Document ID: EPA-HQ-OPP-2010-0820-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2011-07-06T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: Shaunta Hill, 703-347-8961
 
Quimica Agronomica de Mexico, S. de R.L. MI.

PP0E7754

	EPA has received a pesticide petition (PP0E7754) from Quimica Agronomica de Mexico, [S. de R.L. MI., Calle 18 N° 20501, Colonia Impulso, C.P. 31183, Chihuahua, Chih., Mexico] 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.  by establishing an import tolerance for residues of  Gentamicin in or on the raw agricultural commodity cucurbits (crop group 9) and fruiting vegetables (crop group 8) at 0.05 and 0.05 parts per million (ppm).  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 data 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.  As with the regulation of agricultural use of streptomycin and tetracycline, plant metabolism of widely-used antibiotics is not a concern.  The residues detected in food crops are negligible and these products are very resistant to conversion to other products.
      
      

      
      
	2. Analytical method. An analytical method was developed and used to quantitate residues of Gentamicin and Oxytetracycline.  Briefly, residues of Gentamicin were extracted from  samples.  The extraction was conducted with a homogenizer and extracts were centrifuged and decanted into a mixing cylinder.  Extraction buffer and methanol were added to the centrifuge tube, centrifuged, and shaken a total of two times, with each extract combined in the mixing cylinder.  The sample was brought to final volume with water and mixed in preparation for LC/MS/MS analysis.  The limits of quantitation (LOQ), in all matrices, were 0.03 ppm for Gentamicin.  The limit of detection (LOD), in all matrices, was defined as 0.01 ppm for Gentamicin (1/3 the LOQ).  

	3. Magnitude of residues. Fruiting vegetable and cucurbit residue studies show that there will be no quantifiable Gentamicin residues found in the raw agricultural commodities resulting from the proposed use rate and timing for crops grown in Mexico using an analytical method with limit of quantitation (LOQ) of 0.03 ppm.  Processing studies demonstrate that Gentamicin residues do not concentrate in processed fractions.

B. Toxicological Profile

	1. Acute toxicity.  The acute oral LD50 of Gentamicin sulfate in mice has been reported to be 10,000 mg/kg body weight. The low toxicity of Gentamicin sulfate is attributed to the fact that < 1% of oral doses are absorbed across the gastrointestinal tract into systemic circulation.  Gentamicin sulfate is not absorbed through intact skin efficiently enough to cause systemic effects. Acute inhalation studies show low pulmonary absorption of Gentamicin sulfate that resulted in no adverse effects in organs or potentially toxic serum levels. Ocular effects are limited mainly to reversible irritation responses following multiple treatments.  Gentamicin sulfate is a non-sensitizer and is not a primary skin irritant.
      No adverse effect resulting from a single-oral exposure was identified. Therefore, Gentamicin is not expected to pose an acute risk.

	2. Genotoxicty. The Agency has previously concluded that "Gentamicin is not likely to pose genotoxic hazards" (EPA-HQ-OPP-2006-0234-0022).

	3. Reproductive and developmental toxicity. The Agency has concluded "no evidence of increased susceptibility in the developmental studies in rats, rabbits, mice, and guinea pigs.  There is no evidence of increased susceptibility in the 2-generation reproduction study in rats"   (EPA-HQ-OPP-2006-0234-0022).

	4. Subchronic toxicity. There is no 21-day dermal toxicity study because Gentamicin sulfate is not absorbed though intact skin. Likewise there are no Gentamicin sulfate dietary subchronic studies because less than 1% of an oral dose is absorbed into the systemic circulation. Daily subcutaneous injections of Gentamicin sulfate into rats for 28 days resulted in a NOEL of 5 mg/kg body weight/day, which is equivalent to daily oral doses of 500 mg kg body weight/day.

	5. Chronic toxicity. The Agency has set  a chronic reference dose of 0.1 mg/kg/day on the basis of a 90-day toxicity study in the dog where the NOAEL was 10 mg/kg/day.  Uncertainty factors based on interspecies extrapolation (10X), intraspecies variability (10X) and FQPA 1X safety factor were used to calculate the chronic PAD (EPA-HQ-OPP-2006-0234-0022).

	6. Animal metabolism. Metabolism of Gentamicin sulfate is negligible resulting in renal excretion of the unchanged parent compound (EPA-HQ-OPP-2006-0234-0022).

	7. Metabolite toxicology. There are no known metabolites of toxicological concern.

	8. Endocrine disruption. No specific tests have been conducted with Gentamicin sulfate to determine whether the chemical may have an effect in humans that is similar to an effect produced by a naturally occurring hormone. However, a long history of human use has given no indication that would suggest that Gentamicin sulfate produces effects characteristic of the disruption of endocrine hormones.

C. Aggregate Exposure

	1. Dietary exposure. Tolerances have been established for residues of Gentamicin sulfate and Gentamicin in animal tissues resulting from veterinary treatment (21 CFR 556.300). A tolerance of 0.1 ppm is established for negligible residues of Gentamicin sulfate in the uncooked edible tissues of chickens and turkeys. Tolerances are established for total residues of Gentamicin in edible tissues of swine as follows: 0.1 ppm muscle, 0.3 ppm in liver, and 0.4 ppm in fat and kidney.  Quimica Agronomica de Mexico S. de R.L.MI. is requesting additional tolerances for Gentamicin from application as the sulfate salt at 0.05 ppm for fruiting vegetables and cucurbits.

	i. Food. For purposes of assessing the potential aggregate exposure from food under existing and proposed tolerances, dietary exposure is based on a Tier I DEEM-FCID v 2.16 (tolerance level residues assumed with 100% crop treated) which is a worst-case estimate of the level of residues consumed. 
      No adverse effect resulting from a single-oral exposure was identified. Therefore, no acute dietary endpoint was selected. Gentamicin is not expected to pose an acute risk.
      A chronic NOEL of 10 mg/kg/day determined for Gentamicin in a 90-day toxicity study in the dog was used for the dietary risk assessment. Ten-fold safety factors were applied for intra- and interspecies variables. The chronic exposure values using mean consumption data were 0.000193 mg/kg body weight/day for the general population and 0.000379 mg/kg body weight/day for children 3-5 years, the most exposed subpopulation group.

	ii. Drinking water. There are no potential drinking water sources of exposure to Gentamicin for the general population to residues of Gentamicin due to the fact the action being requested is to establish an import tolerance, only and there is no domestic registration of Gentamicin.

	2. Non-dietary exposure. There are no potential non-dietary sources of exposure to Gentamicin for the general population to residues of Gentamicin.

D. Cumulative Effects	The USEPA has not determined that Gentamicin sulfate has a common mechanism of toxicity with other substances. For the purposes of this petition, only the potential risks of Gentamicin in its aggregate exposure will be considered.

E. Safety Determination

	1. U.S. population. No adverse effect resulting from a single-oral exposure was identified; therefore, no acute dietary endpoint was selected. Therefore, Gentamicin is not expected to pose an acute risk.
	A chronic NOAEL of 10 mg/kg/day determined for Gentamicin in a 90-day toxicity study in the dog was used for the dietary risk assessment. Ten-fold safety factors were applied for intra- and interspecies variables. Chronic dietary exposure to Gentamicin from food only exposure utilizes <1.0% of the chronic reference dose for the general population group.

	2. Infants and children. 
	Chronic dietary exposure to Gentamicin from food utilizes 0.8% of the cRfD for children 3-5 years, the most sensitive subpopulation group.

F. International Tolerances  Canada, Mexico or the Codex Alimentarius Commission have not established maximum residue levels for residues of Gentamicin in food commodities.