### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460



### MEMORANDUM

DATE: 9 / 9 / 2015 O FFI CE OF CHEM I CA L S AFE TY

AND PO LLU TI ON PREVE NT I ON



### SUBJECT: Acrolein: Human Health Assessment Scoping Document in Support of Registration

Review



### PC Code: 000701 DP 

### Barcode: 427578



### MRID No.: Not Applicable



### Petition No.: Not Applicable



### Assessment Type: Single Chemical

TXR 

### No.: Not Applicable 

### Registration No.: 10707-9

, 10707-10

, 71173-1 

### Regulatory Action: Registration Review Scoping



### Case No.: 2005



### CAS No.: 107-02-8



### MRID No.: Not Applicable 40 

### CFR: Not Applicable

FROM:

THROUGH: 

# r;,1

TO: Wade Britton

, MPH, Risk & 

### ORE Assessor

Austin Wray

, Ph

. D

., Toxicologis '
Thurston Morton

, Chemist

Risk Assessment Branch IV ( BIV)'

Health Effects Division (HED, 7509P)

Nathan Mottl

, Biologist

# /./~**~** Risk Assessment and Science Support Branch (RASSB)

Antimicrobial Division (AD

, 751 OP)

Charles W

. Smith III

, Acting Branch Chief

._ _. "-----__.....,.

RABIV / HED(7509P)**~~,/~** 

### Laura Parsons

, Associate Branch Chief**~(,IV G**  

### RASSB / AD (7510P)

Kelly Ballard

, Chemical Review Manager

Risk Management and Implementation Branch V

Pesticide Re-evaluation Division (7508P)

Attached i s AD ' s and HED 's human health scoping document for acrolein to support Regi s tration Review.

Page 

### 1 of23

### Page 2 of 23 Executive Summary

The AD and HED a crolein Registration Review t eams have evaluated the scientific database for the pesticide acrolein [2

- Propenal] to determine the scope of the work necessary to support the existing registrations. Acrolein has two pesticidal use patterns: 1) as an herbicide for control of vegetation in agricultural irrigation canals and

, in some states

, irrigation reservoirs and 2) as a bacteriocide in injection systems associated with petroleum production

. Although the
bacteriocidal and herbicidal use patterns are assessed separately by AD and HED , respectively,
this Registration Review document addresses both.

Currently, there are nine total active registration s of acrolein: one Section 3 registration (EPA Reg. No. 10707

- 9, Magnacide H Herbicide, 95% active ingredient) and six Special Local Needs (SLN) registration s (EPA Reg. Nos. CA780039, ID900005, NE030003, OR910018, UT03000 1, WA040017) for acrolein used as aquatic herbicide ; and two Section 3 registrations as a bacteriocide (EPA Reg. No. 10707

- 10, Magnacide B Microbicide, 95% active ingredient; EPA Reg. No. 71173

- 1, AcroCide TM 

### , 96% active ingredient)

. All products are packag ed as liquids and stored under an inert gas blanket. There are currently no pending PRIA actions for acrolein.

As an aquatic herbicide, acrolein is injected directly below the surface of moving water for control of submerged aquatic weeds and algae in ir rigation canals and, in some states, irrigation
reservoirs. It is used in oilfield water systems to reduce sulfate reducing bacteria that produces corrosive hydrogen sulfide in oilfield water systems including: hydraulic fracking fluids; oilfield

water injection wells; water systems; water floods; oil production systems; and water disposal
systems . Applications are conducted by pumping acrolein from pressurized containers into closed injection well piping systems. All acrolein products are applied thro ugh a closed system.

AD and HED have evaluated the status of the human health risk assessments for acrolein to determine whether sufficient data are available, and whether any updates are required to support Registration Review

. Further, all available data and human health risk assessments for acrolein with respect to its toxicity, exposure, and usage databases, as well as the most updated agency science policy and risk assessment methodologies to determine the scope of the work necessary
to support Registration Review have been considered

.

The most recent human health risk assessment was conducted for purpose of issuance of the reregistration eligibility document (RED) for acrolein in 2008 1 

### . The risk assessment was
inclusive of both th e bacteriocidal and herbicidal uses patterns

The acrolein toxicity database is adequate to conduct Registration Review for registered uses. The Hazard and Science Policy Council (HASPOC) waived the requirement for the neurotoxicity battery and immunotoxic ity study and no other studies are required at this time 2 

### . Ocular, respiratory, stomach

, and dermal tissues at the portal of entry are the primary targets of acrolein

1 B. Daiss. Acrolein HED Risk Assessment for Registration Eligibility Decision (RED) Document. 3/25/2008.
D348777.

2 U. Habiba. Acrolein: Summary of Hazard and Science Policy (HASPOC) Meeting of July 9, 2015: Recommendations on the Need for the Neurotoxicity Battery (Acute and Subchronic) and Immunotoxicity Study.
7/9/2015. TXR # xxxxxx )

### Page 3 of 23 toxicity and dictate endpoint selection. Co

- critical endpoints for eye, nose

, and throat irritation

, and decreased respiratory rate from a human health inhalation study were used to se lect points of departure for short

- term occupational and residential bystander inhalation exposure. These are the only potential exposure scenarios that have pre viously been assessed based on the current use
patterns

.

The residue chemistry database for acrolein is in adequate to support current Registration Review data requirements. HED previously required an additional nature of the residue study in root and

tu ber as part of the RED. While HED reviewed a protocol for this study in 2011; the study has
not been submitted to date . The need for additional residue chemistry data and tolerances will be evaluated when this study is submitted and reviewed. The acrole in RED also stated if the reservoir SLNs were supported that an enforcement method would be required however a method has not been submitted at this point in time

. T he need for tolerances in/on fish and
shellfish will also be evaluated if the registrant continues to support the SLN use in reservoirs.

The dietary exposure database is adequate to support current registration requirements. A dietary risk assessment was not previously conducted for either the bactericidal or herbicidal uses of
acrolein

. Ri sks from drinking water exposures were not previously assessed because the Environmental Fate and Effects Division (EFED) did not establish estimated d rinking water concentrations (EDW Cs) for use in risk assessment. However, based on EFED’s problem
formul ation document in support of Registration Review , there is the potential for acrolein in irrigation water to leach into groundwater and, as a result, EFED may conduct a drinking water assessment if deemed necessary following further consideration of the av ailable groundwater monitoring data

. If a dietary assessment is required, the toxicity database will need to be reassessed for the establishment of dietary endpoints.

In the 2008 human health risk assessment

, a dietary cancer assessment was conducted i n consideration of the Indigenous Peoples of the western region of the US who rely heavily on
subsistence diets as their food source. The dietary cancer assessment considered exposures of subsistence fishermen to glycidol, a metabolite of acrolein in fish . The resulting dietary cancer
risk estimate of 1.2 x 10

- 6 

### was calculated.

There are no proposed or current registrations for products containing acrolein that allow residential use. Therefore, residential handler and post

- application exposure assessmen ts will not be needed during Registration Review

. Residential bystander exposures resulting from spray drift are not anticipated for acrolein since all applications are required to be conducted by means of closed systems. However, r esidential bystander exposures resulting from volatilization may occur as supported by air monitoring data collected for the herbicidal use. During Registration Review, the agency will consider all available air monitoring data and determine whether there is
the need for a volatilization risk assessment for acrolein. Residential e xposures from swimming in acrolein treated irrigation canals are not expected. Per label changes required by the acrolein RED, the current Magnacide H label states that a crolein can only be applied in canals/reservoirs with posted no swimming signs

.

A quantitative or qualitative aggregate assessment was not previously required for acrolein since there were no anticipated dietary (food or drinking water) exposure to residues of acrolein, and

### Page 4 of 23 there are no residential uses of the chemical. Further, the metabolite of acrolein, glycidol, only forms in fish and depurates quickly. Although a dietary cancer assessment was conducted for glycidol from exposures to subsistence fishermen, exposures to glycidol via drinking water, inhalation, and dermal pathways are not expected. Therefore, a quantitative aggregate assessment

was not required. An aggregate assessment may be necessary if EDWCs are deemed necessary by EFED, or to reflect the most recent dietary exposure polic ies

.

Occupational handler exposures were assessed in the most recent occupational risk assessment s conducted by AD and HED in 2008

. All acrolein products are applied thro ugh a closed application system and, therefore, dermal exposures are not anticipated. The principal registrant s , Baker Petrolite and Multi

- Chem, both have comprehensive training program s to ensure that applicators are competent in the application, handling, and storage procedures required for the bacte riocidal and herbicidal use s

. Further, stringent personal protective equipment are required througho ut all application activities. With use of the label required inhalation PPE, an organic vapor respirator, inhalation handler risks are not of concern.

Occupational p ost

- application exposures to acrolein may also occur depending on the length of time the worker remains in the area following completion o f the application and equipment disassembly. For the herbicidal use, depending on the extent to which w orkers remain in the vicinity of the treated canal after acrolein has been applied and that the requirement for use of a respirator is no longer applicable, worker post

- application inhalation exposure s to acrolein

vapors may potentially exceed HED’s level of concern. O ccupational post

- application exposures could also occur from the bacteriocidal use. Acrolein vapors could potentially result from underground flow back water draining out of the well into water holding ponds after fracking. During registrat ion review, post

- application air monitoring data are needed for the antimicrobial oil well use pattern.

An updated occupational exposure assessment may be required during Registration Review to incorporate any additional air monitoring data of acrolein f ollowing the 2008 risk assessment s to determine if the PPE required during set up and breakdown of application equipment are adequately protective of potential inhalation exposures , and to determine what impact these data
have on inhalation risks for applicators present between set up and break do wn of application equipment, as well as for the post

- application workers remaining in the vicinity of treated canals

.

1.0 Introduction

Acrolein is an herbicide used for control of vegetation in agricultural irrigation canals and in some states, irrigation reservoirs, and as a bacteriocide in injection systems associated with petroleum production . There are currently nine total active registration s of acrolein: one Section 3 registration (EPA Reg. No. 10707

- 9, Magnacide H Herbicide) and six Special Local Needs (SLN) registration s for acrolein used as aquatic herbicide ; and two Section 3 registrations as a
bacteriocide (EPA Reg. No. 10707

- 10, Magnacide B Microbicide ; EPA Reg. No. 71173

- 1,
AcroCide TM 

### , 96% active ingredient )

. The most recent risk assessment s were conducted by AD
and HED for purpose of issuance of the RED for acrolein in 2008. The RED was inclusive of
both the herbicidal and microbiocidal use patterns. There are currently no pending PRIA actions
for acrolein.

### Page 5 of 23 2.0 Hazard Characterization/Assessment

The acute, sub

- chronic, and chronic toxicity profile tables for acrolein are included in
Attachment 2. Few guideline studies were available to select endpoints for risk assessment; therefore, non

- guideli ne studies from a 2005 re view of acrolein toxicity by Agency for Toxic Substances and Disease Registry (ATS DR ) were used to address the gaps in the toxicity
database.

Acrolein induces toxicity in exposed organisms through formation of irreversible adduct s with
macromolecules. It is acutely toxic after exposure via dermal, inhalation

, or oral route and is a strong dermal and eye irritant (all Category I). Sub

- chronic and chronic toxicity manifests initially in tissues at the portal of entry

. Eye, throat

, and nasal irritation, and depressed respiratory rate were common symptoms of acrolein toxicity in humans after inhalation

exposure. Similarly, ocular and respiratory tissue damage (discharge, squamous metaplasia of trachea, necrosis and hemorrhage of lu ngs, pulmonary edema) were characteristic of inhalation exposure at higher doses in rodents and non

- rodents. Oral exposure in rodents and non

- rodents induced epithelial hyperplasia and lesions in the stomach

. S kin irritation was the primary
adverse effec t following dermal exposure. Changes in body weight, body weight gain, and serum chemistry were secondary to

, or concurrent with

, damage in the stomach and respiratory
tissues. Acrolein exposure to pregnant rodents disrupted fetal skeletal development an d led to reduced fetal weight at doses engendering maternal toxicity. No reproductive effects were
observed

. No obvious or egregious instances of neurotoxic and immun o toxic effects were reported in the database to indicate increased sensitivity in the im mune or nervous system.

Equivocal results from the guideline and literature studies preclude definitive characterization of acrolein mutagenicity and its carcinogenicity potential

. As a result, the International Agency for Research on Cancer (IARC) and EPA concluded the database is not adequate to classify the carcinogenicity of acrolein. Despite ambiguous results in the database , HED does not believe
cancer studies are required for reregistration based on registered use patterns, anticipated exposure l evels, and available data which does not indicate carcinogenicity. However, glycidol, a metabolite of acrolein, is considered a probable human carcinogen to humans by the IARC.

Previously, toxicity endpoints, points of departure (PODs), and uncertainty/ safety factors, were selected for inhalation exposure pathways only. These same values will be used for the Registration Review and are presented in Attachment 3. The E nvironmental Fate and Effects Division (EFED ) is currently reviewing the available mon itoring data to determine if leaching of contaminated irrigation water into groundwater poses a drinking water risk for humans. Pending the EFED recommendation, the toxicity database may need to be reassessed and new endpoints established for dietary expo sure.

Conclusions: The toxicity database is adequate to assess risk for the registered uses of acrolein.

T he following studies are required for acrolein in accordance with current t oxicology d ata requirements (40 CFR 158.500) : acute neurotoxicity study (870.6200), sub

- chronic neurotoxicity study (870.6200), and i mmunotoxicity study (870.7800). HASPOC waived the requirement for
these studies based on t he fo l lowing considerations: 1) its known corrosive mode of action in

### Page 6 of 23 portal of entry tissues at doses l ower than those required to elicit systemic toxicity, 2) a lack of evidence in guideline and literature studies for biologically significant neurotoxic and immunotoxic effects at doses lower than the current human inhalation point s of departu re, 3) and
the abundance of resources available for assessing dietary exposure that can be used in lieu of an oral guideline study , if necessary

. No new data is required for this assessment and we do not anticipate modifying the PODs and endpoints from previous risk as sessments unless a dietary assessment is required.

3.0 Residue Chemistry

The following paragraphs are a summary of the residue chemistry database.

Nature/Magnitude of the Residue

- Crops: 14 

### C

- Acrolein was applied to lettuce leaves in four applications, e ach at a rate of 0.1 lb. a.i./acre. Acrolein is readily incorporated into natural products in lettuce. The only residue of concern is acrolein on the day of application. P revious
to the acrolein RED , two additional plant metabolism studies were required to demonstrate that the metabolism observed in lettuce is typical of general metabolism of acrolein in plants. However, in support of the RED, HED determined only one additional study on a root and tuber crop (pref erably radish) was required (T. Morton, D3 34663, 9/27/2007) and subject to Data Call

In (DCI). This study should reflect furrow irrigation. If this outstanding study demonstrates
metabolism consistent with the lettuce metabolism then no tolerances or additional data will be required. However, if metabolism is not consistent an enforcement analytical method will be required along with magnitude of the residue in irrigated crops.

A protocol was reviewed in 2011 for a radish nature of the residue study. HED reiterated that all
residues over 0.0 1 ppm total radioactive residue (TRR) or 10% of the TRR should be
identified/characterized . Exhaustive attempts should be taken to identify >70% of the TRR including but not limited to acid hydrolysis, base hyd rolysis, and enzyme extraction.

Nature/Magnitude of the Residue

- Ruminants: Baker Performance Chemicals Inc. submitted data depicting the metabolism of [ 14 

### C]acrolein in lactating goats. The qualitative nature of the residue in ruminants is adequately understood. The TRR, expressed as [ 14 

### C]acrolein equivalents,
were 1.67

- 9.41 ppm in milk, 9.14 ppm in liver, 1.71 ppm in kidney, 0.36 ppm in muscle, and 0.16 ppm in fat of a lactating goat orally dosed with [ 14 

### C]acrolein at 8.7 ppm (based on water consumption) for five consecutive days. R adioactive residues peaked on day 4 in milk. Acrolein was not found in any tissue sample.

Analytical Enforcement Methods: Currently there are no established tolerances for acrolein
residues. Therefore, no enforcement method has been submitted. The ac rolein RED stated if the
SLN use of acrolein in reservoir s were supported , as is the case currently for California, Oregon, and Utah, an enforcement method is required

. These data are outstanding since the reservoir use continues to be supported.

Conclu sions : The need for additional residue chemistry data will be evaluated once the root and tuber nature of the residue study is submitted. The need for tolerances in crops will be reevaluated once the nature of the residue study in a root and tuber crop i s submitted. In

### Page 7 of 23 addition, the need for tolerances in/on fish and shellfish will be evaluated if the registrant continues to support the SLN use in reservoirs.

4.0 Dietary Exposure

An acute and chronic dietary risk assessment of acrolein was not previously conducted as dietary exposures to acrolein are not expected based on the use pattern, available data on metabolism, and post

- irrigation reentry intervals. Acrolein is not applied directly to any crops; however, water from the irrigation canal s ystems may be used on cropland immediately after application of the herbicide. A specific holding time is required before irrigation water can be discharged into natural water systems. The antimicrobial use pattern of oil and gas is not expected to resul t in exposure to drinking water. Risks from drinking water exposures were not previously assessed because OPP’s EFED did not establish quantitative estimated EDWC s for use in risk assessment. However, based on EFED’s problem formulation document in suppo rt of Registration Review, there is the potential for acrolein in irrigation water to leach into groundwater and, as a result, EFED may conduct a drinking water assessment if deemed necessary following further consideration of the available groundwater mon itoring data.

The Indigenous Peoples of the western region of the U.S. rely heavily on subsistence diets as
their food source. In the 2008 human health risk assessment, a cancer assessment of dietary exposure of subsistence fishermen in irrigation distr icts of the western United States was conducted for glycidol , a metabolite of acrolein

. The assessment was b ased on data provided by
EFED on acrolein concentrations in fishable waters and data from EPA on the location and fishing habits of tribes living i n areas proximate to treated canals. HED used the mean subsistence fish intake amounts, glycidol radioactive residues from the nature of the residue study in fish, the number of times acrolein would be used per year, and the glycidol Q 1 

### * to
determine the exposure and risk from the use of acrolein to Native American subsistence fishermen. The resulting risk estimate was 2.4 x 10

- 6



### . An average LC 50 

### of 0.34 ppb was calculated from a range of LC 50 

### s for edible fish. When this average LC 50 

### was used, a dietary
risk estimate of 1.2 x 10

- 6 

### was calculated.

Conclusions: The dietary exposure database is adequate to support current registration requirements. As a part of Registration Review

, dietary endpoints may need to be selected, a

non

- cancer dietary exposure assessment may be required, and a revised cancer dietary
assessment for subsistence fisherman may also be required if EDWCs are deemed necessary by

EFED

.

5 .0 Residential Exposure

There are no proposed or current registrations for products containing ac rolein that allow residential use. Therefore, residential handler and post

- application exposure assessments will not be needed during Registration Review

. Residential exposures from swimming in acrolein treated irrigation canals are not expected. Per la bel changes required by the acrolein RED, the

current Magnacide H label states that a crolein can only be applied in canals/reservoirs with posted no swimming signs

.

### Page 8 of 23 Spray Drift and Volatilization : Residential bystander exposures resulting from spray dr ift are not anticipated for acrolein since all applications are required through means of closed systems. Applications of the herbicide use are metered via closed system into irrigation canals and reservoirs, and the bacteriocide application is pumps acrol ein from pressurized containers into closed injection well piping systems. Residential bystander exposures resulting from volatilization may occur as supported by air monitoring data collected by the California Air Resources Board (CARB) and industrial hy giene monitoring data submitted by the registrant,
Baker Petrolite . During Registration Review , the agency will consider all available air monitoring data and determine whether there is the need volatilization risk assessment for
acrolein

.

Conclusions: There are no proposed or current registrations for products containing acrolein that
allow resid ential use and, t herefore, a residential exposure assessment will not be needed during Registration Review

. Bystander exposures from spray drift are not anti cipated from acrolein use and will not be examined during Registration Review. The need for a volatilization risk
assessment for acrolein will be examined during Registration Review

.

6.0 Aggregate Risk Assessment

A quantitative or qualitative non

- cancer aggregate assessment was not previously required for acrolein since there were no anticipated dietary (food or drinking water) exposure s to residues of acrolein, and there are no residential uses of the chemical. Further, the metabolite of acrolein, glyc idol, only forms in fish and depurates quickly. Although a dietary cancer assessment was previously conducted for glycidol from exposures to subsistence fishermen, exposures to glycidol via drinking water, inhalation, and der mal pathways are not expected.

Conclusions: As a part of Registration Review, a non

- cancer aggregate assessment may be required if EDWCs are deemed necessary by EFED.

7.0 Occupational Exposure

Acrolein has two pesticidal use patterns that could result in the potential for occupationa l exposures: 1) as an herbicide for control of vegetation in agricultural irrigation canals and

, in

some states

, irrigation reservoirs and 2) as a bacteriocide used in injection systems associated with petroleum production . The assessment of occupational risks from these use patterns are considered by HED an AD, respectively. The most recent qualitative occupational risks assessments for these use patterns were conducted to support the 2008 acrolein RED

.

Occupational e xposures are expected from the herbicidal use of acrolein in irrigation canals and

, in some states, reservoirs

. The application of acrolein is required by means of a closed application system and, as a result, dermal exposure is not anticipated. Further, comprehensive training programs are required by both of the principal registrants, Baker Petrolite and Multi

Chem, and stringent personal protective equipment (PPE) are required (i.e., full face air purifying respirator, chemical resistant gloves made of butyl rubber) througho ut all application
activities. With use of the label required inhalation PPE, full face air purifying respirator, the
estimated MO Es are ≥ 30 and, therefore, are not of concern. P ost

- application exposures to

### Page 9 of 23 acrolein from the herbic idal use may also occur depending on the length of time the worker remains in the area following completion o f the application and equipment disassembly. Therefore, depending on the extent to which workers remain in the vicinity of the
treated canal after acrolein has been applied and that the requirement for use of a respirator is no longer applicable, MOEs for worker post

- application exposure may potentially exceed HED’s
level of concern.

Occupational exposures are also expected from the bacteriocide us e of acrolein in oilfield water
systems to reduc e sulfate reducing bacteria that produces corrosive hydrogen sulfide in oilfield water systems. The products are applied by pumping acrolein from pressurized containers into closed injection well piping systems. The current product labeling requires closed delivery and loading systems with cylinders or skids that utilize dr y coupling and metering pumps by certified applicators wearing appropriate PPE (i.e., organic vapor respir ator

, long pants and long

- sleeved
shirt

, chemical resistant gloves made of butyl rubber , and shoes and socks ) in case of leaks during setup. Assuming certified applicators follow the proper label precautions for PPE and engineering controls specified in the RED and the guidance from the comprehensive training

program , the a gency expects that occupational handler exposures to the oil field uses will be negligible

.

Although acrolein bacteriocide applications are conducted using closed systems, occupational bystander post

- application exposure to acrolein vapors could potentia lly occur from underground
flow back water draining out of the well into water ho lding ponds after fracking. Most of the
flowback water used is pumped into storage tanks and later injected deep underground, recycled

, or transported to a wastewater treatment facility. However, some of the flowback water can be found in water holding p onds

. There could be potential concern from acrolein vapors from
flowback water based on the inhalation toxicity and the high vapor pressure of acrolein (220 mm Hg at 20o C). Accordingly, post

- application air monitoring data are need for the oil well use
pattern.

Conclusions : An updated occupational exposure assessment may be required during Registration Review to incorporate any additional air monitoring data of acrolein following the 2008 risk assessments to determine if the PPE required during set up and breakdown of application equipment are adequately protective of potential inhalation exposures, and to determine what impact these data have on inhalation risks for applicators present between set up and break do wn of application equipment, as well as for the post

- application workers remaining in the vicinity of
treated canals and the vicinity of oil/gas wells

. During registration review, post

- application air monitoring data are needed for the antimicrobial oil well use pattern.

8.0 Public Health and Pesticide Epidemiology Data

The a gency has reviewed the available incident data for acrolein 3 

### and concludes that based on the low frequency and low severity of cases involving acrolein reported in both the Incident Data System (IDS) and Sentinel Event Not ification System for Occupational Risk (SENSOR)

- Pesticides, there does not appear to be a concern at this time that would warrant further investigation. The a gency will continue to monitor the incident information and if a concern is

3 S. Recore and E. Evans. Acrole in : Tier I Review of Human Incidents and Epidemiology. 6/30/2015. D427918.

### Page 10 of 23 triggered, additional analysis will be included in the risk assessment.

9.0 Tolerance Assessment and International Harmonization

There are no US/Codex/Canadian MRLs established on Acrolein

.

10 .0 Environmental Justice

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

most recent acrolein human

- health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minorit y Populations and Low

Income Populations 4 

### .” The OPP typically considers the highest potential exposures from the legal use of a pesticide when conducting human health risk assessments, including, but not limited to, people who obtain drinking water from s ources near agricultural areas, the variabilit y of diets within the U.S., and people who may be exposed when harvesting crops. Should these highest exposures indicate potential risks of concern, OPP further refines the risk assessments to
ensure that the risk estimates are based on the best available information.

The 2008 human health risk assessment included an assessment of dietary exposure of subsistence fishermen to glycidol, a metabolite of acrolein in fish . This assessment was based on data on acro lein concentrations in fishable waters and the location and fishing habits of tribes living in areas proximate to treated canals

.

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

.

12. 0 Human Studies

Past acrolein 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. One such study ( l isted below) was determined to require a review of its ethical conduct and was subject to review by the Human Studies Review Board (HSRB)

. The HSRB reviewed the study

at a June 2007 meeting and determined it to be ethically acceptable and sufficiently sound from a scientific perspective to be used to estimate a safe level of acute inhalation exposure to acrolein 5



### .

4 http://www.epa.gov/compliance/environmentaljustice/resources/policy/exec_order_12898.pdf

5 http://epa.gov/osainter/hsrb/files/meeting

- materials/jun

- 27

- 29

- 2007

- public

- meeting/june2007hsrbfinal121807.pdf

### Page 11 of 23 MRID 46769601 : Weber Tschopp, T. Fischer, R. Gierer and E. Grandjean (1977) Experimentally Induced Irritating Effects of Acrolein on Man. Int. Arch. Occup. Environ. Hlth. 1977 (40): 117

- 130 Institute for Hygiene and Occupational Physiologe, Swill Federal Engineering College, Zurich

.

M any other studies, involving exposure to many different pesticides, c omprise generic pesticide exposure databases such as the Pesticide Handlers Exposure Database (PHED), the Agricultural Handler Exposure Task Force (AHETF) Database, 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 ti me 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.

13. 0 Risk Assessmen t Updates and Data Deficiencies

No data deficiencies were identified for acrolein . EPA notes the following risk assessment updates will need to be completed during Registration Review:

o Toxicology:

o No new data is required for acrolein and we do not ant icipate modifying the PODs and endpoints from the previous risk assessment unless a dietary assessment is required based on EFED analysis of available groundwater data

.

o Residue Chemistry/Dietary Exposure:

o The need for additional residue chemistry data and potential tolerances in crops
will be evaluated once the previously reuired root and tuber nature of the residue study is submitted.

o The need for an enforcement method and tolerances in/on fish and shellfish will be evaluated if the registrant contin ues to support the SLN use in reservoirs.

o A revised dietary exposure assessment may be required if EDWCs are deemed necessary by EFED, or to reflect the most recent dietary exposure polic ies

.

o Occupational/Residential Exposure:

o Updated occupational exp osure assessments may be required to incorporate any additional air monitoring data of acrolein following the 2008 risk assessments to determine if the PPE required during set up and breakdown of application equipment are adequately protective of potential inhalation exposures, and to determine what impact these data have on inhalation risks for applicators present between set up and break down of application equipment and the post

- application workers remaining in the vicinity of treated canals.

o The need for a volatilization risk assessment will be evaluated following consideration of all available air monitoring data for acrolein.

o Post

- application air monitoring data are needed for the oil well (bacteriocide) use
pattern (GDLN 875.2500).

### Page 12 of 23 14 .0 References

Table 14.0. Memoranda Relevant to Registration Review

Author Barcode Date Title

U. Habiba TXR ??? July 9, 2015 Acrolein: Summary of Hazard and Science Policy Council (HASPOC) Meeting of July 9, 2015:
Recommendations on the Need for the Neurotoxicity Battery (Acute and Subchronic) and Immunotoxicity Study.

S. Recore and

E. Evans D427918 June 30, 2015 Acrolein : Tier I Review of Human Incidents and Epidemiology

T. Morton D334828 October 13, 2011 Acrolein : Review of The Nature of the Residue in Radish Study Draft Protocol.

A. Johnson, J.

Pates NA September 2008 Reregistration Eligibility Decision (RED) for Acrolein.
List B. Case No. 2005.

B. Diass
et al. D3 48777 March 25, 2008 Acrolein: HED Risk Assessment for Reregistration Eligibility Decision (RED).

B. Diass D348776 March 25, 2008 Acrolein: Occupational and Residential Exposure
Assessment and Recommendations for the Reregistration Eligibility Decision (RED)

T

. Morton D350876 March 25, 2008 Acrolein: Revised Dietary Risk and Exposure Estimate For Acrolein Through Subsistence Diets for Indigenous People of United States.

T

. Morton D334663 September 27,
2007 Acrolein: Revised Product and Residue Chemistry
Considerations

T

. Morton D225281
and D94393 July 26, 2007 Acrolein. Nature of the Residue in Poultry and
Ruminants

N. Mottl D321012 August 24, 2007 Acrolein: Occupational Risk Assessment of Antimicrobial Uses for the Reregistration Eligibility Decision (RED) Document.



### Attachment 1: Chemical Identity Tables Attachment 2: Acrolein Acute, Subchronic, and Chronic Toxicity Profile
Attachment 3: Summary of Toxicity and Endpoints for Acrolein (from the 2008 Risk Assessment)
Atta chment 4 : Summary of Residues of Concern for Acrolein.

### Page 13 of 23 Attachment 1: Chemical Identity Tables

The nomenclature and physicochemical properties of acrolein and the metabolite of acrolein, glycidol, are provided in Tables A.1 .1

- A. 1. 3.

Table A.1. 1. Test Compound Nomenclature Compound Acrolein

Chemical Structure 

## O

Common Name acrolein Synonyms 2

- propenal, acrylaldehyde, acraldehyde, acrylic aldehyde, allyl aldehyde, propenal, trans acrolein, acquinite, aqualin, aqualine, biocide, crolean, ethylene aldehyde, MAGNACIDE, MAGNACIDE H, NSC 8819, prop

- 2

- en

1

- al, 2

- propene

- 1

- one, slimicide, prop

- 2

- enal

CAS # 107

- 02

- 8

PC Code 000701

Table A.1

. 2. Physicochemical Properties of Acrolein Molecular Weight 56.1 Boiling Point 53°C Melting Point

- 81°C Specific Gravity 0.0839 Vapor Density 1.94 (air = 1) Vapor Pressure 220 torr 20° C Flashpoint

- 15oF (

- 26.1oC) Solubility 208 g/L at 20oC soluble in water, alcohol, ether, and acetone. Description Clear, colorless to yellow liquid

. Table A. 1. 3

. Physicochemical Properties of Glycidol (CAS 556

- 52

- 5)

Chemical Structure



### O O H

Synonyms 1,2

- Epoxy

- 3

- Hydroxy Propane; 2,3

- Epoxy

- 1

- propanol; 2,3

- epoxypropanol;

2

- hydroxymethyloxirane; 3

- hydroxy

- 1,2

- epoxypropane;; glycide; glycidyl alcohol; Glycidol; Molecular Weight 74.1 Boiling Point 166° C (decomposes) Melting Point

- 45°C Specific Gravit y 0.0839 Vapor Density 2.15 (air = 1) Vapor Pressure 120 Pa 25° C Flashpoint 72 oC) Solubility Miscible.

Octanol Water Partition Coefficient (Log p
ow ) - 0.95

Description Clear, colorless liquid

### Page 14 of 23 Attachment 2: Acrolein Acute, Subchronic, and Chronic Toxicity Profile

Table A.2.1. Acute Toxicity Profile

- Acrolein

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

870.1100 Acute oral

- rat 41257001 LD 50 = 11 mg/kg I

870.1200 Acute dermal

- rabbit 00141028 LD 50 = 231 mg/kg I

870.1300 Acute inhalation

- rat 40945404 LC 50 = 0.019 mg/L I

870.2400 Eye irritation

- rabbit 00141025 Severely irritating I

870.2500 Dermal irritation

- rabbit 00141026 Severely irritating I

870.2600 Skin sensitization Sustin and Breienstein, 1990 Suggestive/
limited data

### Page 15 of 23 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Acrolein

Guideline No./ Study Type/Animal Species
and Strain MRID No. or Study Authors (year)/ Classification /Doses Results

870.3100

Subchronic oral toxicity

- rat NTP (1995)

Non

- guideline 0.75, 1.25, 2.5, 5.0 or 10 mg/kg/d in 0.5% methyl cellulose via gavage for 13
wks LOAEL = 2.5 mg/kg/day in males; 1.25 mg/kg/day in females, based on forestomach squamous epithelial hyperplasia

NOAEL = 1.25 mg/kg/day in males; = 0.75 mg/kg/day in
females Abnormal breathing and nasal discharge, hemorrhage, and
necrosis and chronic

- active inflammation of the forestomach and glandular stomach and mortality at 10 mg/kg/day. Hemorrhage of glandular stomach at 5 mg/kg/day.

870.3100

Subchronic oral toxicity

- mice NTP (1995)

Non

- guideline 0, 1.25, 2.5, 5.0, 10.0, 20.0 mg/kg/d in 0.5% methyl cellulose via gavage for 13
wks LOAEL = 2.5 mg/kg/day in females; 1.25 mg/kg/day in males, based on forestomach squamous epithelial hyperplasia
NOAEL = 1.25 mg/kg/day in females, No NOAEL for
males. No clinical signs of toxicity. Glandular stomach lesions in the 10 and 20 mg/kg/day males and 20 mg/kg/day females.

870.3100

Subchronic oral toxicity

- rat Arumugam et al (1999)

Non

- guideline

0, 2.5 mg/kg/day for 45 days
via intubation in distilled water to 5 male rats/group. Acrolein resulted in severe depletion of liver cystolic GSH. Electron microscopy revealed loss of mitochondrial lamellae of the cristae accompanied with a 41% decrease in
mitochondrial GSH. Citric acid c ycle enzymes were also reduced 30 to 56%. The activities of GSH peroxidase and superoxide dismutase were increased significantly (p<0.001). Because GSSG was unchanged, GSH depletion was presumed to result from conjugation with acrolein.

870.3200

21 day dermal toxicity

- rabbit 00141030 (1982) Acceptable/Guideline

, 0, 7, 21 or 63 mg/kg/day. 6 hrs/day, 5 days/week for 3
weeks. Sy stemic LOAEL = 7 mg/kg/day based on decreased body weight gain, and food consumption in both sexes, and

min imal to moderate multifocal interstitial pneumonia and moderate bilateral interstitial nephritis in the females. Systemic NOAEL was not established

D ermal LOAEL = 7 mg/kg/day based on dermal irritation: slight to moderate reddening with swelling and firmness of the test site, and scab formation with peeling and microscopic findings in the treated skin (minimal to marked necrosis, hyperkeratosis, parakeratosis, an d acanthosis).
Dermal NOAEL was not established.

870.4100a
Chronic oral toxicity

– rats

Male Fischer 344 rats Lijinsky and Reuber (1987)

Non

- guideline 0, 6, 14, or 36 mg/kg/day, 5 days/week for 104

- 124 weeks via drinking water. One group
of 20 female rats administered the high dose only. (Note: The two highest doses exceed the
oral LD 50 in rats) Adrenocortical tumors (5/20) and hyperplastic nodules of the adrenal cortex (2/20) were found only in females in the high concentration group. The increased incidence of adrenocortical tumors was considered by the authors to be marginally significant as judged by the Fisher’s exact test (p=0.091) and signific ant for adrenocortical tumors plus hyperplastic nodules (p=0.022). According to the authors, this type of tumor is rare in untreated female Fischer 344 rats; there was one reported in concurrent controls. The historical incidence is approximately 4.8% base d on the findings of Solleveld et al. (1984) for untreated female F

- 344 rats allowed to die naturally. Significant increases in tumor
incidence were not found in male rats. There was no

treatment

- related mortality.

### Page 16 of 23 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Acrolein

Guideline No./ Study Type/Animal Species
and Strain MRID No. or Study Authors (year)/ Classification /Doses Results

870.4100b
Chronic oral toxicity

– dog 41 071701 (1987) Acceptable/Guideline
0, 0.1, 0.5, 1.5

- 2 mg/kg/day in gelatin capsules for 53
weeks LOAEL = 2.0 mg/kg/day based on vomiting in both sexes. In the range finding study, 2 mg/kg/day for 2

- 6 days resulted in dose dependent weight loss, decreased food consumption and vomiting (occasionally red

- tinged). At a dose of 10 mg/kg/day and above in the ran ge finding study, vomiting preceded death of animals.
NOAEL = 0.5 mg/kg/day

870.3465

Inhalation

- humans 47060601 (1997) Acceptable/Non

- guideline
Human volunteers were exposed to acrolein in a 30
cubic meter chamber at a 0.1 hourly air exchange rate in 3 trials: (1) A continuous exposure at constantly increasing acrolein concentrations, (2) Discontinuous short exposures to successively increasing concentrations, and (3)
Constant concentration for one
hour. Threshold for measured effects: Eye irritation 0.09 ppm Nasal irritation 0.15 ppm Eye blink frequency 0.26 ppm Breathing frequency 0.30 ppm Throat irritation 0.30 ppm

870.3465

Inhalation

– rats

F344 Kutzman (1981);

Kutzman et al (1985);
Costa et al (1986)

Non

- guideline 0, 0.4, 1.4, or 4.0 ppm (0, 0.9, 3.2, 9.2 mg/m 3 )/6 hr/day, 5 days/week for 13 weeks 1. High mortality at 4 ppm. 2. Increase in lung collagen at 1.4 and 4 ppm (p<0.05). 3. Elastin content in 4 ppm group twice controls. 4. Bronchial necrosis and pulmonary edema at 4 ppm.
5. Paren chymal restriction at 0.4 ppm and obstructive lesions at 4.0 ppm. 6. No cytogenic or sperm abnormalities

870.3465

Inhalation

- Rats

Female dahl, selected for susceptibility or
resistance to salt induced hypertension Kutzman et al (1984, 1986)

Non

- guideline 0, 0.4, 1.4, or 4.0 ppm (0, 0.9, 3.2, 9.2 mg/m 3 )/6 hr/day, 5 days/week for 13 weeks 1. All susceptible 4 ppm rats died after 11 days and 60% of resistant rats survived to end of study. 2. Lungs of susceptible rats had severe airway necrosis with edema and hemorrhage but only proliferative changes with
resistant rats. 3. No differences in histopath between rat groups at lower
doses. 4. No effect of exposure on blood pressure changes.

870.3465

Inhalation

– rats, monkeys, guinea pigs, dogs Lyon et al . (1970)
Non

- guideline 0, 0.22, 1.0 and 1.8 ppm (0, 0.5, 2.3, and 4.1 mg/

m 3 ) acrolein for 24 hr/day for 90 days 1. Ocular and nasal discharges in dogs and monkeys at 1 ppm; severe at 1.8 ppm. 2. Squamous metaplasia of trachea in all monkeys at 1.8

ppm. 3. Two dogs at 1.8 ppm had confluent bronchopneumonia. 4. Evidence of pulmonary inflammation (guinea pigs at 1 ppm) and focal liver necrosis (rats and guinea pigs at 1 ppm). 5. Nonspecific inflammatory changes in a variety of tissues
in both rats and guinea pigs at 1.8 ppm.

LOAEL = 1 ppm (2.3 mg/m 3 ) based on inflammation in several organs of one or more species.
NOAEL = 0.22 ppm (0.5 mg/m 3 )

### Page 17 of 23 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Acrolein

Guideline No./ Study Type/Animal Species
and Strain MRID No. or Study Authors (year)/ Classification /Doses Results

870.3465

Inhalation

– rats

Male SPF OFA rats Bouley et al. (1975, 1976, cited in IRIS 2003),

Non

- guideline 0 or 0.55 ppm (0 and 1.3 mg/ m 3 ) acrolein. Exposure length and duration not stated, measurements were reported for exposures up to 77 days. Study limitation: one exposure and histopathology. Decreased body weight (<80% of controls) by Day 60. Nasal irritation (sneezing) in exposed rats between Days 7 and 21. Sneezing subsequently disappeared. A significant decrease in the number of alveolar macrophages in exposed rats. Liver weights not affected after 22 days of exposure but liver/body weight r atios were decreased in exposed animals after Day 15. Lung/body weight ratios were unchanged after Day 15 or 32, but were significantly elevated (p<0.002) after 77 days. No effect on hepatic alcohol dehydrogenase after 15 days of exposure. Serum alkaline p hosphatase was unchanged at days 15, 32 and 77. On the other hand, serum acid phosphatase was increased on day 15 (p<0.001), but not on days 32 and 77. An LD 50 inhaled dose of Salmonella
enteritidis resulted in a higher death rate in treated animals than controls at 18 days, but not at 63 days.

870.3465

Inhalation

- rats Catilina et al (1966)

Non

- guideline 262 ppm for 10 minutes/day
over 8 wks Caused peribronchial hemorrhage and bronchial lumen
obstruction

870.3465
Inhalation

– rats, hamsters, rabbits Feron et al. (1978)

Non

- guideline 0, 0.4, 1.4 or 4.9 ppm (0, 0.9, 3.2, 9.2 mg/C) to groups of 12 rats, 20 hamsters, and 4 rabbits 6 hours/day, 5 days/week for
13 weeks At 4.9 ppm mortality in rats, ocular and nasal irritation, growth depression and histologic changes in the respiratory tract in all species. At mid dose, squamous metaplasia and neutrophilic infilitration of the nasal mucosa in the rat;
minimal inflammator y changes in the hamster. No effects in
the mid and low dose rabbits. Intermediate

- duration MRL of 0.00004 ppm based on LOAEL of 0.4 ppm of nasal epithelial metaplasia. The rat was the most sensitive at the lowest exposure. The duration adjusted LOAEL in humans + 0.4 ppm x 24 hr x 5/7 days = 0.071 ppm. Adjusting for the rat and human respiratory surface area for rat (15 cm2) and human (200 cm2), the LOAEL HEC = 0.012 ppm. Adjusting for 300 UF (10 X for LOAEL, 3X for extrapolation from
animals to Humans usi ng domestric adjustments, 10 X for human variability), the MRL is 0.012/300 = 0.00004 ppm.
NOAEL is less than 0.4 ppm

870.3800 Inhalation Reproduction

– rats

Fischer 344 rats Kutzman (1981)

Non

- guideline 0, 0.4, 1.4, or 4.0 ppm 0, 0.9, 3.2 or 9.2 mg/ m 3 ) via inhalation to 8/sex/group for 6 hr/day, 5 days/week (62 exposure days) and the
animals were evaluated 13.3
weeks after initiation of

exposure. Exposed and control male rats were mated with unexposed females for 6 days and also exposed females were mated with unexposed and exposed males. Parameters evaluated were corpora lutea, viable embryos, early and late deaths, and preimplantation losses. There were no treatment

- related effects on reproductive performance. Decreased pulmonary
function was observ ed at 4 ppm.

### Page 18 of 23 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Acrolein

Guideline No./ Study Type/Animal Species
and Strain MRID No. or Study Authors (year)/ Classification /Doses Results

870.3800 Inhalation Reproduction

– rats

3 male and 21 female
SPF OFA rats Bouley et al (1975)

Non

- guideline 1.3 mg/ m 3 (0.6 ppm) continuously via inhalation,
mated on the 4 th day of exposure. Exposures continued for 22 more days when
females sacrificed. No significant differences in the number of and mean weight of fetuses (no data given) were reported. While the results were negative, the minimal results reporting limits

con clusions that can be drawn from this study.

870.3800 2 generation reproduction

– rats

Crl:CD (SD)BR rats 41869101 (1992) Acceptable/Guideline 0, 1, 3, or 6 mg/kg/d via oral

gavage Maternal LOAEL = 6 mg/kg/day based on mortality at 6 mg/kg in both F0 and F1 males and females and F1 mid

- dose animals, most of the latter showing signs of respiratory distress and histopathological lesions in the lungs and stomach (erosions of glandular mucosa and hyperplasia/hyperkeratosis of the forestomach). Respiratory effects may be attributed to possible aspiration of gavage solution. . Significant depressions in body weight gains were noted in the high

- dose groups and achieved statistical significance in the mid

- dose animals on several occasions.
Maternal NOAEL = 3 m g/kg/day

Reproductive LOAEL was not observed. Reproductive parameters (i.e., mating performance and fertility indices)
were unaffected. No treatment

- related gross or microscopic effects were observed in the reproductive tissues of any of
the F0 or F1 ani mals. Reproductive N OAEL = 6 mg/kg/day (HDT)

Offspring LOAEL = 6 mg/kg/day based on mortality and decreased pup body weights in the F1 generation Offspring NOAEL = 3 mg/kg/day

870.3700 Developmental study

– rabbits

Pregnant New Zealand
white rabbits (20/group) 40392401 (1987) Acceptable/Guideline

, 0, 0.1, 0.75, or 2.0 mg/kg

- day via gavage for days 7 through 19 of presumed gestation and subjected to caesarean sectioning on day 29. Range finding study at 0, 0.5, 1.0, 2.0 4.0 or 6.0 mg/kg/day. Maternal LOAEL = 2 mg/kg/day based on decreased body weights, body weight gains and food consumption. In the range finding study, maternal death, abortion, clinical signs, gastric ulceration, sloughing of the gastric mucosa, and complete litte r resorption at ≥ 4 mg/kg/day
Maternal NOAEL = 0.75 mg/kg/day

Developmental LOAEL was not observed. Fetal malformations were distributed evenly among the groups
and were consistent with historical control data. Developmental NOAEL = 2 mg/kg/day, highest dose
tested.

### Page 19 of 23 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Acrolein

Guideline No./ Study Type/Animal Species
and Strain MRID No. or Study Authors (year)/ Classification /Doses Results

870.3700 Developmental Toxicity

Rat

Sprague

- Dawley CD (40
time

- mated females/group) 00156438 (1982) Acceptable/Guideline

, 0, 3.6, 6 or 10 mg/kg/day via gavage from GD 7 through 19 Maternal LOAEL = 3.6 mg/kg/day based on mortality with no clinical signs but in a 2

- gen repro study,(MRID 41869101) mortality at 3 mg/kg/day with histopathology in
the forestomach was observed.
Maternal NOAEL = < 3.6 mg/kg/day Developmental LOAEL = 10 mg/kg/day ba sed on decreased fetal weights and litter weights and on incomplete ossification of the skeleton and general retarded development of fetuses. Developmental NOAEL = 6 mg/kg/day.

870.4100

24

- Month Chronic/Carcinogenicity Feeding

- Rats

Sprague

- Dawley (70

- 75/sex/dose) 41306401 (1989) 46568001 (2002) 46568002 (2005) Acceptable/guideline

95

- 98% a.i.

0, 0.05, 0.50, or 2.5 mg/kg/day via gavage for 2 years LOAEL = 0.5 mg/kg/day based on increased mortality in
both sexes.
NOAEL = 0.05 mg/kg/day Equivocal evidence of carcinogenicity. After 24 months in the 2.5 mg/kg/day males, there was increased incidence of mammary gland adenoma (8% vs. 3% in concurrent 0

- 1.5% in. Combined adenoma and carcinoma (<=10%) approximated the historical control range (<=7.1%). Hepatocellular adenoma (8%) exceeded the concurrent (1%) and historical (0

- 3.5%) controls. Combined adenoma and carcinoma in the liver (<=8%) was within the historical control range (<=14.5%). Initial analysis of the pancreatic neoplasm suggested an increase in the incidence of pancreas acinar cell adenoma but a revised diagnosis according the
criteria of Eustis et al. (1990) showed it was not related to treatment. Dosing was considered adequate based o n increased mortality in both sexes.

870.4200 Carcinogenicity

– Mice

CD

- 1 Swiss albino mice (70

- 75/sex/dose) 41334901 (1989) Acceptable/guideline

,

96.0% a.i.

0, 0.5, 2.0 or 4.5 mg/kg/day by gavage for 78 weeks LOAEL = 4.5 mg/kg/day based on increased mortality. No
adverse treatment

- related effects were observed on clinical signs, body weights, body weight gains, food consumption, hematology, and organ weights, gross or microscopic pathology.
NOAEL = 2.0 mg/kg/day Not carcinogenic in mice in this test.

870.7485
Metabolism and pharmacokinetics

- rats 42031001 (1991) 43177101 (1994) 73275901 (1994) Parent et al (1996) Parent et al 1998) Single dose 2.5 mg/kg (iv or oral), or 2.5 mg/kg after 14 days of unlabeled acrolein (oral), or single 15 mg/kg (oral). Radiolabel monitored in expired air, urine, and feces. >96% of radioactivity was recovered in excreta within the first 24 hours. Tissue concentrations (including blood) of radioactivity were mi nimal. Time course of excretion for all groups was similar except for delayed excretion in the high

dose group. No acrolein detected in excreta or tissues. The radiolabel in feces associated with a homopolymer of acrolein, apparently formed in the gastroin testinal tract. The main pathway of acrolein metabolism is the addition of GSH to the activated double bond followed by conversion to mercapturic acid. A second pathway is epoxidation of the double bond followed by attack on the epoxide by glutathione. A t hird pathway is addition of water to acrolein
to form 3

- hydroxypropionaldehyde, which can be further metabolized and ultimately incorporated into normal metabolic pathways.

### Page 20 of 23 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Acrolein

Guideline No./ Study Type/Animal Species
and Strain MRID No. or Study Authors (year)/ Classification /Doses Results

870.5900

In vitro sister chromatid exchange

CHO cell cultures 00141032 (1982) Acceptable/Guideline 0, 0.3, 0.5, or 0.75 μg /mL (

- S9) for 29

- 31 hrs or 0, 0.1, 0.3, or 0.5 μg /mL (+S9) for 4
hours. Acrolein was tested up to cytotoxic concentrations (0.75 μg
/mL

- S9 and 0.5 μg /mL +S9). No significant increases (p<0.01) in the number of SCEs/cell were observed at any concentration in either condition. The positive controls induced the appropriate response. There was no evidence of SCE induced over background.

870.5900

In vitro sister chromatid exchange

Cultured human lymphocytes Wilmer et al . (1986)

– IRIS
Non

- guideline
0.001

- 40 μM Acrolein at concentrations of 5, 15, and 20 μM, but not lower doses, induced significant increases in sister chromatid exchanges.

870.5375

In vitro mammalian
chromosomal aberration

assay

-

CHO cell cultures 00141033 (1982) Acceptable/Guideline 0, 0.0, 0.2, 0.4, 0.6, 0.8, 1.0 or 2.0 μg /mL (

- S9) for 6 hrs or 0, 0.6, 0.8, 1.0, 1.5 or 2.0 μg /mL (+S9) for 2 hours. Acrolein was tested up to cytotoxic concentrations (2.0 μg
/mL without S9 and > 1.5 μg /mL with S9). No marked increases in break frequency were observed at any concentration in the presence or absence of S9. The positive controls induced the appropriate response. There was no evidence that Acrolein induced a clastogenic effect in the presence or absence of S9

- activation.

870.5300

In vitro mammalian cell gene mutation assay

CHO cell cultures

– HGPRT locus: hypoxanthineguanine phosphoribosyl
transferase 41579501 (1989) Acceptable/Guideline 0 to .002 uL/mL (

- S9) at 0 to 0.006 2.0 uL/mL (+S9). Acrolein was tested up to cytotoxic concentrations ( > 0.003 μL/mL +S9 and > 0.0008 μL/mL

- S9). No reproducible signifi cant increases in the mutant frequency were observed in the presence or absence of S9. The positive controls induced the appropriate response in all trials. There was no
evidence that Acrolein induced mutant colonies over background in the presence or ab sence of S9

- activation.

870.5100
Bacterial reverse mutation assay

Salmonella TA100 and
TA104 Foiles et al (1989)

Non

- guideline 4, 7, and 10 μM Acrolein induced formation of deoxyguanosine adducts at concentrations of 10 μM, but not 4 or 7 μM, in Salmonella tester strain TA104. Lack of response at the lower doses suggests the presence of a saturable repair mechanism. Increasing adduct formation with dose was seen in tester strain TA100 at concentrations of 4 mM and greater.

870.5300

In vitro mammalian cell gene mutation assay

CHO cell culture Foiles et al (1990)

Non

- guideline
0.1

– 1 mM Deoxyguanosine adduct formation increased progressively at concentrations ranging from 0.1 to 1 mM in Chinese hamster ovary cells (CHO).

870.5300

In vitro mammalian cell gene mutation assay

Human fibroblast cells Curren et al (1988)

Non

- guideline
0.2

– 5 μM Acrolein was highly mutagenic to human fibroblast cells that were deficient in DNA repair (cells from xeroderma pigmentosum patients). It induced a positive dose

- response between 0.2 and 0.8 μM but it did not induce an increase in the mutant frequency of normal fibroblasts

### Page 21 of 23 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Acrolein

Guideline No./ Study Type/Animal Species
and Strain MRID No. or Study Authors (year)/ Classification /Doses Results

870.5300

In vitro mammalian cell gene mutation assay

V79 ce lls deficient in DNA repair Smith et al (1990)

Non

- guideline 0.1, 0.5, 1, and 2 μM Acrolein was mutagenic in V79 cells deficient in DNA repair. Normal V79 cells were not tested.

870.5375

In vitro mammalian
chromosome aberration

test

CHO cells Au et al (1980)

Non

- guideline In vitro chromosomal studies of acrolein have produced weakly positive findings in Chinese hamster ovary (CHO)
cells

870.5300

In vitro mammalian cell gene mutation

Human fibroblast cells Kawanishi et al (1998)

Non

- guideline
0

– 54 mM The majority of the mutations in human fibroblasts were base substitutions (76%) followed by deletions and insertions (24%). Single base substitutions were most frequently found (46%), multiple base substitutions accounted for 18%, and tandem (two ad jacent) base substitutions were 12%. Of the base substitutions, G:C to
T:A transversions accounted for 44% of the total and G:C to
A:T transitions for 24%.

870.5100 Bacterial reverse assay

E. coli LM102, LM103,
LM119 Vander Veen et al (2001)

Non

- guideline Acrolein reacts with guanine residues to form 8

- hydroxypropanodeoxyguanosine that was not mutagenic in
either wild

- type or DNA repair deficient E. coli

870.5100
Bacterial reverse mutation assay

E. coli AB1157, 1886; ES1481; MO199, 211, 22 0, 221, 230, 232, 233, 234, 933, 934, 936, 937, 939; MV1185, 11932; NR9232; RK1517; SH2101; YG7210 Yang et al . (2001)

Non

- guideline Acrolein was non

- mutagenic in E. coli

870.5300

In vitro mammalian cell gene mutation

S. typhimurium TA98, TA100, TA104, TA1535,
TA1538 IRIS literature summary (2003)
Non

- guideline In tests for frameshift mutation TA98 gave some positive responses while TA1538 was negative with S

- 9 and all negative with S+9 except one positive for TA98. Tests for
base r epair and point mutations (TA100, TA104 and TA1535) were positive in some tests with TA100, in most tests with TA104, but not
with TA1535. TA104 has been reported to be more sensitive to carbonyl compounds (Marnett et al., 1985).

### Page 22 of 23 Attachment 3: Summar y of Toxicity and Endpoints for Acrolein (from the 2008 Risk Assessment)

Table A. 3.1. Summary of Toxicological Doses and Endpoints for Acrolein for Use in Human Risk Assessments Exposure Scenario Dose Used in Risk
Assessment Uncertainty/Safety

Factor Study and Toxicological Effect

Acute Dietary (General Population including infants and children) Acute oral (dietary and drinking water) exposure to acrolein is not expected based on use patterns, physical

- chemical properties, and plant metabolism data. Therefore, acute RfDs are not required and were not selected for this assessment. Chronic Dietary (All Populations) Chronic oral (dietary and drinking water) exposure to acrolein is not expected based on use
patterns, physical

- chemical properties, and plant metabolism data. Therefore, chronic RfDs are not required and were not selected for this assessment. Incidental Oral (all durations) There are no residential uses for acrolein. Therefore, incidental oral exposure endpoints are not required and not selected for this assessment. Dermal (all durations) Worker dermal exposures are not expected based on use patterns and personal protective equipment requirements. There are no residential uses for acrolein and dermal exposures to residential bystanders are not expected based on use patterns and physical

- chemical properties. Therefore dermal exposure endpoints are not required and have not been selected
for this assessment.

Short

– Term Inhalation (1

- 30 days) Minimal LOAEL = 0.09 ppm (0.21 mg/m 3 ) LOC = 30

10 X for intraspecies
variation and 3 X for lack
of a NOAEL Human volunteers exposed by inhalation for 60 minutes (Weber

Tschopp et al. 1977) based on a minimal effect LOAEL of 0.09 ppm for eye irritation. The LOAEL of 0.3 ppm for nasal and throat irritation and decreased respiratory rate is
considered co

- critical for endpoint
selection. Cancer (oral, dermal and inhalation) “The potential carcinogeni city of acrolein cannot be determined because the existing “data are inadequate for an assessment of human carcinogenic potential for either the oral or inhalation route of exposure.” (IRIS 2003).

To quantify the carcinogenic response of glycidol, a mult istage model analysis was performed to derive a cancer slope factor of 0.16 mg

- 1 kg

- 1 day

- 1 at a 0.95 confidence level. (See Appendix)

### Page 23 of 23 Atta chment 4 : Summary of Re sidues of Concern for Acrolein

Table 4 .1 . Parent, Metabolites and Degradates Considered for Risk Assessment

Matrix Compound of Potential Concern Residue included in Risk Assessment

Plant Acrolein No

Livestock Acrolein No

Fish Glycidol Yes Drinking Water Acrolein, 3

- Hydroxypropanal No