Document ID: EPA-HQ-OPP-2012-0939-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2013-03-27T04:00Z

--------------------------------------------------------------------------------

--------------------------------------------------------------------------------

--------------------------------------------------------------------------------

--------------------------------------------------------------------------------

OFFICE OF CHEMICAL SAFETY
AND POLLUTION PREVENTION
                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460

      	
      
      
                                                                               

MEMORANDUM

DATE:		December 31, 2012

SUBJECT:	Human Toxicology Scoping Document for the Registration Review of Gibberellins.

				Registration Review Case #: 	4110
				PC Code: 					043801, 043802 and 116902				
				CAS #:						77-06-5, 125-67-7 and 8030-53-3, respectively
				Chemical Class: 				Biochemicals

FROM:		Angela L. Gonzales, Biologist 	/s/
            Biochemical Pesticides Branch
            Biopesticides & Pollution Prevention Division (7511P)
            				
TO:			Leonard Cole, Senior Regulatory Specialist
				Biochemical Pesticides Branch
            Biopesticides & Pollution Prevention Division (7511P)

ACTION REQUESTED

In support of the development of the Final Workplan for Registration Review, the following scoping document contains the human health assessment for the following biopesticide active ingredients: 1) gibberellic acid; 2) gibberellic acid, monopotassium salt; and 3) gibberellin A4 mixture with gibberellin A7.

Executive Summary

All human health assessment data requirements under 40 CFR 158.2050 have been fulfilled for the active ingredients.  Since the last registration review of these active ingredients, the Agency has received some additional mammalian toxicology data for which Agency reviews could not be located. Also, according to the Agency's Incident Data System, there have been reports of human incidents resulting from the use of pesticide products containing gibberellic acid as the active ingredient. During the course of registration review, the Agency will review of all of these data and determine if a reevaluation of the current risk assessments is warranted.  

I. Background

Gibberellic Acid (A3)

As a pesticide, gibberellic acid is a plant growth regulator (PGR) used to promote flowering and elongation of stems and roots and to stimulate fruit growth and maturation. The chemical naturally occurs in plants and in some microbes. (Gibberellins Fact Sheet, 2001)

The chemical was first registered by the Agency in 1971. There are currently 65 registered products containing the active ingredient; 35 products contain gibberellic acid as the sole active ingredient, 29 products contain the chemical along with one or more other plant growth regulators and 1 product contains the chemical and a microbial active ingredient. There are 10 manufacturing-use products (MPs) and 55 end-use products (EPs) that contain gibberellic acid as an active ingredient. 

Gibberellic Acid, Monopotassium Salt

Currently, there are no pesticide products registered by the Agency containing this active ingredient, thus a review of the available data and risk assessments will not be conducted for this chemical.

Gibberellin A4 Mixture with Gibberellin A7

Gibberellin A4 (GA4) and gibberellin A7 (GA7) are isomers of gibberellic acid and thus are significantly similar in structure and function. The mixture of the two gibberellins is used as a PGR in pesticide formulations for the same purposes as GA3.

The GA4 and GA7 mixture was first registered by the Agency in 1994. There are currently 14 registered products containing the active ingredients; 7 products contain the mixture as the sole active ingredient and 7 products contain the mixture along with one or more other PGRs. There are 2 MPs. 

II. Tolerances

40 CFR § 180.1098   Gibberellins [Gibberellic Acids (GA3 and GA4 + GA7), and Sodium or Potassium Gibberellate]; exemption from the requirement of a tolerance.

An exemption from the requirement of a tolerance is established for residues of gibberellins [gibberellic acids (GA3 and GA4 + GA7), and sodium or potassium gibberellate] in or on all food commodities when used as plant regulators on plants, seeds, or cuttings and on all food commodities after harvest in accordance with good agricultural practices.  [64 FR 31505, June 11, 1999]

III. Incidents

Gibberellic Acid (A3)

According to the Incident Data System, there have been six reports of human incidents resulting from the use of pesticide products containing GA3 as the active ingredient. During the course of registration review, the Agency will conduct an assessment of the incident data to determine if the current risk assessments will need to be reevaluated. 

Gibberellin A4 Mixture with Gibberellin A7

According to the Incident Data System, there have been no reports of incidents resulting from the use of pesticide products containing GA4 and GA7 mixture as the active ingredient.

IV. Toxicity Profile

Because GA3 and the GA4 and GA7 mixture are significantly similar in structure and function, they are considered collectively in the toxicity assessment. Sufficient data have been provided to fulfill the biochemical pesticide data requirements under 40 CFR 158.2050 for the current use patterns for the active ingredients. The data available to the Agency are summarized in Table 1 below. Several mutagenicity studies and a skin sensitization study have been submitted to the Agency since the last review of these active ingredients. The reviews of these studies were not able to be located, thus they will be reviewed during the course of registration review. 

Table 1. Human Health Assessment Data Requirements for Gibberellins (40 CFR § 158.2050)
                           Study/OCSPP Guideline No.
                                    Results
                         Toxicity Category/Description
                                     MRID
                           Acute oral toxicity (rat)
                                  (870.1100)
                          LD50 > 5,000 mg/kg (GA3)
                                      IV
                                   44081306
                                       
                  LD50 > 5,000 mg/kg (GA4 and GA7 mixture)
                                      IV
                                   40873201
                                       
                  LD50 > 5,000 mg/kg (GA4 and GA7 mixture)
                                      IV
                                   44264705
                        Acute dermal toxicity (rabbit)
                                  (870.1200)
                        LD50 > 2,000 mg/kg[1] (GA3)
                                      III
                                   44081307
                                       
                LD50 > 2,000 mg/kg[1] (GA4 and GA7 mixture)
                                      III
                                   40873202
                                       
                LD50 > 2,000 mg/kg[1] (GA4 and GA7 mixture)
                                      III
                                   44264706
                       Acute inhalation toxicity	 (rat)
                                  (870.1300)
                           LC50 > 4.94 mg/L (GA3)
                                      IV
                                   44081308
                                       
                 LC50 > 2.98 mg/L[2] (GA4 and GA7 mixture)
                                      III
                                   40873203
                                       
                   LC50 > 5.44 mg/L (GA4 and GA7 mixture)
                                      IV
                                   44264707
                        Primary eye irritation (rabbit)
                                  (870.2400)
             Mildly irritating-effects cleared within 7 days (GA3)
                                      III
                                   44081309
                                       
   Moderately irritating-effects cleared within 7 days (GA4 and GA7 mixture)
                                      III
                                   40873204
                                       
     Mildly irritating-effects cleared within 7 days (GA4 and GA7 mixture)
                                      III
                                   44264708
                      Primary dermal irritation (rabbit)
                                  (870.2500)
                             Non-irritating (GA3)
                                      IV
                                   44081310
                                       
                     Non-irritating (GA4 and GA7 mixture)
                                      IV
                                   40873205
                                       
                     Non-irritating (GA4 and GA7 mixture)
                                      IV
                                   44264709
                       Dermal sensitization (guinea pig)
                                  (870.2600)
                            Not a sensitizer (GA3)
                                       
                                   44081311
                                       
                   Mildly sensitizing (GA4 and GA7 mixture)
                                       
                                   40873206
                                       
                    Not a sensitizer (GA4 and GA7 mixture)
                                       
                                   44264710
                             90-Day oral toxicity 
                                  (870.3100)
NOAEL = 10,000 ppm in rats
LOAEL = 25,000 ppm based on alterations in clinical chemistry, decreased food consumption, decreased body weight, increases in relative organ weights (brain, kidney and testis) and gross and histopathological changes in the kidney (GA4 and GA7 mixture)
                                       
                                   41616601
                                       
NOAEL = 10,000 ppm in rats
LOAEL = 50,000 ppm based on occurrence of soft stools in both males and females, increased blood urea nitrogen (BUN) levels and increased liver and kidney weights in females. (GA3)
                                       
                                   41617501
                                       
NOAEL = 600 mg/kg/day in male dogs, 1,000 mg/kg/day in female dogs
LOAEL = 1,000 mg/kg/day in males based on a reduction in body weight gain and food efficiency, increased liver weight and gross and histopathological changes in the thymus and adrenal glands. 
                                       
                                   45695901
                            90-Day dermal toxicity
                                  (870.3250)
Waived. Products containing the active ingredients are not purposefully applied to the skin and prolonged exposure is not anticipated based on the active ingredients' use pattern as PGRs. 
                                       
                                       
                          90-Day inhalation toxicity
                                  (870.3465)
Waived. Significant repeated inhalation exposure as a gas, vapor or aerosol is not expected based on the use pattern of the active ingredients.
                                       
                                       
                                 Mutagenicity 
                  (Bacterial reverse mutation test; 870.5100)
Not mutagenic under the conditions of the studies (GA3 and GA4  and GA7 mixture)
                                       
                                   40261601
                                   40873207
                                   44264711
                                 Mutagenicity 
           (Unscheduled DNA synthesis in mammalian cells; 870.5550)
Not mutagenic under the conditions of the studies. (GA3 and GA4  and GA7 mixture)
                                       
                                   40261603
                                   40873209
                                 Mutagenicity 
          (In vivo mammalian erythrocyte micronucleus test; 870.5395)
Not mutagenic under the conditions of the study. (GA4 and GA7 mixture)
                                       
                                   40873208
                                 Mutagenicity
            (In vitro mammalian cell gene mutation test; 870.5300)
Not mutagenic under the conditions of the study. (GA4 and GA7 mixture)
                                       
                                   44264712
                                 Mutagenicity
           (In vitro mammalian chromosome aberration test; 870.5375
Evidence of clastogenic activity observed at >= 1,000 ug/ml without S9 activation and at >= 2,000 ug/ml with S9 activation.[3] (GA4 and GA7 mixture)
                                       
                                   44264713
                            Developmental toxicity 
                                  (870.3700)
Maternal NOAEL > 1,000 mg/kg/day[1] in rats. Developmental NOAEL is not available. (GA3)
                                       
                                   40155201
                                   40746801
                                       
Maternal and developmental NOAEL = 300 mg/kg/day in rabbits.
Maternal and developmental LOAEL = 1,000 mg/kg/day based on increased mortality, increased abortion rates, clinical signs of toxicity and gross pathological observations (GA4 and GA7 mixture)
                                       
                                   41143201
[1]Highest dose tested.
[2]Highest respirable dose achieved. 
[3]Although clastogenic activity was observed in this in vitro study, the active ingredients are considered not likely to be mutagenic. This conclusion is based on the negative results observed in all of the other mutagenicity studies, one of which was an in vivo study. 

VI. References

U.S. EPA Biochemical Fact Sheet for Gibberellins. Issued January, 2001. <http://www.epa.gov/opp00001/chem_search/reg_actions/registration/fs_G-106_01-Jan-01.pdf>

cc:  A. L. Gonzales, L. Cole, BPPD Science Review File, IHAD/ARS
 	  A. L. Gonzales, FT, PY-S: 12/31/12