 

increased in severity with dose, ranging from increased liver weights and inflammation at 

lower doses to necrosis at higher doses. Clinical signs of toxicity that could be neurotoxic 

and/or agonal are also observed at concentrations/dose levels of furfural that cause 

pulmonary toxicity and mortality by the oral and dermal routes. 

There was no evidence of qualitative or quantitative susceptibility seen in the gavage 

developmental rat and rabbit studies or in the gavage two-generation reproduction study in 

rats. 

Since the time of the 2012 risk assessment, the Cancer Assessment Review Committee 

(CARC) determined furfural and furfuryl alcohol (soil degradate of furfural) both to be 

individually classified as "Likely to Be Carcinogenic to Humans" (TXR No. 0056891). 

Furfural was given this classification based on cholangiocarcinoma 1 of the liver, a rare 

tumor type, observed in male rats, liver tumors in male and female mice, and 

hepatocellular neoplasms in each sex of mice with compounds structurally very similar to 

furfural. Furfuryl alcohol's classification was based on nasal tumors in male rats and 

kidney tumors in male mice. The CARC recommended the low dose extrapolation method 

(Q1*) for quantification of human cancer risk2. The most potent oral slope factor [Qi* 

(mg/kg/dayY1

] , of furfuryl alcohol, based upon male rat nasal combined tumor rates, is 

1.31x10-1 in human equivalents (TXR No. 0056959). The most potent unit risk, Q1* 

(mg/kg/day)-1 of furfural based on male mouse liver combined tumor rates is 3.49x 10-2 in 

human equivalents (TXR No. 0056864). 

1 Note: The registrant submitted a Pathology Working Group (PWG) re-read of the cholangiocarcinomas in 

male rats given furfural and identified them as non-neoplastic). Since mode of action (MOA) studies for the 

furfuryl alcohol tumors are currently on-going, a CARC meeting will be held when all the data are reviewed. 2 Mode of action studies are currently being developed by the registrant for the tumor types seen in animals 

treated with furfural or furfuryl alcohol. 

Page 4 of 20 
Furfural Scoping Document D424668 

Dose Response/Endpoint Selection 

Points of departure (PODs) were selected for both acute and chronic dietary (drinking 

water only) and occupational/residential exposure scenarios. Previously, an acute reference 

dose (RID) for all populations of 0.01 mg/kg/day was selected from a developmental 

toxicity study in rats based on clinical signs of toxicity (bilateral exopthalmia, tremors, 

head held low) seen at 50 mg/kg/day (POD= l 0 mg/kg/day) with a total uncertainty factor 

of 1 OOOx (I OX intraspecies variation, 1 OX interspecies extrapolation, and I OX database 

uncertainty factor for missing studies). However, since the 2012 risk assessment, the ACN 

study was submitted (MRID 48998502) and the registrant submitted a request to reevaluate the acute dietary endpoint and to use the ACN study for the acute dietary 

endpoint. Part of their rationale was that the previously selected endpoint using the 

developmental toxicity study in the rat was not the result of a single exposure. The agency 

considered this information and based on current updated policies, determined that the 

previous endpoint was not the result of a single exposure and that acute neurotoxicity study 

is the more appropriate study to be used for the acute dietary endpoint (0419653, 

9/23/2014) for registration review. The no observed adverse effect level (NOAEL) is 80 

mg/kg/day and the lowest observed adverse effect level (LOAEL) is 200 mg/kg/day based 

on mortality and effects on Functional Observational Battery (FOB) parameters and motor 

activity in both males and females. This study is appropriate for the acute dietary endpoint 

for the general population since the effects occurred following a single oral dose. Based on 

the submission of an acceptable/guideline ACN study, there is no longer a data gap, and 

the 1 OX database uncertainty factor may be removed for registration review. The updated 

aRfD will be 0.8 mg/kg/day with a total uncertainty factor of 100 (lOX intraspecies 

variation, I OX interspecies). 

The remaining endpoints have not changed since the 2012 risk assessment (See 

Attachment 3). For registration review, a residential level of concern MOE of 100, rather 

than I 000, should be used for the incidental oral endpoint because all data gaps have now 

been satisfied and the 1 OX database uncertainty factor has been removed. 

The current uses for furfural are non-food (i.e., turf and ornamentals); therefore, an FQPA 

assessment of this chemical has not been conducted. 

Conclusions: There are no outstanding toxicology data requirements. The Agency does 

not anticipate the need to update any endpoints, PODs, or uncertainty factors during 

Registration Review, with the possible exception of the cancer slope factor (Q1 *). 

Page 5 of20 
Furfural Scoping Document D424668 

Residue Chemistry 

The currently registered uses (golf courses, sod farms, athletic fields, and ornamentals) are 

considered non-food; therefore, the need for residue chemistry data had previously not 

been applicable. However, since the 2012 risk assessment, the registrant submitted a 

request to classify uses on all food/feed crops as non-food, and provided data in association 

with the proposed use that is currently under evaluation. HED's ChemSAC discussed this 

request and concluded that additional metabolism data on a root crop (and potentially on 

oilseed) will be needed in order for the Agency to make a determination on whether or not 

uses of furfural on food/feed crops should be considered non-food uses. 

Conclusions: 

Additional metabolism data are recommended to be required in order for use on all 

food/feed crops to be considered non-food. 

Dietary Exposure Including Drinking Water 

Previously, acute and chronic dietary exposure analyses (drinking water only) were 

performed in order to support a Section 3 request for the use of furfural on turf and 

ornamentals (T. Morton, D372769, 1/27/10). The dietary exposure analyses were based on 

residues in drinking water only. The maximum acute dietary exposure (water only) was 

estimated to be 0.059 mg/kg/day. This is approximately 7.4% of the updated aRfD 

discussed previously, which is below HED's LOC (<100% of the aRfD). The chronic 

dietary exposure analysis (water only) indicated that the most highly exposed population 

subgroup is All Infants (<l year old), which utilized < l % of the cRID. The risk estimates 

for the general U.S. population and all other regulated population subgroups are below 

HED's level of concern (<100% of the cRfD). As discussed previously, at the time of the 

2012 risk assessment, the agency had not classified the human carcinogenic potential of 

furfural; subsequently, furfural and furfuryl alcohol (soil degradate of furfural) were both 

individually classified as "Likely to Be Carcinogenic to Humans". 

Conclusions: 

Updated dietary exposure and risk assessments will be necessary to reflect changes to the 

acute dietary endpoint and point of departure (POD), the cancer re-classification, and 

possible revisions of the estimated drinking water concentrations (EDWCs). The 

assessments will use the newest version of DEEM and reflect updated consumption 

information. 

Residential Exposure 

Residential handler exposure is not expected for the registered uses on turf and 

ornamentals. However, bystander inhalation exposure via volatilization is possible for 

individuals living/working nearby the application sites. Adequate field volatility data are 

available to estimate flux values; these were entered into the Probabilistic Exposure and 

Risk model for Fumigants (PERFUM) for use in estimating air concentrations and buffer 

Page 6 of20 
Furfural Scoping Document D424668 

zones for bystander inhalation exposure. The term "buffer zone" equates to the distance 

downwind at which a specific concentration of concern (i.e., COC = HEC/UF) is met, 

based on the desired statistical parameters. 

The bystander inhalation assessment indicated that when a I -acre field has been treated, 

whole field buffer zones were estimated to range from 0 to 140 meters for the 75th through 

95•h percentiles, respectively, depending on the flux data set used. For a 40-acre field, they 

range from 140 to 1230 meters for the 75th through 95th percentiles, respectively. It should 

be noted that the use of the term "buffer zone" does not imply any regulatory decision. In 

the context of risk assessment, it is only considered as the predicted distance for a specific 

COC. The current label lists buffer zones for a I-acre field to be 15 feet (approximately 5 

meters) for irrigation via in-ground pop-up sprinkler systems and 75 feet (approximately 

25 meters) for all other types of sprinkler systems. For a 40-acre field, the label indicates a 

buffer zone of 725 feet (approximately 220 meters). These label-required buffer zones are 

within the ranges calculated based on the COC. Buffer zones are also required for other 

non-greenhouse uses of furfural, and there also are restrictions regarding how close 

furfural can be used near facilities such as hospitals and schools. 

The requirement for a chemical-specific turf transferrable residue (TTR) study was waived 

because a dislodgeable foliar residue (OFR) study (MRlO#: 47146202) was provided to 

support use in greenhouses. These DFR data were used to estimate turf transferable 

residues, and are considered protective because the results of the DFR study indicate that 

residues decline to negligible levels within 4 hours of application. Therefore, post 

application exposure to furfural residues on treated athletic fields/golf courses is expected 

to be negligible for recreational athletes/golfers, and a quantitative assessment was not 

conducted. 

While spray drift may occur as a result of applications of furfural , exposure to furfural 

residues is expected to be negligible based on the previous discussion (i.e., exposure from 

direct contact with treated areas is expected to be negligible). Therefore, potential for 

exposure associated with spray drift will not be quantitatively evaluated during the 

Registration Review. 

Conclusions: 

The residential exposure database is adequate to support the Registration Review process 

for furfural. Although no residential risks of concern were identified in previous risk 

assessments, updated residential bystander risk estimates resulting from off-site transport 

(i.e., volatili zation) associated with occupational applications are likely to be necessary 

given the cancer re-classification and any changes to uncertainty factors. 

Page 7 of 20 
Furfural Scoping Document 0424668 

Aggregate Risk Assessment 

In accordance with the Food Quality Protection Act (FQPA), HED must consider and 

aggregate pesticide exposures and risks from three major sources: food, drinking water, 

and residential exposures. The aggregate risk assessment evaluates the combined risk from 

dietary exposure (food and water) and any non-occupational (residential) uses. While 

there is a common effect identified in the toxicity studies selected to assess oral and dermal 

exposure (neurotoxicity), postapplication exposure to furfural residues is expected to be 

negligible based on the results of the DFR study. The inhalation endpoint is based on a 

portal of entry effects which are not appropriate to aggregate with the oral exposure. Thus, 

an aggregate risk assessment from exposure to furfural is not expected under Registration 

Review. 

Occupational Exposure 

Occupational handler and post-application exposures are expected based on the registered 

uses of furfural. The most recent occupational and residential exposure (ORE) risk 

assessment was conducted in 2012 to evaluate use on athletic fields and ornamentals. The 

LOC is for dermal and inhalation MO Es less than I 00. 

Handler 

The results of the handler occupational exposure and risk assessment indicate that dermal 

risks are not of concern when gloves are worn, as well as coveralls for hand-held spraying 

activities (which are required on the label); dermal MOEs range from 190 to 1,400. 

Inhalation risks are not of concern when a respirator is worn for mixing/loading and 

applying as a drench to ornamentals (not currently specified on the label); inhalation 

MOEs range from 130 to 2,200. 

Postapplication 

The occupational postapplication inhalation assessment indicates that when a 1-acre field 

has been treated, whole field buffer zones were estimated to range from 0 to 140 meters for 

the 75Lh through 95L11 percentiles, respectively, depending on the flux data set used. For a 

40-acre field, they range from 140 to 1230 meters for the 75Lh through 95th percentiles, 

respectively. The current label lists buffer zones for a I-acre field to be 15 feet 

(approximately 5 meters) for irrigation via in-ground pop-up sprinkler systems and 75 feet 

(approximately 25 meters) for all other types of sprinkler systems. For a 40-acre field, the 

label indicates a buffer zone of 725 feet (approximately 220 meters). These label-required 

buffer zones are within the ranges calculated based on the COC. 

As discussed previously, the results of the DFR study indicate that furfural residues decline 

to negligible levels within 4 hours of application. Therefore, occupational postapplication 

exposure to furfural residues on treated turf is expected to be negligible, and a quantitative 

assessment was not conducted. The furfural technical material has been classified in 

Toxicity Category III for acute dermal toxicity, Category IV for acute dermal irritation, 

and Category II for primary eye irritation. Per the Worker Protection Standard (WPS), a 

24-hr restricted entry interval (REI) is required for chemicals classified under Toxicity 

Category II and a 12-hr REI is required for chemicals classified under Toxicity Category 

Page 8 of20 
Furfural Scoping Document D424668 

III and IV. The proposed furfural label indicates an REI of 12 hours, which is adequate 

given the results of the DFR study. This product is intended for use on outdoor 

ornamentals, sod and seed farms, which are within the scope of the WPS, therefore, the 

REl on the label is appropriate. Furfural is also intended for athletic fields and golf 

courses, to which the WPS does not apply; the label correctly contains language cautioning 

unprotected persons to keep out of treated areas until sprays have dried. The REI for most 

greenhouse post-application activities is 12 hours; the REI for cutting flowers is 9 days. 

Conclusions: 

The occupational exposure database is adequate to support the Registration Review 

process for furfural. Although no occupational risks of concern were identified in previous 

risk assessments, updated occupational exposure and risk assessments are likely to be 

necessary given the cancer re-classification. 

Public Health and Pesticide Epidemiology Data 

Both the OPP Incident Data System (IDS) and the Centers for Disease Control and 

Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel 

Event Notification System for Occupational Risk-Pesticides (SENSOR) databases were 

consulted for pesticide incident data on the active ingredient furfural (D426362). Furfural 

is not included in the Agricultural Health Study (AHS). The purpose of the database 

search was to identify potential patterns in the frequency and severity of the health effects 

attri buted to furfural exposure. 

Conclusion: The Agency has reviewed the available incident data and concludes that there 

does not appear to be a concern that would warrant further investigation, since there were 

no incidents involving furfural reported to either IDS or SENSOR-Pesticides. The Agency 

will continue to monitor the incident information and if a concern is triggered, additional 

analysis will be included in the risk assessment. 

Tolerance Assessment and International Harmonization 

No tolerances are established for residues of furfural, and are not needed for the currently 

registered uses of furfural. 

Environmental Justice 

Potential areas of environmental justice concerns, to the extent possible, were considered 

in this human health risk assessment, in accordance with U.S. Executive Order 12898, 

"Federal Actions to Address Environmental Justice in Minority Populations and Lowlncome Populations," 

(http://epa.gov/compliance/ej/resources/policy/exec order 12898.pdD. As a part of every 

pesticide risk assessment, OPP considers a large variety of consumer subgroups according 

to well-established procedures. In line with OPP policy, HED estimates risks to population 

subgroups from pesticide exposures that are based on patterns of that subgroup's food and 

water consumption, and activities in and around the home that involve pesticide use in a 

Page 9 of 20 
Furfural Scoping Document 0424668 

residential setting. Extensive data on food consumption patterns are compiled by the 

United States Department of Agriculture's (USDA's) National Health and Nutrition 

Examination Survey (NHANES), What We Eat in America (NHANES/WWEIA) and are 

used in pesticide risk assessments for all registered food uses of a pesticide. These data are 

analyzed and categorized by subgroups based on age and ethnic group. Additionally, OPP 

is able to assess dietary exposure to smaller, specialized subgroups and exposure 

assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures based on home use of pesticide products and associated 

risks for adult applicators and for children, youths, and adults entering or playing on 

treated areas following application are evaluated. Further considerations are currently in 

development as OPP has committed resources and expertise to the development of 

specialized software and models that consider exposure to bystanders and farm workers as 

well as lifestyle and traditional dietary patterns among specific subgroups. 

Cumulative 

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity 

finding as to furfural and any other substances and furfural does not appear to produce a 

toxic metabolite produced by other substances. For information regarding EPA's efforts to 

determine which chemicals have a common mechanism of toxicity and to evaluate the 

cumulative effects of such chemicals, see the policy statements released by EPA's Office 

of Pesticide Programs concerning common mechanism determinations and procedures for 

cumulating effects from substances found to have a common mechanism on EPA's website 

at http://www.epa.gov/pesticides/cumulative/. 

Human Studies 

Past furfural 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. These data, which include studies from the Pesticide Handlers Exposure 

Database Version 1.1 (PHED 1.1 ); the Agricultural Handler Exposure Task Force 

(AHETF) database; the Agricultural Re-entry Task Force (ARTF) database; and other 

registrant-submitted exposure monitoring studies, are subject to ethics review pursuant to 

40 CFR 26, have received that review, and are compliant with applicable ethics 

requirements. For certain studies that review may have included review by the Human 

Studies Review Board. Descriptions of data sources as well as guidance on their use can 

be found at http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html. 

Data Deficiencies and Risk Assessment Updates for Registration Review 

• Residue Chemistry: The ChemSAC concluded that an exaggerated-rate nature of the 

residue study in a root crop are recommended to be required, in which both the tuber and 

leaves would need to be analyzed. If this study shows a similar metabolic profile to the 

Page 10 of20 
Furfural Scoping Document D424668 

studies previously submitted, then all uses on food/feed could be considered non-food. If 

it does not, then an additional nature of the residue study in an oilseed would be required. 

• Toxicology: There are no outstanding toxicology data requirements. The Agency does not 

anticipate the need to update any endpoints, PODs, or uncertainty factors during 

Registration Review with the possible exception of the cancer slope factor (Q1 *). 

• Dietary: Updated dietary exposure and risk assessments will be necessary to reflect 

changes to the acute dietary endpoint and point of departure (POD) as well as the cancer 

re-classification. The assessment will use the newest version of DEEM and reflect 

updated consumption information. 

• ORE: Updated occupational/residential exposure and risk assessments will likely need to 

be conducted to reflect any significant changes to uncertainty factors and the cancer reclassification. 

Page 11 of 20 
Furfural Scoping Document D424668 

References 

Table I. Memoranda Relevant to Registration Review. 

Author BarcodefIXR Date Title No. 

Brunsman, TXR No. 12119/2013 Furfural Quantitative Risk Assessment Based on 

L. 0056864 f144/N Rats and B6C3 FI Mouse Gavage Studies 

Brunsman, TXR No. 6/26/2014 REV ISED Furfural Alcohol Quantitative Risk 

L. 0056959 Assessment Based on F344/N Rat and B6C3FI 

Mouse Inhalation Studies 

Kidwell, J. 0419653 9/2/20 14 Furfural: Re-evaluation of the Acute Dietary 

Endpoint 

Leshin, J. D418688/ 6/10/2014 Furfural: Summary of Hazard and Science Policy 

TXR Council (HASPOC) Meeting of April 10, 2014: 

No.0056939 Recommendations on the Requirement for a 

Subchronic Neurotoxicity Study 

Morton. T D372769 1/27/2010 Furfural: Acute and Chronic Dietary (Drinking 

Water Only) Exposure Analysis for the Section 3 

Registration Action. 

Morton, T D405498 11 /8/2012 Furfural. Non-Food Use Determination 

O'Rourke, K. 0 389907; 8/8/2012 Furfural: Human-Health Risk Assessment for Use 

et al. 0 395 132 on Athletic Fields and Outdoor Ornamentals; 

Revised Assessment for Golf Course Turf and 

Sod Farms 

Recore, S 0426362 3/25/2015 Furfural: Tier I Review of Human Incidents 

Rowland, J TXRNo. 2/6/2014 Furfural and Furfuryl Alcohol: Report of the 

0056891 Cancer Assessment Review Committee 

Attachments 

Attachment 1. Chemical Identity of Furfural 

Attachment 2. Toxicity Profile Tables 

Attachment 3. Furfural Endpoints and Doses for Risk Assessment 

Page 12 of 20 
Furfural Scoping Document 

Attachment l 

Common 

name: 

IUPAC 

name: 

CAS 

name: 

CAS#: 

Furfural Technical 

2-Furaldehyde or furfural 

2-Furancarboxaldehyde 

98-01-0 I 

H CH -CH 

Molecular Weight: 

Boiling point: 

Density: 

Water solubility ( 20°C): 

\ II \\ 

C-C CH 

II \ I 

0 0 FUR FL 

96. 1 g/mol 

161.7°C 

Solvent solubility (mg/Lat 20°C): 

I. I 6g/mL at 20°C 

7.81 g/100 mL 

alcohol (infinite) 

ether (infinite) 

Vapor pressure: 

Dissociation constant (pKa): 

Octanol/watcr partition coefficient 

Log(Kow): 

UVNisible absorption: 

miscible in octanol. acetone. xylene. 

ethyl acetate. methylene ch loride and 

methanol 

2.6 mm I lg (at 20°C) 

Docs not demonstrate a dissociation 

constant between pKa2 and pKalO. 

0.35 at 20°c 

14 591.3 cm2/mole (pl I 7) 

15324.2 cm2/molc (pH 1.94) 

14584.8 cm2/mole (pll 10.12) 

Page 13 of20 

0 424668 
Furfural Scoping Document D424668 

Attachment 2 

Table Al. Acute Toxicity Profile - Furfu ral 

Guideline No. Study Type MRID(s) Results Toxicity Category 

870.1100 Acute oral in rats 46011009 LDso => I 02 mg/kg II 

(Rana, 2002) 

870.1200 Acute dermal in rats 46406102 LDso > 2,000 mg/kg 111 * 

(Moore. 2004) 

870.1300 Acute inhalation in rats. 46106302 LCso = 0.54-1.63 111 

(Merkel, 2003) mg/L 

870.2400 Acute eye irritation in rabbits. 4601 1012 Severe. Irritant. II 

(Joseph. 2003) 

870.2500 Acute dermal irritation in 46011013 Slight. Irritant. IV 

rabbits. (Joseph, 2003) 

870.2600 Ski n sensitization in Guinea 460 11 0 14 Non sensitizer. Neg. 

pigs. (Joseph, 2003) 

* There have been several Acute Dermal LDso studies submitted in support of furfural: 

Joseph, S. A. (2003). Acute Dermal Toxicity Study of Furfural in Rats. Jai Research Foundation, Department of 

Toxicology, Valvada, Valsad, Gujrat, India. Study No. 3950 dated 5-23-03. MRlD 460 1101 0 - Toxicity Category I 

Mukherjee, A. (2003) Acute Dermal Toxicity Study of MultiguardTM Protect in Rats. Jai Research Foundation, 

Dept. of Toxicology, Valvada - 396108, Dist. Valsad, Gujarat, India. JRF Study No. 4228. Study Completion Date: 

12 May 2003. MRlD 46028102. Unpublished - Toxicity Category I 

Moore, G. (2004) Acute Dermal Toxicity Study in Rats. Laboratory Study No.: 15621. Unpublished study prepared 

by Product Safety Laboratories. September 27, 2004. MRID 46406102 - Toxicity Category Ill 

Moore, G. (2004) Acute Dermal Toxicity Study in Rats - Defined LOSO. Laboratory Study No.: 15139. 

Unpublished study prepared by Product Safety Laboratories. September 27, 2004. MRJD 46406 103 - Toxicity 

Category Ill 

Moore, G. (2004) Acute Dermal Toxicity Study in Rats - Defined LD50. Laboratory Study No.: 16080. 

Unpublished study prepared by Product Safety Laboratories. November 18, 2004. MRID 46424 10 I - Toxicity 

Category Ill 

Page 14 of 20 
Furfural Scoping Document D424668 

Table A3. Subcbronic, Chronic a nd Other Toxicity Profile fo r Furfu ra l 

Guideline No./ MRID No. (year)/ Results 

Study Type Classification /Doses 

Non-guideline 4856370 I (20 11 ) LOA EL = Not observed 

Acceptable/Non-guideline NOA EL= 40 mg/m3 

Acute inhalation 0, 10, 20, 40 mg/m3 for 6 with complete hours. Satellite group with 14 

recovery day recovery period 

870.3100 4601 IOl5 (1990) NTP 1990 Study (publication). 

90-Day oral toxicity Acceptable/Non-guideline Systemic Toxicity NOAEL = 45 mg/kg/day 

rats 0, 11 , 22, 45, 90, 180 Systemic Toxicity LOAEL = 90 mg/kg/day based on 

mg/kg/day liver pathology - cytoplasmic vacuolization of 

(gavage in corn oil) hepatocytes. 

Limited pa r ameters measured. 

870.3100 46011015 (1990) NTP 1990 Study (publication). 

90-Day oral toxicity Acceptable/ Non-guideline Systemic Toxicity NOAEL < 75 mg/kg/day 

mice. 0, 75, 150,300, 600, 1200 Systemic Toxicity LOAEL <= 75 mg/kg/day based on 

mg/kg/day relative liver weights. 

(gavage in corn oil) Limited parameters measur ed. 

870.3100 4601 1015 (2001) WHO (published review article), Food Additive 

90-Day oral toxicity Summary/Non-guideline Series 46 (200 I) 

rats. (WHO published review Systemic Toxicity NOAEL = 60 mg/kg/day 

a rticle) Systemic Toxicity LOAEL = 90 mg/kg/day based on 

0, 30, 60, 90, 180 mg/kg/day liver effects. 

(microencapsulated and mixed 

into feed) 

870.3200 46465501 (2004) Systemic Toxicity NOAEL => I 00 mg/kg/day (HOT). 

28-Day dermal Unacceptable/G uideline Systemic Toxicity LOAEL > I 00 mg/kg/day. 

toxicity in rats. 0, 25, 50 and I 00 mg/kg Transient effects included drowsiness, dyspnea, clonic 

convulsion, hyperactivity, tremor, vocalization, 

generalized effects from exposure to furfural 

No dem1al irritation noted. 

870.3200 4691720 I and 46917202 (2006) Systemic Toxicity NOAEL = 250 mg/kg/day Acceptable/G uideline 28-Day dermal 0, I 00, 250, 500, or I 000 Systemic Toxicity LOAEL = 500 mg/kg/day based on 

toxicity in rats. mg/kg bw/day, 6 hours/day for adverse clinical signs (males), an increase in motor 

5 days/week activity (males) and increased mortality (males and 

females). 

No dermal irritation noted. 

870.3250 

90-Day dermal 28 day study fulfills this requirement 

toxicity in rats 

870.6200a 48998502 (main) (2012) NOAEL = 80 mg/kg Acute Neurotoxicity Acceptable/Guideline LOA EL = 200 mg/kg based on mortality and effects on - rat 0, 30, 80, 200 mg/kg FOB parameters and motor activity in males and 

[48998501 (range finding) females 

(20 12) 

Page 15 of20 
furfural Scoping Document D424668 

Table A3. Subchronic, Chronic a nd Other Toxicity Profile fo r Furfura l 

G uideline No./ MRID No. (year)/ Results 

Study Type Classifica tion /Doses 

0, 50, I 00, 150 mg/kgj 

870.6200b 

Waived by HASPOC (TXR No. 0056939; Subchronic 

Neurotoxicity - rat D418688;6/l 0/201 4) 

870.3465 46426504 and 46426505(200 I) NTO (Netherlands) 2001 (study publication). 

28-Day inhalation Acceptable/G uideline Systemic Toxicity NOAEL < 20 mg/m3 . 

toxicity in rats 0, 20, 40, 80, 160,320,640, Systemic Toxicity LOA EL =< 20 mg/m3. (LDT) all 

1280 mg/m3 

dose levels showing nasal epithelium pathology. 

870.3465 4741910 1 (2008) Portal of Entry NOAEL was 8 mg/m3 (equivalent to 

28-Day inhalation Acceptable/Guideline an analytical concentration of 0.007 mg/L). 

0 (air), 2, 4, 8, or 20 mg/m3 Portal of Entry LOAEL was 20 mg/m3 (equivalent to toxicity in rats (equivalent to analytical an analytical concentration of 0.017 mg/L) based on 

concentrations of 0, 0.002, microscopic inflammatory changes in the nasal cavity 

0.004, 0.007, and 0.017 mg/L, Level 3, characterized by transitional respiratory 

respectively) for 6 hours per epithelial hyperplasia and mixed inflammatory cell 

day, 5 days/week for 4 weeks infiltration. This is a portal of entry local adverse 

effect. 

870.3465 

90-Day inhalation 28 day study fulfills this requirement 

toxicity in rats 

870.3700 46147601 (1997) Materna l Systemic Toxicity NOAEL = I 0 mg/kg/day 

Prenatal Acceptable/G uideline (from rangefinder) 

developmental in w/rangefinder Maternal Systemic Toxicity LOA EL = 50 mg/kg/day 

rats Primary study: 0, 50, I 00, 150 (from primary) based on clinical signs. 

mg/kg/day Developmental Toxicity NOAEL => 150 mg/kg/day 

Range finder 4662940 I ( 1996) Developmental Toxicity LOAEL > 150 mg/kg/day, no 

0, I 0, 50, I 00, 150, 250, 500, treatment related effects noted in the primary study, no 

I 000 mg/kg/day relevant observations in the rangefinding study. 

(gavage in water) 

870.3700 46207303 (2004) Maternal Systemic Toxicity NOAEL = 225 

Prenatal Acceptable/G uideline mg/kg/day 

developmental in w/rangefinder Maternal Systemic Toxicity LOA EL = 300 mg/kg/day 

rabbits Primary study: 0, 25, 75, 225 based on decreased bw, bwg - primary study combined 

mg/kg/day with rangefinder study data 

Rangefinder: 46207302 (2003) Developmental Toxicity NOAEL = 225 mg/kg/day 

0, 25, 50, I 00, 150, 300 Developmental Toxicity LOA EL= 300 mg/kg/day 

mg/kg/day based on decreased fetal bw - primary study combined 

(gavage in water) with rangefinder study data 

870.3800 49 13920 I (2013) Parental and Reproductive NOAEL=60 mg/kg/day 

Reproduction and Acceptable/Guideline Parental and Reproductive LOAEL could not be 

fertility effects determined 

0, 20, 40 or 60 mg/kg/day Offspring NOA EL = 60 mg/kg/day 

Offspring LOA EL could not be determined. 

870.6300 Not required Developmental 

Page 16 of20 
Furfural Scoping Document D424668 

Table A3. Subchronic, Chronic and Other Toxicity Profile for Furfura l 

G uideline No./ MRID No. (year)/ Results 

Study Type Classification /Doses 

neurotox1city 

870.4100 46011016 (1990) NTP 1990 Study (publication). 

Chronic toxicity Acceptable/Non-guideline. Systemic Toxicity NOAEL not identified 

Rats 0, 30, or 60 mg/kg/day Systemic Toxicity LOAEL = 30 mg/kg/day based on 

(gavage in oil) liver histopathology. 

Limited parameters measured. 

870.4100 46011016 ( 1990) NTP 1990 Study (publicatio n) 

Chronic toxicity - Acceptable/Non-guideline. Systemic Toxicity NOA EL => 175 mg/kg/day 

mice 0, 50, 100, or 175 mg/kg/day Systemic Toxicity LOA EL > 175 mg/kg/day 

(gavage in corn oil) Limited parameters measured. 

870.4200 46011016 (1990) NTP 1990 Study (publication). 

Carcinogenicity Acceptable/Non-guideline Systemic Toxicity NOAEL = 30 mg/kg/day 

rat. 0, 30, 60 mg/kg/day Systemic Toxicity LOAEL = 60 mg/kg/day based on 

(gavage in corn oil) liver effects (pathological observations). 

Limited parameters measured. 

Low incidence of chola ngiocarcinomas in ma les 

870.4300 46011016 ( 1990) NTP 1990 Study (publication) 

Carcinogenicity Acceptable/Non-guideline Systemic Toxicity NOAEL => 175 mg/kg/day 

mouse. 0, 50, I 00, 175 mg/kg/day Systemic Toxicity LOA EL > I 75 mg/kg/day 

Limited parameters measured. 

Adenomas (M/F) and adenocarcinomas (M) of the 

liver 

Gene Mutation 4601 1017 ( 1999) Negative for bacterial reverse mutation assay 

870.5100 Acceptable/Guideline 

Gene Mutation 46011018 (2003) Negative for in vivo gene mutation 

870.5100 Acceptable/Non-guideline bacterial gene incorporation into genome of transgenic 

mice 

CA/SCE 460 1101 9 (2003) Negative and Acceptable/Guideline: 

870.5375, 870.5385, Compilation of7 reports Reverse Gene Mutation, In vitro mammalian gene 

870.5900, 870.59 I 5 mutation and chromosomal aberrations , In vivo 

Chromosomal Aberrations, SCE, Gene Mutation -

Drosophilia 

Unacceptable/Guideline - Expert Panel Report, SCE 

in human Lymphocytes, in vitro cytogenetic assays 

UDS 460 I I 020 (2003) Negative for DNA damage/repair, rec-assay, UDS in 

870.5500, 870.5560 Compilation of 9 reports rat hepatocytes - Acceptable/Guideline 

DNA damage, summary reports - Unacceptable 

870.7485 47750502 ( 1992) Furfural was rapidly absorbed and e liminated at all 

Metabolism and Acceptable/Non-guideline dose levels (80% within 24 hours, 85% within 72 

pharniacokinetics 0.127, 1.15, 12.5 mg/kg hours out of a recovery of 90%). The urine was the 

(gavage in corn oil) major route of elimination (85% within 72 hours). 

Minor routes were feces (<2%) and exhalation as 

carbon dioxide (<7%). Furfural was retained in tissues 

Page 17 of20 
Furfural Scoping Document 0424668 

Table A3. Subchronic, Chronic and Other Toxicity Profile fo r Furfu ra l 

Guideline No./ MRID No. (yea r)/ Results 

Study Type Classification /Doses 

at low levels oTiess tllan 1% oTtlle administered dose 

(range 0.1 ± 0.1% at 0.127 mg/kg to 0.6 ± 0.1% at 12.5 

mg/kg), indicating low potential for bioaccumulation. 

870.7600 None. 

Dermal penetration 

870.7800 4899930 I (2012) NOA EL for systemic toxicity = 80 mg/kg/day 

28-day Acceptable/Guideline LOA EL for systemic toxicity could not be determined. 

lmmunotoxiciry in 0, 20, 40, 60, 80 mg/kg/day 

rats NOAEL for immunotoxicity = 80 mg/kg/day 

LOA EL for immunotoxicitv could not be determined. 

Non-guideline = studies eit her from the open lite ra ture, studies not meeting guideline requirements, but 

contain useful info rma tion or range-finding studies 

Page 18 of20 
Furfural/043301 Scoping Document Dxxxx 

Attachment 3 

Table X: Summary of Toxicological Doses and Endpoints for Furfural for Use in Humanhealth Risk Assessments (to be used for Re2istratio11 Review) 

Exposure/ Point of Uncerta inty Level of Concern Study and Toxicological Effects Scenario Depa rture Factors for Risk Assessment 

Acute Neurotoxicity Study Rat 

Acute Dietary UFA= IOx (MRID 48998502) 

(general NOAEL = 80 UFH= IOx 

Acute RFD = LOA EL = 200 mg/kg/day based on 

population) mg/kg/day 0.8 mg/kg/day effects on FOB parameters, motor 

activity and mortality in males and 

fema les. 

UFA= JOx Chronic Rat (MRID 46011016) 

Chronic UFH= IOx Chronic RID = Systemic Toxicity LOAEL = 30 

Dietary (All LOAEL = 30 UFL = 3X 0.1 mg/kg/day mg/kg/day based on liver 

Populations) mg/kg/day (LOAEL to pathological observations (centri lobular 

NOA EL necrosis and cystic degeneration). 

extrapolation)) NOA EL not established. 

Incidental Developmental Rat (MRID 

Oral Short- Residential LOC for 46147601 ) 

Term (1-30 NOAEL= 10 UFA= !Ox MOE = 100 Maternal LOAEL = 50 mg/kg/day 

days) and mg/kg/day UFH= IOx (This is also based on clinical signs of toxicity 

Intermediate applicable to the (one hour post-dosing, bilateral 

Tenn ( 1-6 young) exophthalmia, tremors, and head held 

months) low). 

Dermal Short- 28-Day Dermal Rat (MRID 

Term (I-30 Occupational LOC 

46917201; 46917202) 

days) and NOAEL = 250 UFA= I Ox for MOE = 100 Systemic Toxicity LOAEL = 500 

Intermediate- mg/kg/day UFH= IOx Residential MOE = mg/kg/day, based on adverse clinical 

Term ( I- 6 100 signs (males), an increase in motor 

months) activity (males) and increased 

mortality (males and females). 

Dermal 

Long-Term No long term dermal exposure expected 

(> 6 months) 

Page 19 of 20 
Furfural/04330 l Scoping Document Dxxxx 

Table X: Summary of Toxicological Doses and Endpoints for Furfural for Use in Humanhealth Risk Assessments (to be usedfor Registration Review) 

Exposure/ Point of Uncertainty Level of Concern Study and Toxicological Effects Scenario Departure Factors for Risk Assessment 

Port-of-entry 

NOAEL = 40 Acute Inhalation Rats (MRlD 

mg/m3 Residential and 4856370 I) Port-of-entry LOA EL = 

Inhalation UFA=3x Occupational LOC 20 mg/m3

, based on very slight/slight 

Acute Bystander and UFH= IOx for MOE = 30 nasal lesions in males hat were fully 

Occupational reversible within 2 weeks of a single 

HEC = 6.63 exposure. 

mg/m3 

Port-of-entry 

NOAEL = 8 

Inhalation mg/m3 

Short-Term (2.09 mg/kg/day 1

) 28-Day Inhalation Rats (MRlD 

( 1-30 days) UFA=3x Residential and 4741910 I) Port-of-entry LOA EL = 

and Bystander HEC = Occupational LOC 20 mg/m3 based on nasal epithelial 

Intermediate- 0.9Smg/m3 UFH= lOx for MOE = 30 pathology seen throughout all of the 

Term (1- 6 treated animal groups. 

months) Occupational 

HEC = 1.33 

mg/m3 

Inhalation 

Long-Term No long tenn inhalation exposure expected 

(> 6 months) 

Cancer (oral, Furfural and Furfuryl Alcohol were both classified by CARC as "Likely to Be Carcinogenic to dermal, 

inhalation) Humans" with Q1*'s (TXR No. 005689 1, 2/6/2014) 

1 Inhalation NOAEL = 2.09 mg/kg/day. The dose in mg/L was converted to mg/kg/day using the following 

equation: Dose (mg/kg/day) = (NOAEL (0.008 mg/L) * Respiration rate of a young adult Sprague-Dawley rat 

( 10.26 L/hr) * Study daily exposure duration (6 hr/day)) I Body weight of a young adult Sprague-Dawley rat (0.236 

kg). 

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UF" = extrapolation from animal to human (interspecies). UF11 =potential variation in 

sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of 

concern. NIA = not applicable. 

Page 20 of20