### Gibberellins PC Code: 043801, 043802 and 116902 Ty pe of Review: Toxicology (Registration Review)

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION 

### UNITED ST **AT ES ENVIRONMENT**  **AL PROTECTION A** **GENCY**

WA SHINGTON, D.C. 20460



## MEMORANDUM **DATE:** December 31 , 2012 **SUBJECT** : Human T oxicology 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 **Che mi**  **cal Class:** Biochemical s 

## 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, monopot assium 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, a ccording to the Agency ’s Incident Data Sy stem, 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 wi ll review of all of these data and determine if a reevaluation of the current risk assessments is warranted.

**I. Background**

### Gibberellins PC Code: 043801, 043802 and 116902 Ty pe of Review: Toxicology (Registration Review) 2



## Gibberellic Acid (A 3 

## ) As a pes ticide, 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 regist ered b y the Agency in 1971 . There are currently 6 5 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 p roduct s (MP s) 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

co ntaining 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 A 7 

## Gibberellin A4 

## (GA 4 

## ) and gibberellin A 7 

## (GA 7 

## ) 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 GA 3 

## . The GA4 

## and GA 7 

## mixture was first registered b y 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. Tolerance s**  **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**

### Gibberellins PC Code: 043801, 043802 and 116902 Ty pe of Review: Toxicology (Registration Review) 3



## Gibberellic Acid (A 3 

## ) According to the Incident Data Sy stem, there have been six reports of human incidents resulting from the use of pesticide products containing GA 3 

## 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 A 7 

## According to the Incident Data Sy s tem, there have been no reports of incidents resulting from the use of pesticide products containing GA 4 

## and GA 7 

## mixture as the active ingredient

. **I V**  **. Toxicity Profile**  Because GA 3 

## and the GA 4 

## and GA 7 

## mixture are significantly similar in structure and function, they are considered collectivel y 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 p atterns 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 revie ws of these studies were not able to be located, thus they will be reviewed during the course of registration review.

### Gibberellins PC Code: 043801, 043802 and 116902 Ty pe of Review: Toxicology (Registration Review) 4

**Table 1 . Hum**  **an 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) LD 50 > 5,000 mg/kg **(GA 3**  **)** IV 44081306 LD 50 > 5,000 mg/kg **(GA 4**  **and GA 7**  **mi xture)**  IV 40873201 LD 50 > 5,000 mg/kg **(GA 4**  **and GA 7**  **mi xture)**  IV 44264705 Acute dermal toxicity (rabbit) (870.1200) LD 50 > 2,000 mg/kg 1 **(GA 3**  **)** III 4 4081307 LD 50 > 2,000 mg/kg 1 **(GA 4**  **and GA 7**  **mix ture)**  III 40873202 LD 50 > 2,000 mg/kg 1 **(GA 4**  **and GA 7**  **mix ture)**  III 44264706 Acute inhalation toxicity (rat) (870.1300) LC 50 > 4.94 mg/L **(GA 3**  **)** IV 44081308 LC 50 > 2.98 mg/L 2 **(GA 4**  **and GA 7**  **mi xture)**  III 40873203 LC 50 > 5.44 mg/L **(GA 4**  **and GA 7**  **mi xture)**  IV 44264707 Primary eye irritation (rabbit) (870.2400) Mildly irritating

- effects cleared within 7 days **(GA 3**  **)** III 44081309 Moderately irritating

- effects cleared within 7 days

**(GA 4**  **and GA**  **7 mix**  **ture)** III 40873204 Mildly irritating

- effects cleared within 7 days **(GA 4** 

**and GA 7**  **mix ture)**  III 44264708 Primary dermal irritation (rabbit)

(870.2500) Non

- irritating **(GA 3**  **)** IV 44081310 Non

- irritating **(GA 4**  **and GA 7**  **mi xture)**  IV 40873205 Non

- irritating **(GA 4**  **and GA 7**  **mi xture)**  IV 44264709 De rmal sensitization (guinea pig)

(870.2600) Not a sensitizer **(GA 3**  **)** 44081311 Mildly sensitizing **(GA 4**  **and GA 7**  **mi xture)**  40873206 Not a sensitizer **(GA 4**  **and GA 7**  **mix ture)**  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 i n the kidney **(GA 4**  **and GA 7**  **mix ture)**  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. **(GA 3**  **)** 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 **(GA 3**  **and GA 4**  **and GA 7**  **mix ture)**  40261601 40873207 44264711 Mutagenicity (Unscheduled DNA synthesis in mammalian cells; 870.555 0) Not mutagenic under the conditions of the studies. **(GA 3**  **and GA 4**  **and GA 7**  **mix ture)**  40261603 40873209 Mutagenicity ( In vivo mammalian erythrocyte micronucleus test; 870.5395 ) Not mutagenic under the conditions of the study. **(GA 4**  **and GA 7**  **mix ture)**  40873208 Mutagenicity ( In vitro mammalian cell gene mutation

test; 870.5300) Not mutagenic under the conditions of the study. **(GA 4**  **and GA 7**  **mix ture)**  44264712

### Gibberellins PC Code: 043801, 043802 and 116902 Ty pe of Review: Toxicology (Registration Review) 5

**Table 1 . Hum**  **an Health Assessment**  **Data Requirements for Gibberellins**  **(40 CFR § 158.2050) Study/OCSPP**  **Guideline No. Results**  **Toxicity Category/Description**  **MRID** Mutagenicity ( In vitro mammalian chromosome aberration test; 870.5375 Evidence of clastogenic activity observed at ≥ 1,000 μg/ml without S9 activation and at ≥ 2,000 μg/ml with S9 activation. 3 **(GA 4**  **and GA 7**  **mi xture)**  44264713

Developmental toxicity (870.3700) Maternal NOAEL > 1,000 mg/kg/day 1 in rats. Developmental NOAEL is not available. **(GA 3**  **)** 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 **(GA 4**  **and GA 7**  **mix ture)**  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 whic h was an in vivo study. 

## VI **. References** U.S. EPA Bi ochemical Fact Sheet for Gibberellins . I ssued 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 Fil e , IHAD/ARS A. L . Gonzales , FT, PY

- S: 12/31 /12