2,4-D. The core USA EPA studies to assess toxicity (safety) of 2,4-D are industry funded.

 2013-06-24 044EPA Reregistration Eligibility Decision for 2,4-D.

Core Studies Financed by Whom?

NOTES: This paper lists the actual studies used in the USA EPA Reregistration Eligibility Decision (RED) for 2,4-D under the section III ‘A. Human Health Risk Assessment’.

The studies under the Human Health Risk Assessment section are the core studies that demonstrate that 2,4-D is safe to the general population, the results of these studies become the levels of accepted safe consumption of the pesticide for humans and animals.

Carcinogenicity studies also contribute to providing carcinogenicity rating of 2,4-D, that of Group D – Non-carcinogenic to humans.  The finding of Group D is essential to ongoing sales of the pesticide to the producer of the pesticide, as it carries with it a much lower restriction than that of ‘carcinogenic’.

June 2005 is the most recent USA EPA revision of 2,4-D – the Reregistration Eligibility Decision (RED). 

It is possible to examine the EPA IRIS database however it gives only a limited amount of studies.

June 2005 EPA 2,4-D RED provides the relevant studies in ‘Tables’  – previously the EPA had written up complete study descriptions to advise these results.  The 2005 2,4-D RED simply advises the MRID and author details provided.  There is less public information than in previous years.  It is more difficult to identify who actually paid for the study.

As these studies in the original EPA 2,4-D RED are provided in ‘Tables’, the supplier/financer/author of the studies are not directly accessible.  This paper endeavours to provide the missing links and demonstrate who these orgaanisations are.

Many studies listed on the original EPA 2,4-D RED have been cross referenced in this paperwith the WHO/FAO 2,4-D Toxicological Evaluation studies in order to better identify the supplier/author.

This paper seeks to only identify the studies used to identify toxicological safety of 2,4-D, therefore other information is confusing and unnecessary and can be found in the original EPA 2,4-D RED.

Note: Industry Task Force II on 2,4-D Research Data includes Dow Agrosciences (USA); Nufarm Ltd (Aust.) and Agro-Gor Corporation (USA & Argentina). Many studies held with the EPA do not hold the study sponsors details.  The European Union includes these details in their Review Report for the Active Substance 2,4-D (The EU equivalent of this 2,4-D RED). This documents contains the information of providers, in many cases the individual organisations that contributed towards the Industry studies. I have cross referenced to identify the study providers and you will find these abbreviations in the body of this paper.

(INT)=INTERAG, (BAS)=BASF, (GIL)=GILMORE INC, (FAR)= FARMLAND, (GOR)= P.B.I. GORDON, (TRA)=TRANSBASS, (AHM)= A.H. MARKS, (AZC)= AKZO, (CHL)= CHEMIE LINZ, (AGL)= AGROLINZ, (DAS,
DOE)=DOW, (MOB & FER)= MOBAY BAYER & FERMMENTA, (RPA, ROP)= RHONE-POULENC, (AGR)= AGROGOR (consortium Agrolinz ñ PBI Gordon), (NUF)= NUFARM

The contents page below ONLY includes references to the Section Heading on the original EPA 2,4-D RED if there is an indication of a study that will provide parameters of toxicological safety to the human population (ie. be used as a reference to establish whether 2,4-D is safe or not).

Therefore ONLY pages with references to studies (the study number, the MRID); or NOAELs (No Observeable Effect Level which are the result of a study) which gives a dose considered to be of no toxicity – are included in the following Contents page as they are deemed useful for the purpose of this paper.

2,4-D – the Reregistration Eligibility Decision (RED)

Contents:           EPA RED Page No.              

III. Summary of 2,4-D Risk Assessment 15

A. Human Health Risk Assessment 15

1. Toxicity of 2,4-D   15

a. Toxicity Profile    15

b. Safety and Database Uncertainty Factors    18

c. Carcinogenicity     19

d. Cumulative Assessment   20

e. Endocrine Effects  20

NB. This article also includes data supplied 2010 as a result of this 2005 RED demand for more data.

f. Toxicological Endpoints for Risk Assessment  20

4. Residential & Other Non-occupational Exposure     27

a. Toxicity   28

b. Residential Handler    29

c. Residential Postapplication Risk   32

d. Recreational Swimmer Risk    34

5. Aggregate Exposure and Risk     38

a. Acute Aggregate Risk Assessment  38

b. Chronic Aggregate Risk Assessment   40

c. Short-term Aggregate Risk Assessments    41

d. Cancer Aggregate Risk     42

6. Occupational Risk    43

a. Occupational Toxicity 43

8. Cancer Epidemiology Studies  52

Appendix B               178

Additional carcinogenicity studies not included in main body of 2,4-D RED.

Summary

 

 1.     Toxicity of 2,4-D

(a)   Toxicity Profile.

Table 6. Acute Toxicity Data for 2,4-D acid, 2,4-D ester forms and 2,4-D amine salts. P.16

ACUTE ORAL

00101605 Johnson, D.; Myer, J.; Moxon, P.; et al. (1981) Determination of Acute Oral LD50 in Fischer 344 Rats: 2,4-Dichlorophenoxyacetic Acid, Technical: 490- 001. Rev. (Unpublished study received Dec 21, 1981 under unknown admin. no.; prepared by International Research and Development Corp., submitted by Dow Chemical U.S.A., Midland, MI; CDL:247499-C).  INT, BAS, GIL, FAR, GOR, TRA, AHM, AZC, CHL, DOE, MOB&FER, ROP, NUF**

41920901 Shults, S.; Brock, A.; Killeen, J. (1990) Acute Oral Toxicity (LD50) Study in Rats with Diethanolamine Salt of 2,4-D: Lab Project Number:90-0161: 3592- 90-0161-TX-001. Unpublished study prepared by Ricerca, Inc. 37 p.  PBI/Gordon Inc., Kansas City, MO, USA.

00157512 Jeffrey, M.; Battjes, J.; Eisenbrandt, D. (1986) DMA 6 Weed Killer: Acute Oral Toxicity Study in Fischer 344 Rats. Unpublished study prepared by Dow Chemical U.S.A. 15 p.

00252291 Alexander, H.; Mayes, M.; Gersich, F.; et al. (1983) The Acute Toxicity of (2,4-Dichlorophenoxy) Acetic Acid Isopropylamine Salt to Representative Aquatic Organisms: ES-626. (Unpublished study received Jan 18, 1984 under 464-596; submitted by Dow Chemical U.S.A., Midland, MI; CDL:252291-D)

41709901 Lilja, H. (1990) Acute Oral Toxicity Study (LD50): Hivol-44: Amended Report: Lab Project Number: 88G-0274. Unpublished study prepared by Toxikon Corp. 17 p.

41413501 Berdasco, N.; Schuetz, D.; Jersey, G. et al. (1989) 2,4-Dichlorophenoxyacetic Acid Triisopropanolamine Salt: Acute Oral Toxicity Study in Fischer 344 Rats: Lab Project Number: K-008866-002A. Unpublished study prepared by The Dow Chemical Co. 33 p.

40629801 Jeffrey, M.; Battjes, J.; Lomax. L. (1987) 2,4-D Butoxyethyl Ester, Technical: Acute Oral Toxicity Study in Fischer 344 Rats: Lab. Proj. ID K-007722-006A. Unpublished study prepared by Dow Chemical Co. 30 p

41209001 Mahlburg, W. (1988) Acute Oral Toxicity Study of DPD Ester in Sprague Dawley Rats: Project ID 88.3505.002; Study No. 89-19A. Unpublished study prepared by Food & Drug Research Laboratories. 95p.  Funded by Platte Chemical Company.

ACUTE DERMAL

00101596 Mayhew, D.; Johnson, Y.; Kingery, A. (1981) Acute Dermal Toxicity Study in Albino Rabbits with ITF-5; 2, 4-Dichlorophenoxyacetic Acid, Sodium Salt: Project No. WIL-81233. (Unpublished study received Jul 23, 1981 under unknown admin. no.; prepared by WIL Research Laboratories, Inc., submitted by Dow Chemical U.S.A., Midland, MI; CDL:247496-F)

41920911 Shults, S.; Brock, A.; Killeen, J. (1991) Acute Dermal Toxicity Study in Albino Rabbits with Diethanolamine Salt of 2,4-D: Lab Project Number: 90-0162: 3592-90-0162-TX-001. Unpublished study prepared by Ricerca, Inc. 25 p.   PBI/Gordon Inc., Kansas City, MO, USA.

00157513  Carreon, R.; Schuetz, D.; Lomax, L. (1986) DMA 6: Acute Dermal Toxicity Study in New Zealand White Rabbits: Study No. M-003637- 001. Unpublished study prepared by Dow Chemical U.S.A. 20 p.

00252291 – there appear to be no cited reference either held that are available to the public.

41709902 Lilja, H. (1990) Single Dose Dermal Toxicity: Hivol-44: Amended Report: Project Number: 88G-0272. Unpublished study prepared by Toxikon Corp. 14 p.

41413502 Berdasco, N.; Schuetz, B.; Yano, B. et al. (1989) 2,4-Dichlorophe- noxyacetic Acid Triisopropanolamine Salt: Acute Dermal Toxicity Study in New Zealand White Rabbits: Lab Project Number: K-008866 -002D. Unpublished study prepared by The Dow Chemical Co. 19 p.

40629802 Jeffrey, M.; Battjes, J.; Zimmer, M. (1987) 2,4-D Butoxyethyl Ester Technical: Acute Dermal Toxicity Study in New Zealand White Rab- bits: Lab. Proj. ID K- 007722-006D. Unpublished study prepared by Dow Chemical Co. 27 p.

41209002 Mahlburg, W. (1988) Acute Dermal Toxicity Study of DPD Ester in New Zealand White Rabbits: Project ID: 88.3505.003; Study No. 89-19A. Unpublished study prepared by Food & Drug Research Laboratories. 39 p.  Funded by Platte Chemical Company.

ACUTE INHALATION

00161660 Auletta, C.; Daly, I. (1986) An Acute Inhalation Toxicity Study of 2,4- D Acid in the Rat: Final Report: Project No. 86-7893. Unpublished study prepared by Bio/dynamics Inc. (Monsanto) 39 p.

41986601 Jackson, G.; Hardy, C. (1991) Diethanolamine Salt of 2,4-D: Acute Inhalation Toxicity in Rats/4-Hour Exposure: Lab Project Number RIC 15/901290: 90- 0163. Unpublished study prepared by Huntingdon Research Centre Ltd. OR Ricerca Laboratories, Painsville, OH, USA.  26 p.  PBI/Gordon Inc., Kansas City, MO, USA.

00157514 Streeter, C.; Battjes, J.; Lomax, L. (1985) DMA-6 Sequestered Weed Killer: Acute Aerosol Inhalation Study with Rats. Unpublished study prepared by Dow Chemical U.S.A. 13 p

40085501 Heydens, W. (1986) Acute Toxicity of Landmaster II Administered by Inhalation to Male and Female Sprage-Dawley Rats: Monsanto Reference No. EHL 86125. Unpublished study prepared by Monsanto Co., Environmental Health Laboratory. 45 p

40352701 Maedgen, J. (1986) Rat Acute Inhalation Toxicity: Tech. Isopropyl Ester of 2,4- D: Proj. No. 4377-86. Unpublished study prepared by Stillmeadow, Inc. 15 pSumitomo Chemical Company Co. Ltd. Tokyo, Japan.

41957601 Nitschke, K.; Stebbins, K. (1991) 2,4-D TIPA: Acute Inhalation Toxicity Study with Fischer 344 Rats: Lab Project Number: K-008866- 015. Unpublished study prepared by Dow Chemical Co. 33 p.

40629803 Streeter, C.; Battjes, J.; Yano, B. (1987) 2,4-D Butoxyethyl Ester, Technical: An Acute Aerosol Inhalation Study in Fischer 344 Rats: Lab. Proj. ID K-007722- 007. Unpublished study prepared by Dow Chemical Co. 22 p.

42605202 Cieszlak, F. (1992) 2,4-Dichlorophenoxyacetic Acid, 2-Ethylhexyl Ester: Acute Aerosol Inhalation Toxicity Study with Fischer 344 Rats: Lab Project Number: K-020054-015. Unpublished study prepared by Dow Chemical Co. 37 p.

PRIMARY EYE IRRITATION

41125302 Kirsch, P. (1983) Report on the Study of the Irritation to the Eye of the White Rabbit Based on Draize of 2,4-D: Doc. No. BASF: 83/ 0192. Unpublished study prepared by BASF Aktiengesellschaft. 10 p.

41920902 Shults, S.; Brock,A.; Killeen, J. (1990) Primary Eye Irritation Study in Albino Rabbits with Diethanolamine Salt of 2,4-D: Lab Project Number 90-0164: 3592- 90-0164-TX-001. Unpublished study prepared by Ricerca, Inc. 30 p. PBI/Gordon Inc., Kansas City, MO, USA.

00157515 Carreon, R. (1986) DMA 6: Primary Eye Irritation Study in New Zealand White Rabbits. Unpublished study prepared by Dow Chemical U.S.A. 9 p.

00252291 – there appears to be no cited reference either held that are available to the public.

40352702 Maedgen, J. (1986) Rabbit Eye Irritation: Tech. Isopropyl Ester of 2,4-D: Proj. No. 4374-86. Unpublished study prepared by Still- meadow, Inc. 16 p. Sumitomo Chemical Company Co. Ltd. Tokyo, Japan.

41413504  Berdasco, N.; Mizell, M. (1989) 2,4-D Acid isopropanolamine  Salt: Primary Eye Irritation Study in New Zea- land White Rabbits: Lab Project Number: K-008866-002C. Unpublished study prepared by The Dow Chemical Co. 14 p.

40629804 Jeffrey, M. (1987) 2,4-D Butoxyethyl Ester, Technical: Primary Eye Irritation Study in New Zealand White Rabbits: Lab. Proj. ID K-007722-006C. Unpublished study prepared by Dow Chemical Co. 11 p.

44725303 Cieszlak, F.; Brooks, K. (1998) Esteron 6E: Acute Primary Eye Irritation Study in New Zealand White Rabbits: Lab Project Number: 971165. Unpublished study prepared by The Dow Chemical Company. 16 p.

PRIMARY SKIN IRRITATION

42232701 Berdasco, N. (1992) 2,4-Dichlorophenoxyacetic Acid: Primary Dermal Irritation Study in New Zealand White Rabbits: Lab Project Number: K-002372-060. Unpublished study prepared by Dow Chemical Co. 14 p.

41920903 Shults, S.; Brock, A.; Killeen, J. (1990) Primary Dermal Irritation Study in Albino Rabbits with Diethanolamine Salt of 2,4-D: Lab Project Number: 90- 0165: 3592-90-0165-TX-001. Unpublished study prepared by Ricerca, Inc. 18 p. Industry Task Force II on 2,4-D Research Data,  Indianapolis, Indiana, USA.

00157516 Jeffrey, M. (1986) DMA 6 Weed Killer: Primary Dermal Irritation Study in New Zealand White Rabbits. Unpublished study prepared by Dow Chemical U.S.A. 9 p.

00252291 – there appear to be no cited reference either held that are available to the public.

40352703 Maedgen, J. (1986) Rabbit Skin Irritation: Tech. Isopropyl Ester of 2,4-D: Proj. No. 4375-86. Unpublished study prepared by Still- meadow, Inc. 11 p. Sumitomo Chemical Company Co. Ltd. Tokyo, Japan.

41413505 Mizell, M. (1989) 2,4-Dichlorophenoxyacetic Acid, Triisopropanol- amine Salt: Primary Dermal Irritation Study in New Zealand White Rabbits: Lab Project Number: K-008866-002B. Unpublished study prepared by The Dow Chemical Co. 13 p.

40629805 Jeffrey, M. (1987) 2,4-D Butoxyethyl Ester, Technical: Primary Dermal Irritation Study in New Zealand White Rabbits: Lab. Proj. ID K-007722-006B. Unpublished study prepared by Dow Chemical Co. 10 p.

41413505 Mizell, M. (1989) 2,4-Dichlorophenoxyacetic Acid, Triisopropanol- amine Salt: Primary Dermal Irritation Study in New Zealand White Rabbits: Lab Project Number: K-008866-002B. Unpublished study prepared by The Dow Chemical Co. 13 p

DERMAL SENSITIZATION

00161659 Gargus, J. (1986) Dermal Sensitization Study in Guinea Pigs: 2,4- Dichlorophenoxyacetic Acid: Final Report: Project No. 2184-105. Unpublished study prepared by Hazleton Laboratories, Inc. 10 p.  INT, BAS, GIL, FAR, GOR, TRA, AHM, AZC, CHL, DOE, MOB&FER, ROP, NUF

41920904 Shults, S.; Brock, A.; Killeen, J. (1990) Dermal Sensitization Study (Closed Patch Repeated Insult) in Guinea Pigs with Di- ethanolamine Salt of 2,4-D: Lab Project Number: 90-0166: 3592- 90-0166-TX-001. Unpublished study prepared by Ricerca, Inc. 37 p.  PBI/Gordon Inc., Kansas City, MO, USA.

41642805 Robbins, G. (1989) Guinea Pig Sensitization Study (Buehler): Dri-D Amine: Lab Project Number: F2013. Unpublished study prepared by Cosmopolitan Safety Evaluation, Inc. (C.S.E.) 17 p.

41233701 Carreon, R.; Wall, J. (1984) XRM-4725 Herbicide Formulation: DermalSensitization Potential in the Guinea Pig: Project Study ID: HET M-004725- 003. Unpublished study prepared by Dow Chemical U.S.A. 11 p.

40352704 Maedgen, J. (1986) Guinea Pig Skin Sensitization: Tech. Isopropyl Ester of 2,4-D: Proj. No. 4376-86. Unpublished study prepared by Stillmeadow, Inc. 15 p.  Sumitomo Chemical Company Co. Ltd. Tokyo, Japan.

41413506 Berdasco, N. (1989) 2,4-Dichlorophenoxyacetic Acid Triisopropanol- amine Salt: Dermal Sensitization Potential in the Hartley Albino Guinea Pig: Lab Project Number: K-008866-002E. Unpublished study prepared by The Dow Chemical Co. 14 p.

40629806 Jeffrey, M. (1986) Butoxy Ethyl 2,4-Dichlorophenoxyacetate: Dermal Sensitization Potential in the Hartley Albino Guinea Pig: Lab. Proj. ID K- 007722-005. Unpublished study prepared by Dow Chemical Co. 10 p.

41209006 Mahlburg, W. (1988) Dermal Sensitization Study in Guinea Pigs with DPD Ester: Project ID: 88.3505.006; Study No. 89-19A. Unpublished study prepared by Food & Drug Research Laboratories. 38 p. Funded by Platte Chemical Company.

b. Safety and Database Uncertainty Factors

Is there now a FQPA safety factor? I am unable to identify whether 10X database uncertainty factor is still required.

c. Carcinogenicity

Extract: A Science Advisory Board/Scientific Advisory Panel Special Joint Committee reviewed available epidemiological and other data on 2,4-D in 1992 and concluded that “the data are not sufficient to conclude that there is a cause and effect relationship between 2,4-D and non-Hodgkins lymphoma.”  2,4-D has been classified as a Category D chemical (i.e., not classifiable as to human carcinogenicity), by the EPA/OPP Cancer Peer Review Committee in 1996 (a). The Agency requested further histopathological examinations of rat brain tissues and mouse spleen tissues in question (b). These exams were submitted and reviewed, and on March 16, 1999, the Agency notified the 2,4-D Task Force that the Agency would continue to classify 2,4-D as a Group D carcinogen.

The Agency has twice recently reviewed epidemiological studies linking cancer to 2,4-D. In the first review, completed January 14, 2004 (c), (authored by Jerry Blondell) EPA concluded there is no additional evidence that would implicate 2,4-D as a cause of cancer (EPA, 2004). The second review  of available epidemiological studies occurred in response to comments received during the Phase 3 Public Comment Period for the 2,4-D RED. EPA’s report, dated December 8, 2004 (d) and authored by EPA Scientist Jerry Blondell, Ph.D., found that none of the more recent epidemiological studies definitively linked human cancer cases to 2,4-D.

 

Safe Says Who has reviewed the following EPA/OPP Cancer Peer Review Committee findings & Blondell papers in order to establish which organisations supplied the studies for these reviews that resulted in a classification of Category D (not classifiable as to human carcinogenicity).*

  1. EPA Memorandum dated Jan 28, 1997. Subject: Carcinogenicity Peer Review (4th) of 2,4-Dichlorophenoxyacetic acid (2,4-D).  Authors: Jess Rowland & Esther Rinde.
  2. EPA Memorandum dated May 23, 1996.  Subject: 2,4-Dichlorophenoxyacetic acid: Review of a Chronic Toxicity/Carcinogenicity Study in Rats, a carcinogenicity study in mice and a re-review of a developmental toxicity study in Rats.  Author: Jess Rowland.
  3. EPA Memorandum dated January 14, 2004. Subject: Review of 2,4-D Incident Reports; Authors: Jerome Blondell, Ph.D. and Monica Hawkins, M.P.H., Review of 2,4-D Incident Reports, DP Barcode D297233, Chemical#030001-81, includes all salts, esters).    Carcinogenicity portion of review reproduced within the December 8 Blondell paper.  Paper only contains incident reports and epidemiological studies.  Not toxicity studies.
  4. d.      EPA Memorandum dated December 8, 2004.  Subject:  Review of recent 2,4-D cancer epidemiology studies.  Chemical#030001-81 (includes all salts, esters), DP Barcode 311464.  Author: Jerome Blondell  

 

*See document:  2,4-D studies used for EPA declaration Carcinogenicity Group D Classification.

 

d. Cumulative Assessment.

Extract: FQPA requires EPA to consider “available information” concerning the cumulative effects of a particular pesticide’s residues and “other substances that have a common mechanism of toxicity” when considering whether to establish, modify, or revoke a tolerance. Potential cumulative effects of chemicals with a common mechanism of toxicity are considered because low-level exposures to multiple chemicals causing a common toxic effect by a common mechanism could lead to the same adverse health effect as would a higher level of exposure to any one of these individual chemicals.  2,4-D is a member of the alkylphenoxy herbicide class of pesticides. A cumulative risk assessment has not been performed as part of this human health risk assessment because the Agency has not yet made a determination whether or not phenoxy herbicides have a common mechanism of toxicity.  

e. Endocrine Effects

Extract: “Based on currently available toxicity data, which demonstrate effects on the thyroid and gonads following exposure to 2,4-D, there is concern regarding its endocrine disruption potential. There have been no studies on 2,4-D that specifically assess its endocrine disruption potential. The Agency has determined that a repeat 2-generation reproduction study using the most recent protocol is required to address both the concern for thyroid effects (comparative assessment between the young and adult animals) and immunotoxicity, as well as a more thorough assessment of the gonads and reproductive/developmental endpoints.”

2010 Response to the above Agency request:

EPA memorandum: November 30, 2010.               Regulatory Action: RED Follow-up.

Subject: 2,4-D: Review of Extended 1 Generation Reproduction Study and Dose-Range Finding and Pharmacokinetic Titration Studies.

In response to the data call-in (DCI) for 2,4-D, an extended one-generation reproduction study (MRID 47972101) was submitted.  Also submitted were a dose-range finding study (MRID 47417901) and a pharmacokinetic/titration (MRID 47417902) study.

Marty, M.S., Zablotny, C.L., Andrus, A.K., Boverhof, D.R., Bus, J.S., Perala, A.W., Saghir, S. and Yano, B.L. 2010. 2,4-D: an extended one-generation dietary toxicity  study in Crl:CD(SD) rats. Unpublished Study Report of The Dow Chemical Company,  Midland, Michigan. Laboratory project study ID 081104. January 30, 2010.  Unpublished.  MRID 47972101.

Saghir, S. A., Zablotny, C.L., Marty, M.S., Perala, A.W., Yano, B.L.. A dietary Dose Range-Finding and Pharmacokinetic Study of 2,4- dichlorophenoxyacetic acid (2,4-D) in the pregnant CRL:CD (SD) Rat and its Offspring in Preparation for a Subsequent F1-Extended One Generation Toxicity Study in Rats.  Unpublished Study Report of The Dow Chemical Company, Midland, Michigan. . Laboratory project study ID  071153 and 071153A. May 2 2008. Unpublished.  MRID 47417901.

Saghir, S. A., Perala, A. W. and Clark, A. J. 2008b. A dietary titration study of 2,4-D acid pharmacokinetics in female CRL:CD(SD) rats.  Laboratory Project Study ID 071210. Unpublished Report of Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan. Laboratory project study ID 071210, April 29, 2008.   MRID 47417902

End ‘Agency Request’ data.

 

f. Toxicological Endpoints for Risk Assessment

Table 7: Toxicity Endpoints for Risk Assessment p.21

Human Health Risk Assessment.

[a] Acute Toxicity (this includes Acute Dietary, Short-term incidental oral, Short term dermal, Intermediate term dermal, short term inhalation, Intermediate term inhalation):

NOAEL = 25 mg/kg/day.  UF = 1000           Acute Rfd = 0.025 mg/kg/day

MRID 00130407: Rodwell, D.; Werchowski, K.; Mercieca, M.; et al. (1983) A Teratol- ogy Study in Fischer 344 Rats with 2,4-Dichlorophenoxyacetic Acid: Project No. WIL81135. Final rept. (Unpublished study received Jun 1, 1983 under unknown admin. no.; prepared by WIL Research Laboratories, Inc., submitted by 2-4 D Task Force, Washington, DC; CDL:251031-A)

(Short term: 1-30 days, also Intermediate term: 91 days; oral, inhalation & dermal)

MRID 00130408: Nemec, M.; Kopp, S.; Leist, P.; et al. (1983) A Range-finding Teratology Study in Fischer 344 Rats with 2,4-Dichlorophenoxyacetic Acid: Project No. WIL-22002. Final rept. (Unpublished study received Jun 1, 1983 under unknown admin. no.; prepared by WIL Research Laboratories, Inc., submitted by 2-4 D Task Force, Washington, DC; CDL:251032-A)                        (Short term: 1-30 days, also Intermediate term: 91 days; Oral, inhalation & Dermal).

MRID 00130407 & 00130408 provide the NOAEL for the RfD – reference dose for 2,4-D for the EPA.

[b] Chronic Toxicity (This includes Chronic Dietary, Long Term Dermal, Long Term Inhalation):

NOAEL = 5 mg/kg/day.  UF = 1000              Chronic Rfd = 0.005 mg/kg/day

MRID 43612001 (1995) Jeffries T, Yano B., Ormand J et al. 1995.  2 year 2,4-D Chronic Toxicity/Oncogenicity Studies in Fischer 344 Rats.  Unpublished. Prepared by Dow Chemical Co.

[c] Acute Dietary  – Carcinogenicity :

NOAEL = 67 mg/kg/day.  UF = 1000           Acute Rfd = 0.067 mg/kg/day

MRID 43115201: Mattsson J, McGuirk R, Yano B (1994a). 2,4-Dichlorophenoxyacetic acid (2,4-D): Acute neurotoxicity study in Fischer 344 rats. Lab Project Number K-002372-066. Unpublished study prepared by The Dow Chemical Co. 451 p. (Single dose study).

[d] Intermediate Term Incidental Oral (1-6 months):

NOAEL = 15 mg/kg/day.

MRID 41991501: Schulze G. (1991).  90 day Subchronic Toxicity Study in Rats with 2,4-D.  Prepared by Hazleton Labs America. (Covance)  Subchronic toxicity in Rats G.Schulze 1991. Unpublished.  Paid for by: RHONE-POULENC, AGROGOR (consortium Agrolinz ñ PBI Gordon), NUFARM, DOW, BASF, A.H. MARKS.

 

4. Residential and Other Non-occupational Exposure.

a. Toxicity.

Table 9. Toxicity Endpoints for Assessing Residential Risk for 2,4-D P 28.

[a] Acute Toxicity (this includes Acute Dietary, Short-term incidental oral, Short term dermal, Intermediate term dermal, short term inhalation, Intermediate term inhalation):

MRID 00130407: Rodwell et al. (1983): A teratology Study in Fischer 344 Rats with 2,4-D. Unpublished. (Short term: 1-30 days, also Intermediate term: 91 days; oral, inhalation & dermal) Prepared by WIL Research Laboratories, Inc., submitted by 2,4-D Task Force, Washington DC;

MRID 00130408: Nemec et al. (1983a): A range finding teratology study in Fischer rats with 2,4-D. Unpublished.  (Short term: 1-30 days, also Intermediate term: 91 days; Oral, inhalation & Dermal). Prepared by WIL Research Laboratories, Inc., submitted by 2,4-D Task Force, Washington DC.

[b] Intermediate Term Incidental Oral (1-6 months):

MRID 41991501: Schulze G. (1991).  90 day Subchronic Toxicity Study in Rats with 2,4-D.  Prepared by Hazleton Labs America. (Covance)  Subchronic toxicity in Rats G.Schulze 1991. Unpublished.  Paid for by: RHONE-POULENC, AGROGOR (consortium Agrolinz ñ PBI Gordon), NUFARM, DOW, BASF, A.H. MARKS.  MRID 43612001

[c] Chronic Toxicity (This includes Long Term Dermal, Long Term Inhalation):

MRID 43612001 (1995) Jeffries T, Yano B., Ormand J et al. 1995.  2 year 2,4-D Chronic Toxicity/Oncogenicity Studies in Fischer 344 Rats.  Unpublished. Prepared by Dow Chemical Co.

Study NOAEL’s as per Table 7.

b. Residential Handler    P. 29

Residential Handler Risk estimates  P.31

Based on toxicological criteria and potential for exposure, the Agency has conducted both a dermal and an inhalation exposure assessment. Risk assessment for short-term inhalation exposure is based on a rat developmental study

c. Residential Postapplication Risk

Table 11. Children Post-Application Exposure to Turf Treated with 2,4-D.  P.34

The acute NOAEL is 67 mg/kg/day for neurotoxic effects observed in the acute neurotoxicity study.  MRID 43115201      Dow Chemical Co.

The short term NOAEL is 25 mg/kg/day for maternal effects observed in the developmental study.  MRID 00130407 & 00130408         2,4-D Task Force

Table 12. Adult Acute/Short Term MOEs for Exposure to Turf Treated with 2,4-D.  P.34

The acute/short term NOAEL is 25 mg/kg/day for developmental effects observed in the developmental study.  The LOAEL was 75 mg/kg/day based on skeletal abnormalities from a developmental toxicity study in rats.  MRID 00130407 & 00130408  2,4-D Task Force

d. Recreational Swimmer Risk

Table 13. Maximum Swimming Water Concentrations for 2,4-D Aquatic Applications P.37

Exposure duration for adults: Acute/Short term based on NOAEL of 25 mg/kg/day. MRID 00130407 & 00130408   2,4-D Task Force

Exposure duration for children: Acute 67 mg/kg/day  MRID 43115201     Dow Chemical Co.

Short term 25 mg/kg/day  MRID 00130407 & 00130408    2,4-D Task Force

 

5. Aggregate Exposure and Risk.

a. Acute Aggregate Risk Assessment.

‘The highest risks (58 percent of the aPAD) are for females 13-49 years old because these risks are based upon the lower NOAEL of 25 mg/kg/day.’  MRID 00130407 & 00130408

Table 15. 2,4-D Aggregate Acute MOEs  P.39

NOAEL is 25 mg/kg/day for females 13-49 MRID 00130407 & 00130408    2,4-D Task Force

67 mg/kg/day for all other population subgroups  MRID 43115201            Dow Chemical Co.

b. Chronic Aggregate Risk Assessment

The highest risks (38 percent of the cPAD) are for children 1-2 years old.

Table 16. Chronic DWLOC Calculations

NOAEL of 5 mg/kg/day  MRID 43612001                 Dow Chemical Co.

Table 17. 2,4-D Aggregate Chronic Risks P.41

NOAEL of 5 mg/kg/day  MRID 43612001                 Dow Chemical Co.

c. Short-term Aggregate Risk Assessments

Table 19. 2,4-D Aggregate Short-Term MOEs Including Turf Exposures P.42

NOAEL is 25 mg/kg/day  MRID 00130407 & 00130408        2,4-D Task Force

d. Cancer Aggregate Risk

2,4-D was classified as a Category D chemical, i.e., not classifiable as to human carcinogenicity, by the EPA/OPP Cancer Peer Review Committee in 1996. Thus, no aggregate cancer assessment is warranted.

 

 

6. Occupational Risk P.43

Table 20. Toxicological Endpoints for the Occupational Risk Assessment P.44.

  1. a.      Occupational Toxicity.

Short term dermal & Inhalation: Oral Study NOAEL 25 mg/kg/day

MRID 00130407 &00130408          2,4-D Task Force

Intermediate term dermal & Inhalation: Oral Study NOAEL 15 mg/kg/day.   MRID 41991501    Dow Chemical Co.

Long term dermal & Inhalation: Oral study NOAEL 5 mg/kg/day

MRID 43612001                 Dow Chemical Co.

Cancer:  Classification: Group D [not classifiable as to human carcinogenicity]

 

8. Cancer Epidemiology Studies   P.52

Same content as under A. Human Health Risk Assessment: c. Carcinogenicity.

 

Appendix B

Additional combined chronic toxicity/carcinogenicity studies included in Appendix B.

Appendix B: Data Supporting Guideline Requirements for the Reregistration of 2,4-D.

Additional Combined Chronic Toxicity/ Carcinogenicity Study:  Appendix B

MRID 43879801 Stott, WT, Johnson KA, Gilbert K et al (1995).  2,4-D Acid: Dietary Oncogenicity Study in Male Mice B6C3F1 Mice – 2 year Final Report. Study ID K-002372-063M. Unpublished. The Toxicology Research Laboratory, Dow Chemical Co. Michigan.

MRID 43597201 Stott, W.; Johnson, K.; Gilbert, K.; et al. (1995) 2,4-Dichlorophenoxyacetic Acid: Dietary Oncogenicity Study in B6C3F1 Mice–Two Year Final Report: Lab Project No. K-002372- 063F. Unpublished study prepared by the Dow Chemical Co. 724 p.

 

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