Executive Summary

The Health Effects Division (HED) Hexazinone Registration Review Team has evaluated the
status of the human health assessm ents for the triazine-dione herb icide to determine the scope of work necessary to support Registration Review. Hexazinone is an herbicide registered for use on alfalfa, blueberries, pasture and ra nge grasses, pineapples and sugar cane. It was first registered on November 1975 for general weed contro l in non-cropland areas. The Tolerance Reassessment Eligibil ity Decision (TRED) for hexazinone was revised on August 22, 2002. Exposures can be expected to occur via the di etary, drinking water, a nd occupational (handler and post-application) routes for hexazinone.

Hexazinone is a triazine herbicide, which is st ructurally and toxicologi cally dissimilar to the other triazines herbicides, such as atrazine. The selectivity of triazine herbicides depends on the plant’s ability to degrade or metabolize the parent compound. Sensitive plants have limited ability to metabolize hexazinone. Hexazinone acts through inhibition of photosynthesis.

The toxicology database for hexazinone has been determined to be nearly complete. The newly established data requirements for registrati on of a pesticide (food and non-food uses) under 40 CFR Part 158 will be requested for hexazinone. A 28 day inhalation study was previously requested due to concern for the use pattern (a 90 day inhalation study was submitted; however, it does not meet the present guideline or GLP requirements). An immunotoxicity study will be required under a data call-in (D CI) in the near future. Following the data evaluation, HED will determine if these studies will impact th e toxicity endpoints for hexazinone.

Tolerances for residues of hexazinone in/on plant, livestock, and processed commodities are currently expressed in terms of the combined residues of hexazinone and its metabolites (calculated as hexazinone). The tolerance expression should be m odified to include the specific metabolites (A, B, C, C-1, C-2, D, E and F) by th e appropriate chemical name (See Table 1). Reassessed tolerances range from 0.1 ppm to 250 ppm. Tolerances are reassessed for alfalfa (hay and forage), blueberry, pineapple, sugarcane and pasture grass forage and hay as well as for secondary residues in cattle, goat, horse, sheep and milk. The registrant submitted field trial data for hexazinone and five of its metabolites (A-E) in/on warm-season pasture grass forage and hay and a reasonably balanced dietary burden (RBDB) was recalculated.

Also, the data requirements for field accumulation in rotational crops are only partially satisfied.
The data from the limited field trials indicate th at quantifiable residues occur in field corn stover and wheat straw, extended field rotational crop tria ls for corn stover, sorghum stover, and wheat straw to support a 12-month rotational interval and a tolerance for inadvertent hexazinone residues are required.

The Environmental Fate and Effects Division (EFE D) has determined that a new drinking water
assessment should be conducted which considers the potential for hexazinone formation during water treatment. Upon receipt of the revised drinking water assessment, new acute and chronic dietary exposure and risk assessments will be required which incorporate current consumption information, updated residue values and percen t crop treated information while directly incorporating drinking water va lues into the assessment.

Page 2 of 23There are currently no registered residential uses for hexazinone; however, it is registered for use on industrial turf grass with ground spray applica tion. Given that no language exists on the label restricting the use of this herbicid e on turf grass to be used in residential settings, the turf grass application could result in poten tial postapplication residential e xposure. A residential exposure and risk assessment may be necessary for this scenario based on use on turf grass once new toxicological endpoints are determined.

No occupational handler and post-application ex posure or risk estimates were quantitatively assessed as part of the 2002 TR ED. No toxicological endpoints we re identified at that time; therefore, an exposure and risk assessment was not performed.

An updated occupational handler exposure assess ment is necessary. The mixer/loader and applicator scenarios must be assessed in accordance with current guidelines and standard operating procedures for all scenarios and use s ites that are currently registered. For postapplication exposure, there are ma ny cultural practices which require hand labor that may lead to the exposure of fieldworkers engaged in task su ch as harvesting, irrigati on, scouting or weeding. Exposure and risk estimates will need to be upda ted with the most current transfer coefficient values anticipated to be devel oped based on data from the Agricultural Reentry Task Force and as discussed at the 2008 meeting of the FIFRA Scie ntific Advisory Panel me eting on this issue. Once the hazard endpoints are updated, a new oc cupational handler risk assessment and postapplication exposure and risk assessment will be needed for registration review. The existing Restricted Entry Interv al (REI) of 48 hours appears to be adequate.

New acute, short-term, and chronic aggregate risk assessments will be required to support registration review. These assessments should incorporate any new PoDs and/or uncertainty
factors identified.

Prior to a final registration revi ew decision for hexazinone, the Agen cy will determine if there is any new information, such as new hazard or exposu re data or changes to the use pattern, which would affect the cumulative risk assessment. Should the Agency determine that new information on hexazinone is available that could potenti ally impact the cumulative risk assessment and result in a risk of concern, the Agency will revisit the cumulative risk assessment.

Introduction

Hexazinone is a triazine-dione he rbicide registered for use on al falfa, blueberries, pasture and range grasses, pineapple, and sugarcane. It is al so registered for use on ornamental plants, forest trees, and non-crop areas. Hexazinone is used to control a variety of weed species including geratum, alder, and alexander grass and works through inhibition of photos ynthesis. Hexazinone is a proprietary chemical of E.I. du Pont de Ne mours Inc. which is the sole producer and primary registrant of this broad spectrum herbicide. HED has evaluated the most recent human health exposure and risk assessments for hexazinone to determine if suffici ent data are available and if updates are needed to support registration review. HED has considered the most recent exposure and risk assessments for this chemical, updates to its toxicity, exposure and usage databases, and the latest Agency science policy and risk assessment methodologies.

Page 3 of 23Chemical Identity

Tolerances for residues of hexazinone [3-cycl ohexyl-6-(dimethylamino)-1-methyl-1,3,5-triazine2,4-(1H, 3H)-dione] in/on plant, animal, and processed commodities are currently expressed in
terms of the combined residues of hexazinone an d its metabolites (calculated as hexazinone). Permanent tolerances are established for plant and animal commodities under 40 CFR §180.396(a). Hexazinone tolerances with regiona l (Florida sugarcane) registrations are established under 40 CFR §180.396(c). Current tole rances range from 0.2 to 5.0 ppm on raw agricultural commodities, 8.0-10.0 ppm on agricu ltural feed items, and are 0.1 ppm for secondary residues in meats and milk. The Agency has determined that tolerances for hexazinone residues in eggs and poultry tissue ar e not required based on the results of the respective poultry metabolism and feeding stud ies (CFR §180.6(a)(3)). Th e chemical structure
and nomenclature of hexazinone and its metabol ites and the physicochemical properties of technical grade hexazinone are presented in Tables 1 and 2.

Hazard Identification/Toxicology

Hexazinone is a triazine herbicide, which is st ructurally and toxicologi cally dissimilar to the other triazines herbicides, such as atrazine. The selectivity of triazine herbicides depends on the plant’s ability to degrade or metabolize the parent compound. Sensitive plants have limited ability to metabolize hexazinone. Hexazinone acts through inhibition of photosynthesis.

The toxicology database for hexazinone has been determined to be nearly complete. The newly established data requirements for registrati on of a pesticide (food and non-food uses) under 40 CFR Part 158 will be requested for hexazinone. A 28 day inhalation study was previously requested due to concern for the use pattern (a 90 day inhalation study was submitted in 1976, EPA MRID# 00063972; however, it does not meet th e present guideline or GLP requirements), also an immunotoxicity study will be required under a DCI in the near future. Following the data evaluation, HED will determine if these stud ies will impact the toxicity endpoints for
hexazinone.

Hexazinone has low acute toxicity by the oral (Category III), dermal (Category IV) and inhalation routes (Category III) of exposure. Primary eye irrita tion was severe, causing corneal opacity and moderate irritation in unwashed eyes (Category I). Hexazinone also causes mild skin irritation and is classified Category IV for skin irritation (see Table 4). Hexazinone is not a skin sensitizer in the guinea pig. Hexazinone is classified as “not likely” to be a human carcinogen based on carcinogenicity studies in rats and mice.

Hexazinone is not known to be an endocrine di sruptor. However, EPA is required under the FFDCA, as amended by FQPA, to develop a scre ening program to determine whether certain substances (including all pesticid e active and other ingredients) “may have an effect in humans that is similar to an effect pr oduced by a naturally occurring es trogen, or other such endocrine effects as the Administrator may designate.” Following the recommendations of its Endocrine Disruptor Screening and Testi ng Advisory Committee (EDSTAC), EPA determined that there were scientific bases for including, as part of the program, androgen and thyroid hormone systems, in addition to the estrogen horm one system. EPA also adopted EDSTAC’s recommendation that the Program include evaluations of potential effects in wildlife. When the

Page 4 of 23appropriate screening an d/or testing protocols being consid ered under the Agency’s Endocrine Disrupter Screening Program (EDSP) have b een developed and vetted, hexazinone may be subjected to additional screening and/or testing to better characte rize effects related to endocrine disruption.

There is no evidence of qualitative or quantitative susceptibility in prenatal developmental or post-natal reproduction studies; he xazinone is not a developmenta l or reproductive toxicant in the rat. A rabbit developmental study showed possible skeletal anomalies and delayed ossification at the highest dose tested; however, this study is classified as unacceptable, but potentially upgradable, due to technical deficiencies. The registrant conducted a second prenatal developmental toxicity study in rabbits for wh ich a NOAEL for developmental effects could be adequately determined and there was no increase in susceptibility noted (both the fetal and maternal endpoints were based on decreased body weights).

An acute dietary endpoint was identified for fe males 13-50 years of age. The endpoints of decreased male and female fetal weight, increased incidence of kidneys with no papilla and an increased incidence of misaligned sternebrae in the fetuses were identified from a developmental toxicity study in rats. Be cause the toxic endpoint for acu te dietary exposure concerns in utero exposure, the risk assessment is performed for females of ch ildbearing age (females 13-50), since only members of this group are at risk for being pregnant at the time of exposure. The dose selected for establishing the acute reference do se (RfD) is the developmental No Observed Adverse Effect Level (NOAEL) of 400 mg/kg/day. The chronic di etary endpoint was identified in an oral toxicity study in the dog and is ba sed upon severe body weight decrement, clinical chemistry changes in the liver and microscopic lesions in the liver [N OAEL=5.0 mg/kg-bw/day]. Toxicological endpoints were established for acu te and chronic dietary exposure scenarios as well as dermal (intermediate- and long-term) and inhalation (short-, in termediate-, and longterm) exposure scenarios. Incidental oral endpoi nts are now selected because of a potential postapplication exposure from the indicated la bel use on industrial turf. See Table 5.

Conclusions As specified in the new 40 CFR Part 158 data requirements, an immunotoxicity study on hexazinone will be required, as is a neurotoxicit y battery. The Agency also requires a 28-day inhalation study. Once all data have been received and reviewed, the Agency will determine if there is any new information, such as the points of departure and safety factors used for risk assessment purposes for hexazinone which would affect the cumulative risk assessment.

Residue Chemistry

The existing residue chemistry database for hexa zinone is adequate for risk assessment purposes. The qualitative nature of the residue(s) of hexazin one in plants and animals has been adequately
identified/characterized and is understood.

The HED Metabolism Assessment Review Comm ittee (MARC) has reviewed the hexazinone toxicology and metabolism data (meeting dates 01/29/02 and 03/12/ 02) and recommends that the tolerance expression for plant material should include hexa zinone (parent) and metabolites A, B, C, D, and E. The tolerance expression for milk should include he xazinone (parent) and metabolites B, C, C-2, and F, and the toleran ce expression for ruminant tissue should include

Page 5 of 23hexazinone (parent) and metabolites B and F. Th e tolerance expression should be modified to include the specific metabolites (A, B, C, C-2, D, E and F) by the appropriate chemical name (See Table 1). The MARC also recommended that for the purposes of risk assessment estimates of dietary exposure and risk should be based on residue estimates of hexazinone and metabolites B, C, C-1, C-2, and F for ruminant commodities and metabolites A, B, C, D, and E for plant commodities. The Agency has determined that tolerances for hexazinone residues in eggs and poultry tissue are no t required based on the results of the respective poultr y metabolism and feeding studies (CFR §180.6(a)(3)). Adequate analytical methods exist for data collection and tolerance enforcement. Adequate storage stability, processed f ood, and magnitude of the residue in plants and animals data exist.

Residue data are not adequate to reassess tolerances for pastur e and rangeland grass (forage and hay) and a recommendation has been made to rev oke those tolerances and to withdraw this use from the product labels. The Hexazinone Residu e Chemistry Chapter (TRED, 05/20/02) required data depicting magnitude of the residues of hex azinone and metabolites A, B, C, D, and E in/on grass forage and hay harvested 0 day following a single broadcast applicat ion of representative
formulations at 1.125 lb ai/A. A tolerance of 10 ppm for grass forage (listed as “grasses, pasture” and “grasses, range” under 40 CFR §18 0.396) was established based on residue data reflecting basal soil application only. The regist rant submitted field trial data for hexazinone and its five metabolites (A-E) in/on warm-season pasture grass forage and hay; the HED has reviewed these data and found them to be adequate ; therefore, this require ment is fulfilled. See Table 7 for recommended tolerances. Since grasses are major feed items, the established hexazinone tolerances for milk and the fat, meat, and meat byproducts of livestock will need to be reassessed and a reasonably balanced dietary burden (RBDB) will need to be recalculated.
The RBDB of hexazinone to beef cattle are base d on using the average residues for dairy cattle (108 ppm) and the HAFT for beef cattle (19.3 ppm).

Additionally, the data requirement s for field accumulation in rota tional crops are only partially satisfied based on a recent review of a limited field crop rotation study (MRID 45084101).
Because the data from the limited field trials indi cate that quantifiable residues occur in field corn stover and wheat straw, extended field rotati onal crop trials for corn stover, sorghum stover, and wheat straw to support a 12-month rotationa l interval and a tolerance for inadvertent hexazinone residues are required.

Conclusions
The database for hexazinone is considered adequate for risk assessment; however, data deficiencies have been identified including a fi eld rotational crop study for corn and wheat. The Agency is recommending new tolerances on all commodities listed under 40 CFR §180.396 (see Table 7).

Dietary Exposure and Risks

An unrefined (tolerances and 100% crop treated) dietary risk assessment was completed in 2002 using DEEM (J.Punzi, D279898, 07/30/02).

Acute An acute dietary endpoint was only identified for females 13-50 years of age. Estimated acute dietary (food only) risk for females age 13-50 as sociated with the use of hexazinone and its

Page 6 of 23metabolites do not exceed the Agency’s level of concern. The acute dietary risk estimate for females 13-50 years of age is approximately 1% of the acute population ad justed dose (aPAD) at
the 95 th percentile.

Chronic Chronic dietary (food) risk estim ates associated with the use of hexazinone do not exceed the Agency’s level of concern for any populati on subgroup, including the most highly exposed subgroup children 1-6. The chronic dietary risk for children ages 1-6 year s is approximately 15% of the chronic population adjusted dose (cPAD) and approximately 4% for the U.S. population.

Drinking Water At the time of the most recent assessment, drinki ng water residues were not incorporated directly into the DEEM program. In the 2002 hexazinone risk assessment, the Agency performed surface and groundwater modeling to estimate drinking wate r concentrations which were then compared to the Drinking Water Level of Comparis on (DWLOC). The GENEEC and PRZM-EXAMS
models were used to estimate surface water c oncentrations and Screening Concentration in Ground Water (SCI-GROW) was used to estimat e groundwater concentr ations. This model simulated hexazinone and its metabolites in drinking water concentrations (for the alfalfa use) of 130 μg/L for the surface water peak untreated wa ter concentration. The results of the SmallScale Prospective Groundwater Mo nitoring Study were used to estimate concentrations of hexazinone and its degradates in groundwater (42 μg/L). Th e DWLOC calculated for acute aggregate risk for females 13-50 years old wa s 12,000 μg/L. HED concluded with reasonable certainty that residues of hexazinone and its me tabolites in drinking wa ter will not contribute significantly to the acute human h ealth risk and that the acute aggregate exposure from residues
of hexazinone and its metabolite s in food and drinking water will not exceed the Agency’s level of concern for acute aggregate exposure for females 13-50 years old.

The DWLOC calculated for chronic aggregate ri sk for all populations range from 427-1680

μ g/L. Because the estimated environmental con centrations (EECs) are less than the calculated DWLOC, HED concluded with reasonable certainty that re sidues of hexazinone and its metabolites in drinking water will not contribute significantly to the chronic human health risk and that the chronic aggregate exposure from residues of hex azinone and its metabolites in food and drinking water will not exceed the Agency’s level of concern for chronic aggregate exposure for any sub-population.

Conclusions It will be necessary for HED to conduct a new dietary exposure assessment for hexazinone including new and updated information and policie s. Further, HED’s policy with respect to drinking water risk assessment has been revise d since the most recent human health risk
assessment based on concerns that the DWLOC approach may underestimate risk for some subpopulations. Once the Environmental Fate and Effects Division (EFED) has updated the drinking water assessment, HED will need to revisit potential risks from drinking water by directly incorporating dr inking water estimates into the acute and chronic aggregate dietary risk

assessment. A drinking water assessment will be conducte d to support future human health risk.

Page 7 of 23Residential Exposure and Risks

There are no residential uses of hexazinone; howev er, it is registered fo r use on industrial turf grass with ground spray application. Given that no language exists on the label restricting the use of this herbicide on turf grass to be used in re sidential settings, the turf grass application could result in potential postapplica tion residential exposure. A re sidential exposure and risk assessment may be necessary for this scenario based on use on turf grass once new toxicological endpoints are determined. If information beco mes available or label language is amended restricting the use of i ndustrial turf grass on residences, pl aces of recreation, schools, and other comparable areas, a residential exposure and risk assessment may not be warranted.

Aggregate Risk Assessment

The aggregate risk assessment evaluates the co mbined risk from dietary exposure (food and drinking water) and any non-occupa tional (residential) uses. Th e hexazinone aggregate risk assessment will include only dietary exposure (fo od and drinking water). As stated above under dietary risk, new acute and ch ronic dietary risk assessments are required to support the registration review of hexazi none and residential exposure to hexazinone from the use on industrial turf grass has not been assessed for the potential for residential exposure. Once the new toxicity data have been reviewed and new toxicity endpoints have been selected, a new aggregate risk assessment will be needed to support the registration review of hexazinone.

Conclusions Revised acute, short-term, and chronic aggregat e risk assessments will be required to support registration review of hexazinone.

Occupational Exposure and Risks

Hexazinone is marketed as a li quid, soluble granules, water dispersible granules, and pellets. Hexazinone can also be used to impregnate dry bulk fertilizers and for stem injection applications. Hexazinone is used to control a vari ety of pests in crops in cluding alfalfa, high and low brush blueberry, pineapple, and sugarcane. It can also be used to control pests in noncropland sites, Christmas trees, forestry site pr eparation, industrial areas , as brush control in reforestation areas, rangeland, past ures, yellow poplar plantings, and on industrial turf grass. Foliar and soil applications may be made by ch emigation, injection, ground, or aerial equipment which may include fixed-boom sprayer, tank-type sprayer, backpack, ha ndgun, tubular injection equipment, aerial (helicopter only), and by hand (hand dispersed pellets).

Occupational Handlers No occupational handler and post-application ex posure or risk estimates were quantitatively assessed as part of the 2002 TR ED. No toxicological endpoints we re identified at that time; therefore, an exposure and risk assessment was not performed.

An updated occupational handler exposure assess ment is necessary. The mixer/loader and applicator scenarios must be assessed in accordance with current guidelines and standard operating procedures for all scenarios and use site s that are currently registered. Once the hazard

Page 8 of 23endpoints are updated, a new occupational handler ri sk assessment will be needed for registration
review.

Occupational Post-application Workers No occupational handler and post-application ex posure or risk estimates were quantitatively assessed as part of the 2002 TR ED. No toxicological endpoints were identified at that time therefore an exposure and risk assessment was not performed.

There are many cultural practices which require ha nd labor that may lead to the exposure of fieldworkers such as harvesting, irrigation, scout ing or weeding. Exposure and risk estimates will need to be updated with the most current transfer coefficient valu es that will be developed based on data from the Agricultural Reentry Task For ce and as discussed at the 2008 meeting of the FIFRA Scientific Advisory Panel meeting on this issue. Once the hazard endpoints are updated, a new occupational post-application exposure and ri sk assessment will be needed for registration review. The existing Restricted Entry Interval (RE I) of 48 hours appears to be adequate. For
those use sites that are not covered within th e Worker Protection Standard, the Agency had previously established an entry restriction for hexazinone end products stated as follows: “Do not
enter or allow others to enter the treated area until sprays have dried” to apply to all applications other than the pell et formulation.

Public Health and Pesticide Epidemiology Data

The EPA is supplying the following incident re port to fulfill our requirement to docket
summaries of incident data that were reported to the Agency, as we ll as to ensure human incident data are part of the problem formulation phase of registration review. For this evaluation, both the OPP Incident Data System (IDS) a nd the Centers for Disease Control and Prevention/National Institute for Occupational Sa fety and Health (CDC/N IOSH) Sentinel Event Notification System for Occupa tional Risk (SENSOR) database were consulted for poisoning incident data on the active ingred ient hexazinone. For IDS, we iden tified 0 incidents occurring in the United States from 2002 to the pr esent for the single chemical only.

For the NIOSH SENSOR database, there are eigh t cases reported that involve the active ingredient hexazinone (from 1998-2005). Of these eight cases , those that involve only hexazinone and where exposure was determined to be definite, proba ble or possible were reviewed in detail, as these cases provide more certain information about the potential effects of hexazinone exposure. These criteria eliminated six cases. One of the remaining cases was a 57 year old male who was exposed through spray drift. He reported dermal symptoms. The other case was a 40 year old male who reported ocul ar and upper respiratory symptoms. No other details were reported about this case. There we re no fatalities and both cases were ranked low severity.

Based on the low severity and low number of incide nt cases, there does no t appear to be a risk concern at this time that would warrant further investigation. The Agency will continue to
monitor the incident information and if a con cern is triggered, additional analysis will be included in the risk assessment. (M. Hawkins, Updated Review of Hexazinone Incident Reports, 11/24/2009)

Page 9 of 23Tolerance Assessment and International Harmonization

Tolerances for hexazinone on raw agricultura l commodities are currently established under 40 CFR §180.396 and are expressed in terms of the combined residues of the herbicide hexazinone (3-cyclohexyl-6-(dimethylamino)-1-methyl-1,3,5-tr iazine-2,4(1H,3H)-dione) and its metabolites, calculated as hexazinone. The tolerance expressi on must be revised in accordance with the most current guidance as follows: Tolerances for hexazinone on raw agricultural commodities are currently established under 40 CFR §180.396 and ar e expressed in terms of the combined residues of the herbicide hexazinone (parent) and metabolites A, B, C, D, and E. The tolerance expression for milk should include hexazinone (par ent) and metabolites B, C, C-2, and F, and the tolerance expression for ruminant tissue should include hexazinone (parent) and metabolites B and F. The tolerance expression should be modified to include the specific metabolites (A, B, C, C-2, D, E and F). The Agency has determined that tolerances for hexazin one residues in eggs and poultry tissue are not required based on the re sults of the respective poultry metabolism and feeding studies (CFR §180.6(a)(3)). The chemical structure and nomenclatures are summarized
in Table 1. There are no Codex Alimentarius Commission and Mexico ma ximum residue limits (MRLs) for hexazinone.

Environmental Justice

Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, "Federal Actions
to Address Environmental Just ice in Minority Populations an d Low-Income Populations," http://www.epa.gov/compliance/resour ces/policies/ej/exec_order_12898.pdf . The Office of Pesticide Programs (OPP) typicallyconsiders the highest potential exposures from the legal use of a pesticide when conducting human health ri sk assessments, including, but not limited to, people who obtain drinking water fro m sources near agricultural ar eas, the variability of diets within the U.S., and people who may be expos ed when harvesting crops. Should these high exposures indicate potential risks of concern, OPP will further refi ne the risk assessments to
ensure that the risk estimates are ba sed on the best available information.

Cumulative Risk Assessment

The Food Quality Protection Act (F QPA) requires the Agency to c onsider the cumulative risks of chemicals sharing a common mechanism of toxi city. The preliminary evaluation of common mechanisms of toxicity indicated that hexa zinone would not have a common mechanism of toxicity sufficient to be groupe d with the triazines.

Prior to a final registration revi ew decision for hexazinone, the Agen cy will determine if there is any new information, such as new hazard or exposure data or information on changes to the use pattern, which would affect the cumulative risk assessment. Should the Agency determine that
new information on hexazinone is available that could potentially impact the cumulative risk assessment and result in a risk of concern, the Agency will revisit the cumulative risk

assessment.

Page 10 of 23Human Studies

Future exposure and risk assessments will rely in part on the use of the Pesticide Handlers Exposure Database (PHED), the Agricultural Handlers Exposure Task Force (AHETF), and the Agricultural Reentry Task Force (ARTF). All data from PHED have been reviewed and found to be compliant with requirements for the ethical conduct of such studies. Studies conducted as part of the AHETF prior to 2006 have gone through appropriate ethics review. Protocols and subsequent reviews for studies conducted after 2006 will be addressed by the Human Subjects Review Board. In addition, data from the ARTF would be used to calculate current worker postapplication risks. These data have been reviewed and found acceptable from an ethical perspective. As the studies in PHED, AHETF, and ARTF are considered appropriate (or et hically conducted) they will be used for incorporation into futu re risk assessments.

. Data Requirements

HED does not anticipate that additional residue chemistry, toxicology or occupational/residential exposure data will be required for the hexazinone registration review process, with the exception of the following studies listed below:

• Immunotoxicity Study (OPPTS 870.7800).

• Neurotoxicity Battery

• A 28-day inhalation study

• A field rotational crop study for corn and wheat

References

Author Barcode Date Title

John Punzi D279899 May 20, 2002 Residue Chemistry Chapter for the Tolerance Reassessment Eligibility Decision (TRED)

John Punzi D279898 July 30, 2002 Acute and Chronic Dietary Exposure Assessments for
the TRED

TXR#0051049 August 8, 2002 Second Report of the FQPA Safety Factor Committee

TXR#0051033 August 12, 2002 Third Report of the Hazard Identification Assessment
Review Committee

TXR#0051040 August 20, 2002 The Revised Toxicology Chapter for the TRED for
Hexazinone

Carol Christensen D275621 August 22, 2002 Revised HED Chapter for the Hexazinone Tolerance Reassessment Eligibility Decision

P.Yvonne Barnes D328433 May 18, 2006 Protocol Review for the Magnitude of Residues of Hexazinone in Pasture Grass Forage and Hay Sheila Piper D339967 October 16, 2009 Magnitude of the Residue for Hexazinone in WarmSeason Pasture Grass Forage and Hay Following Application of Velpar DF Herbicide

Monica Hawkins

-- November 24,

2009 Updated Review of Hexazinone Incident Reports

Page 11 of 23Tables

Table 1: Chemical Structures of Hexazinone and its Regulated Metabolites (Metabolites A through F) Table 2: Physicochemica l Properties - Hexazinone Table 3: Toxicology Data Requirements Table 4: Acute Toxicity Profile - Hexazinone Table 5: Summary of Toxicological Doses and E ndpoints for Hexazinone for Use in Dietary and Non-Occupational Human Health Risk Assessments Table 6: Rationale for Requi ring the Toxicological Data Table 7: Tolerance Summary for Hexazinone

Table 1: Chemical Structures of Hexazinone and its Regula ted Metabolites (Metabolites

through F) A

Common Name/Code
Chemical name Structure

Hexazinone

3-cyclohexyl-6-(dimethylamino)-1- methyl-1,3,5-triazine-2,4-(1H,3H)-
dione N

N N O

O

CH 3 N

CH 3 CH 3

IUPAC 3-cyclohexyl-6-(dimethylamino)-1-methyl-1,3,5-triazine-2,4-
dione

PC Code 107201

Chemical Abstracts Number 51235-04-2

R egistration Review Case Number. 0 266

Metabolite A

3-(4-hydroxycyclohexyl)-6- (dimethylamino)-1-methyl-1,3,5- triazine-2,4-(1H,3H)-dione

Metabolite A-1 is hydroxylated at the 2- position of the cyclohexyl ring;
Metabolite A-2 is hydroxylated at the 3-position of the cyclohexyl ring. N

N N O

O

CH 3 N

CH 3 CH 3 OH

Metabolite B

3-cyclohexyl-6-(methylamino)-1- methyl-1,3,5-triazine-2,4-(1H,3H)-
dione

Page 12 of 23Page 13 of 23 Table 1: Chemical Structures of Hexazinone and its Regula ted Metabolites (Metabolites A through F)

Common Name/Code
Chemical name Structure

N

N N O

O

CH 3 N H CH 3

Metabolite C

3-(4-hydroxycyclohexyl)-6- (methylamino)- 1-methyl-1,3,5-triazine-2,4-(1H,3H)-
dione

Metabolite C-1 is hydroxylated at the 2- position of the cyclohexyl ring;
Metabolite C-2 is hydroxylated at the 3- position of the cyclohexyl ring. N

N N O

O

CH 3 N H CH 3 OH

Metabolite D

3-cyclohexyl-1-methyl-1,3,5-triazine2,4,6-(1H,3H,5H)-trione N

N NH O

O

CH 3 O

Metabolite E

3-(4-hydroxycyclohexyl)-1-methyl1,3,5-triazine-2,4,6-(1H,3H,5H)-trione N

N NH O

O

CH 3 O OH

Metabolite FTable 1: Chemical Structures of Hexazinone and its Regula ted Metabolites (Metabolites A through F)

Common Name/Code
Chemical name Structure

3-cyclohexyl-6-amino-1-methyl1,3,5-triazine-2,4-(1H,3H)-dione

N

N N O

O

CH 3 NH 2

Table 2. Physicochemical Properties - Hexazinone

Parameter Value Reference

Melting point/range 113.5 oC

pH Not Applicable, a solid
Water solubility 25 oC is 2.98g/100g.
Solvent solubility (g/100mL) Methanol 265, Acetone79, and Hexane 0.3 g/100 g.

Vapor pressure 1.9 x 10 -7 mm Hg at 25 oC

Chemical class/use triazinones

Page 14 of 23Table 3. Toxicology Data Requirements

Technical Test

Required Satisfied

870.1100/§81-1 Acute Or al Toxicity............................................... 870.1200/§81-2 Acute Derm al Toxicity.......................................... 870.1300/§81-3 Acute Inha lation Toxicity...................................... 870.2400/§81-4 Primary Ey e Irritation ........................................... 870.2500/§81-5 Primary Dermal Irritation...................................... 870.2600/§81-6 Dermal Sensitization ............................................. Yes

Yes

Yes

Yes

Yes

Yes Yes

Yes

Yes

Yes

Yes

Yes

870.3100/§82-1 Oral Subchronic Toxicity (rodent) ........................ 870.3150/§82-1 Oral Subchronic Toxicity (nonrodent) .................. 870.3200/§82-2 21/28-Day De rmal Toxicity .................................. 870.3250/§82-3 90-Day De rmal Toxicity ....................................... 870.3465 §82-4 90-Day Inhalation Toxicity ................................... Yes

Yes

Yes

No 1

No 2 Yes

Yes

Yes

Yes

No

870.3700/§83-3 Prenatal Developm ental Toxicity (rodent) ............ 870.3700/§83-3 Prenatal Developmental Toxicity (nonrodent) ...... 870.3800§83-4 Multigeneration Re productive Toxicity ................ Yes

Yes

Yes Yes

Yes

Yes

870.4100/§83-1 Chronic Toxi city (rodent)...................................... 870.4100/§83-1 Chronic Toxic ity (nonrodent)................................ 870.4200/§83-2 Carcinoge nicity (rat) ............................................. 870.4200/§83-2 Carcinogenicity (mouse) ....................................... 870.4300/§83-5 Chronic/Carcinogenicity ....................................... Yes

Yes

Yes

Yes

Yes Yes

Yes

Yes

Yes

Yes

870.5100/§84-2 Mutagenicity—Gen e Mutation - bacterial............. 870.5300/§84-2 Mutagenicity—Gene Mutation - mammalian ....... 870.5375/§84-2 Mutagenicity—Struct. Chromosomal Aberrations 870.5395/§84-2 Mutagenicity—Struct. Chromosomal Aberrations 870.5550/§84-2 Mutagenicity—Oth er Genotoxic Effects............... Yes

Yes

Yes

Yes

Yes No 3

Yes

Yes

Yes

Yes

870.6100/§81-7 Acute Delayed Ne urotoxicity (hen) ...................... 870.6100/§82-5 90-Day Neur otoxicity (hen) .................................. 870.6200/§81-8 Acute Neurotoxicity Screening Battery (rat).......... 870.6200/§82-7 90-Day Neurotoxicity Screening Battery (rat) ....... 870.6300/§83-6 Developmen tal Neurotoxicity......................... No 4

No 4

Yes

Yes -

- No 5

No 5

-

870.7485/§85-1 General Metabolism............................................... 870.7600/§85-2 Dermal Penetration................................................. Yes

No 6 Yes

No

Special Studies for Ocular Effects 7 Acute Oral (rat)...........................................................
Subchronic Oral (rat) .................................................. Six-month Oral (dog).................................................. -

-

- -

-

-

1 Study not required for exposure pattern. 2 A 28-day inhalation study is required. 3 Another study is not required. 4
Required for organophosphates only. 5 No required by exposure pa ttern Studies are required. 6 Study is optional. 7
Not required for this class of pesticides.

Page 15 of 23Table 4. Acute Toxicity Profile - Hexazinone

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

870.1100

§81-1 Acute oral toxicity - rat 41235004
(1989) LD 50 = 1200 mg/kg III

870.1200

§81-2 Acute dermal toxicity - rabbit 00104974
(1973) LD 50 > 5278 mg/kg IV

870.1300

§81-3 Acute inhalation toxicity - rat 41756701
(1990) LC 50 > 3.94 mg/L (4 hour) III

870.2400

§81-4 Acute eye irritation - rabbit 00106003
(1982) Severe,
irreversible corneal opacity I

870.2500

§81-5 Acute dermal irritation - rabbit 00106004
(1982) Mild IV

870.2600

§81-6 Skin sensitization – guinea pig

Buehler Method 4123005
(1989) Not a skin
sensitizer NA

Table 5. Summary of Toxicological Doses and Endpoints for Hexazinone for Use in Dietary and Occupational Huma n Health Risk Assessments

Exposure/
Scenario Point of Departure Uncertainty/FQPA Safety Factors RfD, PAD,
Level of
Concern for
Risk

Assessment Study and Toxicological Effects

Acute Dietary
females 13-50 years of age NOAEL

400 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x Acute RID =

4.0 mg/kg/day Developmental Toxicity – Rat LOAEL is 900 mg/kg/day based on decreased male and female fetal weight, kidneys with no papilla (malformation) and misaligned sternebrae (variation). Acute Dietary general population including infants
and children An appropriate endpoint attributable to a single dose was not identified in the oral studies (including rat and rabbit developmental studies) for all populations

Chronic Dietary (All Populations) NOAEL=

5.0 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x Chronic RfD

= 0.05 mg/kg/day

cPAD = 0.05 mg/kg/day Chronic Feeding - Dog LOAEL = 41.24/37.57 (m/f) mg/kg/day based on severe body weight decrements and clinical chemistry changes.

Incidental Oral Short-Term (1- 30 days) and
Intermediate Term (1-6 months) NOAEL=
25.9/31.6 (m/f) mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x Residential
LOC for

MOE = 100 Subchronic Feeding - Dog LOAEL = 440/451 (m/f) mg/kg/day based on decreased body weight gains, increased liver weights with clinical chemistry changes (both sexes).

Page 16 of 23Table 5. Summary of Toxicological Doses and Endpoints for Hexazinone for Use in Dietary and Occupational Huma n Health Risk Assessments

Exposure/
Scenario Point of Departure RfD, PAD,

Uncertainty/FQPA

Safety Factors Level of Study and Toxicological Effects
Concern for
Risk

Assessment

Dermal ShortTerm (1-30 days) No hazard was identified in the dermal toxicity study in the rabbit submitted to fulfill the guideline recommendation. No systemic toxicity was seen up to the limit dose following repeat dermal application.

Dermal
IntermediateTerm (1-6 months) 1 NOAEL= 5.0 (oral) mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x Residential
LOC for

MOE = 100 Chronic Feeding - Dog LOAEL = 41.24/37.57 (m/f) mg/kg/day based on severe body weight decrements and clinical chemistry changes.

Inhalation ShortTerm (1-30 days) 2 NOAEL= 50 (oral) mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x Residential
LOC for

MOE = 100 Developmental Toxicity - Rabbit LOAEL = 125 mg/kg/day based on decreases in maternal food consumption, dose related decease in body weight and fetal body weights.

Inhalation
IntermediateTerm (1-6 months) 2 NOAEL= 5.0 (oral) mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x Residential
LOC for

MOE = 100 Chronic Feeding - Dog LOAEL = 41.24/37.57 (m/f) mg/kg/day based on severe body weight decrements and clinical chemistry changes.

Dermal ShortTerm (1-30 days) No hazard was identified in the dermal toxicity study in the rabbit submitted to fulfill the guideline recommendation. No systemic toxicity was seen at the limit dose following repeat dermal application.

Dermal
IntermediateTerm (1-6 months) 1 NOAEL= 5.0 (oral) mg/kg/day UF A =10x

UF H =10x Occupational
LOC for

MOE = 100 Chronic Feeding - Dog LOAEL = 41.24/37.57 (m/f) mg/kg/day based on severe body weight decrements and clinical chemistry changes.

Inhalation ShortTerm (1-30 days) 2 NOAEL= 50 (oral) mg/kg/day UF A =10x

UF H =10x Occupational
LOC for

MOE = 100 Developmental Toxicity - Rabbit LOAEL = 125 mg/kg/day based on decreases in maternal food consumption, dose related decease in body weight and fetal body weights.

Inhalation
Intermediateterm (1-6 months) 2 NOAEL= 5.0 (oral) mg/kg/day UF A =10x

UF H =10x Occupational
LOC for

MOE = 100 Chronic Feeding - Dog LOAEL = 41.24/37.57 (m/f) mg/kg/day based on severe body weight decrements and clinical chemistry changes. Cancer (oral, dermal, inhalation) Classification: “D” – Not Classifiable as to human carcinogenicity potential.

Point of Departure (POD) = A data point or an estimate d point that is derived from observed dose-response data and used to mark the beginning of extra polation 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 A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. Limit Dose = in oral and dermal systemic toxicity studies, 1000 mg/kg/day.

1 Since an oral NOAEL was selected, a 12.5% dermal absorption factor should be used for route to route

exposures. 2 Absorption via the inhalation route is assumed to be equivalent to oral absorption.

Page 17 of 23Table 6a. Guideline Number: 870.3465 Study Title: 28-Day Inhalation Toxicity Rationale for Requiring the Data A 28 day repeat inhalation study was recommende d instead of a full 90 day study based on use patterns. The 28-day inhalation toxicity study ev aluates the potential hazard of a pesticide chemical following repeated inhalation exposures. Th is study is critical for pesticides with use pattern in which there is potential for repeated human exposures (e.g., professional applicators, green house use etc) exposure. The study de sign simulates the route of human exposure (inhalation). In this study animals are exposed (nose/whole body) to aero sol concentrations of the test material for 6 hours/day, 5 day/week for 28 days. A detailed toxicological examination including the histop athology of the respiratory system is conducted. This is route-specific study would provide data for hazard characteri zation, dose response assessment, and a dose and endpoint for assessing potenti al risks via the i nhalation route. Practical Utility of the Data How did the Agency make its re-registration decision without these data?

A subchronic inhalation study provide s critical scientific inform ation needed to characterize potential hazard to human population on the respir atory system from pesticide exposure. A 28-day repeated exposure study that follows th e Test Guidelines (870.3465) will characterize hazard and provide data for a much accurate inhalation risk assessment.

How will the data be used?

This study will identify hazard (i.e., provide a dose and endpoint) following longer repeated exposures, this data will be used in risk assessm ents. If the Agency does not have this data, a 10X database uncertainty factor may be appl ied for conducting a risk assessment from the
available studies.

Page 18 of 23Page 19 of 23 Table 6b. Guideline Number: 870.7800 Study Title : Immunotoxicity Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticid e (food and non-food uses).

The Immunotoxicity Test Guideline (OPPTS 870 .7800) prescribes functional immunotoxicity testing and is designed to evaluate the potenti al of a repeated chemical exposure to produce adverse effects (i.e., suppressi on) on the immune system. I mmunosuppression is a deficit in the ability of the immune system to respond to a challenge of bacterial or viral infections such as tuberculosis (TB), Severe Acquired Respir atory Syndrome (SARS), or neoplasia. Because the immune system is highly complex, studi es not specifically conducted to assess immunotoxic endpoints are inadequate to characterize a pesticide’ s potential imm unotoxicity. While data from hematology, lymphoid organ we ights, and histopathology in routine chronic or subchronic toxicity studies may offer usef ul information on potenti al immunotoxic effects, these endpoints alone are insuffici ent to predict immunotoxicity.

Practical Utility of the Data

How will the data be used?

Immunotoxicity studies provi de critical scientific informati on needed to characterize potential hazard to the human population on the immune system from pesticide exposure. Since epidemiologic data on the effects of chemical exposures on immune parameters are limited and are inadequate to characterize a pesticide’s potential immunotoxicity in humans, animal studies are used as the most sensitive endpoint for risk assessment. These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure scenarios and are considered a primary data source for reli able reference dose calculation. For example,
animal studies have demonstrated that immunotox icity in rodents is one of the more sensitive manifestations of TCDD (2,3,7,8-tetrachloro dibenzo-p-dioxin) among developmental, reproductive, and endocrinologic toxicities. A dditionally, the EPA has established an oral reference dose (RfD) for tributyltin oxide (TBTO) based on observed immunotoxicity in animal studies (IRIS, 1997).

How could the data impact the Agency's future decision-making?

If the immunotoxicity study shows th at the test material poses eith er a greater or a diminished risk than that given in the in terim decision’s conclusion, the risk assessments for the test material may need to be revised to reflect the magnitude of potential ri sk derived from the new
data.

If the Agency does not have this data, a 10X da tabase uncertainty factor may be applied for conducting a risk assessment from the available studies.Table 6c. Guideline Number: 870.6200Study Title:Neurotoxicity Battery (Acute and Subchronic Studies)Table 6c. Guideline Number: 870.6200Study Title: Neurotoxicity Screening BatteryRationale for Requiring the DataRationale for Requiring the DataThis is a new data requirement under 40 CFR Part 158 as a part ofthe data requirements for registration of a pesticide (food and nonfood uses).The Neurotoxicity Screening Battery (OPPTS 870.6200) is designedto evaluate the potential adverseeffects on the nervous system fromexposure to pesticide chemicals.The Agency believes that theguideline studies are inadequate intheir assessment of behavioraleffects and do not use optimal methods to evaluate the potentialtoxicity to the nervous tissue structure and function. To detect andcharacterize these potential effects more fully, a battery of moresensitive testing is required. The objective of this neurotoxicitybattery testing is to evaluate the incidence and severity of thefunctional and/or behavioral effects, the level of motor activity, andthe histopathology of the nervous system. The acuteneurotoxicitystudy is required to detect possible effects resulting from a singleexposure. The subchronic neurotoxicitystudy is intended to detectpossible effects resulting from repeated or long-term exposures.An acute neurotoxicity study with hexazinone was submitted and there were nosigns of neurotoxicity from a single dose.However, a subchronic neurotoxicitystudy with hexazinone were not conducted, hexazinone showed no indicationof being a neurotoxicant in the provided long term studies and there was noevidence of neurotoxicity in open literature searches, however, the submittedstudies did no examine neurotoxicity endpoints. These data are now requiredunder the revised CFR 158.340.Practical Utility of the DataPractical Utility of the DataHow will the data be used?The acute and subchronic neurotoxicity studies provide criticalscientific information needed to characterize potential hazard to thehuman population on the nervous system from pesticide exposure.These studies can provide data ona wide range of functional testsfor evaluating neurotoxicityincluding sensory effects,neuromuscular effects, learningand memory and histopathology ofHow did the Agency make its re-registration decision without this data?For many chemicals, the amount of toxicitydata that is available for hexazinonewould be considered to beacomplete toxicity database.In fact, the Agency wasable to select doses andendpoints for conducting a risk assessment from theavailable studies. However, the toxicitydatabase for hexazinone does not includeany long term neurotoxicitystudies and there is uncertainty of the neurotoxicitypotential of hexazinone as none ofthe submitted longer term studiesPage 20 of 23Page 21 of 23the nervous system For example, animal studies withorganophosphorous chemicals have shown neurotoxicity to be theprimary toxic endpoints (e.g., cholinesterase inhibition) of concernsin rodents and non-rodents. These animal studies can be used toselect endpoints and doses for usein risk assessment of all exposurescenarios and are considered a primary data source for reliablereference dose calculation. The Agency has established an oralreference dose (RfD) for assessing dietary risks for a number ofchemicals (e.g., organophoshates and carbamates) whereneurotoxicity was the most sensitive endpoint of concern.How could the data impact the Agency's future decision-making?If the acute or subchronic neurotoxicity studies show thathexazinone poses either a greater ora diminished risk than thatgiven in the interim decision’sconclusion, the risk assessmentsforhexazinone may need to be revised to reflect the magnitude ofpotential risk derived from the new data.If the Agency does not have this data, a 10X database uncertaintyfactor may be appliedwhen conducting a risk assessment using thecurrently available studies.measured neurotoxicity endpoints.How will the data be used?After the review and evaluation ofthe subchronic neurotoxicity study,itispossible that Agency could chooseadose and endpoint from the subchronicneurotoxicity study for the deriving the acute RfD.How could the data impact the Agency’s future decision-making?If the acute RfD changes, then the hexazinone acute dietary risk assessmentwould need to be conducted. At present there were no effects observed in oraltoxicity studies including developmental toxicity studiesin rats or rabbits thatcould be attributable to asingle dose (exposure). The riskwould then be identifiedfor the acuteRfD.Table 7. Tolerance Summary for Hexazinone
Commodity Proposed
Tolerance

(ppm) Established
Tolerance

(ppm) Recommended Tolerance (ppm) Comments;

Correct Commodity Definition

Tolerances for combined residues of hexazinone (3-cyclohexyl-6-(d imethylamino)-1-methyl-1,3,5- triazine-2,4(1H,3H)-dione) and its metabolites, calculated as hexazinone [40 CFR 180.396]
Alfalfa green forage

-- 2.0 2.0
Alfalfa, hay

-- 8.0 4.0

Alfalfa, seed

-- -- 2.0 HED is requesting the registrant to propose a
tolerance for hexazinone
residues of concern in/on alfalfa seed of 2.0 ppm based upon a residue field trial study at 1.5x the maximum registered rate on alfalfa grown for

seed

. Blueberry

-- 0.2 0.6 Tolerance should be
increased based on the combined LOQ (0.55 ppm) of the enforcement
method. Cattle, fat

-- 0.1 0.1

Cattle, meat

-- 0.1 0.5
Cattle, meat byproducts

-- 0.1 4.0

Goat, fat

-- 0.1 0.1

Goat, meat
-- 0.1 0.5
Goat, meat byproducts

-- 0.1 4.0
Grass, forage

-- 10 250
Grass, hay

-- -- 230
Hog, fat

-- 0.1 0.1

Hog, meat
-- 0.1 0.5
Hog, meat byproduct

-- 0.1 4.0

Horse, fat

-- 0.1 0.1

Horse, meat
-- 0.1 0.5
Horse, meat byproduct

-- 0.1 4.0

Milk

-- 0.1 11
Pineapple

-- 0.5 0.6 Tolerance should be
increased based on the combined LOQ (0.55 ppm) of the enforcement
method. Sheep, fat

-- 0.1 0.1

Page 22 of 23Page 23 of 23 Table 7. Tolerance Summary for Hexazinone
Commodity Proposed
Tolerance

(ppm) Established
Tolerance

(ppm) Recommended Tolerance (ppm) Comments;

Correct Commodity Definition
Sheep, meat byproduct

-- 0.1 4.0
Sugarcane, cane
-- 0.2 0.6 Tolerance should be
increased based on the combined LOQ (0.55 ppm) of the enforcement
method. Sugarcane, molasses

-- 5.0 4.0