# i

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact : [ P.V. Shah, 703

- 308

- 1846 ]

INSTRUCTIONS: Please utilize this outline in preparing the pesticide petition. In cases where the outline element does not apply, please insert “NA

- Remove” and maintain the outline. Please do not change the margins, font, or format in your pesticide petition. Simply re place the instructions that appear in green , i.e., “ [ insert

company name ] ,” with the information specific to your action.

TEMPLATE:

[ ISK Biosciences Corporation ]

[ 1E7900 ]

EPA has received a pesticide petition ( [ 1E7900 ] ) from [ ISK Biosciences Corporation ]
, [ 7470 Auburn Road, Suite A, Concord OH 44077 ] proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.920 to estab lish an exemption from the requirement

of a tolerance for [ Calcium gluconate (CAS. No. 299

- 28

- 5) ] [under 40 CFR 180.920

w hen used as an inert ingredient as a sequestrant, binder and filler in pesticide

formulations applied pre

- harvest to all raw agricultural commodities ]. EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the sufficiency

of the submitted d a ta at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism

. [ NA

- Remove. No specific plant metabolism data is available, nor is it required for the establishment of a tolerance exemption.]

2. Analytical method. [ NA

- Remove based on the fact that this information is not required for the establishment of a tolerance exemption.]

3. Magnitude of residues. [ [NA

- Remove based on the fact that this information is not required for the establishment of a tolerance exemption. There is no specific crop residue information available for calcium gluconate and this information is typically not available nor required f or the establishment of a tolerance exemption for inert ingredients.]2

B. Toxicological Profile

Gluconic acid and its inorganic salts have been evaluated by the Joint FAO/WHO Expert Committee on Food Additives (JECFA), which determined that these substances were of very low toxicity and allocated an acceptable daily intake of "not specified" (JECFA, 1999). The calcium, magnesium, potassium, and sodium gluconates were previously evaluated by JECFA as individual compounds or in other group categorie s as inorganic salts and salts of organic acids. It was concluded that they are freely ionizable and that it was appropriate to allocate

ADIs on the basis of data on their corresponding anion (gluconic acid)

. Calcium gluconate was added to the CODEX General Standard for Food Additives (GSFA)

in 1999. Calcium gluconate is include d in the F ood and Drug Administration (F DA ) list of direct food substances generally recognized as safe (GRAS List ) and is commonly co nsumed as a mineral supplement and is used for the treatment of hypocalcemia.

1. Acute toxicity. [ Toxicological studies considered by JECFA in their

e valuation of gluconic acid and its inorganic salt s included acute oral toxicity studies in the rat, mouse, rabbit and hamster with LD 50 values ranging from >2000 mg/kg to 7850 mg/kg ]

2. Genotoxicty. [ Gluconic acid and its inorganic salts ha ve been tested in in

vitro assays which demonstrate d that gluconic acid was not mutagenic with or

without metabolic activation .]

3. Reproductive and developmental toxicity. [ N o observable adverse effects were noted at limit dose levels (i.e., > 1000 mg/kg/day) or at the highest doses tested

4. Subchronic toxicity. [ In various subchronic studies evaluated by JECFA, no

observable adverse effects were noted at limit dose levels (i.e., > 100 0 mg/kg/day) or at the highest doses tested

.

5. Chronic toxicity. [ In various, chronic studies evaluated by JECFA, no

observable adverse effects were noted at limit dose levels (i.e., > 100 0 mg/kg/day) or at the highest doses tested

.

6. Animal metabolism. [ Calcium gluconate dissociates under normal physiologic conditions into gluconic acid

, as do all of the inorganic salts of gluconic

acid . Intraperitoneal administration of calcium gluconate resulted in excretion of primarily unchanged gluconate anion in the urine; the remainder was metabolized. Twenty percent of a dose of calcium gluconate was absorbed from the intes tine .]

7. Metabolite toxicology

. NA

- remove

8. Endocrine disruption

. [ There is no information that suggests that calcium gluconate is an endocrine disrupter.]3

C. Aggregate Exposure

1. Dietary exposure. NA

- remove

i. Food. NA

- remove

ii. Drinking water

. No drinking water exposure is anticipated.

2. Non

- dietary exposure

. NA

- remove

D. Cumulative Effects

EPA has not made a common mechanism of toxicity finding as to calcium gluconate and any other substances, and calcium gluconate does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action,

therefore , EPA has not assumed that calcium gluconate has a common mechanism of toxicity with other substances.

E. Safety Determination

1. U.S. population. [ Calcium gluconate exhibits low acute toxicity. The closely related compounds, sodium gluconate and gluconic acid, exhibit low sub

- chronic toxicity and rapid metabolism and excretion. The strong structural similarity of calcium gluconate to sodium gluconate and gluc o n ic acid makes it reasonable to

consider that it will have similar toxicity and metabolism. This metabolism pattern is important because it explains why the toxicity of these compounds is low. Consequently, it may be stated that there is a reasonable certainty that no harm will result to the general population and to infants and children from aggregate exposure to residues of calcium glucon ate from the proposed use in pesticide

formulations.

2. Infants and children

. [ At this time, there is no concern for potential sensitivity to infants and children resulting from exposures to calcium gluconate . In its evaluation of gluconic acid and sodium gluconate, JECFA reported no quantitative or qualitative evidence of increased susceptibility following the prenatal exposure to mice, rats, hamsters and rabbits in developmental toxicity studies (JECFA, 1999) at doses ranging up to 780 mg/kg/day (t he highest dose tested). A safety factor analysis has not been used to assess the risk. For these reasons the additional tenfold safety factor for the protection of infants and children is

unnecessary.

F. International Tolerances

[There are no known international tolerances for calcium gluconate ]4