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

OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION

MEMORANDUM

DATE: 10/3112013

SUBJECT : 2,4

- DB: Human Health Risk Assessment Seep i ng Document i n Support of Registration Review

PC Code : 030801 DP Barcode: D41 0363

MRID No.: Not Applicable

Petition No. : Not Applicable Registration No .: Not Applicable Regulatory Action : Registration Review Seeping

Assessment Type: Single Chemical,

Non

- Aggregate Reregistration Case No.: Not Applicable

TXR No .: Not Applicable CAS No. : 94-82

- 6

FROM:

THROUGH: Wade Britton, MPH, Risk**Assesso nd**  ORE

Linda Tay l?r, Ph.D.: Toxicologis f r 

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Peter Savma, Chemist**~** 

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Risk Assessment Branch V / VII

Health Effects Division (HED;**7~09P)**

Michael Metzger, Branch Chi * e ( /} / } (} )

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TO : Jill Bloom, Chemical Review Manager

Risk Management and Implementation Branch II (RMIB II)

Pesticide Re

- Evaluation Division (PRD; 7508P)

Attached is the Health Effe cts Division ' s (HED) human health risk as sessment seeping

document for 2,4-DB to support th e r eg is tration r e vi e w proc e ss.2,4-DB: Human Health Risk Assessment Scoping Document in Support of Regist ration Review

Page 2 of 22 Executive Summary

HED has considered the available risk assessm ents for 2,4-DB and its toxicity, exposure and usage databases, as well as the most current Agency science and assessment policies. HED performed this evaluation in order to determine the scope of work necessary to support the

established tolerances and existi ng registrations during registrati on review. The primary source of information for this evaluation was the most recent 2,4-DB human health risk assessment (HHRA) 1 conducted to support the January 2005 USEPA registration eligibil ity decision (RED) for 2,4-DB 2

.

2,4-DB [4-(2,4-dichlorophenoxy) buty ric acid] is a plant growth regulator and herbicide registered for use on alfalfa, clover, peanuts, s oybean, peppermint, spearmint, and trefoil. It is manufactured as the acid and the dimethylamine salt; no other salt or este r products are currently registered. End-use products ar e formulated either as solubl e, emulsifiable, or flowable concentrates. 2,4-DB can be applied either as a broadcast application earl y season or a directed spray late season by aerial or ground equipment. Maximum label applicat ion rates for food/feed crops range from 0.25 lb ae (acid equivalents)/A to 1.5 lb ae/A. There are no registered residential uses of 2,4-DB.

Because of similarities in metabolism and degrad ation in animals, plants , and the environment, 2,4-DB and 2,4-DB-DMAS [4-(2,4-dichlorophenoxy )butyric acid dimethylamine salt], the dimethylamine salt form of 2,4-DB, were cons idered equivalent by HED in the 2004 HHRA. For the purpose of this document, 2,4-DB a nd 2,4-DB-DMAS are also co nsidered equivalent,

unless otherwise noted.

The toxicity database for 2,4-DB and 2,4-DB -DMAS is incomplete, but sufficient for characterization of potential developmental, repr oductive, carcinogenetic, mutagenic, neurotoxic,

and immunotoxic effects. HED recommends th at an inhalation toxicity study (870.3465) be required for the registration review of 2,4-DB. Once these data have been received and reviewed, their impact on th e endpoints, points of departure (PODs), and uncertainty factors/safety factors (UF/SFs) for the inhalati on exposure risk assessment will be evaluated. Further, the need for a dermal risk assessment and the endpoint selection for the chronic dietary risk assessment may need to be reevalua ted, based on updated policies and procedures.

The major target organs for 2,4-DB and 2,4-DB-DMAS are the kidney and liver. Developmental toxicity was not observed in the rabbit but was observed in the ra t at the same dose level where maternal mortality was observed. Reproductive toxi city was not observed in the rat. 2,4-DB is

classified as “not li kely to be a human carcinogen.” 2,4- DB does not appear to be a frankly neurotoxic chemical, and there is no con cern for immunotoxicity. 2,4-DB and 2,4-DB-DMAS are not acutely toxic by the oral, dermal, and i nhalation routes of exposure based on lethality

studies. Neither chemical is a sk in irritant; 2,4-DB is a mild eye irritant, but 2,4-DB-DMAS is a severe eye irritant and both are negative for dermal sensitization.

1 2,4-DB and 2,4-DB-DMA Human Health Risk Assessment. K. Farwell. 6/20/2004. D290486.

2 http://www.epa.gov/opp00001/reregistration/24d/2,4-DB: Human Health Risk Assessment Scoping Document in Support of Regist ration Review

Page 3 of 22 The 2,4-DB residue chemistry data base is incomplete and consid ered inadequate to support the registration review process. In order to address residue chemis try data deficiencies for 2,4-DB, HED recommends that additional geographically repr esentative field trial data be required for clover forage and hay. Acute and chronic dietary risk assessments 3 were last performed to support the 2005 RED. There are cu rrently no acute or chronic diet ary (food and water) risks of concern for 2,4-DB. During regi stration review, updated dietary exposure assessments may be conducted if there are any significan t changes to the toxicological PODs or FQPA and other UFs, or if clover hay and forage geogr aphic distribution residue data are submitted. In addition, any significant changes to the estimated drinki ng water concentrations (EDWCs) may also necessitate changes to the dietary assessment.

While there are curren tly no registered residential uses of 2,4-DB, residential bystander exposures resulting from off-site transport (i.e., sp ray drift or volatilization) may occur as a result of occupational applications of 2,4-DB. The n eed for a bystander risk assessment for 2,4-DB will be considered during registration review.

The occupational exposure databa se is adequate to support the registration review process for 2,4-DB. The previous occ upational exposure assessment 4 covered all exposure scenarios relevant to 2,4-DB and no occupational handler or post-application ri sks of concern were identified with use of appropriate persona l protective equipment (PPE). An updated occupational handler assessment may be performe d if warranted by signif icant changes to the current scenario-specific surrogate handler -exposure data, PODs, or UFs.

Chemical Use Profile

2,4-DB is a plant growth regulator and herbicide used for the contro l of broadleaf weeds. It is registered for use on alfalfa, clover, peanuts, soybean, peppermint, spearmint, and trefoil with permanent tolerances established under 40 CF R §180.331(a). There are no residential uses registered for 2,4-DB. End-use products are form ulated either as soluble, emulsifiable, or flowable concentrates. 2,4-DB can be applied either as a broad cast application early season, or a directed spray late season aer ially or by ground equipment.

The nomenclature and physiochemical propertie s of 2,4-DB can be found in Attachment 1.

Hazard Identification/Toxicology

2,4-DB and 2,4-DB-DMAS are members of the dichlorophenoxy class of compounds that function by mimicking the action of auxins, plant growth hormones.

The toxicity database for 2,4-DB and 2,4-DB -DMAS is incomplete, but sufficient for characterization of potential developmental, repr oductive, carcinogenetic, mutagenic, neurotoxic,

and immunotoxic effects. In rats , 2,4-DB is rapidly absorbed orally and eliminated mainly in the

3 2,4-DB Acute and Chronic Dietary Exposure Assessments for the Reregistration Eligib ility Decision. F. Fort.

7/13/2004. D291221.

4 2,4-DB: Occupational and Residential Exposure and Risk Assessment for the Reregistration Eligibility Decision (RED) Document. T. Dole. 5/3/2004. D3006292,4-DB: Human Health Risk Assessment Scoping Document in Support of Regist ration Review

Page 4 of 22 urine. 2,4-DB-DMAS dissociates to 2,4-DB, af ter which they share the same metabolic pathway. 2,4-D and conjugated dichlorophenol are the major metabolites for both chemicals. Although data specific to 2,4-DB-D MAS are limited to a rat subchr onic oral toxi city study, a rat developmental toxicity study, a s ubchronic dermal toxicity study in rabbits, and a mutagenicity battery, the toxicity and eff ect dose levels for both chemicals are generally similar.

The major target organs for 2,4-DB and 2,4-DB-DMAS are the kidney and liver. Kidney toxicity is manifested as d ecreased kidney weights and increa sed incidence of non-neoplastic pathology (tubular degeneration/infa rcts) in rats, and increased ki dney weight in dogs. Liver toxicity is manifested as incr eased liver weights, increased liv er enzymes, and hepatocellular hypertrophy in rats and dogs. The effects are consistent across time and species and do not appear to progress over time. Although absorpti on and distribution of chlorophenoxy herbicides and other organic acids generally are similar across all mammalian species evaluated, the decreased capacity of the dog to eliminate orga nic acids results in higher blood levels and a longer elimination half-l ife relative to those found in the rat and other mammalian species. Consequently, effects are seen at lower dose levels in the dog than in the rat. Because of this difference, the rat is a better predictor of the poten tial toxicity of 2,4-DB and 2,4-DB-DMAS in humans than the dog, and doses and endpoints from rat studies we re used in all 2,4-DB risk

assessments.

Developmental toxicity was not observed in the rabbit but was obs erved in the rat at the same dose level where maternal mortality was observe d. Reproductive toxicity was not observed in the rat. The 10X FQPA SF for th e protection of infants and children has been reduced to 1X for the following reasons: (1) There is no increased qualitative or quantitative susceptibility in the rat or rabbit developmental toxi city studies; (2) the doses a nd endpoints selected for risk assessment are protective of the qualitative susceptibility observe d in the rat reproduction study; (3) the NOAEL and LOAEL from the rat reproducti on study are well characterized; and (4) the databases are considered to be complete for the purpose of risk assessment.

2,4-DB is classified as “not lik ely to be a human carcinogen” not requiring a quantitative cancer

risk assessment. This is based on the lack of evidence of carcinogenicity in mice and rats, and there is no concern for mutagenicity. 2,4-DB does not appear to be a frankly neurotoxic chemical, and there is no concern for i mmunotoxicity. 2,4-DB and 2,4-DB-DMAS are not acutely toxic by the oral, dermal, and inhalation routes of exposure based on lethality studies.

Neither chemical is a skin irri tant; 2,4-DB is a mild eye irritant, but 2,4-DB-DMAS is a severe eye irritant and both are negativ e for dermal sensitization.

Acute and subchronic neurotoxic ity studies in rats and an immunotoxicity study, which are required in accordance with new data requireme nts for conventional pesticide registration (40 CFR Part 158), have not been submitted. Ho wever, based on a weight-of-evidence (WOE) approach, considering all the available 2,4-DB hazard and exposure information, the HED Hazard and Science Policy Council (HASPOC) c oncluded that the acute and subchronic neurotoxicity studies and the im munotoxicity study are not need ed for 2,4-DB at this time 5

.

5 2,4-DB/2,4-DB-DMA: Summary of Hazard and Science Policy Council (HASPOC) Meeting of July 25, 2013: Recommendations on the Requirement of a Subchronic Inhalation Study, an Immunotoxicity Study, and the Acute and Subchronic Neurotoxicity Studies for 2,4-DB/2,4-DB-DMA. U. Habiba. 8/13/2013. TXR No. 0056727.2,4-DB: Human Health Risk Assessment Scoping Document in Support of Regist ration Review

Page 5 of 22 Based on current policies, HED recommends that a rep eat dose inhalation toxi city study in rats is required due to the potential for repeated inhalation exposure to aerosolized formulations of 2,4- DB and 2,4-DB-DMAS. The t oxicity study should be conducte d using aerosolized 2,4-DBDMAS, the more caustic of the two forms. The HASPOC determined that a 28-day inhalation toxicity study is needed to better estimate risk for occ upational inhalation exposure.

The acute, subchronic, and chr onic toxicity profile tables for 2,4-DB and 2,4-DB-DMAS are

included in Attachment 2. Toxic ity endpoints, PODs, and UF/SFs we re selected for oral, dermal, and inhalation exposure pathways for the Hu man Health Risk Assessment conducted in 2004 (D290486), and these are shown in Attachment 3.

Upon receipt and review of the outstanding toxico logy data and considera tion of all available data, the endpoints for risk assessment and all uncertainty factors will be re-evaluated during registration review to reflect updated data and uncertainty f actor policies, and a new risk assessment done, if necessary.

Conclusions: The toxicity data base for 2,4-DB and 2,4-DB-DMAS is considered incomplete, but is adequate for assessing potential carci nogenetic, mutagenic, deve lopmental, neurotoxic, immunotoxic, and reproductive effects. An inha lation toxicity study (870.3465) is anticipated to be required for registration review. Once those data have been receiv ed and reviewed, their impact on the endpoints, PODs, and UF/SFs fo r the inhalation exposure risk assessment will need to be evaluated. During re gistration review, the need for a dermal risk assessment and the endpoint selection for the chroni c dietary risk assessment may n eed to be reevaluated, based on updated policies and procedures.

Dietary Exposure

Residue Chemistry

For 2,4-DB, the nature of the residue is adequate ly understood in both plants and livestock based

on the available metabolism and residue studies. The HED Metabolism committee concluded 6,7

that the residue of concer n for tolerance expression a nd risk assessment is 2,4-DB per se , and that 2,4-D need not be included. In maintaining cons istency with 2,4-D, tolerances, limits established for residues in 2,4-DB should be expressed as parent, including bot h free and conjugated,

determined as the acid.

The following tolerances were reassessed and recommended for the 2005 2,4-DB RED: alfalfa, forage (0.70 ppm); alfalfa, hay (2.0 ppm); clover, forage and clover, hay (insufficient data available); peppermint, tops and spearmint, t ops (0.20 ppm); soybean, seed (0.50 ppm), soybean, forage (0.70 ppm), soybean, hay (2.0 ppm); peanut (0.05 ppm); trefoil, forage (0.70 ppm) and trefoil, hay (2.0 ppm). The RED reaffirmed that the appropriate tolerance for 2,4-DB is 0.05 ppm (LOQ) in the meat byproducts of cattle, goats, hogs , horses, and sheep. The 2,4-DB ruminant and poultry feeding studies that were performed bore residue levels in livestock commodities below

6 2,4-DB: Metabolism Committee Question Re: Regulation of Metabolites in Plant and Animal Commodities. D.

Miller. 11/14/1995. D220888.

7 2,4-DB: Results of the 1/16/96 Meeting of the HED Me tabolism Committee. D. Miller. 01/29/96. D221954.2,4-DB: Human Health Risk Assessment Scoping Document in Support of Regist ration Review

Page 6 of 22 the level of quantitation (0.05 ppm for all tissu es and 0.01 ppm for eggs and milk) at all the feeding rates tested 8 . There is no reasonable expectation of the transfer of residues of 2,4-DB from feedstuffs to livestock meat, fat or milk; th erefore, the current use of 2,4-DB with respect to

these commodities should be classified as Cate gory 3 under 40 CFR 180.6(a), and tolerances for residues of 2,4-DB in milk and in meat and fat of cattle, goats, hogs, horses, and sheep are not required.

Adequate tolerance enforcement methods are currently available. 2,4-DB is completely recovered (>80%) by FDA MultiResidue Test Method 402 (PAM Vol I, updated 10/97). The Pesticide Analytical Manual (P AM) Vol. II, lists Method I, a GC method with microcoulometric detection, for the enforcement of tolerances for 2,4-DB residues; this method is the PAM Vol. I method for chlorophenoxy acid residues in food.

The 2,4-DB residue chemistry data base is incomplete. Residue chemistry deficiencies were identified in the 2004 HHRA including revised labe ls to prohibit the grazing and feeding of soybean forage and hay; the development of pl ant and livestock tolerance enforcement methods; additional clover forage and hay fi eld trials; and the replenishmen t of reference standards.

Since the time of the 2004 HHRA, th e majority of the residue chem istry deficiencies have been addressed. Label changes required to prohibit the grazing of soybean forage or the feeding of soybean hay within 60 days of application a nd the replenishment of standards have been completed. Further, HED determined that the plant and livestock tolerance enforcement method deficiency is satisfied because 2,4-DB is co mpletely recovered by FDA Multiresidue Test Method 402 (PAM Vol I) for enforcement, and PAM Vol II lists a GC method with

microcoulometric detection for confirmation. Fina lly, reference materials have been replenished and are valid through 9/22/2015.

Additional data are needed to support establishe d tolerances for clover forage and hay. HED recommends these data be required because the ge ographic distribution of the trials represented in the previously submitted data is inadequate. OCSPP Guidelines call for trials from Region 1 (1 trial), Region 2 (1), Region 4 (1), Region 5 (3), Region 6 (1), Region 7 (1), Region 8 (1), Region 9 (1), Region 10 (1), and Region 11 (1). The data which have been provided thus far only address two geographically similar regions . As a result, ten additional trials are recommended from Region 1 (1), Region 2 (1), Re gion 4 (1), Region 5 (3), Region 6 (1), Region 7 (1), Region 8 (1), and Region 9 (1), at the ma ximum labeled rate of 1.3 lb ae/A with a PHI of 60 days.

Food Exposures

Current tolerance levels are esta blished at 0.2 ppm based on neglig ible residues found in alfalfa, clover, mint, peanut, trefoil, soybean, and soybe an hay. As explained above, no tolerances for livestock commodities or food/feed processe d commodities have been established.

8 2,4-DB [4-(2,4-cholorophenoxy) butyric acid] and 2,4-DB dimethylamine salt (PC Codes030801, 030819): Revised Product Chemistry and Residue Chemistry Summar y Documents for the Registration Eligibility Decision Document (RED). D. Drew. 7/19/2004. D291212.2,4-DB: Human Health Risk Assessment Scoping Document in Support of Regist ration Review

Page 7 of 22 Acute and chronic dietary risk assessments we re last performed to support the 2005 RED for 2,4- DB. The assessments were conducted using th e Dietary Exposure Evaluation Model (DEEMFCID  ) Version 1.30. This model used food consumption data for assessment from the USDA’s Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998.

An unrefined (tolerance level a nd 100% crop treated) acute and chronic dietary risk assessment was conducted for all supported 2,4-DB food uses. Ac ute dietary risk estimates were determined for females 13 to 49 years old since this is the only population subgroup for which an acute dietary endpoint was identified. For 2,4-DB there is no endpoint attributable to a single dose from oral toxicity studies for acute dietary risk assessment for the general population including infants and children. Therefore, only females 13-50 years of age were determined to have an endpoint for acute dietary risk assessment base d upon the supporting rat developmental toxicity study that was performed.

Risk estimates at the 95 th percentile of exposure were <1% of the aPAD and, therefore, are not of concern. Chronic dietary risk es timates were also determined to be below the 100% threshold level of concern for the general U.S. populat ion (<1% of the cPAD) and all its population subgroups. The most highly exposed population s ubgroup was found to be all infants <1 year old with an exposure of 2.2% of the cPAD.

Drinking Water Exposures

Drinking water exposures can potentially occu r through run-off resulting from the outdoor applications of 2,4-DB made for controlling broadl eaf weeds. To assess this potential exposure for the 2005 RED, highly conservative estimated drinking water concentr ations (EDWCs) were generated using PRZM/EXAMS modeling for surface water and SCI-GROW modeling for groundwater 9 . No degradation products of 2,4-DB we re included in this assessment.

For the 2005 RED, EDWCs were not directly incorporated into D EEM in the dietary assessment. At the time, HED was instead calculating es timated drinking water levels of comparison (DWLOCs) and comparing them to EDWCs to dete rmine whether or not the risk estimates were of concern. The DWLOC is the highest concentr ation of 2,4-DB that could occur in drinking water resulting in risk estimates below the leve l of concern consideri ng the exposure from food sources. The resulting surface and ground wa ter acute EDWCs of 319 ppb and 0.51 ppb were

found to be below the calculated acute DWLO C of 18,000 ppb for females 13-49 years old, and are therefore not of concern. Chronic EDWCs of 72 ppb and 0.51 ppb for surface and groundwater were likewise found to be below th e chronic DWLOCs of 1,050 ppb for the general U.S. population and 290 ppb for all infants < 1 y ear old, and are theref ore not of concern.

A new dietary assessment may be necessary if new drinking water estimates are provided, or if changes occur to the risk assessment endpoints, po ints of departure, or uncertainty factors.

Conclusions : The 2,4-DB residue chemistry database is incomplete and inadequate to support registration review due to the need for obtaining additional geogr aphically representative field

9 2,4-DB: Drinking Water Assessment for the Health Eff ects Division (HED) Reregistration Eligibility Decision Document. A. Al-Mudallal, Chemist. 7/8/2003. D279637.2,4-DB: Human Health Risk Assessment Scoping Document in Support of Regist ration Review

Page 8 of 22 trial data for clover forage and hay. During registration review, updated dietary exposure assessments may be conducted upon submission of the additional clover forage and hay data, and/or if there are any significant changes to the toxicol ogical PODs or FQPA and other UFs. In addition, any significant changes to the EDWCs ma y also necessitate changes to the dietary

assessment.

Residential (Non-Occupational) Exposure

There are no registered reside ntial uses of 2,4-DB and, theref ore, a quantitative exposure/risk

assessment for direct residentia l applications is not necessary during registration review.

Residential Bystander Exposures

Residential exposures resulting from off-site tr ansport (i.e., spray drift or volatilization) may occur as a result of agricultural applications of 2,4-DB. The Agency is in the process of evaluating these types of exposures and may, as appropriate, develop polic ies and procedures to identify the need for and, subsequently, the wa y to incorporate these pos t-application exposures into the Agency's risk assessments. The need for spray drift and volat ilization risk assessment for 2,4-DB will be examined during Registration Review

.

Conclusions: There are no registered re sidential uses of 2,4-DB and, therefore, a quantitative exposure/risk assessment for direct residential application is not neces sary during registration review. The potential for residential exposures resulting from off-site transport (e.g., spray drift or volatilization) may need to be quantitativ ely evaluated for 2,4-DB during the registration review process.

Aggregate Risk Assessment

In accordance with the Food Qua lity Protection Act (FQPA), HED must consider and aggregate pesticide exposures and risks from three majo r sources: food, drinking wa ter, and residential exposures. There are no regist ered residential uses for 2,4- DB; therefore, a quantitative aggregate assessment for direct residential appl ications is not necessa ry during registration review. The acute and chronic ag gregate risk assessments for 2,4-DB included food and drinking water only.

Acute

The 2004 HHRA acute aggregate risk assessment a ddressed exposure to 2,4-DB residues in food and water using the DWLOC approach describe d above. The resulting surface and ground water acute EDWCs of 319 ppb and 0.51 ppb were found to be below the calculat ed acute DWLOC of 18,000 ppb for females 13-49 years old, and are therefore not of concern.

Chronic

Chronic DWLOCs were calculate d based on chronic dietary expos ures to 2,4-DB in food and water. The most highly exposur e population subgroup was all in fants < 1 year old. Chronic2,4-DB: Human Health Risk Assessment Scoping Document in Support of Regist ration Review

Page 9 of 22 EDWCs of 72 ppb and 0.51 for surface and groundwat er were likewise found to be below the chronic DWLOCs of 1,050 ppb for the general U.S. population and 290 ppb for all infants < 1 year old, and are therefore not of concern.

Conclusions : In 2004 there were no aggregate (food a nd water) risk estimates of concern for 2,4-DB. During registration re view, updated aggregate assess ments may be conducted as required to include any significan t change that might occur for toxicological PODs, FQPA and uncertainty factors, dietary exposure estimates , or EDWCs. Emergi ng policies related to pesticide drift and volatilization assessments may dictate further changes to the existing aggregate risk assessment.

Occupational Exposure

Occupational Handler Exposure

The active ingredient 2,4-DB, including its di methylamine salt, 2,4-DB DMAS, are registered for use on alfalfa, peanuts, mint, and soybeans wi th one or two applications allowed per growing season. 2,4-DB is formulated as soluble, emulsifi able, or flowable concentrates. 2,4-DB can be applied either as a broadcast app lication early season, or a directed spray late season aerially or by ground equipment resulting in the potential for occupational exposures.

Occupational handler exposure s cenarios include: mixing/loadi ng all formulations; applying formulations by aerial or groundboom equipment; a nd flagging. Occupational handler exposures are expected to be short- and in termediate-term in duration. Due to the lack of dermal hazard for short-term exposures to 2,4-DB, only inhalation exposures were assessed for this exposure duration. Both dermal and inhalation exposures were assessed for intermediate-term risks and these exposures were combined because the endpoint is based on the same study.

As previously assessed for the 2004 RED, s hort-term inhalation and intermediate-term (combined dermal and inhalation) occupational handl er exposure/risks were not of concern to the Agency (i.e. an MOE ≥ 100) at some level of PPE.

Recommended unit exposures for oc cupational handler as sessments have generally been derived from the Pesticide Handlers Exposure Database (PHED). However, rece ntly both the Outdoor Residential Exposure Task Force (ORETF) and th e Agricultural Handler Exposure Task Force (AHETF) have produced pesticide handler exposure monitoring data that the Agency is using in place of PHED ( http://www.epa.gov/pesticides/sci ence/handler-exposure-data.html ). As more reliable data become available, the Agency will continue to replace existing data. Reviewers will incorporate new exposure monitoring data, as necessary, during registration review.

Conclusions: An updated occupational handler asse ssment may be required under registration

review if warranted to reflect the most recent occupational handler surrogate exposure data 10 and by any significant change in exposure assessmen t methodology, toxicological PODs, or UFs.

10 Outlined in the “Occupational Pesticide Handler Un it Exposure Surrogate Refe rence Table” available at http://www.epa.gov/pesticides/science/handler-exposure-data.html2,4-DB: Human Health Risk Assessment Scoping Document in Support of Regist ration Review

Page 10 of 22 Further, the need for a dermal exposure/risk assessment may be reeval uated during registration

review.

Occupational Post-application Exposure

Occupational post-applica tion dermal exposures can occur from post-emergent, broadcast foliar uses of 2,4-DB. 2,4-DB is typically applied on ce or twice per season and, therefore, it is anticipated that exposures are primarily short-term in nature; however, becau se there is no hazard for short-term dermal exposures these we re not assessed for the 2004 RED. Although considered unlikely, intermediate-term post-appli cation dermal exposure/risks were assessed to address exposures over this time course. The intermediate-term dermal POD was used to

conduct this assessment. Due to the conservative nature of the assessment of intermediate-term post-application exposures to 2,4- DB, average (typical) applicati on rates were used. Chemicalspecific dislodgeable foliar residue (DFR) da ta were not available for 2,4-DB; default dislodgeable residue inputs were used for fo liar post-application e xposure scenarios.

As assessed for the 2004 RED, intermediate-term pos t-application dermal exposures were not of concern on the day of a pplication (Day 0).

Recommended transfer coefficients for occupa tional post-application a ssessments are derived from Agricultural Reentry Task Force (ARTF) exposure monitoring studies ( http://www.epa.gov/pesticides/sci ence/post-app-exposure-data.html ). These transfer coefficients were updated in 2012 based on a reanal ysis and submission of new monitoring data. Reviewers will incorporate new exposure monito ring data, as necessary, during registration

review.

In accordance with the updated Part 158 data requi rements (2007), one or more DFR studies are required when a pesticide has residential or occupational uses that could result in postapplication dermal exposure. As part of the recent revision to the Health Effects Division’s 2012 Standard Operating Procedures for Resi dential Pesticide Exposure Assessment , HED analyzed a

number of DFR studies and select ed a new default value for the fr action of the application rate available to be dislodged after a foliar application (F AR ). This default value is 25% (previously 20%). Of the analyzed DFR studies, the maximum F AR value seen was 89% or 3.6 times higher

than the default residue transfer value. Ther efore, a calculated MOE of approximately 4 times higher than the LOC, i.e. an MOE > 400 if th e LOC = 100, using the default dislodged residue value should provide an adequate margin of safe ty for any potentially higher residues seen in a chemical-specific DFR study ( Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Folia r Residue (DFR) Studies . 6/7/2012, Exposure Science Advisory Council). In a screening level a ssessment, some of the estimated dermal post-application MOEs for 2,4-DB were less than 4 times the LOC (< 400). It should be noted, however, that the assessment of intermediate-term post-applicatio n exposures to 2,4-DB wa s highly conservative for the following reasons: intermediate-term pos t-application exposure is unlikely given that 2,4-DB is applied only once or twice per season; and the use of an intermediate-term POD from a subchronic oral study to assess dermal exposures , especially given the lack of short-term dermal hazard. Due to the conservative nature of the post-application exposure assessment and2,4-DB: Human Health Risk Assessment Scoping Document in Support of Regist ration Review

Page 11 of 22 lack of risks of concern (i.e., MOEs are > 100) using the default DFR data, chemical specific DFR data are not being re quired at this time. Restricted Entry Interval (REI)

2,4-DB is Acute Toxicity Category III or IV for acute dermal, inha lation, and oral toxicity, and primary skin irritation. 2-4-DB is Acute Toxi city Category IV for pr imary eye irritation. However, 2,4-DB-DMAS is Acute Toxicity Categor y I for eye irritation. Therefore, regardless of the lack of occupational post-application e xposures/risks of concern on Day 0, a 48 hour REI is required under the Worker Protection Standard (WPS).

Conclusions: The occupational exposure database is complete for 2,4-DB. There were no occupational handler or post-application e xposure estimates of concern. An updated occupational handler or post-a pplication exposure assessment ma y be required under registration review if warranted by any significant change in exposure assessment methodology, toxicological PODs, or UFs. The need for occu pational dermal exposure/risk assessment may be reevaluated during regi stration review.

Public Health and Pesticide Epidemiology Data

The Agency has reviewed the HED has evaluated the available incident data 11 and concludes that based on the low frequency and severity of incide nt cases reported for 2,4-DB, there does not appear to be a concern at this time that woul d warrant further investigation. The Agency will

continue to monitor the incident information a nd if a concern is triggered, additional analysis

will be included in the risk assessment.

Tolerance Assessment and International Harmonization

Permanent tolerances are established under 40 CFR §180.331(a) for the registered uses of 2,4- DB on alfalfa, clover, peanuts, soybean, peppermint, spearmint, and trefoil. There are currently no Mexican, Canadian or Codex MRLs estab lished for 2,4-DB on any crop or livestock commodities and, as a result, in ternational harmonization of maximum residue limits is not currently required.

Environmental Justice

Potential areas of environmental ju stice concerns, to the extent po ssible, were considered in the

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

"Federal Actions to Address Environmental Ju stice in Minority Populations and Low-Income Populations," http://www.epa.gov/fedreg/eo/eo 12898.htm. The Office of Pesticide Programs (OPP) typically considers the highest potential expos ures from the legal use of a pesticide when conducting human health risk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural area s, the variability of diets within the U.S. (including different ages, regi ons, and ethnicities), and peopl e who may be exposed when harvesting crops. Should these highest exposures i ndicate potential risks of concern, OPP further

11 2,4-DB: Tier I Review of Human Incidents: E. Evans and S. Recore. 9/4/2013. D4145462,4-DB: Human Health Risk Assessment Scoping Document in Support of Regist ration Review

Page 12 of 22 refines the risk assessments to ensure that th e risk estimates are based on the best available

information.

Cumulative Risk Assessment

The FQPA requires the Agency to consider the cumulative risks of chemicals sharing a common mechanism of toxicity. 2,4-DB is a member of the alkylphenoxy herbicide class of pesticides. This class also includes MCPA, 2,4-D and 2,4-DP. Although the various phenoxy herbicides have similar structural component s, HED has not made a determination that they have a common mode of toxic action. Therefore, a cumulative risk assessment has not been performed for these compounds.

Human Studies

Past 2,4-DB risk assessments rely in part on da ta from studies in which adult human subjects were intentionally exposed to a pesticide or ot her chemical. These data, which include studies from Pesticide Handlers Exposure Database Ve rsion 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) data base; the ARTF database; and the Outdoor Residential Exposure Task Force (ORETF) database, are (1) s ubject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with appli cable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 12

.

Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews num erous studies to asse ss potential adverse outcomes from exposure to chemicals. Collectiv ely, these studies includ e acute, subchronic and chronic toxicity, including asse ssments of carcinogenicity, ne urotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include e ndpoints which may be susceptible to endocrine influe nce, including effects on endocri ne target organ histopathology, organ weights, estrus cyclicity, sexual maturatio n, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess gr owth, developmental and reprod uctive effects in different taxonomic groups. As part of its most recent registration decision for 2,4-DB, EPA reviewed these data and selected the most sensitive endpoint s for relevant risk assessment scenarios from the existing hazard database. However, as requi red by FFDCA section 408(p), 2,4-DB is subject to the endocrine screening pa rt of the Endocrine DisruptorScreening Program (EDSP).

EPA has developed the EDSP to determine whet her certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or ot her such endocrine effect s as the Administrator may designate.” The EDSP employs a two-tiered approach to making th e statutorily required

12 http://www.epa.gov/pesticides/science/handler-exposure-data.html and http://www.epa.gov/opp00001/science/residential-exposure-sop.html2,4-DB: Human Health Risk Assessment Scoping Document in Support of Regist ration Review

Page 13 of 22 determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrog en, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go th rough Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stag e of the EDSP where EPA will determine which, if any, of th e Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify a ny adverse endocrine-related eff ects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pest icide active ingredients and 9 inert ingredients. A second list of

chemicals identified for EDSP scr eening was published on June 14, 2013 13 and includes some pesticides scheduled for Registration Review and chemicals found in water

. For further information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening battery, pleas e visit our website. 14

In the interim, EPA is making no human health or environmental safety findings associated with the EDSP screening of 2,4-DB. Before completing this Registration Review, the Agency will

make an EDSP FFDCA secti on 408(p) determination.

Risk Assessment Updates and Data Deficiencies

During registration review, updated exposure asse ssments may be conducted if there are any significant changes to 2,4-DB t oxicological endpoints, PODs, or FQPA and other UFs, and/or standard operating procedures, exposure data or assumptions. Data required and submitted during registration review will be considered for use in new 2,4-DB human health risk assessments. Any significant changes to the ED WCs may necessitate ch anges to the dietary exposure assessment. Further, the need for a re sidential bystander risk assessment of exposure resulting from off-site transport (i.e., spray drift or volatilizat ion) will be considered during registration review.

The following data deficiencies were identified for 2,4-DB:

Toxicology: 870.3465: 90-day Inhalation study 15

Residue Chemistry: 860.1500: Ten additional fiel d trials on clover forage and hay are required as recommended in the following Regions: 1 (Reg ion 1), 1 (Region 2), 1 (Region 4), 3 (Region 5), 1 (Region 6), 1 (Region 7), 1 (Region 8), and 1 (Region 9).

13 See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of

chemicals.

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

15 28-day inhalation study will be sufficient.2,4-DB: Human Health Risk Assessment Scoping Document in Support of Regist ration Review

Page 14 of 22 References

Table 1. Memoranda Relevant to Registration Review 1

. Author Barcode Date Title
K. Farwell D290486 6/20/2004 2,4-DB and 2,4-DB-DMA Human Health Risk Assessment

E. Evans and S.

Recore D414546 9/4/2013 2,4-DB: Tier I Review of Human Incidents

F. Fort D291221 7/13/2004 2,4-DB Acute and Chronic Di etary Exposure Assessments for the Reregistration Eligibility Decision

T. Dole D300629 5/3/2004 2,4-DB: Occupational and Residential Exposure and Risk Assessment for the Reregistration Eligibility Decision (RED) Document

D. Drew D291212 7/19/2004 2,4-DB [4-(2,4-cholorophenoxy) butyric acid] and 2,4-DB dimethylamine salt (PC Codes030801, 030819): Revised Product Chemistry and Re sidue Chemistry Summary Documents for the Registration Eligibility Decision Document (RED).

U. Habiba TXR No.

0056727 8/13/2013 2,4-DB/2,4-DB-DMA: Summary of Hazard and Science Policy Council (HASPOC) Meeting of July 25, 2013: Recommendations on the Requ irement of a Subchronic Inhalation Study, an Immunotoxi city Study, and the Acuteand Subchronic Neurotoxicity Studies for 2,4-DB/2,4-DBDMA.

A. Al-Mudallal D279637 7/8/2003 2,4-DB: Drinking Water Assessm ent for the Health Effects Division (HED) Reregistration Eligibility Decision

Document

D. Miller D220888 11/14/1995 2,4-DB: Metabolism Committee Question Re: Regulation

of Metabolites in Plant and Animal Commodities

D. Miller D221954 1/29/1996 2,4-DB: Results of the 1/16/96 Meeting of the HED

Metabolism Committee

1. This table only includes references to final versions. Previous versions of these docum ents are available, but have been super seded.

Attachments:

Attachment 1: Chemical Identity and Physicochemical Properties Attachment 2: 2,4-DB and 2,4-DB-DMAS Acute, Subchronic, and Chronic Toxicity Profile Attachment 3: 2,4-DB Toxicological Doses and Endpoints2,4-DB: Human Health Risk Assessment Scoping Document in Support of Regist ration Review

Page 15 of 22 Attachment 1. Chemical Iden tity and Physicochemical Properties

The chemical structures of 2,4-DB and 2,4-DB -DMAS, and physiochemical properties of 2,4- DB are presented in Tables A.1 and A.2 below.

Table A.1. Chemical Structure and Nomenclature of 2,4-DB and 2,4-DB-DMAS

Compound Chemical Structure

Common name 2,4-DB

Company code number None specified

IUPAC name 4-(2,4-dichlorophenoxy)butyric acid

Chemical abstract name 4-(2,4-dichlorophenoxy)butanoic acid

CAS registry number 94-82-6

Compound Chemical Structure

Common name 2,4-DB-DMAS

Company code number None specified

IUPAC name 4-(2,4-dichlorophenoxy)butyric acid dimethylamine salt

Chemical abstract name 4-(2,4-dichlorophenoxy)butyric acid dimethylamine salt

CAS registry number 2758-42-1

Table A.2. Physiochemical Properties of 2,4-DB

Parameter Value Reference

Melting point/range 113.5-117.5 °C D198970, 9/30/94, F. Toghrol

pH (20 °C) 4.31 (1% w:v) D198970, 9/30/94, F. Toghrol

Density (22 °C) 1.461 D198970, 9/30/94, F. Toghrol

Water solubility (25 °C) 46 ppm D161375, 7/9/91, F. Toghrol

Solvent solubility (25 °C) 100 g/L in acetone

50 g /L in ethanol D161375, 7/9/91, F. Toghrol

Vapor pressure 7.1 x 10 -7 mm Hg at 23.6 °C DEB No. 6823, 8/3/90, G. Makhijani

Dissociation constant, pK a 3.0 x 10 -5 DEB No. 6823, 8/3/90, G. Makhijani

Octanol/water partition coefficient, Log(K OW ) 2.62 DEB No. 6823, 8/3/90, G. Makhijani2,4-DB: Human Health Risk Assessment Scoping Document in Support of Regist ration Review

Page 16 of 22 Table A.2. Physiochemical Properties of 2,4-DB

Parameter Value Reference

UV/visible absorption spectrum Three distinct bands at 202, 229, and 284 nm; no appreciable

differences in the extinction coefficients between acidic, neutral, and basic solutions. D286840, 1/9/03, S. Malak2,4-DB: Human Health Risk Assessment Scoping Document in Support of Regist ration Review

Page 17 of 22 Attachment 2. 2,4-DB and 2,4-DB-DMAS Acute, Subchronic, and Chronic Toxicity Profile

Acute Toxicity - 2,4-DB Technical

Guideline

No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute Oral 00128854

0092159 LD 50 = 1935 mg/kg

LD 50 = 1715 mg/kg III

870.1200 Acute Dermal 0128854 LD 50 = > 2000 mg/kg III

870.1300 Acute Inhalation 41774001 LC 50 > 2.3 mg/L IV

870.2400 Primary Eye Irritation 0128854

00092160 Eye irritation with complete clearing by day 7 III

870.2500 Primary Skin Irritation 0128854 No irritation IV

870.2600 Dermal Sensitization 43593904 Not a dermal sensitizer

—

Acute Toxicity - 2,4-DB-DMAS (26%)

Guideline

No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute Oral 41224401 LD50 = 3583 m g /k g III

870.1200 Acute Dermal ( rabbit ) 41224402 LD50 > 2000 m g /k g III

870.1300 Acute Inhalation 41370101 LC50 > 7.98 m g /L IV

870.2400 Primary Eye Irritation 41958001 Pers istent corneal opacity, iritis,

er y thema I

870.2500 Primar y Skin Irritation 250871 Irritation score = 0.99 IV

870.2600 Dermal Sensitization 43968911 Not a dermal sensitizer

—

Subchronic, Chronic, and Other Toxicity Profile – 2,4-DB

Guideline No./

Study Type MRID No. (year)/

Classification /Doses Results

870.3100 90-Day oral toxicity

rats 00104739 (1969) acceptable/guideline 0, 316, 1000 or 3160 ppm (0, 15.8, 50 or 158 mg/kg/day LOAEL =1000 ppm (50 mg/kg/day)., based on decreased body weight gain, increased relative liver and kidney weight, microscopic alterations in the liver, kidneys and stomach.

NOAEL = 316 ppm (15.8 mg/kg/day)

870.3150 90-Day oral toxicity dogs 00092165 (1969) acceptable/guideline capsules at 8, 25 or 80 mg/kg/day; group of 4 dogs/sex was also treated with capsules at 2.5 mg/kg/day for three LOAEL = 25 mg/kg/day, based on death (sacrifice in

extremis ), clinical signs of toxic ity, decreased body weight, decreased hematology parameters, altered clinical chemistry parameters, increased relative weight of liver, kidney and spleen, and gross and microscopic necropsy evidence of generalized toxicity.2,4-DB: Human Health Risk Assessment Scoping Document in Support of Regist ration Review

Page 18 of 22 Subchronic, Chronic, and Other Toxicity Profile – 2,4-DB

Guideline No./

Study Type MRID No. (year)/

Classification /Doses Results

months. NOAEL = 8 mg/kg/day

870.3200 21-day dermal -

rabbit 41551301 (1989) acceptable/guideline 0, 500, 1000, 2000 mg/kg/day The LOAELs for systemic toxi city and dermal irritation

were not established. The NOA ELs for systemic toxicity and dermal irritation were 2000 mg/kg/day (HDT).

870.3700a

Prenatal developmental in

rats MRID 41382701 (1990) acceptable/guideline 0, 31.25, 62.5 or 125 mg/kg/day Maternal LOAEL = 62.5 mg/kg /day, based on decreased body weight (days 6-16) and body weight gain (days 0-20).

One maternal death was attri buted to treatment at 125 mg/kg/day. Maternal NOAEL = 31.25 mg/kg/day.

Developmental LOAEL = 125 mg/kg/day, based on decreased fetal body weight, skeletal malformations/ variations, microphthalmia, retr oesophageal aortic arches. Developmental NOAEL = 62.5 mg/kg/day.

870.3700b

Prenatal developmental in

rabbits MRID 41529902 (1990) acceptable/guideline 0, 15, 30 or 60 mg/kg/day Maternal LOAEL = 60 mg/kg/day, based on mortality, clinical signs of toxicity (loss of coordination, reduced activity, ataxia, prostration, and/or yellow discharge from eyes) and decreased body weight gains. Maternal NOAEL = 30 mg/kg/day.

Developmental LOAEL was not determined. Developmental NOAEL = 60 mg/kg/day (HDT).

870.3800 Reproduction and fertility effects MRID 40257503 (1986) acceptable/guideline 0,60, 300 or 1500 ppm (Males: 0, 5, 25 or 112 mg/kg/day and Females: 0, 6, 30 and 133 mg/kg/day) Parental LOAEL = 1500 ppm (112 mg/kg/day in males and 133 mg/kg/day in females), based on increased water consumption, decreased food consumption and body weight,

increased food conv ersion ratio, organ weight changes and macroscopic renal findings. Parental NOAEL = 300 ppm ( 25 mg/kg/day in males and 30 mg/kg/day in females).

Offspring LOAEL = 1500 ppm (112 mg/kg/day in males and 133 mg/kg/day in females), based on increased mortality, decreased mean litter weight and increased incidence of necropsy findings (small thymus, distended bladder with bloody/dark urine and ocular opacity). Offspring NOAEL = 300 ppm (25 mg/kg/day in males and 30 mg/kg/day in females).

No effect upon reproductive parameters.

870.4100b Chronic toxicity in dogs MRID 42006301 (1990) acceptable/guideline 0, 75, 225 or 450 (reduced from 675 ppm after week 6) (0, 2.39, 6.07 and 12.94 mg/kg/day for males; 2.15, 7.06 and 14.16 mg/kg/day for females) LOAEL = 75 ppm (2.39 and 2.15 mg/kg/day in males and females, respectively) based on clinical pathology changes (increased BUN, ALT and AST), decreased liver and kidney weights (females) and microscopic changes in the kidney.

NOAEL has not been established.2,4-DB: Human Health Risk Assessment Scoping Document in Support of Regist ration Review

Page 19 of 22 Subchronic, Chronic, and Other Toxicity Profile – 2,4-DB

Guideline No./

Study Type MRID No. (year)/

Classification /Doses Results

870.4200 Carcinogenicity in

mice 40257502 (1987) acceptable/guideline 0, 25, 250 or 750 ppm (equivalent to 0, 3.75, 37.5 and 112.5 mg/kg/day based on 7 ppm in the diet equals 1 mg/kg/day) LOAEL = 750 ppm (112.5 mg/kg/day), based on increased mortality in males and increased absolute and relative organ weights (liver and kidney in both sexes, heart in males), gross pathological changes in liver and kidney (males) and increased amyloidosis and hepatocellular enlargement (males).

NOAEL = 250 ppm (37.5 mg/kg/day)

870.4300 Chronic Toxicity/ Carcinogenicity in

rats MRID 40257501(1987) acceptable/guideline 0, 60, 600 or 1800 ppm (equivalent to 0, 3, 30 or 90 mg/kg/day based on 1 ppm equals 0.05 mg/kg) LOAEL in males = 1800 ppm (90 mg/kg/day) based on decreased body weight, body weight gain and food consumption, clinical pathology changes and necropsy alterations (decreased kidney weights, increased incidence of kidney foci and infarcts and liver mononuclear infiltration and spongy degeneration). LOAEL in females = 600 ppm (30 mg/kg/day), based on decreased body weight gain and food consumption. NOAEL in males = 600 ppm (30 mg/kg/day) NOAEL in females = 60 ppm (3 mg/kg/day).

870.5265

Gene Mutation - Ames assay MRID 40257504 (1987) Acceptable/guideline 0, 1, 10, 100, 500, 1000, 2500, 5000, or 10000 μg/plate TA1535, TA1537, TA1538, TA98, TA100 Negative for mutagenic activity with and without S9

870.5300

Forward mutation

assay (CHO/HGPRT) MRID 40257505 (1987)Unacceptable/nonguideline Negative without S9; weakly or presumptively positive with

S9

870.5375

In vitro

chromosomal

aberration MRID 40257506 (1987) Acceptable/guideline 250, 500, 750, 1000 μg/mL Without S9 positive; with S9, negative. Significant increase in chromo somal aberrations in CHO cells at 750 and 1000 μg/mL without S9 (17.25 hr exposure); increases at 250 and 500 μg/mL not statistically significant; no increase at up to 1000 μg/mL with S9 with 2 hr exposure; ppt at 1890 μg/mL

870.5550

Unscheduled DNA synthesis MRID 40257507 (1987) Acceptable/guideline 0.997-99.7 μg/mL No evidence of UDS induction at doses at which there was >50% cell viability; lethal at >99,7 μg/mL; some evidence of cytotoxicity at 24.9-99.7 μg/mL

870.7485

Metabolism and pharmacokinetics in

rats 41981601 (1991) acceptable/guideline Single i.v. and oral doses and multiple oral dosing. Radioactivity recovery in urine was 71.5-97.6% of dose and 3.5-13.8% in feces. Major metabolites were 2,4-D and conjugated 2,4-DCP.

870.7485

Metabolism and pharmacokinetics in

rats MRID 44774101(1999) acceptable/guideline Single oral dose and 2

bile-duct cannulated

males. Biliary excretion and enterohepa tic recirculati on occurred. Metabolite G was identified 4-(2,4-dichlorophenoxy)-3- hydroxybutyric acid. The distribution of metabolites in the present study was comparable to the distribution observed in the previous rat metabolism study.2,4-DB: Human Health Risk Assessment Scoping Document in Support of Regist ration Review

Page 20 of 22 Subchronic, Chronic, and Other Toxicity Profile – 2,4-DB-DMAS

Guideline No./

Study Type MRID No. (year)/

Classification /Doses Results

870.3200 21-day dermal -

rabbit 41529901 (1990) acceptable/guideline 0, 250, 750 or 1500 mg/kg/day The systemic LOAEL was not established. The systemic NOAEL was 1500 mg/kg/day. The dermal irritation LOAEL was 750 mg/kg/day based on erythema, desquamation and fissuring which were more severe than control lesions. The dermal NOAEL was 250 mg/kg/day.

870.3100 90-Day oral toxicity

rodents 41775401 (1990) acceptable/guideline 0, 60, 600 or 1800 ppm (0, 4.16, 41.86 and 130.37 mg/kg/day for males and 0, 4.96, 51.36 and 153.64 mg/kg/day for females) LOAEL = 600 ppm (41.86 mg/kg/day in males and 51.36 mg/kg/day in females), based on decreased body weight and body weight gain (females), increased kidney weights and

increased incidence of tubular degeneration (females). NOAEL = 60 ppm (4.16 mg/kg/day in males and 4.96 mg/kg/day in females).

870.3700a

Prenatal developmental in

rats 42536101, 42595201 (1991) acceptable/guideline 0, 31.25, 62.5 or 125 mg/kg/day Maternal LOAEL = 62.5 mg/kg/day, based on emaciation and decreased body weight gain and food consumption.

There were 3 maternal deaths a ttributed to treatment at 125 mg/kg/day. Maternal NOAEL = 31.25 mg/kg/day.

Developmental LOAEL = 125 mg/kg/day, based on an increase in early resorptions per dam, skeletal malformations, microphthalmia, and a decrease in fetal weight. Developmental NOAEL = 62.5 mg/kg/day.

870.5300

In vitro Forward mutation assay (CHO/HGPRT) MRID 41810701 (1990) Acceptable/guideline Did not induce forward mutation at the HGPRT locus in

CHO cells with or without metabolic activation

870.7600 Dermal penetration

rat 44729501 (1998) Dermal absorption factor = 23%. This value is from a 120 ug/cm 2 exposure determined at 96 hours after a wash at 10

hours.2,4-DB: Human Health Risk Assessment Scoping Document in Support of Regist ration Review

Page 21 of 22 Attachment 3. 2,4-DB Toxicological Doses and Endpoints

Summary of Toxicological Doses and Endpoints - 2,4-DB

Exposure

Scenario Dose for Risk

Assessment and

Uncertainty

Factor Special FQPA Safety

Factor and Level of

Concern Study and Toxicological Effects

Acute Dietary (Females 13-50 years of age) NOAEL = 62.5 mg/kg/day

UF = 100

Acute RfD = 0.6 mg/kg/day FQPA SF = 1X

aPAD = acute RfD FQPA SF = 0.6 mg/kg/day Rat developmental toxicity. LOAEL = 125 mg/kg/day based on skeletal variations/ malformations, microphthalmia, post-implantation loss

Acute Dietary (General population including infants and children) None N/A No appropriate endpoint attributable to a single dose from oral toxicity studies.

Chronic Dietary (All populations) NOAEL= 3 mg/kg/day

UF = 100

Chronic RfD = 0.03 mg/kg/day FQPA SF = 1X

cPAD = chronic RfD FQPA SF = 0.03 mg/kg/day Chronic/carcinogenicity study in rats. LOAEL = 30 mg/kg/day based on decreased body weight gain and food consumption in females 1

Short-Term

Dermal (1 to 30 days) None N/A Quantitation not required. No systemic toxicity via the dermal route and there are no developmental concerns.

2 IntermediateTerm

Dermal (1 to 6 months) Oral NOAEL = 15.8 mg/kg/day Residential MOE = 100

Occupational

MOE = 100 Subchronic rat toxicity (2,4-DB study) LOAEL = 50 mg/kg/day based on decreased body weight gain, increased relative liver/kidney weight, and microscopic changes

2 Long-Term Dermal (> 6 months) Oral NOAEL = 3 mg/kg/day

(dermal absorption = 23%) Residential MOE = 100

Occupational

MOE = 100 Chronic/carcinogenicity study in rats. LOAEL = 30 mg/kg/day based on decreased body weight gain and food consumption in females.

Short-Term

Inhalation (1 to 30 days) Oral NOAEL = 31 mg/kg/day

(inhalation absorption = 100%) Residential MOE = 100

Occupational

MOE = 100 Rat developmental toxicity. LOAEL = 62.5 mg/kg/day based on decreased maternal body weight, body weight gain, and food consumption, and clinical signs (emaciation, few feces)

Intermediate-Term

Inhalation (1 to 6 months) Oral NOAEL = 15.8 mg/kg/day

(inhalation absorption = 100%) Residential MOE = 100

Occupational

MOE = 100 Subchronic rat toxicity (2,4-DB study). LOAEL = 50 mg/kg/day based on decreased body weight gain, increased relative liver/kidney weight, and microscopic changes

Long-Term

Inhalation (>6 months) Oral NOAEL = 3 mg/kg/day

(inhalation Residential MOE = 100

Occupational

MOE = 100 Chronic/carcinogenicity study in rats. LOAEL = 30 mg/kg/day based on decreased body weight gain and food consumption in females.2,4-DB: Human Health Risk Assessment Scoping Document in Support of Regist ration Review

Page 22 of 22 Summary of Toxicological Doses and Endpoints - 2,4-DB

Exposure

Scenario Dose for Risk

Assessment and

Uncertainty

Factor Special FQPA Safety

Factor and Level of

Concern Study and Toxicological Effects

absorption = 100%)

Cancer None N/A Classified "not likely to be a human carcinogen".

1 Endpoint should be reevaluated, base d on the minimal decrease in BW. 2 Dermal assessment should be reevaluated based on current policy (no systemic toxicity at limit dose; no developmental concerns; no progression of kidney/liver toxicity with duration of exposure). UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no observed adverse effect level, LOAE L = lowest observed adverse effect level, PAD = population adjusted dose, (a = acute, c = chr onic), RfD = reference dose, MOE = margin of exposure, LOC = level of concern, NA = Not Applicable