Proposed Registration Decision: Iodosulfuron-Methyl-Sodium Technical Herbicide

18 April 2008
ISBN: 978-0-662-48477-6 (978-0-662-48478-3)
Cat. No.: H113-9/2008-6E (H113-9/2008-6E-PDF)
(PRD2008-06)

Table of Contents

• Overview
  • Proposed Registration Decision for Iodosulfuron-Methyl-Sodium Technical Herbicide and End-Use Product Tribute Solo 32 DF Herbicide
  • What Does Health Canada Consider When Making a Registration Decision?
  • What Is Iodosulfuron-Methyl-Sodium Technical Herbicide?
  • Health Considerations
  • Environmental Considerations
  • Value Considerations
  • Measures to Minimize Risk
  • Next Steps
  • Other Information

• Science Evaluation

• 1.0 The Active Ingredient, Its Properties and Uses
  • 1.1 Identity of the Active Ingredient
  • 1.2 Physical and Chemical Properties of the Active Substances and End-Use Product
  • 1.3 Directions for Use
  • 1.4 Mode of Action

• 2.0 Methods of Analysis
  • 2.1 Methods for Analysis of the Active Ingredient
  • 2.2 Method for Formulation Analysis
  • 2.3 Methods for Residue Analysis

• 3.0 Impact on Human and Animal Health
  • 3.1 Toxicology Summary
  • 3.2 Determination of Acceptable Daily Intake
  • 3.3 Determination of Acute Reference Dose
  • 3.4 Occupational and Bystander Risk Assessment
  • 3.5 Food Residues Exposure Assessment

• 4.0 Impact on the Environment
  • 4.1 Fate and Behaviour in the Environment
  • 4.2 Effects on Non-Target Species
    • 4.2.1 Effects on Terrestrial Organisms
    • 4.2.2 Effects on Aquatic Organisms

• 5.0 Value
  • 5.1 Effectiveness Against Pests

• 6.0 Toxic Substances Management Policy Considerations

• 7.0 Summary
  • 7.1 Human Health and Safety
  • 7.2 Environmental Risk
  • 7.3 Value

• 8.0 Proposed Regulatory Decision

• List of Abbreviations

Overview

Proposed Registration Decision for Iodosulfuron-Methyl-Sodium Technical Herbicide and End-Use Product Tribute Solo 32 DF Herbicide

Health Canada's Pest Management Regulatory Agency (PMRA), under the authority of the  Pest Control Products Act and Regulations, is proposing conversion from conditional to full registration of iodosulfuron-methyl-sodium technical herbicide and Tribute Solo 32 DF Herbicide for control of certain broadleaf and grassy weeds in field corn.

An evaluation of available scientific information found that, under the approved conditions of use, the end-use product has value and does not present an unacceptable risk to human health or the environment.

This Proposed Registration Decision is a consultation document that summarizes the science evaluation of iodosulfuron-methyl-sodium and presents the reasons for the decision. It also proposes additional risk-reduction measures that will be required to further protect human health and the environment.

This Overview describes the regulatory process and the key points of the evaluation, while the Science Evaluation provides detailed technical information on the human health, environmental and value assessment of iodosulfuron-methyl-sodium.

The PMRA will accept written comments on this proposal up to 45 days from the date of publication of this document. Please forward all comments to Publications (please see contact information on the cover page of this document).

What Does Health Canada Consider When Making a Registration Decision?

The key objective of the Pest Control Products Act is to prevent unacceptable risks to people and the environment from the use of pest control products. Health or environmental risk is considered acceptable if there is reasonable certainty that no harm to human health, future generations or the environment will result from use or exposure to the product under its conditions or proposed conditions of registration.¹ The Act also requires that products have value² when used according to the label directions. Conditions of registration may include special precautionary measures on the product label to further reduce risk.

To reach its decisions, the PMRA applies modern, rigorous risk-assessment methods and policies. These methods consider the unique characteristics of sensitive subpopulations in humans (e.g. children) as well as organisms in the environment (e.g. those most sensitive to environmental contaminants). These methods and policies also consider the nature of the effects observed and the uncertainties present when predicting the impact of pesticides. For more information on how the PMRA regulates pesticides, the assessment process and risk-reduction programs, please visit the PMRA's website at www.pmra-arla.gc.ca.

Before making a final registration decision on iodosulfuron-methyl-sodium, the PMRA will consider all comments received from the public in response to this consultation document. The PMRA will then publish a Registration Decision document on iodosulfuron-methyl-sodium, which will include the decision, the reasons for it, a summary of comments received on the proposed registration decision and the PMRA's response to these comments.

For more details on the information presented in this Overview, please refer to the Science Evaluation section of this consultation document.

What Is Iodosulfuron-Methyl-Sodium Technical Herbicide?

Iodosulfuron-methyl-sodium is a postemergence herbicide, i.e. a herbicide applied after the crop has emerged above the ground. It is applied to field corn using ground application equipment to control broadleaf and grassy weeds. Iodosulfuron-methyl-sodium inhibits the activity of acetolactate synthase (ALS), which is the key enzyme in the biosynthesis of the branch-chain amino acids, isoleucine, leucine and valine. Although the actual sequence of phytotoxic processes is unclear, plant death results from events occurring in response to inhibition of the ALS enzyme.

Health Considerations

Can Approved Uses of Iodosulfuron-Methyl-Sodium Technical Herbicide Affect Human Health?

Iodosulfuron-methyl-sodium is unlikely to affect your health when used according to label directions

Exposure to iodosulfuron-methyl-sodium may occur through diet (food and water). When assessing health risks, two key factors are considered: the levels where no health effects occur and the levels to which people may be exposed. The dose levels used to assess risks are established to protect the most sensitive human population (e.g. children and nursing mothers). Only those uses where exposure is well below levels that cause no effects in animal testing are considered acceptable for registration.

Toxicology studies in laboratory animals describe potential health effects from varying levels of exposure to a chemical and identify the dose where no effects are observed. The health effects noted in animals occur at doses more than 100 times higher (and often much higher) than levels to which humans are normally exposed when using iodosulfuron-methyl-sodium products according to label directions.

Iodosulfuron-methyl-sodium caused eye irritation in animals and the end-use product, Tribute Solo 32 DF Herbicide, caused dermal irritation and sensitization in animals. Therefore, the label statement Warning Skin Irritant, Potential Skin Sensitizer is required. Iodosulfuron-methyl-sodium did not cause cancer in animals and was not genotoxic. There was also no indication that iodosulfuron-methyl-sodium caused damage to the nervous system and there were no effects on reproduction. The first signs of toxicity in animals given daily doses of iodosulfuron-methyl-sodium over longer periods of time were effects on the liver, kidneys and blood parameters. The risk assessment protects against these effects by ensuring that the level of human exposure is well below the lowest dose at which these effects occurred in animal tests.

When iodosulfuron-methyl-sodium was given to pregnant animals, effects on the developing fetus were observed at doses that were not toxic to the mother, indicating that the fetus was more sensitive to iodosulfuron-methyl-sodium than the adult animal. However, these effects occurred only at doses that were much higher than the doses producing the most sensitive effect in the database, which was used for the risk assessment. Consequently, sufficient protection already exists for the developing fetus. Therefore, there is no need for further reduction in the allowable level of human exposure to iodosulfuron-methyl-sodium as all groups, including sensitive populations, are adequately protected.

Residues in Water and Food

Dietary risks from food and water are not of concern

Aggregate dietary intake estimates (food plus water) revealed that the general population and infants, the subpopulation that would ingest the most iodosulfuron-methyl-sodium relative to body weight, are expected to be exposed to less than 0.10% of the acceptable daily intake. Based on these estimates, the chronic dietary risk from iodosulfuron-methyl-sodium is not of concern for any population subgroup. Animal studies revealed no acute health effects.

The Food and Drugs Act prohibits the sale of adulterated food, that is, food containing a pesticide residue that exceeds the established maximum residue limit (MRL). Pesticide MRLs are established for Food and Drugs Act purposes through the evaluation of scientific data under the Pest Control Products Act. Food containing a pesticide residue that does not exceed the established MRL does not pose an unacceptable health risk.

Corn residue trials conducted throughout the United States using iodosulfuron-methyl-sodium were acceptable. The MRL for iodosulfuron-methyl-sodium in or on field corn grain has been established in Table II of the Food and Drugs Act(15 April 2005).

Occupational Risks From Handling Tribute Solo 32 DF Herbicide

Refer to Regulatory Note REG2004-04, Iodosulfuron-methyl-sodium,for a detailed assessment of the toxicological database for iodosulfuron-methyl-sodium and the end-use product, Tribute Solo 32 DF Herbicide.

Environmental Considerations

What Happens When Iodosulfuron-Methyl-Sodium Technical Herbicide Is Introduced Into the Environment?

Iodosulfuron-methyl-sodium is toxic to terrestrial plants; therefore, buffer zones are required during application.

Iodosulfuron-methyl-sodium enters the environment when used as a herbicide on corn. Iodosulfuron-methyl-sodium is slightly persistent in soil and water, while the major breakdown products range from non-persistent to persistent in soil and water. Based on laboratory mobility data, iodosulfuron-methyl-sodium and its major breakdown product would be expected to leach through the soil profile beyond 30 cm with the potential to enter groundwater. Under field conditions at an Ontario site, however, this potential was not realized due to rapid breakdown. Based on low volatility, iodosulfuron-methyl-sodium residues are not expected in the air.

Iodosulfuron-methyl-sodium and its major breakdown product presents a low risk to wild mammals, birds, earthworms, bees and other arthropods. As is expected for a herbicide, the end-use product adversely affects terrestrial and aquatic plants in adjacent areas.

Value Considerations

What is the Value of Tribute Solo 32 DF Herbicide?

Tribute Solo 32 DF Herbicide, a postemergence herbicide, controls both grasses and broadleaf weeds in field corn.

A single application of Tribute Solo 32 DF Herbicide provides effective control of a range of broadleaf and grassy weeds in field corn. It is also compatible with integrated weed management practices and with conventional crop production systems. Since Tribute Solo 32 DF Herbicide is applied after weeds have emerged, farmers can better assess whether the herbicide is necessary or suitable for particular weed species.

Tribute Solo 32 DF Herbicide had been granted conditional registration with one of the conditions that the lowest effective rate for common ragweed be established. The registrant has since decided not to support the claim of common ragweed control, and therefore this claim has been removed from the Tribute Solo 32 DF Herbicide label. The condition of registration has now been adequately addressed from a value perspective and no further data are required.

Measures to Minimize Risk

Registered pesticide product labels include specific instructions for use. Directions include risk-reduction measures to protect human and environmental health. These directions must be followed by law.

Key risk-reduction measures being proposed on the label of Tribute Solo 32 DF Herbicide to address the potential risks identified in this assessment are as follows.

Key Risk-Reduction Measures

Human Health

Since there is a concern with users coming into direct contact with iodosulfuron-methyl-sodium on the skin, anyone mixing or loading Tribute Solo 32 DF Herbicide must wear a long-sleeved shirt, pants and chemical-resistant gloves, and anyone applying the product must wear a long-sleeved shirt and pants.

Environment

Toxic to aquatic organisms and non-target terrestrial plants. Observe buffer zones specified under directions for use.

Field sprayer application: do not apply during periods of dead calm. Avoid application of this product when winds are gusty. Do notapply with spray droplets smaller than the American Society of Agricultural Engineers medium classification. Boom height must be 60 cm or less above the crop or ground.

Do not apply by air.

Buffer zones:

The buffer zones specified in the table below are required between the point of direct application and the closest downwind edge of sensitive terrestrial habitats (such as grasslands, forested areas, shelter belts, woodlots, hedgerows, rangelands, riparian areas and shrublands) and sensitive aquatic habitats (such as lakes, rivers, sloughs, ponds, prairie potholes, creeks, marshes, streams, reservoirs, wetlands and estuarine/marine habitats).

Method of Application	Crop	Buffer Zones (metres) Required for the Protection of Aquatic habitat	Buffer Zones (metres) Required for the Protection of Terrestrial habitat
Field sprayer	Corn	1	1

When a tank mixture is used, consult the labels of the tank-mix partners and observe the largest (most restrictive) buffer zone of the products involved in the tank mixture.

Next Steps

Before making a final registration decision to convert iodosulfuron-methyl-sodium from a conditional to full registration, the PMRA will consider all comments received from the public in response to this Consultation Document. The PMRA will then publish a Registration Decision document, which will include its decision, the reasons for it, a summary of comments received on the proposed decision and the Agency's response to these comments.

Other Information

At the time the PMRA makes its registration decision, it will publish a Registration Decision document on iodosulfuron-methyl-sodium (based on the Science Evaluation section of this consultation document and REG2004-04, Iodosulfuron-methyl-sodium). In addition, only the test data referenced in this Consultation Document will be available for public inspection, upon application, in the PMRA's Reading Room (located in Ottawa).

Science Evaluation

1.0 The Active Ingredient, Its Properties and Uses

1.1 Identity of the Active Ingredient

Refer to Regulatory Note REG2004-04, Iodosulfuron-methyl-sodium, for the identity of theactive substance and its impurities.

1.2 Physical and Chemical Properties of the Active Substances and End-Use Product

Technical Product-Iodosulfuron-Methyl-Sodium

Property	Result
Colour and physical state	Beige crystalline powder
Nominal concentration	92.0%
Odour	Weak non-characteristic odour
Density at 20°C	1.76 g/cm3
Vapour pressure	Temperature (°C) 20 25	Vapour pressure (Pa) 2.6 × 10-9 6.7 × 10-9
pH	Not specified
Solubility in water at 20°C	pH 7.6 (unbuffered) 4 5 7 9 10	Solubility (g/L) 60 0.02 0.17 25 65 45
n-Octanol-water partition coefficient at 25°C	pH 4 5 6 7 9 10	log Kow 1.96 1.07 0.07 - 0.70 - 1.22 - 1.15

Refer to Regulatory Note REG2004-04, Iodosulfuron-methyl-sodium, for a detailed chemical assessment of iodosulfuron-methyl-sodium.

1.3 Directions for Use

Refer to Regulatory Note REG2004-04, Iodosulfuron-methyl-sodium, for detailed directions for use of iodosulfuron-methyl-sodium and Tribute Solo 32 DF Herbicide.

1.4 Mode of Action

Refer to Regulatory Note REG2004-04, Iodosulfuron-methyl-sodium, for the mode of action of iodosulfuron-methyl-sodium.

2.0 Methods of Analysis

2.1 Methods for Analysis of the Active Ingredient

The methods provided for the analysis of the active ingredient and the impurities in iodosulfuron-methyl-sodium have been validated and assessed to be acceptable for the determinations.

2.2 Method for Formulation Analysis

The method provided for the analysis of the active ingredient in the formulation has been validated and assessed to be acceptable for use as an enforcement analytical method.

2.3 Methods for Residue Analysis

A detailed assessment of the methods of analysis for iodosulfuron-methyl-sodium and end-use product Tribute Solo 32 DF Herbicide are presented in Regulatory Note REG2004-04, Iodosulfuron-methyl-sodium.

3.0 Impact on Human and Animal Health

3.1 Toxicology Summary

A detailed review of the toxicological database available for the technical grade active ingredient, iodosulfuron-methyl-sodium, has been completed. Required toxicity data as presented in Regulatory Note REG2004-04, Iodosulfuron-methyl-sodium, were submitted to the PMRA.

1. Acute neurotoxicity study
   Clinical signs suggestive of a neurotoxic potential, such as squatting posture, ataxic and uncoordinated gait, increased salivation, prostration and prone position, were noted in the rat acute oral study at high doses only and in moribund dogs with bronchopneumonia and pleurisy in the 90-day dietary study. Furthermore, in the rat developmental study the incidence of increased salivation (commonly observed in gavage studies) was observed in the absence of any other treatment-related finding. Based on the considerations outlined above, it was determined that the effects observed did not support the requirement for a neurotoxicity study.
2. Rabbit developmental toxicity study with an adequate high dose
   The rabbit developmental study did not produce adverse effects at the highest dose tested (400 mg/kg bw/day), which is not the limit dose (1000 mg/kg bw/day). Therefore, the study is considered unacceptable. However, effects would only be expected to occur at doses above 400 mg/kg bw/day, which already provides an adequate margin of safety of 5479 for the acceptable daily intake (ADI). As a result, a new study at higher doses would not impact the risk assessment and is not required.
3. A mouse oncogenicity study with an adequate high dose
   The dose levels tested in this study were viewed as inadequate to assess the carcinogenic potential of iodosulfuron-methyl-sodium in this species. In the 80-week dietary study, there was no evidence to indicate that iodosulfuron-methyl-sodium was oncogenic in the mouse at dose levels up to and including 277 mg/kg bw/day (the highest dose tested), which was the lowest observed adverse effect level (LOAEL). The maximum tolerated dose (MTD) was not achieved in this study but when viewed in light of a negative carcinogenicity study (rat two-year dietary) and negative mutagenicity outcomes in various in vitro and in vivo assays, iodosulfuron-methylsodium exhibits a very low oncogenic hazard. A new study would not be expected to reveal any positive data with regard to carcinogenicity at doses relevant to the risk assessment given the weight of evidence. Therefore, no further studies are required at this time.
4. A rat 21/28-day repeat dose dermal toxicity study to further characterize potential hazard and risk via the dermal route of exposure
   This study was not provided. However, acceptable modes of exposure were obtained using the one-year oral (feeding) dog study no observed adverse effect level (NOAEL) for the current use pattern. Therefore, no study is required unless there is an expansion of the use pattern.

In rats, iodosulfuron-methyl-sodium was rapidly and extensively absorbed, greater than 93, 79 and 70% of the orally administered single low- (10 mg/kg bw), repeat mid- (100 mg/kg bw) and single high-doses (500 mg/kg bw), respectively. Maximal plasma concentrations (C_max) were achieved within 3.6-6.0 and 7.3-7.6 hours following single low- and single high-dose administration, respectively. A comparison of the area under the curve following oral and intravenous low-dose administration indicated a calculated absorption rate or bioavailability of approximately 86 and 63% of the administered dose for males and females, respectively. No significant tissue accumulation was evident, i.e. less than 0.5% of the administered dose remaining in the tissue/carcass at sacrifice (72 hours after dosing). The major route of excretion was via the urine with the majority of the administered dose being eliminated within 24 hours, and was generally complete within 72 hours. Elimination was biphasic, showing a fast initial elimination followed by a slower terminal phase. Following single low-dose administration, approximately 93.9-97.6 and 4.3-7.3% of the administered dose was recovered in the urine and feces, respectively. Following high-dose administration, urinary excretion was reduced to 69.1-71.5% of the administered dose in males and approximately 78.4-85.5% of the administered dose in females. Fecal excretion was increased slightly to approximately 24.5-26.5% of the administered dose in males and approximately 14.9-17.0% of the administered dose in females. Radioactivity was not detected in exhaled air following dosing. Absorption, plasma kinetics, distribution and elimination in dogs were comparable to those in rats. The majority of the administered dose was excreted as the unchanged parent compound, accounting for approximately 48.7-86.3 and 1.1-11.1% of the administered dose in the urine and feces, respectively. Metabolites were identified as AE F145740 (approximately 0.9-4.5% of the administered dose), AE F148741 (approximately 1.5-8.2% of the administered dose) and AE F168532 (approximately 0.3-6.6% of the administered dose). Each of these metabolites was present in both the urine and feces. Unidentified metabolites were also isolated in the feces (approximately 0.6-1.2% of the administered dose). Each of the other metabolites was present at less than 0.6% of the administered dose. There were no significant differences in the metabolic profiles between sexes or dose levels, nor following repeated dosing in the rat or between the rat and dog.

Iodosulfuron-methyl-sodium has low acute toxicity by the oral, dermal and inhalation routes of exposure; it is moderately irritating to the eyes, minimally irritating to the skin and is not considered to be a skin sensitizer. The metabolites of iodosulfuron-methyl-sodium tested have low acute toxicity by the oral and dermal routes of exposure. The formulation, Tribute Solo 32 DF Herbicide, has low acute toxicity by the oral, dermal and inhalation routes of exposure; it is mildly irritating to the eyes, moderately irritating to the skin and is considered to be a potential skin sensitizer. The formulants were on the United States Environmental Protection Agency Lists 3, 4A or 4B, and were of no toxicological concern.

Iodosulfuron-methyl-sodium was tested in a battery of in vitro (bacterial and mammalian cell gene mutation assays, an unscheduled DNA synthesis assay, as well as mammalian cell chromosomal aberration assay) and in vivo (mouse micro nucleus assay) mutagenicity studies. There was no evidence of genotoxicity potential in any of these assays; therefore, the weight of evidence suggests that iodosulfuron-methyl-sodium was not genotoxic under the conditions of the tests performed.

The subchronic and chronic toxicity of iodosulfuron-methyl-sodium was investigated in the mouse, rat and dog. No repeat-dose dermal toxicity study was available. In mice, treatment-related findings were noted in the liver in the 90-day and 80-week dietary studies. Increased liver weights, centrilobular hepatocellular hypertrophy and centrilobular fat deposition were noted at 2100 and 7000 ppm in the 90-day dietary study and at 1750 ppm in the 80-week dietary study. In the 90-day dietary study, the hypertrophied cells exhibited lipofuscin deposition, possibly due to a degradation of the subcellular organelles in the cytoplasm. An increased incidence of focal necrosis was also noted at 7000 ppm in the 90-day dietary study. Centrilobular mononuclear infiltration and pigmentation of the centrilobular hepatocytes, possibly due to lipofuscin deposition, were also noted at 1750 ppm in the 80-week dietary study. In the 90-day dietary study, lower body weight (bw) and body weight gain (bwg) were noted in males at 7000 ppm. The NOAEL for the 90-day dietary study was 700 ppm (equal to 119 mg/kg bw/d) for males and 2100 ppm (equal to 401 mg/kg bw/d) for females. The NOAEL for the 80-week dietary study was 350 ppm (equal to 54.2 and 57.6 mg/kg bw/d for males and females, respectively). The MTD was not achieved in this study. However, when viewed in light of negative carcinogenicity in the rat two-year dietary study and negative mutagenicity outcomes in various in vitro and in vivo assays, iodosulfuron-methyl-sodium exhibits very low oncogenic hazard. There was no evidence to indicate that iodosulfuron-methyl-sodium was oncogenic in mice at dose levels up to and including 1750 ppm (the highest dose tested [HDT]). A new study would not be expected to reveal any positive data with regard to carcinogenicity at relevant doses, given the weight of evidence. Therefore, no further studies are required.

In rats, treatment-related findings were limited to lower bw and bwg in the 90-day and two-year dietary studies. Lower bw and bwg were noted at 5000 and 10 000 ppm (approximately 10-15 and 15-20%, respectively) in the 90-day dietary study and at 7000 ppm (approximately 25-33%) in the two-year dietary study. Elevated alanine aminotransferase (ALAT) activity (approximately 11%) and slight centrilobular hepatocyte enlargement were noted in males at 10 000 ppm in the 90-day dietary study; however, in the absence of correlating findings in other liver function markers or changes in liver weight, these findings were considered to be an adaptive response and not treatment-related. The NOAEL for the 90-day dietary study was 1000 ppm (equal to 67 and 74 mg/kg bw/d for males and females, respectively). The NOAEL for the two-year dietary study was 700 ppm (equal to 29.7 and 39.1 mg/kg bw/d for males and females, respectively).

Dogs appear to be the most sensitive species tested. Dietary concentrations of 1200 ppm and above caused dose-dependent hematological and histopathological findings indicative of anaemia in the 90-day and one-year dietary studies. Hematological findings were generally characterized by a lower red blood cell (RBC) count, and hemoglobin (HGB) and hematocrit (HCT) at 1200 ppm and above. At 7200 ppm, the decreased RBC parameters were noted throughout treatment with the decrease gradually developing and becoming more severe as treatment progressed. Peripheral anaemia appeared to develop gradually, probably by natural turnover of erythrocytes, since there was no evidence of hemolytic processes or hemorrhaging. Examination of the bone marrow smears revealed decreased late normoblasts at 1200 ppm and above, decreased erythroblasts at 7200 ppm and an increased myeloid to erythroid ratio (M:E) at 7200 ppm. Histopathological findings were characterized by severe generalized hematopoietic hyperplasia in the bone marrow at 1200 ppm and above, and extramedullary hematopoiesis in the spleen and liver at 7200 ppm. Hematopoietic hyperplasia was evident in sections of the stifle joint in which the epiphyseal medullary cavities of the femur and tibia were filled with cells of the myeloid and erythroid series as well as developing megakaryocytes. This correlated with increased incidences of juvenile forms of both the myeloid and erythroid series as indicated by an increase in the number of immature granulocytes present, a reduction in the number of erythroblasts present and an increase in the M:E ratio noted at 7200 ppm. There was no clinical chemistry or histopathological finding to indicate peripheral blood loss via hemolysis or hemorrhaging to account for the hematological and histopathological findings indicative of anaemia; this suggests that these findings may be due to interference of the test substance with cell maturation in the hematopoietic tissue.

In the 90-day dietary study, increased ALAT and aspartate aminotransferase (ASAT) activity and increased liver weight were noted at 1200 and 7200 ppm; however, there was no correlating histopathological finding in the liver. Increased creatine phosphokinase (CPK) activity was also noted at 1200 ppm and above in the 90-day dietary study. At 7200 ppm, the increased creatine phosphatase kinase activity correlated with lower creatinine levels and may be due to muscle loss/injury. This would also correlate with lower bw, bwg and food efficiency noted at 7200 ppm. Other treatment-related findings noted at 7200 ppm in the 90-day dietary study included the following:

• unsteady gait
• hunched posture and prostration
• increased liver, spleen and kidney weight
• pigmentation of the Kupffer cells and slight centrilobular congestion in the liver
• subcapsular tubular necrosis with cyst formation
• interstitial nephritis and hyaline droplets in the kidney
• atrophy of the lymphoid tissue in the spleen.

The NOAEL for the 90-day dietary study was 200 ppm (equal to 8.1 and 8.4 mg/kg bw/d for males and females, respectively). The NOAEL for the one-year dietary study was 1200 ppm (equal to 41.8 mg/kg bw/d) for males and 200 ppm (equal to 7.3 mg/kg bw/d) for females.

In the 80-week dietary study, there was no evidence to indicate that iodosulfuron-methyl-sodium was oncogenic in mice at dose levels up to and including 1750 ppm (HDT); however, the MTD was not achieved in this study. In the rat two-year dietary study, there was no evidence to indicate that iodosulfuron-methyl-sodium was oncogenic in rats at dose levels up to and including 7000 ppm, the HDT. Dosing was considered to be adequate based on decreased bw and bwg (greater than 10%). Iodosulfuron-methyl-sodium was negative for mutagenicity in various in vitro and in vivo assays. Furthermore, registered sulfonyl urea compounds (structurally similar compounds) have been found to be non-carcinogenic. Based on the negative carcinogenicity in the rat two-year dietary study and negative mutagenicity, iodosulfuronmethyl-sodium exhibits very low oncogenic hazard. A new mouse study would not be expected to reveal any positive data with regard to carcinogenicity at relevant doses given the weight of evidence. Therefore, no further studies are required.

There was no evidence in the toxicology database to suggest a significant increase in toxicity with increased duration of exposure in the mouse, rat, or dog, or to indicate a significant difference in gender sensitivity. In the rat two-generation reproduction (one litter per generation) study, reproduction function, reproductive parameters and litter parameters were not influenced by treatment in the first and second parental generations at dose levels up to and including 5000 ppm (equal to 346 and 390 mg/kg bw/d in males and females, respectively), the HDT. In addition, there was no treatment-related systemic finding in the P1/P2 animals. In the offspring, decreased pup survival and mean litter size were noted in the second generation offspring (F₂) pups on lactation days 0 and 4. There was no treatment-related finding in the first generation offspring pups. The NOAEL for parental toxicity was 5000 ppm (equal to 346 and 390 mg/kg bw/d in males and females, respectively). The NOAEL for offspring toxicity was 500 ppm (equal to 34.2 and 39.7 mg/kg bw/d in males and females, respectively). On the basis of the parental and offspring NOAELs, neonates appear to be both qualitatively and quantitatively more sensitive than adults to the toxic effects of iodosulfuron-methyl-sodium. In the rat developmental toxicity study, increased salivation was noted in the dams at 1000 mg/kg bw/d throughout treatment (gestation days 8-17). In the fetuses, increased incidences of poor ossification or non-ossification of sacral vertebral arch, individual skull bones, sternebrae, metacarpal 5 in the forepaw and phalanx III of the first to fifth toes was noted at 1000 mg/kg bw/d. These findings were generally within the historical control range; however, when considered collectively, they may indicate delayed skeletal development at this dose level. The NOAEL for maternal and developmental toxicity was 315 mg/kg bw/d. In the rabbit developmental toxicity study, there was no adverse treatment-related maternal or developmental finding at dose levels up to and including 400 mg/kg bw/d, the HDT. The NOAEL for maternal and developmental toxicity was 400 mg/kg bw/d. On the basis of the maternal and developmental NOAELs noted in the rat developmental toxicity study, there was no quantitative evidence to indicate an increased susceptibility of the fetus to in utero exposure to iodosulfuron-methyl-sodium. However, based on the severity of the findings noted at the respective NOAELs and LOAELs, there appears to be an increased qualitative susceptibility of the fetus to in utero exposure to iodosulfuron-methylsodium. Iodosulfuron-methyl-sodium was not considered teratogenic to rats or rabbits under the conditions tested.

3.2 Determination of Acceptable Daily Intake

The recommended ADI is 0.073 mg/kg bw/d, as calculated in the following equation:

The most appropriate NOAEL recommended to calculate the ADI is 7.3 mg/kg bw/d as determined in the one-year dog dietary study. Treatment-related findings at the LOAEL (43.7 mg/kg bw/d) included gross and histopathological changes to the hematopoietic system. A safety factor (SF) of 100-fold is recommended to account for intra- and inter-species variations. In the two-generation reproduction study, there was decreased pup viability in the F₂ pups on lactation days 0 and 4 in the absence of maternal toxicity in the rat. There was also an increased incidence of apparent delayed skeletal development in the rat developmental toxicity study. The Pest Control Products Act requires an additional 10-fold factor to protect children and pregnant females from relevant endpoints of concern or any database uncertainty regarding a potential for increased sensitivity in these population subgroups. A different factor may be determined to be appropriate on the basis of reliable scientific data. In the case of iodosulfuron-methyl-sodium, the 10× Pest Control Products Act factor can be removed because the sensitivity noted was at doses at least an order of magnitude greater than the NOAEL used for the ADI, and this provides an adequate margin of safety to the effects of concern.

3.3 Determination of Acute Reference Dose

An acute reference dose was not established because iodosulfuron-methyl-sodium was considered unlikely to present an acute hazard. There were no significant treatment-related findings in the acute, short-term, two-generation reproduction or the developmental toxicity studies to indicate a concern in the acute dietary risk assessment.

3.4 Occupational and Bystander Risk Assessment

Refer to Regulatory Note REG2004-04, Iodosulfuron-methyl-sodium, for a detailed assessment of the occupational and bystander database for iodosulfuron-methyl-sodium and the end-use product, Tribute Solo 32 DF Herbicide.

3.5 Food Residues Exposure Assessment

A detailed assessment of the residue chemistry database for iodosulfuron-methyl-sodium and the end-use product, Tribute Solo 32 DF Herbicide, is presented in Regulatory Note REG2004-04, Iodosulfuron-methyl-sodium.

4.0 Impact on the Environment

Refer to Regulatory Note REG2004-04, Iodosulfuron-methyl-sodium, for a detailed assessment of the environmental impact of iodosulfuron-methyl-sodium.

The required information on the n-octanol-water partitioning data for three major transformation products as presented in Regulatory Note REG2004-04, Iodosulfuron-methyl-sodium, was submitted and found to be satisfactory to the PMRA.

Following is the environmental assessment for the currently registered use pattern.

4.1 Fate and Behaviour in the Environment

The n-octanol-water partition coefficient of the iodosulfuron-methyl-sodium major transformation products (AE F059411, AE 0000119 and AE 0034855) indicates that these compounds have limited potential for bioaccumulation/bioconcentration in biological organisms.

4.2 Effects on Non-Target Species

To estimate risk of potential adverse effects on non-target species, a quotient method is used. The risk quotient (RQ) is calculated by dividing the exposure estimate by a value representing the most sensitive toxic endpoint. Risk quotients are initially calculated for a screening-level assessment in order to obtain higher estimates of risk. The screening-level assessment is a realistic worst-case scenario. A safety factor is applied to the aquatic toxicity endpoint to account for interspecies sensitivity as well as protection goals. The PMRA uses a safety factor of two for the acute lethal concentration to 50% (LC₅₀) / effect concentration to 50% (EC₅₀ for invertebrates, algae and plants, and 10 for all other aquatic organisms. Risk quotients for chronic effects are calculated using the no observed effect concentration (NOEC) from chronic toxicity studies. Negligible risk is predicted if the RQ is less than the trigger value of one. If the trigger values are exceeded under the realistic worst-case scenario, then a refinement of the assessment is necessary to evaluate how frequently impacts might be expected in the range of conditions that occur in the field. A refined assessment takes into consideration more realistic exposure scenarios (e.g. drift to non-target habitats and runoff to water bodies) and may consider different toxicity endpoints.

Due to changes in the methods of determining risk, the risk assessment in Regulatory Note REG2004-04, Iodosulfuron-methyl-sodium, was re-examined. The results are as follows.

4.2.1 Effects on Terrestrial Organisms

For terrestrial vertebrates, iodosulfuron-methyl-sodium did not cause mortality or clinical signs of toxicity on an acute (gavage) or reproductive basis. Iodosulfuron-methyl-sodium was found to cause minor weight loss during short-term dietary studies (no observed effect level [NOEL] 67-401 mg/kg bw/d for rats and mice). However, risk quotients calculated under a realistic worst-case scenario indicate that iodosulfuron-methyl-sodium presents a negligible risk to wild mammals and birds following acute, short-term or long-term exposure; all risk quotients were less than one (Appendix I, Table 6).

For terrestrial invertebrates, iodosulfuron-methyl-sodium (technical and formulated product) was not toxic in acute dose-response studies, with LC₅₀ values exceeding the highest dose (limit) tested. Mortality was observed in only two test species, a ground-dwelling predator and a parasitic wasp, beginning at 12 g EP/ha (most sensitive lethal rate to 50% [LR₅₀] = 14.9 g EP/ha). Risk quotients calculated under realistic worst-case scenarios indicate that iodosulfuron-methyl-sodium presents a negligible risk to terrestrial invertebrates following acute or short-term exposure; all risk quotients were less than one (Appendix I, Table 6).

For terrestrial plants, seedling emergence and vegetative vigour were examined and Tribute Solo 32 DF Herbicide affected seedling emergence and vegetative vigour. The most sensitive endpoint was for the seedling emergence dry weight of 14.1 g EP/ha. Risk quotients calculated for seedling emergence exceeded one. Therefore, buffer zone calculations were conducted.

A refined assessment considered that the most likely scenario of exposure to non-target plants is through drift. A buffer zone of one metre was calculated.

4.2.2 Effects on Aquatic Organisms

On an acute basis, iodosulfuron-methyl-sodium has an LC₅₀ an acute basis, iodosulfuron-methyl-sodium has an LC₅₀ value of >86.9 mg a.i./L (NOEC of 28.1 mg a.i./L) for Daphnia magna , > 88 mg a.i./L (NOEC of 88 mg a.i./L) for rainbow trout and >92 mg a.i./L (NOEC of 92 mg a.i./L) for bluegill sunfish. The end-use product Tribute Solo 32 DF Herbicide has an LC₅₀ value of >100 mg EP/L (NOEC of 100 mg EP/L) for Daphnia magna, 2.6 mg EP/L (NOEC of 1.0 mg EP/L) for rainbow trout and 2.8 mg EP/L (NOEC of 1.0 mg EP/L) for bluegill sunfish. Observable effects were reported following long-term exposure of invertebrates (reduced number of offspring at 0.02 mg EP/L). The toxicity of iodosulfuron-methyl-sodium to green and blue-green algae was variable (EC₅₀ values range from 0.041 to >81.5 mg a.i./L). Risk quotients calculated under a realistic worst-case scenario indicate that iodosulfuron-methyl-sodium and Tribute Solo 32 DF Herbicide present negligible risks to invertebrates and fish and algae following short-term or long-term exposure; risk quotients were less than one (Appendix I, Table 6).

Iodosulfuron-methyl-sodium has an EC₅₀ of 0.00083 mg a.i./L (NOEC 0.00039 mg a.i./L) for the aquatic vascular plant, which was the most sensitive aquatic organism tested (Appendix I, Table 6). The EC₅₀ of Tribute Solo 32 DF Herbicide is 0.0025 mg EP/L (NOEC 0.001 mg EP/L). The risk quotient calculated under a realistic worst-case scenario exceeded the trigger value of one (Appendix I, Table 6). Risk quotients calculated for vascular plants exceeded one. Therefore, buffer zone calculations were conducted.

A refined assessment considered that the most likely scenario of exposure to aquatic plants is through drift and runoff. A buffer zone of one metre was calculated.

5.0 Value

5.1 Effectiveness Against Pests

Data were generated from 60 small-plot field trials conducted over a 2-year period at several locations in Ontario, Quebec, Manitoba and northern United States border states under conventional tillage practices. For each trial, an appropriate experimental design was used and an appropriate set of treatments was included to address the pest claims. Treatments were conducted at the labeled rates and a reduced application rate in order to confirm that the requested rates are the lowest to provide effective and consistent control on a weed-specific basis.

Tribute Solo 32 DF Herbicide was granted conditional registration with one of the conditions being that the lowest effective rate for common ragweed be established. The registrant has since decided not to support the claim of common ragweed control and has removed it from the Tribute Solo 32 DF Herbicide label. The registration condition has now been adequately addressed from a value perspective and no further data are required.

Refer to Regulatory Note REG2004-04, Iodosulfuron-methyl-sodium, for a detailed value assessment of Tribute Solo 32 DF Herbicide.

6.0 Toxic Substances Management Policy Considerations

The management of toxic substances is guided by the federal government's Toxic Substances Management Policy, which puts forward a preventive and precautionary approach to deal with substances that enter the environment and could harm the environment or human health. The policy provides decision makers with direction and sets out a science-based management framework to ensure that federal programs are consistent with its objectives. One of the key management objectives is virtual elimination from the environment of toxic substances that result predominantly from human activity and that are persistent and bioaccumulative. These substances are referred to in the policy as Track 1 substances.

During the review process, iodosulfuron-methyl-sodium was assessed in accordance with the Pest Management Regulatory Agency (PMRA) Regulatory Directive DIR99-03, The PestManagement Regulatory Agency's Strategy for Implementing the Toxic Substances ManagementPolicy. Substances associated with the use of iodosulfuron-methyl-sodium were also considered, including major transformation products formed in the environment, microcontaminants in the technical product and formulants in the end-use product, Tribute Solo 32 DF Herbicide. The PMRA has reached the following conclusions:

• Iodosulfuron-methyl-sodium does not meet the Track 1 criteria for persistence in soil, persistence in water, persistence in sediment or bioaccumulation. The half-lives in soil, ranging from 0.8 to 21.8 days under laboratory conditions, are below the criterion of ≥182 days. The half-lives in water, ranging from 12.5 to 19 days in laboratory conditions, are below the criterion of ≥182 days. A half-life value in sediment was not determined; however, the low whole system half-lives, ranging from 13.5 to 23.3 days in laboratory conditions, are below the criterion of ≥365 days. Its log n-octanol-water partition coefficient of -1.22 to 1.96 is below the criterion of ≥5. Iodosulfuron-methyl-sodium does not meet all four Track 1 criteria; therefore, it is not classified as a Track 1 substance.
• The transformation product metsulfuron-methyl (AE F075736) formed in soil and water does not meet the Track 1 criteria for persistence in soil, persistence in water or bioaccumulation. Its half-life values of 20 to 99 days in soil are below the criterion of ≥182 days. Its half-life values of 34.4 to 55.2 days in water are below the criterion of ≥182 days. Its log n-octanol-water partition coefficient of -1.7 is below the criterion of ≥5. Metsulfuron-methyl does not meet all Track 1 criteria; therefore, it is not classified as a Track 1 substance.
• The transformation product AE F161778 formed in soil does not meet the Track 1 criterion for persistence in soil, persistence in water or bioaccumulation. The half-life values of 9.4 to 21 days in soil are below the criterion of ≥182 days. Its half-life values of 2.9 to 21.3 days in water are below the criterion of ≥182 days. The log n-octanol-water partition coefficient is unknown. AE F161778 does not meet all Track 1 criteria; therefore, it is not classified as a Track 1 substance.
• The transformation product AE F059411 formed in soil and water does meet the Track 1 criterion for persistence in soil. The half-life values of 119 to 269 days in soil meet the criterion of ≥182 days. However, they do not meet the criteria for persistence in water or bioaccumulation. The half-life values of 87.6 days in water are below the criterion of ≥182 days. The log n-octanol-water partition coefficient of 1.26 is below the criterion of ≥5. AE F059411 and does not meet all Track 1 criteria; therefore, it is not classified as a Track 1 substance.
• The transformation product AE 0000119 formed in water does meet the Track 1 criterion for bioaccumulation. The log n-octanol-water partition coefficient of 0.89 is below the criterion of ≥5. AE 0000119 does not meet all Track 1 criteria; therefore, it is not classified as a Track 1 substance.
• Technical grade iodosulfuron-methyl-sodium does not contain any contaminants of health or environmental concern identified in the Canada Gazette, Part II, Volume 139, Number 24, pages 2641-2643: List of Pest Control Product Formulants and Contaminants of Health or Environmental Concern.
• The end-use product, Tribute Solo 32 DF Herbicide, does not contain any formulants of health or environmental concern identified in the Canada Gazette, Part II, Volume 139, Number 24, pages 2641-2643: List of Pest Control Product Formulants and Contaminants of Health or Environmental Concern.

Therefore, the use of iodosulfuron-methyl-sodium is not expected to result in the entry of Track 1 substances into the environment.

7.0 Summary

7.1 Human Health and Safety

The toxicological database is adequate to define the majority of the toxic effects that may result from human exposure to iodosulfuron-methyl-sodium. In subchronic and chronic studies conducted in laboratory animals, some treatment-related effects on the liver, kidney and blood parameters were noted. There was no evidence of genotoxicity or oncogenicity. There was no effect on reproduction, but effects on the developing fetus were noted at doses much higher than the dose producing the most sensitive effects in the database. Iodosulfuron-methyl-sodium is not considered a neurotoxicant.

Refer to Regulatory Note REG2004-04, Iodosulfuron-methyl-sodium, for a detailed assessment of the occupational and bystander database for iodosulfuron-methyl-sodium and the end-use product, Tribute Solo 32 DF Herbicide.

7.2 Environmental Risk

Iodosulfuron-methyl-sodium and its major transformation products present negligible risk to wild mammals, birds, plants, earthworms, bees and most other arthropods, aquatic invertebrates, fish, aquatic plants and algae. The end-use product presented a risk to terrestrial and aquatic plants. Therefore, a buffer zone of one metre is required to protect both terrestrial and aquatic areas.

7.3 Value

Tribute Solo 32 DF Herbicide had been granted conditional registration with one of the conditions being that the lowest effective rate for common ragweed be established. The registrant has since decided not to support the claim of common ragweed control, and this claim has therefore been removed from the Tribute Solo 32 DF Herbicide label. The condition of registration has now been adequately addressed from a value perspective, and no further data are required.

Refer to Regulatory Note REG2004-04, Iodosulfuron-methyl-sodium, for a detailed assessment of the value of end-use product Tribute Solo 32 DF Herbicide.

8.0 Proposed Regulatory Decision

Health Canada's Pest Management Regulatory Agency, under the authority of the Pest Control Products Act, is proposing full registration for the sale and use of the technical grade active ingredient iodosulfuron-methyl-sodium and end-use product Tribute Solo 32 DF Herbicide to control certain broadleaf and grassy weeds in field corn. An evaluation of current scientific data from the applicant and scientific reports has resulted in the determination that, under the proposed conditions of use, the end-use product has value and does not present an unacceptable risk to human health or the environment.

List of Abbreviations

°C

degrees Celsius

µg

microgram

1/n

exponent for the Freundlich isotherm

a.i.

active ingredient

AD

administered dose

ADI

acceptable daily intake

ALAT

alanine aminotransferase

ALS

acetolactate synthase

ASAT

aspartate aminotransferase

bw

body weight

bwg

body weight gain

CD

cesarian derived

cm

centimetre

C_max

maximal plasma concentration

CPK

creatine phosphokinase

d

day

DF

dry flowable

DNA

deoxyribonucleic acid

E

reduction in beneficial capacity

EC₂₅

effective concentration on 25% of the population

EC₅₀

effective concentration on 50% of the population

EEC

estimated environmental concentration

EP

end-use product

F

female

F₂

second generation offspring

g

gram

GD

gestation day

GSD

geometrical standard deviation

ha

hectare

HDT

highest dose tested

HCT

hematocrit

HGB

hemoglobin

HPLC

high performance liquid chromatography

ILV

independent laboratory validation

kg

kilogram

K_ow

n-octanol-water partition coefficient

L

litre

LC₅₀

lethal concentration to 50%

LD₅₀

lethal dose to 50%

LOAEL

lowest observed adverse effect level

LOEC

lowest observed effect concentration

LOQ

limit of quantitation

LR₅₀

lethal rate to 50%

m

metre

M

male

M:E

myeloid to erythroid

MAS

maximum average score

mg

milligram

MIS

maximum irritation score

mL

millilitre

MMAD

mass median aerodynamic diameter

MRL

maximum residue limit

MS

mass spectrometry

MTD

maximum tolerated dose

MWHC

maximum water holding capacity

NOAEL

no observed adverse effect level

NOEC

no observed effect concentration

NOEL

no observed effect level

Pa

pascal

pH

-log 10 hydrogen ion concentration

PMRA

Pest Management Regulatory Agency

ppm

parts per million

RAC

raw agricultural commodity

RBC

red blood cell

ROC

residues of concern

ROMD

repeat oral mid dose

RQ

risk quotient

SF

safety factor

SOHD

single oral high dose

SOLD

single oral low dose

TRR

total radioactive residue

TS

test substance

UAN

urea ammonium nitrate

USEPA

United States Environmental Protection Agency

UV

ultraviolet

v/v

volume per volume dilution

WDG

water dispersible granule

WP

wettable powder

wt

weight

w/v

weight/volume ratio

¹ "Acceptable risks" as defined by subsection 2(2) of the Pest Control Products Act.

2 "Value" as defined by Subsection 2(1) of the Pest Control Products Act "...the product's actual or potential contribution to pest management, taking into account its conditions or proposed conditions of registration, and includes the product's (a) efficacy; (b) effect on host organisms in connection with which it is intended to be used; and (c) health, safety and environmental benefits and social and economic impact".