 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES MEMORANDUM November 7, 2005 SUBJECT: Tridemorph HED Risk Assessment for Tolerance Reassessment Eligibility Decision ( TRED) Document PC Code No. 121401; DP Barcode Nos. D322126 & D322128 FROM: Becky Daiss Environmental Health Scientist Reregistration Branch 4 Health Effects Division ( 7509C)

THROUGH: Susan V. Hummel Branch Senior Scientist Reregistration Branch 4 Health Effects Division ( 7509C)

TO: Rosanna Louie Chemical Review Manager Reregistration Branch 2 Special Review and Registration Division ( 7508C)

Attached is Health Effects Division's ( HED's) risk assessment of tridemorph for purposes of issuing a Tolerance Reassessment Eligibility Decision ( TRED) Document for this active ingredient. The disciplinary science chapters and other supporting documentation are incorporated into the risk assessment or included as appendices as follows:

Hazard Identification Assessment; Santhini Ramasamy  Section 4 Residue Chemistry Assessment; Gary Otakie ( D322128, 9/ 1/ 05) Dietary Exposure Assessment; Becky Daiss  Section 5 Page 2 of 30 TABLE OF CONTENTS pg. 1.0 EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.0 INGREDIENT PROFILE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.1 Summary of Registered and Proposed Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.2 Structure, Nomenclature and Physical/ Chemical Properties . . . . . . . . . . . . . . . . . . . . . . 5 3.0 METABOLISM ASSESSMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 4.0 HAZARD CHARACTERIZATION AND DOSE RESPONSE ASSESSMENT . . . . . . 8 4.1 Hazard Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 4.2 FQPA Hazard Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 4.2.1 Adequacy of the Toxicity Data Base . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 4.2.2 Evidence of Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 4.2.3 Developmental Toxicity Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 4.2.4 Reproductive Toxicity Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 4.2.5 Pre and/ or Postnatal Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 4.2.6 Recommendation for a Developmental Neurotoxicity Study . . . . . . . . . . . . . . . 19 4.3 Data Base Uncertainty Factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 4.4 Safety Factor for Infants and Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 4.5 Hazard Identification and Toxicity Endpoint Selection . . . . . . . . . . . . . . . . . . . . . . . . . 20 4.5.1 Acute Reference Dose  General Population . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 4.5.2 Chronic Reference Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 4.5.3 Classification of Carcinogenic Potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 4.5.4 Summary of Endpoints Selected for Risk Assessment . . . . . . . . . . . . . . . . . . . . 22 4.6 Endocrine Disruption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 5.0 DIETARY EXPOSURE ASSESSMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 5.1 Dietary Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 5.2 Magnitude of the Residue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 5.3 Residue Analytical Method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 5.4 Acute and Chronic Dietary Exposure and Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 6.0 CUMULATIVE RISK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 7.0 DATA NEEDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 7.1 Residue Chemistry Data Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 7.2 Toxicology Data Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 APPENDICES 1.0 GUIDELINE TOXICOLOGY DATA SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 2.0 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 Page 3 of 30 1.0 EXECUTIVE SUMMARY This assessment provides information to support the issuance of a risk management decision document known as a Tolerance Reassessment Eligibility Decision ( TRED) Document for tridemorph. EPA's pesticide reregistration process provides for the review of older pesticides ( those initially registered prior to November 1984) under the Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA) to ensure that they meet current scientific and regulatory standards. The process considers the human health and ecological effects of pesticides and incorporates a reassessment of tolerances ( pesticide residue limits in food) to ensure that they meet the safety standard established by the Food Quality Protection Act ( FQPA) of 1996.

Use Profile Tridemorph ( 2,6 dimethyl 4 tridecylmorpholine) is a systemic fungicide used to treat black and yellow sigatoka on banana and plantain plants. It belongs to the morpholine group of compounds ( e. g., fenpropimorph). Calixin 86 OL Fungicide, the only known formulation product, contains 86% tridemorph as the active ingredient. A tolerance has been established under 40 CFR § 180.372 for residues of tridemorph in or on bananas imported into the U. S. at 0.1 ppm. This tolerance was established in 1978. Major countries that intend to export tridemorph treated bananas or plantains are Guatemala, Belize, Honduras, Nicaragua, Costa Rica, Panama, Dominican Republic, Ecuador, Columbia, Mexico, and Venezuela. There are currently no U. S. registrations for tridemorph. BASF is the sole U. S. company supporting tolerances for tridemorph. A petition was submitted by BASF Wyandotte Corporation to establish a tolerance of 50 ppm for the residues of tridemorph in/ on dried tea. We are in the process of evaluating new toxicity data and will consider the BASF petition once we have done so.

Hazard Identification The toxicology database for tridemorph is incomplete. All the available toxicity studies were conducted during the late 1960s or early part of the 1970s and do not meet the current guideline standards. Most of the toxicity studies available in the EPA Files are only summaries and do not provide adequate information to determine the quality of the studies, lack GLP/ Quality Assurance Statements and often the compound tested whether technical or formulation is unknown. However, the available toxicological database for tridemorph is considered adequate to characterize potential hazards for this tolerance reassessment given that it is an import tolerance with a very limited use.

Based on available toxicity data, tridemorph has low acute toxicity ( Category III) for oral exposure and higher acute toxicity for dermal and inhalation exposure routes ( Category II). It exhibits high acute toxicity ( Category I) for eye and skin irritation. There are no acute dermal sensitization studies available for tridemorph. Page 4 of 30 The majority of subchronic and chronic studies available for tridemorph are unacceptable guideline studies due to lack of actual data for verification of conclusions ( only summary information is available). In four week subchronic toxicity studies, testicular toxic effects were reported in rats and dogs. However, these effects were not observed at similar dose levels in the 90 day subchronic studies using rats and dogs. The reason for this discrepancy is not clear. Sedation, nervousness and slight decrease in body weight during first the six months were reported in the chronic rat oral toxicity study.

The available developmental toxicity information indicates increased quantitative and qualitative susceptibility ( increased incidence for developmental anomalies) in rats and increased quantitative susceptibility ( reduction in fetal weight) in mice since the developmental findings occurred in the absence of maternal toxicity. There is no developmental study available in rabbits. The developmental toxic effects in rodents are severe for tridemorph compared to fenpropimorph, a structural homologue. For example, the incidences for cleft palate are higher and occur at lower doses for tridemorph compared to fenpropimorph. Based on the developmental effect concerns ( e. g., cleft palate), tridemorph is currently banned in the United Kingdom. The database for tridemorph lacks an acceptable two generation reproduction toxicity study.

The degree of concern for the prenatal susceptibility effects in rabbits and post natal susceptibility effects in rats could not be determined due to the data gaps. To address the potential degree of concern for infants and children, a 10X database uncertainty factor was added to the acute reference dose derivation and a 30X data base uncertainty factor was added to the chronic reference dose derivation. The addition of a 10X database uncertainty factor also protects for effects to infants and children. Therefore, an additional FQPA safety factor is not required and the FQPA safety factor may be reduced to 1X.

Mutagenicity data are inadequate or lacking. Based on the data available, there is no evidence of tumors in rats treated with tridemorph for 2 years. The structural analogue, fenpropimorph tested negative in mutagenicity studies and it is classified as ` not likely to be carcinogenic to humans'.

Based on the open literature information, tridemorph appears to be rapidly excreted in urine and feces with the half life of ~ 15 hours. Metabolites of tridemorph in rats are not characterized, but evidence suggests oxidation in the tridecyl side chain or in methyl side groups of the morpholine ring. Glucuronide conjugates are found in urine, bile and feces. The mode of action for the toxic effects of tridemorph in mammals is not known. It appears to inhibit synthesis of lipids ( e. g., sterols) and interfere with RNA, DNA and protein synthesis in fungi. It is possible that tridemorph might interfere with synthesis of macromolecules in mammalian cells.

BASF is in the process of submitting a series of toxicity studies ( acute battery, subchronic oral toxicity in rats, chronic oral toxicity in rats, mice and dogs, developmental toxicity studies in rats and rabbits and two generation reproduction study in rats, and a battery of mutagenic tests). The current hazard assessment does not include the review of the recent studies. EPA is Page 5 of 30 requesting these as confirmatory toxicity studies as part of this assessment.

Dose Response Assessment Toxicological endpoints were selected for the dietary exposure route only as this is the only exposure scenario expected for tridemorph since it is not registered for use in the U. S. The acute reference dose ( RfD) is based on developmental effects observed in the rat developmental study. An acute RfD was selected for the subpopulation females 13 49 only. An acute RfD was not selected for the general population or other population subgroups because no effect attributable to a single ( or few) day( s) oral exposure was observed in available animal studies. The chronic RfD is based on the subchronic toxicity study in dogs. An uncertainty factor ( UF) of 100 was applied to the acute and chronic RfDs based on the conventional 100X ( 10X for intraspecies extrapolation and 10X for interspecies variation). An additional 10X UF was added to address the data gaps for the acute and chronic reference dose derivation for tridemorph. The special FQPA safety factor was reduced to 1X for tridemorph.

Risk Assessment and Characterization Risk assessments were conducted for the dietary pathway only as there are no current registrations/ uses for tridemorph in the U. S. HED conducted an unrefined Tier 1 acute and chronic dietary exposure analyses using the Dietary Exposure Evaluation Model with the Food Commodity Intake Database ( DEEM FCID   ) . The dietary exposure assessment indicates that the highly conservative Tier 1 acute and chronic dietary exposure estimates are below HED's level of concern.

2.0 INGREDIENT PROFILE 2.1 Summary of Registered and Proposed Uses There are no U. S. registrations for tridemorph. Tridemorph which is contained in the enduse product, Calixin 86 OL Fungicide, is a emulsifiable concentrate containing 6.26 lb ai/ A registered for use on bananas in Columbia, Costa Rica, Dominican Republic, Ecuador, and Guatemala. It is also proposed for use in Honduras, but no registration is required for this country. Calixin is manufactured by BASF Corporation.

2.2 Structure, Nomenclature, and Physical/ Chemical Properties The nomenclature and physicochemical properties of tridemorph are provided in Tables 1 and 2. Page 6 of 30 TABLE 1. Tridemorph Nomenclature Compound Chemical Structure Common name Tridemorph Company experimental name NA IUPAC name 2,6 dimethyl 4 tridecylmorpholine CAS name CAS: 2,6 dimethyl 4 tridecylmorpholine CAS # 24602 86 6 Current Food/ Feed Site Registration No U. S. registrations. Registered for use in/ on bananas TABLE 2. Physicochemical Properties of the Technical Grade Tridemorph Parameter Value Reference Melting point/ range NA pH NA Density NA Water solubility ( 20 /

C) 11.7 mg/ L EEE Branch Review, R. Ney, 10/ 20/ 75, 00067847.

Solvent solubility ( mg/ L at20 /

C) Miscible with ordinary organic solvents at any rate. EEE Branch Review, R. Ney, 10/ 20/ 75,00067847.

Vapour pressure ( mPa) at 20 /

C 6.4 Dissociation constant ( pKa) NA Octanol/ water partition coefficient Log( KOW) NA UV/ visible absorption spectrum NA 3.0 METABOLISM ASSESSMENT Based on open literature information, tridemorph appears to be rapidly excreted in urine and feces with the half life of ~ 15 hours. Metabolites of tridemorph in rats are not characterized, but evidence suggests oxidation in the tridecyl side chain or in methyl side groups of the morpholine ring. Using the formulation product, glucuronide conjugates are found in urine, bile and feces.

The nature of terminal residue in bananas is considered adequately defined based on data Page 7 of 30 O NH C H 3 CH 3 submitted to the Agency. To determine whether tridemorph is systemic, ring labeled 14Ctridemorph was applied to the leaves of barley, cucumbers and bananas. Plants were sampled at various intervals and analyzed autoradiometrically. While tridemorph was absorbed and translocated rapidly in barley and cucumbers, translocation was slow in bananas as a result of slow penetration of the leaf surface. A banana translocation study conducted in Costa Rica in which banana leaves were treated with either unlabeled or ring labeled 14C tridemorph.. Tridemorph was found to rapidly penetrate into leaves and remain at levels > 2 ppm for at least 4 weeks after treatment. However, partial treatment of leaves indicated that translocation to untreated portions of the leaves was relatively slow. Additionally, a field metabolism study using ring labeled 14C tridemorph was conducted on a banana plantation in Costa Rica. Tridemorph was applied in a manner which simulated commercial practice. Shortly after the last application, the treated leaves and fruiting stems were harvested; the fruit was essentially mature and at a stage typical of commercial harvest. Leaves, peels, and pulp were analyzed for total activity by radiometric techniques. The major component of the total radioactive residue ( TRR) was found to be the parent compound with a small amount of polar material. The majority of the aqueous soluble activity was found to be 2,6 dimethyl morpholine ( DMM). The residues in the peel were also found to be primarily tridemorph, per se, with traces of 2,6 dimethyl morpholine found in the aqueous phase. No attempt was made to characterize the trace amount of residue ( 0.02  0.04 ppm) in the pulp. Tridemorph per se is the residue of concern. As there are no animal feed items proposed, the Agency concluded that the metabolism in animals was adequately understood, and the intended use will be in Category 3 of 40 CFR Section 180.6( a) with respect to secondary residues in meat, milk, poultry and eggs ( i. e., there is no reasonable expectation of finite residues).

A summary of tridemorph parent and metabolite matrices is provided in Table 3.

Table 3. Tabular Summary of Metabolites and Degradates Chemical Name Commodity Matrices Major Residue (> 10% TRR) Matrices Minor Residue (< 10% TRR) Chemical Structure Tridemorph 2,6 dimethyl 4 tridecylmorpholine Banana leaves & peel 87% NA See Table 1 Banana pulp NA trace amounts DMM 2,6 dimethylmorpholine Banana remainder ( aqueous phase) 13% NA A summary of compounds included in the risk assessment and tolerance expression is provided in Table 4. Page 8 of 30 Table 4. Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plant Primary Crop Tridemorph Tridemorph Livestock Ruminant & Poultry NA NA NA NA Drinking Water NA NA New residue data indicate the established tolerance must be increased to 1.0 ppm. The current tolerance was determined using only 4 studies. Reassessed tolerances are provided in Table 5.

TABLE 5. Tolerance Summary for Tridemorph Commodity Established/ Proposed Tolerance ( ppm) Recommended Tolerance ( ppm) Comments /( correct commodity definition)

Bananas 0.1 ( established) 1.0 The tolerance should be footnoted to indicate that there are no U. S. registrations associated with tridemorph./ banana 4.0 HAZARD CHARACTERIZATION AND DOSE RESPONSE ASSESSMENT 4.1 Hazard Characterization The toxicology database for tridemorph is incomplete. All the toxicity studies were conducted during the late 1960s or early part of the 1970s and do not meet the current guideline standards. Most of the toxicity studies available in the EPA Files are only summaries and do not provide adequate information to determine the quality of the studies, lack GLP/ Quality Assurance Statements and often the compound tested whether technical or the formulation is unknown.

Based on available acute oral toxicity data, tridemorph is classified as Category III compound. Tridemorph/ Calixin is classified as Category II by both dermal route and inhalation route. Tridemorph/ Calixin is classified as Category I eye irritant as well as skin irritant. There is no dermal sensitization study available for tridemorph.

The developmental toxicity study using the technical ingredient in mice and rats ( Merkle et al., 1984), and Calixin in two strains of rats, subchronic toxicity study using Beagle dogs ( 00151325) are all classified as Acceptable/ Non Guideline studies and provide sufficient information for choosing the endpoints. All other subchronic and chronic studies are Unacceptable Non Guideline studies due to lack of actual data for verification of conclusions ( only summary information is available). Page 9 of 30 The available developmental toxicity information indicates increased quantitative and qualitative susceptibility ( increased incidence for developmental anomalies) in rats and increased quantitative susceptibility ( reduction in fetal weight) in mice since the developmental findings occurred in the absence of maternal toxicity. There is no developmental study available in rabbits. The developmental toxic effects in rodents are severe for tridemorph compared to fenpropimorph, a structural homologue. For example, the incidences for cleft palate are more and occur at lower doses for tridemorph compared to that for fenpropimorph. The database for tridemorph also lacks an acceptable two generation reproduction toxicity study. Based on the developmental effect concerns ( e. g., cleft palate), tridemorph is currently banned in the United Kingdom ( http:// www. pan uk. org/ pestnews/ actives/ tridemor. htm).

Based on the open literature information, tridemorph appears to be rapidly excreted in urine and feces with the half life of ~ 15 hours. Metabolites of tridemorph in rats are not characterized, but evidence suggests oxidation in the tridecyl side chain or in methyl side groups of the morpholine ring. Glucuronide conjugates are found in urine, bile and feces.

The mode of action for the toxic effects of tridemorph in mammals is not known. It appears to inhibit synthesis of lipids ( e. g., sterols) and interfere with RNA, DNA and protein synthesis in fungi. It is possible that tridemorph might interfere with synthesis of macromolecules in mammalian cells.

In four week subchronic toxicity studies, testicular toxic effects were reported in rats and dogs. Degeneration of testes with oligospermia and azoospermia in rats and cryptorchidism ( testes failed to descend), dysplasia and atrophy of the left testes were reported in dogs, both after 28 days of exposure. However, these effects were not observed at similar dose levels in the 90 day subchronic studies using rats and dogs and the reason for this discrepancy is not clear. Sedation, nervousness and slight decrease in body weight during first six months were reported in the chronic rat oral toxicity study.

Mutagenicity of tridemorph is unknown. Based on inadequate data, no evidence of tumors was reported in rats treated with tridemorph for 2 years. The structural analogue, fenpropimorph tested negative in mutagenicity studies and it is classified as ` not likely to be carcinogenic to humans'.

BASF is in the process of submitting a complete series of toxicity studies ( acute battery, subchronic oral toxicity in rats, chronic oral toxicity in rats, mice and dogs, developmental toxicity studies in rats and rabbits and two generation reproduction study in rats, and a battery of mutagenicity tests). These studies were conducted between the 1970s and 1990s and the current hazard assessment does not include the review of these recently submitted studies.

Tables 6 and 7 provide the acute and subchronic/ chronic toxicity profile of tridemorph, respectively. Page 10 of 30 Table 6  8 Acute Toxicity Profile of Tridemorph Study/ Species MRID or Publication ( Year) Results Classificatio n 870.1100 Acute Oral, Rats Rats Rabbits Rats Guinea Pigs Rabbits Mice No MRID* ( 1969) 00151305a ( 1969) No MRID* ( 1970) No MRID* ( 1971) 00151310a ( 1970) No MRID* ( 1969) No MRID* ( 1971) LD50= 1900 mg/ kg bw ( Technical & 7 days) LD50 = ~ 1000 mg/ kg bw ( Technical) LD50 = ~ 2000 mg/ kg bw ( Technical) LD50 = ~ 1100 mg/ kg bw ( Calixin 75% Formulation) LD50 = ~ 1000 mg/ kg bw ( Calixin 75% Formulation) LD50 = ~ 750 mg/ kg bw ( Calixin 75% Formulation?) LD50 = 950 mg/ kg bw ( Calixin 75% Formulation) Category III Category III Category III Category III Category III Category III Category III 870.1200 Acute Dermal, Rabbits Acute Dermal, Rabbits Acute Dermal, Dogs No MRID* ( 1970) No MRID* ( 1970) No MRID* ( 1970) LD50 = ~ 1600 mg/ kg bw ( Technical/ Calixin 75% Formulation?) LD50 = 1800 mg/ kg bw ( Technical/ Calixin 75% Formulation?) LD50 = > 3200 mg/ kg bw( Technical/ Calixin 75% Formulation?) Category II Category II Category III 870.1300 Acute Inhalation, Rats Cats 00151318a ( 1970) No MRID* ( 1970) LC50( 6h): > 0.12 mg/ L? ( Calixin 1%) LC50( 6h): > 16 mg/ L ( Calixin 1%) Category II Category IV 870.2400 Primary Eye Irritation, Rabbits No MRID* Slight erythema, moderate milky corneal inflammation, pus and hemorrhage at day 8 ( Calixin Undiluted/ 75% Formulation?) Slight erythema up to 2 hours and normal at 8 days ( Calixin 1% and 10% Formulation) Category I Category IV 870.2500 Primary Skin Irritation, Rabbits Note: Exposure period varies from 1, 5, 15 minutes to 20 hours. The current guidelines call for maximum 4 hours exposure. Not known what duration produced skin irritant effects. 00151315a ( 1973) Corrosive ( Calixin 75% Formulation 0.5 50% aqueous emulsion) Marked erythema and necrosis at 8 days Moderate Irritation Calixin  0.25% aqueous emulsion) Slight erythema during first 24 hours and returned to normal after 24h. Category I Category IV 870.2600 Dermal Sensitization, Guinea Pigs No Study Identified

870.6200 Acute Neurotoxicity, Rats No Study Identified

8 All the acute studies are classified as Unacceptable / Non Guideline and do not meet the current standards. * Original Study Reports could not be located. Only summary information was available in the R. Coberly Review of 3/ 10/ 76 So the results could not be verified. Often it is not clear whether technical or formulation was tested. No GLP or QA statements provided. aNo GLP or QA statements provided. Page 11 of 30 Table 7: Subchronic, Chronic Toxicity Studies  Tridemorph Study/ Species MRID/ Publication Doses Results/ Classification Developmental/ Reproduction Toxicity 870.3700a Developmental Toxicity, NMRI Mice Merkle et al., 1984** and No MRID* ( 1973) Doses ( Gavage): Control, vehicle control ( olive oil), 27.5, 81.7, and 245.1 mg/ kg/ day, GD6 15 Technical N= 22 29 dams/ group Maternal NOAEL: 81.7 mg/ kg/ day Maternal LOAEL: 245.1 mg/ kg/ day Reduction in placental weight ( 12.5%)

Developmental NOAEL: 27.5 mg/ kg/ day Developmental LOAEL: 81.7 mg/ kg/ day Reduction in fetal weight ( 7.9%)

Highest Dose Tested ( HDT): Cleft palate ( 127/ 305), reduced fetal weight. Also, reduced fetal length and 30 cases of runts were reported. R. Coberly review ( 3/ 10/ 76)

Acceptable/ Non Guideline Note: The doses in the low mid and high doses differed in R. Coberly review ( 3/ 10/ 76) compared to that reported in Merkle et al., publication. The doses in the EPA Summary Report were 32, 95 and 285 mg/ kg for low, mid and high doses, respectively and may not have been adjusted for percent purity. Also, there were slight differences in the incidences in fetal effects ( 127/ 305 versus 127/ 309 for cleft palate). Since the original study submitted to EPA could not be verified, the information from the open literature was used for the hazard assessment. 870.3700a Developmental Toxicity, Sprague Dawley Rats Merkle et al., 1984** and No MRID* ( 1973) Doses ( Gavage): Control, vehicle control ( olive oil), 20.6, 60.2, and 189.2 mg/ kg/ day, GD6 15 Technical N= 21 30 dams/ group Maternal NOAEL: 60.2 mg/ kg/ day Maternal LOAEL: 189.2 mg/ kg/ day Decreased body weight gain ( 910.0%), presence of clinical signs such as apathy, and accelerated respiration, increased mortality during GD10 13 ( 55.1%), increased placental weight ( 818.5%), increased resorption ( 14.19 ± 11.74% versus 7.47 ± 7.11% in vehicle controls)

Developmental NOAEL: 20.6 mg/ kg/ day Developmental LOAEL: 60.2 mg/ kg/ day Increased percent of fetal incidences for overall anomalies, and variations; presence of cleft palate, ( 191/ 370), brachygnathia inferior ( 96/ 370), fused vertebral arches as compared to none in vehicle or untreated controls; increased incidences for cleft thoracic vertebral centrum/ centra ( 36/ 370 versus 10/ 332 in vehicle controls). In R. Coberly review ( 3/ 10/ 76), in addition, reduced fetal weight, length and incompletely descended testes ( 9 cases), fusion of individual sternebrae ( 22 cases) and numerous cases of skeletal retardation were reported at MDT, however, Table 7: Subchronic, Chronic Toxicity Studies  Tridemorph Study/ Species MRID/ Publication Doses Results/ Classification Page 12 of 30 these data can not be verified since the original report is not available.

HDT: Reduced fetal survival ( 163 versus 332 in vehicle controls), decreased fetal weight ( 910%), increased percent of fetuses with overall anomalies, variations/ retardations, fetal incidences for cleft palate ( 54/ 163), brachygnathia inferior ( 2/ 163), syndactyly ( 13/ 163), oligodactyly ( 2/ 163), pseudoankylosis ( 3/ 163), kinky tail ( 6/ 163), dilated renal pelvis and hydroureter ( 3/ 163) were seen as compared to none of these in vehicle or untreated controls. Also, increased incidences for cleft thoracic vertebral centrum/ centra ( 42/ 163 versus 10/ 332 in vehicle controls) were reported. In the R. Coberly Review ( 3/ 10/ 76), in addition, decreased fetal length, anasarca, ( edema) ( 3 cases), fusion of individual vertebrae ( 13 cases), spina bifida of individual sternebrae ( 3 cases), incompletely descended testes ( 6 cases) were reported, however, these data can not be verified since the original report is not available.

Acceptable/ Non Guideline Note: The fetal incidences for cleft palate, brachygnathia inferior were greater for MDT compared to HDT, probably due to poor fetal survival in HDT. The doses in the low mid and high doses differed in EPA file compared to that reported in Merkle et al., publication. The doses in the EPA Summary Report ( R. Coberly Review ( 3/ 10/ 76)) were 24, 70, and 220 mg/ kg for low, mid and high doses, respectively and may not have been adjusted for percent purity. Also, there were slight differences in the incidences in fetal effects ( e. g., 191/ 370 versus 191/ 371 for cleft palate). Since the original study submitted to EPA could not be verified, the information from the open literature was used for the hazard assessment. 870.3700a Developmental Toxicity, Wistar Rats Merkle et al., 1984** Doses ( Gavage): Control, vehicle control ( Tween 60), 0.13, 0.6, and 3.25 mg/ kg/ day, GD7 15, GD1 19 Calixin 75% Formulation Maternal NOAEL: 3.25 mg/ kg/ day Maternal LOAEL: Not Determined Developmental NOAEL: 3.25 mg/ kg/ day Developmental LOAEL: Not Determined Acceptable/ Non Guideline ( Developmental Study using the formulation is not required). Note: Doses are adjusted to a. i. in the formulation N= 26 27 dams/ group GD7 15 Table 7: Subchronic, Chronic Toxicity Studies  Tridemorph Study/ Species MRID/ Publication Doses Results/ Classification Page 13 of 30 N= 21 24 dams/ group GD1 19 870.3700a Developmental Toxicity, Sprague Dawley Rats Merkle et al., 1984** Doses ( Gavage): Control, vehicle control ( Tween 60), 0.13, 0.6, and 3.25 mg/ kg/ day GD7 15, GD1 19 Calixin 75% Formulation Maternal NOAEL: 3.25 mg/ kg/ day Maternal LOAEL: Not Determined Developmental NOAEL: 3.25 mg/ kg/ day Developmental LOAEL: Not Determined Acceptable/ Non Guideline ( Developmental Study using the formulation is not required). Note: Doses are adjusted to a. i. in the formulation N= 22 25 dams/ group GD7 15 N= 24 25 dams/ group GD1 19 870.3800 Three Generation Reproduction Toxicity, Sprague Dawley Rats No MRID* ( 1972) Doses ( diet): 0, 0.25, 0.5, 1.0 mg/ kg/ day 0, 5, 10, 20 ppm Calixin/ Technical? NOAEL: 1.0 mg/ kg/ day LOAEL: Not Determined Unacceptable/ Non Guideline Subchronic Oral Toxicity 870.3100 Subchronic Toxicity, Rats, Sprague Dawley Rats, 28 days No MRID* ( 1975) Doses ( diet): 0, 50, 100 mg/ kg/ day 0, 500, 1000 ppm ( Technical) NOAEL: Not determined LOAEL: 50 mg/ kg/ day Reduction in food consumption in females and decreased body weight in both sexes, degeneration of the testes with oligospermia and azoospermia Unacceptable/ Non Guideline Note: 30/ sex/ group 870.3100 Subchronic Toxicity, Sparague Dawley Rats, 90 days No MRID* ( 1968) Doses ( diet): 0, 5, 10, 20, 40 mg/ kg/ day 0, 50, 100, 200, 400 ppm ( Technical) NOAEL: 20 mg/ kg/ day LOAEL: 40 mg/ kg/ day Decreased body weight gain in females and increased liver weight in both males and females and increased heart and kidney weight of females Unacceptable/ Non Guideline Note: n= 20 25sex/ group 870.3150 Subchronic Toxicity, Beagle dogs, 28 days No MRID* ( 1968) Doses ( diet): 0, 20, 40 mg/ kg/ day 0, 500, 1000 ppm ( Technical) NOAEL: 20 mg/ kg/ day LOAEL: 40 mg/ kg/ day Cryplorchidism ( testes failed to descend), dysplasia and atrophy of the left testes Unacceptable/ Non Guideline Note: n= 1/ sex/ group 870.3150 Subchronic Toxicity, Beagle Dogs, 90 days 00151325** ( 1968) Doses ( diet): 0, 7.8, 15.6, 31.3 mg/ kg/ day 0, 200, 400, 800 ppm ( Technical) NOAEL: 31.3 mg/ kg/ day LOAEL: > 31.3 mg/ kg/ day Acceptable/ Non Guideline Note: n= 3/ sex/ group Subchronic Dermal Toxicity 870.3200 21 Day Dermal Toxicity No acceptable study identified Dermal Absorption No Study Identified Table 7: Subchronic, Chronic Toxicity Studies  Tridemorph Study/ Species MRID/ Publication Doses Results/ Classification Page 14 of 30 Chronic Oral Toxicity 870.4300 Chronic Toxicity, Sprague Dawley Rats, 2 years No MRID* ( 1972) Doses ( diet): 0, 0.5, 1.5, 4.5 mg/ kg/ day 0, 10, 30, and 90 ppm Technical NOAEL: 1.5 mg/ kg/ day LOAEL: 4.5 mg/ kg/ day Sedation, nervousness and slight decrease in body weight during first 6 months No increased evidence of tumors. Unacceptable/ Non Guideline Metabolism 870.7485 Metabolism in Sprague Dawley Rats 00151334* ( 1973) or Hawkins et al., 1974** A single oral dose of 14C  Tridemorph was administered by oral intubation to 4 rats/ sex. Whole body autoradiography was used to establish the distribution of radioactivity in the rat tissues. Urine and feces samples were collected every 24 hours for 5 days. The radioactivity in expired air was trapped for 5 days. The bile ducts of 2 separate rats ( 1/ sex) were cannulated and radioactivity was measured at 24 hour intervals for 2 days. Tridemorph is rapidly absorbed and excreted with a half life of 15 hours. The majority of the radioactivity was excreted in urine ( 39% in males; 36% in females) and feces ( 30% in males and 34% in females) during 24 hours. Bile contained 21.7% and 26.4% of the administered radioactivity after 2 days. At 5 days, 43.5% ( m) and 41.8% ( f) of radioactivity in urine and 45.7% ( m) and 47.8% ( f) of radioactivity in feces were found. The percent of dose administered was 1.6% and 1.3% in air and 3.5% and 3.3% in carcass and viscera for males and females, respectively. The autoradiography revealed radioactivity in the stomach, small intestine and liver at 2 hours post treatment; significant amounts in multiple tissues at 6 hours post treatment, large amounts of radioactivity in the large intestine at 24 hours post treatment and traces of radioactivity in the body at 72 hours post treatment. Four metabolites were detected in urine and two in bile and fecal extracts by thin layer chromatography. The major urinary metabolite was also present in bile and feces but in lesser amounts. Negligible amount of radioactivity was excreted unchanged. Detection of radioactivity in the expired air indicates some breakdown of the morpholine ring. Based on preliminary mass spectrometry findings, the major metabolite in 24 hour urine accounting for 22.3% of the radioactivity was identified as side chain hydroxylated derivative. However, the individual metabolites were not further characterized. Note: The test compound was found to contain mixtures of isomers. Acceptable/ Non Guideline 870.7485 Metabolism in Wistar Rats Waring ( 1974)** 3H Calixin ( 75% a. i.) was administered orally by intubation to female Wistar rats and urine and feces samples were collected daily for 3 days. The radioactivity in bile was measured over 25 hours. Autoradiography was performed to measure the radioactivity in tissues. Majority of the radioactivity was excreted during 24 hours ( 48.3% in urine and 9.2% in feces). Considerable amount of the radio activity in the urine sample was associated with glucuronide ( 18.1%) and sulphate conjugates ( 4.8%). About 10% of the administered radioactivity was found in bile during 25 hours. About 30% of the radioactivity was fairly distributed among different tissues with slightly higher concentrations in liver, kidney, and gut. Only small amounts of the administered dose ( 1.5%) was recovered unchanged. Table 7: Subchronic, Chronic Toxicity Studies  Tridemorph Study/ Species MRID/ Publication Doses Results/ Classification Page 15 of 30 Preliminary mass spec findings suggest the possible hydroxylation at the tridecyl side chain and in the methyl side chain of the morpholine ring. Note: The study is done with formulation and the metabolites are not adequately characterized. Acceptable/ Non Guideline Mutation/ Genotoxicity No Study Identified * Only summary information was available in the R. Coberly review of 3/ 10/ 76. So the results could not be verified. No GLP or QA statements available in the summary information ** No GLP or QA statements provided. Studies are classified as Acceptable/ Non Guideline 4.2 FQPA Hazard Considerations 4.2.1 Adequacy of the Toxicity Data Base The database for tridemorph is incomplete to assess the potential risk for infants and children. The only acceptable Non Guideline studies are developmental toxicity in rats and mice and 90 day subchronic toxicity study in dogs. There are no Acceptable/ Guideline acute toxicity studies available. The subchronic and chronic toxicity studies in rats, chronic toxicity study in nonrodents and carcinogenicity studies in rodents, developmental toxicity study in nonrodents and two generation reproduction toxicity study in rats are all datagaps. However, given that this is an import tolerance with a very limited use, the available toxicological database for tridemorph is considered adequate to characterize potential hazards for this tolerance reassessment. Also, HED is requiring submission of confirmatory toxicological data.

4.2.2 Evidence of Neurotoxicity The database is inadequate to determine any neurotoxic effects. No acute and subchronic neurotoxicity studies are available. The clinical signs such as apathy, accelerated respiration in dams are identified as frank toxic signs associated with mortality. HED is requiring submission of acute and subchronic neurotoxicity studies.

4.2.3 Developmental Toxicity Studies <IP_ADDRESS> Rat Study  Technical Product In a developmental study ( Merkle et al., 1984, R. Coberly Review ( 3/ 10/ 76)), pregnant Sprague Dawley rats ( 21 30/ group) were administered tridemorph ( purity unspecified) in olive oil by gavage at 20.6, 60.2, 189.2 mg/ kg body weight/ day during GD6 15. The control animals included the untreated as well as the vehicle treated groups. The doses were administered in a volume of 5 ml/ kg. The maternal survival in the high dose group was poor as only 13/ 29 dams were available for sacrifice on GD20 ( i. e., 55% of dams died between GD10 13) and the high dose dams exhibited clinical signs such as apathy and accelerated respiration. The mean body Page 16 of 30 weight of the high dose dams were slightly decreased ( 10%) as compared to vehicle controls ( 128.26 ± 17.68g versus 115.62 ± 34.46g) and the results were not statistically significant at p= 0.01. The percent resorptions was slightly higher in mid dose and twice as great in high dose animals as compared to vehicle treated controls ( 7.47 ± 7.11, 7.92 ± 14.76, 9.33 ± 18.98, 14.19 ± 11.74 in vehicle control, low, mid and high dose groups respectively) and was not statistically significant at p= 0.01. The fetal viability was poor in the high dose group ( 163 in HDT versus 332 in controls) possibly due to decreased dam survival since the number of fetuses per litter was not affected due to treatment. The study lacks food consumption data for dams.

The MDT had increased percent of fetal incidences for overall anomalies, and variations. The fetal incidences for cleft palate, ( 191/ 370), brachygnathia inferior ( 96/ 370), fused vertebral arches were high as compared to none in vehicle or untreated controls. Also, increased fetal incidence for cleft thoracic vertebral centrum/ centra ( 36/ 370 versus 10/ 332 in vehicle controls) was observed in mid dose group.

In the HDT, reduced fetal survival ( 163 versus 332 in vehicle controls), decreased fetal weight ( 10%), increased percent of fetuses with overall anomalies, variations and retardations were noticed. The fetal incidences for cleft palate ( 54/ 163), brachygnathia inferior ( 2/ 163), syndactyly ( 13/ 163), oligodactyly ( 2/ 163), pseudoankylosis ( 3/ 163), kinky tail ( 6/ 163), dilated renal pelvis and hydroureter ( 3/ 163) were high as compared to none in vehicle or untreated controls. Also, increased incidences for cleft thoracic vertebral centrum/ centra ( 42/ 163 versus 10/ 332 in vehicle controls) were reported.

The standard deviations were not reported for several fetal parameters such as fetal survival, and developmental effects. Also, the statistical comparison was not done to the vehicle controls and often limited to p value of 0.01 level and therefore, statistical significance at the often used 0.05 level could have been missed in treatment groups.

The maternal LOAEL is 189.2 mg/ kg/ day based on decrease in body weight gain, clinical signs, increased mortality of dams, and increased resorption. The maternal NOAEL is 60.2 mg/ kg/ day. The developmental NOAEL is 20.6 mg/ kg/ day. The developmental LOAEL is 60.2 mg/ kg/ day based on increased percent of fetal incidences for over all malformations and variations, presence of cleft palate, brachygnathia, fused vertebral arches, and increased incidence for cleft thoracic vertebral centrum/ centra.

The study is classified as Acceptable/ Non Guideline and does not meet the guideline requirement for the developmental toxicity study.

Note: The fetal incidences for cleft palate, brachygnathia inferior were greater for MDT compared to the HDT, probably due to poor fetal survival in HDT. In the R. Coberly Review ( 3/ 10/ 76), the doses were 24, 70, and 220 mg/ kg for low, mid and high doses, respectively. In addition to the fetal effects mentioned in Merkle et al., 1984, reduced fetal length and incompletely descended testes ( 9 cases), fusion of individual sternebrae ( 22 cases) and numerous Page 17 of 30 cases of skeletal retardation were reported at MDT. Decreased fetal length, anasarca, ( edema) ( 3 cases), fusion of individual vertebrae ( 13 cases), spina bifida of individual sternebrae ( 3 cases), incompletely descended testes ( 6 cases) were reported at HDT. Also, there were slight differences in the incidences in fetal effects ( e. g., 191/ 370 versus 191/ 371 for cleft palate). However, these data can not be verified since the original report is not available.

<IP_ADDRESS>Mouse Study  Technical Product In a developmental study ( Merkle et al., 1984, R. Coberly Review ( 3/ 10/ 76) pregnant NMRI mice ( 22 29/ group) were administered with tridemorph ( purity unspecified) in olive oil at 27.5, 81.7, 245.1 mg/ kg body weight/ day during GD6 15. The control animals received vehicle alone. The doses were administered in a volume of 2 ml/ kg. The study included three untreated controls and three vehicle treated controls ( one set for each dose).

There were no treatment related effects on body weight gain in dams, number of implantations, or percent resorptions per dam. Weight of the placentas was decreased in high dose dams compared to controls ( 0.08 ± 0.01 versus 0.07 ± 0.01; 12.5%, p< 0.01).

The percent of fetuses with anomalies were 2.98%, 2.29%, 39.15% in low, mid and high dose groups compared to 0.29 to 2.74% in control and vehicle controls. There is a reduction in fetal weight in MDT ( 1.17 ± 0.11 g; 7.9%) and HDT ( 1.13 ± 0.17 g; 11.7%) compared to vehicle controls ( 1.28 ± 0.13 g). There was no overall change in the percent of fetuses with variations or retardations between controls and the treatment. The incidences for cleft palate were 5/ 298, 3/ 259, and 27/ 305 in low, mid and high dose groups compared to 1/ 248 or 0/ 285 in appropriate untreated and vehicle controls.

The study is classified as Acceptable/ Non Guideline and does not meet the guideline requirement for the developmental toxicity study.

The maternal NOAEL is 81.7 mg/ kg/ day and the maternal LOAEL is 245.1 mg/ kg/ day based on reduction in placental weight . The developmental NOAEL is 27.5 mg/ kg/ day. The developmental LOAEL is 81.7 mg/ kg/ day based on reduction in fetal weight.

Note: In the R. Coberly review ( 3/ 10/ 76), the doses in the low, mid and high doses differed in EPA file compared to that reported in Merkle et al., publication. The doses in the EPA file were 32, 95 and 285 mg/ kg for low, mid and high doses, respectively. In addition to the fetal effects mentioned above, 30 cases of runts were reported in HDT and there were slight differences in the incidences for fetal effects ( 127/ 305 versus 127/ 309 for cleft palate). Since the original study submitted to EPA could not be verified, the information from the open literature was used for the hazard assessment.

<IP_ADDRESS> Rabbit Study  Technical Product Page 18 of 30 No study identified in the available database. Anecdotal evidence indicates that rabbits are not sensitive compared to rats as cleft palates were not observed in the rabbit developmental study ( http:// www. pan uk. org/ pestnews/ actives/ tridemor. htm). However, the doses tested were unknown and the information could not be verified.

<IP_ADDRESS> Rat Study  Formulation Product In a developmental study ( Merkle et al., 1984) pregnant Wistar rats or Sprague Dawley rats ( 21 27/ group) were administered with Calixin ( 83% a. i.) orally at dose levels of 0 ( control), 0 ( vehicle control), 0.156, 0.722, 3.909 mg/ kg in a dosing volume of 5 ml/ kg during GD1 19 or GD7 15. The concentration of the vehicle ( Tween 60) used was not provided. The test doses after correction for the active ingredient corresponded to 0.13, 0.6, and 3.25 mg/ kg body weight/ day, respectively. There were no significant changes in the mean body weights, number of implantations per dam, percent resorptions, number of live fetuses per litter, or weight of the placentas in treated groups as compared to either controls. Also, there are no significant changes for fetal survival, fetal weight, fetal or litter incidence for anomalies or variations or retardations in either strain of the animals for both exposure durations. However, there was increased number of fetuses with cleft thoracic vertebral centra in high dose Sprague Dawley rats for GD7 15 ( 2 in untreated controls versus 6 in high dose group). Similarly, the number of fetuses with cleft thoracic vertebral centra in the low dose Wistar rats was higher as compared to controls ( 3 in each controls versus 6 in the low dose group), however, no dose response effects were seen. The study lacks food consumption data for dams. No standard deviations were provided for developmental effects.

The maternal and developmental NOAEL was determined as 3.25 mg/ kg body weight/ day ( for both strain of rats). The LOAEL is not established. This study is classified as Acceptable/ Non Guideline and does not meet the guideline requirement for the developmental toxicity study. No GLP/ QA Statements are available.

<IP_ADDRESS> Other Developmental Toxicity Studies In one earlier report by Schtenberg et al., 1981 ( as cited in Merkle et al., 1984), 75% tridemorph ( presumably the formulation product, Calixin) was reported to produce developmental toxic effects in rats ( strain unspecified) as low as 0.6 mg/ kg. The compound was administered from GD7 15 or GD1 20 up to 65 mg/ kg. Hemorrhages and hydronephrosis in the lower doses ( exact dose levels unspecified) and cleft palate and micrognathia in the highest dose were the common findings observed in rat fetuses. However, this secondary reference published in a foreign language could not be verified. Further this observation was not reproduced, when two strains of rats ( Wistar and Sprague Dawley) were tested using Calixin( 75% a. i.) in the dose range of 0.156 3.909 mg/ kg during GD7 15, or GD1 19 as mentioned above ( Merkle et al., 1984).

4.2.4 Reproduction Toxicity Studies Page 19 of 30 In the R Coberly reivew ( 3/ 10/ 76), no maternal or reproductive or offspring effects were observed when Sprague Dawley rats were administered technical tridemorph in diet at 0, 5, 10 or 20 ppm ( 0, 0.25, 0.5, 1.0 mg/ kg/ day determined based on 5% conversion) for three generations. No changes were observed in body weights, food consumption, water consumption, fertility, litter size, litter weight, pup survival, hearing, eye examination, and gross and histopathological examination.

The NOAEL is determined as 1.0 mg/ kg/ day ( HDT). The LOAEL is not established. This study is Unacceptable/ Non Guideline and does not meet the guideline requirement ( OPPTS 870.3800) for s two generation reproduction study. No GLP/ QA Statements are available. This information presented in the EPA file could not be verified since the original data are not available.

4.2.5 Pre and/ or Postnatal Toxicity <IP_ADDRESS> Determination of Susceptibility There is a quantitative and qualitative susceptibility observed in rat fetuses and quantitative susceptibility observed in mice fetuses upon in utero exposures ( Merkle et al., 1984). In rats, developmental malformations ( cleft palate, brachygnathia inferior, cleft thoracic vertebral centrum/ centra, and fused vertebral arches) and increased percent of fetal incidences for overall anomalies were observed at doses that did not produce any maternal toxic effects. In mice, a slight reduction in fetal weight was observed at doses that did not produce any maternal toxic effects. Susceptibility in rabbits could not be adequately ascertained due to the absence of a rabbit developmental study. Post natal susceptibility could not be determined since there is no acceptable two generation reproduction study.

<IP_ADDRESS> Degree of Concern Analysis and Residual Uncertainties for Pre and/ or Post natal Susceptibility The degree of concern for the quantitative and/ or qualitative susceptibility effects seen in rodents after in utero exposures is low. The developmental findings are of low residual concern due to the fact that: 1) the developmental NOAELs in both the mice and rat studies are clearly defined ( no developmental effects were observed at doses of 27.5 and 20.6 mg/ kg/ day in the mice and rat studies respectively); 2) the dose response curve is clearly understood ( developmental effects were observed at the next highest dose tested both rats ( NOAEL of 60.2 mg/ kg/ day) and mice ( LOAEL of 81.7 mg/ kg/ day)); and 3) the developmental endpoint was selected as the point of departure for risk assessment and is therefore protective of developmental effects. Consequently, there is no additional need for a proposed special FQPA safety factor for residual uncertainty.

The degree of concern for the prenatal susceptibility effects in rabbits and post natal susceptibility effects in rats could not be determined due to data gaps. A 10X database Page 20 of 30 uncertainty factor was added to the acute reference dose derivation and a 30X was added to the chronic reference dose derivation to address gaps in the tridemorph toxicology data base. The 10X database uncertainty factors address the potential degree of concern for infants and children. Therefore, the Special FQPA Safety Factor was reduced to 1X.

4.2.6 Recommendation for a Developmental Neurotoxicity Study Clinical signs such as apathy and accelerated respiration were observed in dams in the developmental rat toxicity study. Since dams had high mortality at the same dose that exhibited clinical signs, these are interpreted as frank toxic signs. For the structural analogue, fenpropimorph, there was little or no evidence to support requiring a neurotoxicity study at this time since the neurotoxic effects occurred at much higher doses than those causing developmental or systemic effects. However, the database is inadequate to determine any neurotoxic effects. An acute and/ or subchronic neurotoxicity study is required. A developmental neurotoxicity study is held in reserve.

4.3 Data Base Uncertainty Factor There is a data gap in the toxicology database for tridemorph ( developmental toxicity study in rabbits, two generation reproduction study in rats and chronic oral toxicity study in rodents and non rodents and acute and subchronic neurotoxicity studies). This necessitates the use of 10X database uncertainty factor ( UF DB ) for acute and chronic dietary risk assessment.

4.4 Safety Factor for Infants and Children Based on the discussion in 4.2.5, and the addition of a 10X database uncertainty factor which protects for effects to infants and children, the special FQPA Safety Factor was reduce to 1X for tridemorph. It is assumed that the exposure databases are complete and the risk assessment does not underestimate the potential risks for infants and children.

4.5 Hazard Identification and Toxicity Endpoint Selection Endpoints were selected for dietary exposure routes only because there are currently no U. S. registrations/ uses for tridemorph and therefore no exposures to workers and/ or homeowners via other routes of exposure ( i. e., incidental oral, dermal, inhalation).

4.5.1 Acute Reference Dose ( aRfD)

<IP_ADDRESS> Females 13 49 Years An aRFD for females 13 49 years was selected based on the developmental toxicity study in rats combined chronic toxicity/ carcinogenicity study in rats in the technical product. Refer to Section <IP_ADDRESS> for a summary of the study and endpoint selection. Page 21 of 30 Acute RfD ( Females 13 49 years) = 20.6 mg/ kg/ day ( NOAEL) = 0.02 mg/ kg/ day 1000 ( UF) Dose and Endpoint Selected for Establishing Acute RfD ( Females 13 49 years): The NOAEL of 20.6 mg/ kg/ day) based on developmental malformations at 60.2 mg/ kg/ day.

Uncertainty Factor ( UF): 1000X ( 10X interspecies extrapolation, 10X intraspecies variation and 10X database uncertainty factor for the data gaps in toxicity studies).

Comments about Study/ Endpoint/ Uncertainty Factor: The study is considered appropriate for the population of concern. The developmental effects ( cleft palate, cleft thoracic vertebral centrum/ centra and brachygnathia inferior ) could be attributed to a single dose. The endpoint selected is protective of the developmental effects seen in rats and mice. For example, cleft palate was the only developmental abnormality reported in mice fetuses and that occurred at high dose tested ( 245.1 mg/ kg/ day). In rats several developmental abnormalities including cleft palate were reported at much lower dose ( 60.2 mg/ kg/ day).

<IP_ADDRESS> General Population Based on available data an acute RfD for the general population was not selected because no effect attributable to a single ( or few) day( s) oral exposure was observed in animal studies.

4.5.2 Chronic Reference Dose ( cRfD)

The chronic RfD was selected based on a subchronic oral toxicity study ( 00151325), in which beagle dogs ( 3/ sex/ group) were administered orally with 0, 200, 400 and 800 ppm tridemorph ( purity unknown) in diet for 90 days. The mean dose levels determined in the study for low mid and high dose groups were 7.8, 15.6, 31.3 mg/ kg/ day, respectively. Observations included clinical signs and measurements in body weight, food consumption, hematology, clinical chemistry, urinalysis, organ weights and histopathology. No effects were observed in any of the above parameters. The NOAEL is determined as 31.3 mg/ kg/ day, ( HDT). The LOAEL is not established.

The study is classified as Acceptable/ Non Guideline and does not meet the guideline requirement for 870.3150, OPP 82 1 due to absence of GLP/ QA statements and the lack of information on purity of the technical compound tested.

Dose and Endpoint Selected for Establishing Chronic RfD ( Gen Population): The NOAEL of 31.3 mg/ kg/ day.

Uncertainty Factor ( UF): 3000X ( 10X interspecies extrapolation, 10X intraspecies variation, 10X database uncertainty factor for the data gaps in toxicity studies, 3X uncertainty Page 22 of 30 Chronic RfD ( General Population) = 31.3 mg/ kg/ day ( NOAEL) = 0.01 mg/ kg/ day 3000 ( UF) factor for the extrapolation of subchronic to chronic study effects).

Comments about Study/ Endpoint/ Uncertainty Factor: The study selected is appropriate for the route of exposure. This was the only Acceptable Non Guideline study available for estimating chronic dietary risk for tridemorph. Since the study did not test high enough and the LOAEL is not established. A database factor of 10X was added since there is no acceptable two generation reproduction toxicity study or chronic toxicity study in rodent and non rodents. Since the endpoint is based on the subchronic study, 3X uncertainty factor was deemed necessary for the extrapolation from subchronic to chronic effects.

4.5.3 Classification of Carcinogenic Potential In a two year dietary study, Sprague Dawley rats( 30/ sex/ group) were fed with 0, 10, 30 and 90 ppm tridemorph ( not clear whether technical or calixin was the compound tested) ( R. Coberly review ( 3/ 10/ 76)). The dose levels based on 5% conversion corresponds to 0.5, 1.5, 4.5 mg/ kg/ day for low mid and high dose groups, respectively ( assuming 100% a. i. was tested). Observations included clinical signs and measurements in body weight, food consumption, hematology, clinical chemistry, urinalysis, organ weights and histopathology. The mortality rate for the 0, 10, 30 and 90 ppm levels was 40%, 30%, 35%, and 36.6%, respectively. Sedation, nervousness and slight decrease in body weight during first 6 months were the only effects reported. The incidence of tumors ( organ not specified) for the 0, 10, 30 and 90 ppm levels was 20%, 20%, 18.4%, and 16.7% respectively. No increased evidence of tumors found.

The NOAEL is determined as 31.3 mg/ kg/ day, ( HDT). The LOAEL is not established. The study is classified as Unacceptable/ Non Guideline and does not meet the guideline requirement for 870.4300, § OPP 83 5. The summary information found in EPA file could not be verified. The information on purity of the technical compound tested is not known and no GLP/ QA statements are available.

The structural analogue, fenpropimorph is classified as ` not likely to be carcinogenic to humans'. No mutagenicity studies are identified in the available database. Fenpropimorph, the structural analogue, tested negative for point mutations in bacteria, for chromosomal aberrations in Chinese hamster lung cells, for increased frequency in micronuclei in mice and for unscheduled DNA synthesis in primary rat hepatocytes.

4.5.4 Summary of Endpoints Selected for Risk Assessment Toxicological doses/ endpoints selected for the maleic hydrazide risk assessment are provided in Table 8. Page 23 of 30 Table 8: Summary of Toxicological Doses and Endpoints for Tridemorph for Use in Human Risk Assessments Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF* and Level of Concern for Risk Assessment Study and Toxicological Effects Acute Dietary ( Females, 13 49 years) NOAEL = 20.6 mg/ kg/ day UF = 1000 Acute RfD = 0.02 mg/ kg/ day FQPA SF = 1X aPAD = acute RfD FQPA SF = 0.02 mg/ kg/ day Developmental Toxicity, Rats ( Merkle et al., 1984) Developmental LOAEL: 60.2 mg/ kg/ day Increased percent of fetal incidences for overall anomalies, and variations; presence of cleft palate, ( 191/ 370), brachygnathia inferior ( 96/ 370), fused vertebral arches; increased incidences for cleft thoracic vertebral centrum/ centra ( 36/ 370 versus 10/ 332 in vehicle controls).

Acute Dietary ( General populations) No endpoint of concern is found suitable to assess risk for this population Chronic Dietary ( All populations) NOAEL = 31.3 mg/ kg/ day UF = 3000 Chronic RfD = 0.01 mg/ kg/ day FQPA SF = 1X cPAD = chronic RfD FQPA SF = 0.01 mg/ kg/ day Subchronic Toxicity, Beagle Dogs ( 00151325) LOAEL: Not established Incidental Oral, Dermal, Inhalation ( all durations) Endpoints for these exposure routes were not selected as tridemorph is reregistered for import tolerance only Cancer ( Oral) No data to determine any cancer effects.

UF = uncertainty factor, FQPA SF = Special FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose ( a = acute, c = chronic) RfD = reference dose, MOE = margin of exposure, LOC = level of concern, NA = Not Applicable * Refer to Section 4.3 4.5 Endocrine Disruption EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances ( including all pesticide active and other ingredients) " may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate." Following recommendations of its Endocrine Disruptor and Testing Advisory Committee ( EDSTAC), EPA determined that there was a scientific basis for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC's recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program ( EDSP).

Based on the available information, tridemorph was reported to cause degeneration of the testes with oligospermia and azoospermia in the subchronic rat and cryptorchidism ( testes failed to descend), dysplasia and atrophy of the testes in the subchronic dog study. However, these findings are preliminary and need to be confirmed. When additional appropriate screening and/ or Page 24 of 30 testing protocols being considered under the Agency's EDSP have been developed, tridemorph may be subjected to further screening and/ or testing to better characterize effects related to endocrine disruption.

5.0 DIETARY EXPOSURE ASSESSMENT 5.1 Dietary Profile A tolerance of 0.1 ppm has been established under 40 CFR § 180.372 for residues of tridemorph in or on bananas imported into the U. S. Currently, there are no U. S. registrations for tridemorph. New residue data indicates the established tolerance must be increased to 1.0 ppm. The qualitative nature of the residues in plants is adequately understood. The residue of concern in plants is tridemorph per se. ( G. Otakie, D322129, 10/ 05)

5.2 Magnitude of the Residue The existing tolerance is based on residue data on bananas submitted in 1976 from three plantations in Costa Rica. In one study, bananas were sampled from 1 hour to 20 days after the last of 10 to 20 applications of tridemorph at a rate of 0.33 lb ai/ A ( 0.83x maximum proposed rate). In a second study, bananas were sampled 1 to 20 days after the last of 11 to 19 applications of tridemorph at the maximum proposed rate. In the third study, bananas were sampled 4 to 18 days after the last of 11 to 21 treatments of tridemorph at 0.83x the maximum proposed rate. In all three studies, fruit were protected by bagging in polyethylene. No detectable residues of tridemorph (< 0.05 ppm) were found in either the peels or pulp in the first two studies. In the third study, tridemorph residues ranged from nondetectable (< 0.01 ppm) to 0.01 ppm in the pulp and from < 0.01 to 0.1 ppm in the peels.

At the time the import tolerance for tridemorph on bananas was established, HED provided case by case advice on requirements for field trials for import tolerances. EPA guidance has since been issued ( 2000). In 2002, 12 field trials were conducted in Columbia ( 2 tests), Guatemala ( 1 test), Costa Rica ( 2 tests), Mexico ( 1 test), Ecuador ( 2 tests), Honduras ( 2 tests), and Martinique ( 2 tests). Tridemorph was applied to bananas as multiple foliar applications. At each test site, a single plot of bananas, containing both bagged and unbagged fruit clusters, received 10 foliar applications of tridemorph at 1x the maximum proposed rate. Applications were made beginning 4 5 months prior to harvest, at retreatment intervals of 9 14 days. Applications were made using ground equipment in all cases but one in which applications were made above the plant canopy to simulate aerial application. Residues of tridemorph in the main tests were < 0.05 ppm (< LOQ) in/ on all samples of bagged whole bananas ( n= 12) harvested at 0 days after treatment ( DAT) and in all associated subsamples of pulp. For unbagged fruit samples harvested at 0 DAT, residues of tridemorph were < 0.05 ppm in/ on 7 out of 12 samples of whole fruit; residues in/ on the remaining 5 samples were 0.054 0.628 ppm. In pulp from unbagged fruits, residues were < 0.05 ppm in/ on 11 subsamples and 0.066 ppm in one subsample. In peel from unbagged fruits, residues were < 0.05 ppm in/ on 7 subsamples and 0.052 0.907 ppm in 5 Page 25 of 30 subsamples. Average tridemorph residues were 0.114 and 0.025 ppm in/ on unbagged and bagged samples of whole bananas, respectively, and 0.028 and 0.025 ppm in pulp samples from unbagged and bagged fruits.

The North American Free Trade Agreement ( NAFTA) issued guidance on the establishment of import tolerances in 2003. The NAFTA guidance document is consistent with the 2000 U. S. guidance. Based on this new guidance, 12 field trials from Columbia ( 2), Ecuador ( 3), Honduras ( 2), and Guatemala ( 2) are required for a banana import tolerance in the U. S. Although the distribution of the banana field trials does not exactly match the distribution recommended by the Agency, the 12 field trails conducted at 1x during 2002 are considered adequate. Based on data from these tests, however, the established tolerance of 0.1 ppm in/ on banana must be increased to 1.0 ppm. Storage stability data, which have not been provided by the registrant, must be submitted.

5.3 Residue Analytical Method Adequate tolerance enforcement methods are listed in PAM Volume II for the determination of tridemorph residues of concern. The analytical enforcement method is a colorimetric method based on the formation of a chloroform soluble tridemorph/ methyl orange addition complex. Residues of tridemorph are confirmed through a GC/ MS procedure. The analytical method is also suitable for the determination of 2,6 dimethylmorpholine ( DMM), a metabolite of tridemorph.

There was no information in the review documents regarding submission of data for FDA multiresidue methods by the petitioner. Tridemorph is not listed in the FDA PESTDATA database dated 11/ 01 ( PAM Volume I, Appendix I).

5.4 Acute and Chronic Dietary Exposure and Risk Acute and chromic dietary risk assessments were conducted using the DEEM ( DEEMFCID   , Ver 2.03) Model which use food consumption data from the USDA's Continuing Surveys of Food Intakes by Individuals ( CSFII) from 1994 1996 and 1998. In these analyses the dietary exposure and risk estimates resulting from food intake were determined for the general U. S. population and various population subgroups. The DEEM   program converts raw agricultural commodity ( RAC) residues into residues in/ on foods as eaten or consumed based on recipes of raw ingredients for each food item. For acute exposure assessments, individual oneday food consumption data are used on an individual by individual basis. The reported consumption amounts of each food item are " matched" in multiple random pairings with residue values and then summed in a probabilistic assessment. The resulting distribution of exposures is expressed as a percentage of the acute Population Adjusted Dose ( aPAD). Chronic dietary exposure is estimated by estimating the residue level in each treated food/ food form, multiplying that estimate by the average daily consumption estimate for that food/ food form, and summing residue intake estimates for all food/ food forms to arrive at a total average estimated exposure. Page 26 of 30 The average estimated exposure is expressed as a percent of the cPAD for the U. S. population and various population subgroups.

The acute and chronic dietary exposure analyses for tridemorph were conducted using unrefined Tier 1 dietary exposure assumptions for all uses. The Tier 1 analysis assumes tolerance level residues, 100% crop treated for all commodities, and DEEM FCID   ( ver 7.81) default processing factors for the processed commodities.

Results of the DEEM acute and chronic dietary exposure analyses are presented in Tables 8 and 9. The results of both the acute and chronic dietary exposure analyses for tridemorph indicate that, for all supported commodities, the dietary exposure estimates are below HED's level of concern. The 95th percentile acute exposure estimates were < 100% of the acute Population Adjusted Dose ( aPAD). The acute dietary exposure estimates for the population subgroup females 13 49 years at the 95th percentile is 9% of the aPAD. The mean chronic dietary exposure estimate for the highest exposed population subgroup, children 1 2 years of age, is 18% of the cPAD.

Table 8. Tridemorph DEEM Tier 1 Acute Dietary Exposure Analysis Population Subgroup aPAD ( mg/ kg/ day) 95th % ile Exposure ( mg/ kg/ day) % aPAD ( 95th %) 99th % ile Exposure ( mg/ kg/ day) % aPAD ( 99th %) 99.9th % ile Exposure ( mg/ kg/ day) % aPAD ( 99.9th %)

Females 13 49 years 0.02 0.0019 9 0.0025 12 0.0043 21 Table 9. Tridemorph Tier 1 Chronic Dietary Exposure Analysis Population Subgroup cPAD ( mg/ kg/ day) Exposure ( mg/ kg/ day) % cPAD General U. S. Population 0.01 0.0004 4 All Infants (< 1 year old) 0.0012 12 Children 1 2 years old 0.0018 18 Children 3 5 years old 0.0009 9 Children 6 12 years old 0.0004 4 Youth 13 19 years old 0.0001 1 Adults 20 49 years old 0.0002 2 Females 13 49 years old 0.0002 2 Adults 50+ years old 0.0004 4 6.0 CUMULATIVE RISK Section 408( b)( 2)( D)( v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider " available information" concerning the cumulative effects of a particular pesticide's residues and " other substances that have a common mechanism of toxicity." Page 27 of 30 EPA does not have, at this time, available data to determine whether tridemorph has a common mechanism of toxicity with other substances. Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to tridemorph and any other substances and, tridemorph does not appear to produce a toxic metabolite produced by other substances which have tolerances in the U. S. For the purposes of this tolerance reassessment action, therefore, EPA has not assumed that tridemorph has a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's OPP concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http:// www. epa. gov/ fedrgstr/ EPA PEST/ 2002/ January/ Day 16/.

7.0 DATA NEEDS 7.1 Residue Chemistry Data Requirements ° Data are required on FDA multiresidue methods. Tridemorph was not listed in the FDA PESTDATA database dated 11/ 01 ( PAM Volume I, Appendix I). ° Storage stability data for tridemorph must be submitted. ° Product Chemistry data must be provided.

7.2 Toxicology Data Requirements ° 870.1100 Acute oral toxicity ° 870.1200 Acute dermal toxicity ° 870.1300 Acute inhalation toxicity ° 870.2400 Acute eye irritation ° 870.2500 Acute dermal irritation ° 870.2600 Skin sensitization ° 870.6200 Neurotoxicity screening battery ° 870.3700b Rabbit developmental toxicity study ° 870.3800 Reproduction and fertility effects ° 870.3100 Subchronic oral toxicity study, rodents ° 870.4300 Combined chronic toxicity/ carcinogenicity oral ( rodent) ° 870.4100b Chronic toxicity oral ( nonrodent) ° 870.5100 Bacterial reverse mutation test ° 870.5300 Gene Mutation  mammalian ° 870.5375 Mammalian chromosomal aberrations ° 870.5395 Mammalian erythrocyte micronucleus test ° 870.5550 Unscheduled DNA synthesis in mammalian cells in culture ° 870.5900 In vitro sister chromatid exchange assay ° 870.6200a Acute Neurotox. Screening Battery ( rat) Page 28 of 30 ° 870.6200b 90 Day Neuro. Screening Battery ( rat) ° 870.7485 Metabolism and pharmacokinetics Page 29 of 30 APPENDICES 1.0 TOXICOLOGY DATA REQUIREMENTS Data requirements ( 40 CFR 158.340) for tridemporph are provided in the following table. Use of the new guideline numbers does not imply that new ( 1998) guidelines were used for studies conducted prior to the establishment of new guidelines.

Test Technical Required Satisfied 870.1100 Acute Oral Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . 870.1200 Acute Dermal Toxicity . . . . . . . . . . . . . . . . . . . . . . 870.1300 Acute Inhalation Toxicity . . . . . . . . . . . . . . . . . . . . 870.2400 Primary Eye Irritation . . . . . . . . . . . . . . . . . . . . . . . 870.2500 Primary Dermal Irritation . . . . . . . . . . . . . . . . . . . . 870.2600 Dermal Sensitization . . . . . . . . . . . . . . . . . . . . . . . . yes yes yes yes yes yes no no no no no

870.3100 Oral Subchronic ( rodent) . . . . . . . . . . . . . . . . . . . . . 870.3150 Oral Subchronic ( nonrodent) . . . . . . . . . . . . . . . . . . 870.3200 21 Day Dermal . . . . . . . . . . . . . . . . . . . . . . . . . . . . 870.3250 90 Day Dermal . . . . . . . . . . . . . . . . . . . . . . . . . . . . 870.3465 90 Day Inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . yes yes no yes no no no*

870.3700a Developmental Toxicity ( rodent) . . . . . . . . . . . . . . . 870.3700b Developmental Toxicity ( nonrodent) . . . . . . . . . . . . 870.3800 Reproduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . yes yes yes no* no no 870.4100a Chronic Toxicity ( rodent) . . . . . . . . . . . . . . . . . . . . 870.4100b Chronic Toxicity ( nonrodent) . . . . . . . . . . . . . . . . . 870.4200a Oncogenicity ( rat) . . . . . . . . . . . . . . . . . . . . . . . . . . 870.4200b Oncogenicity ( mouse) . . . . . . . . . . . . . . . . . . . . . . . 870.4300 Chronic/ Oncogenicity . . . . . . . . . . . . . . . . . . . . . . . yes yes yes yes yes  no  no no 870.5100 Mutagenicity  Gene Mutation  bacterial . . . . . . . . 870.5300 Mutagenicity  Gene Mutation  mammalian . . . . . . 870.5xxx Mutagenicity  Structural Chromosomal Aberrations 870.5xxx Mutagenicity  Other Genotoxic Effects . . . . . . . . . . yes yes yes yes no no no no 870.6100a Acute Delayed Neurotox. ( hen) . . . . . . . . . . . . . . . . 870.6100b 90 Day Neurotoxicity ( hen) . . . . . . . . . . . . . . . . . . . 870.6200a Acute Neurotox. Screening Battery ( rat) . . . . . . . . . 870.6200b 90 Day Neuro. Screening Battery ( rat) . . . . . . . . . . . 870.6300 Develop. Neuro . . . . . . . . . . . . . . . . . . . . . . . . . . . . no no no no no   yes yes reserved 870.7485 General Metabolism . . . . . . . . . . . . . . . . . . . . . . . . 870.7600 Dermal Penetration . . . . . . . . . . . . . . . . . . . . . . . . . yes no ¶ no

Special Studies for Ocular Effects Acute Oral ( rat) . . . . . . . . . . . . . . . . . . . . . . . . . . . . Subchronic Oral ( rat) . . . . . . . . . . . . . . . . . . . . . . . . Six month Oral ( dog) . . . . . . . . . . . . . . . . . . . . . . . no no yes

* Acceptable Non Guideline Studies available. Page 30 of 30 2.0 REFERENCES MRID 00151305 Zeller, H., Hofmann, H. ( 1972) Acute Oral Toxicity of Technical Grade N tridecyl 2,6 dimethylmorpholine to the Rat. Unpublished study prepared by BASF. 1 p.

MRID 00151310 Zeller, H., and Magoley, J. ( 1975) Acute Oral Toxicity of Calixin to Guinea Pigs. Unpublished study prepared by BASF. 2 p.

MRID 00151318 Zeller, H., and Hofmann, H. ( 1975) Acute Inhalation Toxicity of a 1% Aqueous Calixin Emulsion in the Form of a Spray to Rats. Unpublished study prepared by BASF. 2 p.

MRID 00151315 BASF Wyandotte Corp. ( 1973) Primary Dermal Irritation of BAS 2205 F ( Calixin) to the Dorsal Skin of White Rabbits. Unpublished study. 8 p.

MRID 00151325 Leuschner, F., Leuschner, A., Schwerdtfeger, W., et. al. ( 1968) Subacute Oral Toxicity of BAS 220 F to Beagles. Unpublished study prepared by BASF Wyandotte Corp. 84 p.

MRID 00151334 Hawkins, D., Down, W., Chasseaud, L., et. al. ( 1974) The metabolic fate of tridemorph in rats Pestic. Sci. 5: 535 542.

Open Literature Merkle, J., Schulz, V and Gelbke, H. P. 1984. An embryotoxicity study of the fungicide tridemorph and its commercial formulation calixin. Teratology, 29: 259 269.

Hawkins, D. R., Down, W. H., Chasseaud, L. F. et al., 1974. The metabolic fate of tridemorph in rats. Pestic. Sci. 5: 535 542 Waring, R. H.. 1974. The metabolic fate of calixin in rats. Xenobiotica 12: 717 723.


[Federal Register: April 9, 2010 (Volume 75, Number 68)]
[Notices]
[Page 18246-18247]
[DOCID:fr09ap10-134]

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SECURITIES AND EXCHANGE COMMISSION

[Release No. 34-61824, File No. 4-518]

Joint Industry Plan; Notice of Filing and Order Granting
Temporary Effectiveness of Amendment to Plan Establishing Procedures
Under Rule 605 of Regulation NMS

April 1, 2010.
    Pursuant to Section 11A(a)(3) of the Securities Exchange Act of
1934 (``Act'') \1\ and Rule 608 of Regulation NMS,\2\ notice is hereby
given that on March 30, 2010, EDGA Exchange, Inc. (``EDGA'') and EDGX
Exchange, Inc. (``EDGX'') submitted to the Securities and Exchange
Commission (``SEC'' or ``Commission'') an amendment to the national
market system plan that establishes procedures under Rule 605 of
Regulation NMS (``Joint-SRO Plan'' or ``Plan'').\3\ The amendment
proposes to add EDGA and EDGX as participants to the Joint-SRO Plan.
The Commission is publishing this notice and order to solicit comments
from interested persons on the proposed Joint-SRO Plan

amendment, and to grant temporary effectiveness to the proposed
amendment through August 9, 2010.
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    \1\ 15 U.S.C. 78k-1(a)(3).
    \2\ 17 CFR 242.608.
    \3\ 17 CFR 242.605. On April 12, 2001, the Commission approved a
national market system plan for the purpose of establishing
procedures for market centers to follow in making their monthly
reports available to the public under Rule 11Ac1-5 under the Act (n/
k/a Rule 605 of Regulation NMS). See Securities Exchange Act Release
No. 44177 (April 12, 2001), 66 FR 19814 (April 17, 2001).
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I. Description and Purpose of the Amendment

    The current participants to the Joint-SRO Plan are the American
Stock Exchange LLC (n/k/a NYSE Amex, Inc.), BATS Exchange, Inc., Boston
Stock Exchange, Inc. (n/k/a NASDAQ OMX BX, Inc.), Chicago Board Options
Exchange, Incorporated, Chicago Stock Exchange, Inc., Cincinnati Stock
Exchange, Inc. (n/k/a National Stock Exchange\SM\), International
Securities Exchange, LLC, The NASDAQ Stock Market LLC, National
Association of Securities Dealers, Inc. (n/k/a Financial Industry
Regulatory Authority, Inc.), New York Stock Exchange, Inc. (n/k/a New
York Stock Exchange LLC), Pacific Exchange, Inc. (n/k/a NYSE Arca,
Inc.), and Philadelphia Stock Exchange, Inc. (n/k/a NASDAQ OMX PHLX,
Inc.). The proposed amendment would add EDGA and EDGX as participants
to the Joint-SRO Plan.
    Each of EDGA and EDGX has submitted a signed copy of the Joint-SRO
Plan to the Commission in accordance with the procedures set forth in
the Plan regarding new participants. Section III(b) of the Joint-SRO
Plan provides that a national securities exchange or national
securities association may become a party to the Plan by: (i) executing
a copy of the Plan, as then in effect (with the only changes being the
addition of the new participant's name in Section 11(a) of the Plan and
the new participant's single-digit code in Section VI(a)(1) of the
Plan) and (ii) submitting such executed plan to the Commission for
approval.

II. Solicitation of Comments

    Interested persons are invited to submit written data, views, and
arguments concerning the foregoing, including whether the proposed
Joint-SRO Plan amendment is consistent with the Act. Comments may be
submitted by any of the following methods:

Electronic Comments

     Use the Commission's Internet comment form (http://
www.sec.gov/rules/sro.shtml); or
     Send an e-mail to<EMAIL_ADDRESS>Please include
File Number 4-518 on the subject line.

Paper Comments

     Send paper comments in triplicate to Secretary, Securities
and Exchange Commission, 100 F Street, NE., Washington, DC 20549-1090.

All submissions should refer to File Number 4-518. This file number
should be included on the subject line if e-mail is used. To help the
Commission process and review your comments more efficiently, please
use only one method. The Commission will post all comments on the
Commission's Internet Web site (http://www.sec.gov/rules/sro.shtml).
Copies of the submission, all subsequent amendments, all written
statements with respect to the proposed plan amendment that are filed
with the Commission, and all written communications relating to the
proposed plan amendment between the Commission and any person, other
than those that may be withheld from the public in accordance with the
provisions of 5 U.S.C. 552, will be available for Web site viewing and
printing in the Commission's Public Reference Room, 100 F Street, NE.,
Washington, DC 20549, on official business days between the hours of 10
a.m. and 3 p.m. Copies of such submission also will be available for
inspection and copying at the principal office of the Exchange. All
comments received will be posted without change; the Commission does
not edit personal identifying information from submissions. You should
submit only information that you wish to make available publicly. All
submissions should refer to File Number 4-518 and should be submitted
on or before May 10, 2010.

III. Commission's Findings and Order Granting Accelerated Approval of
Proposed Plan Amendment

    The Commission finds that the proposed Joint-SRO Plan amendment is
consistent with the requirements of the Act and the rules and
regulations thereunder.\4\ Specifically, the Commission believes that
the proposed amendment, which permits EDGA and EDGX to become
participants to the Joint-SRO Plan, is consistent with the requirements
of Section 11A of the Act, and Rule 608 of Regulation NMS. The Plan
establishes appropriate procedures for market centers to follow in
making their monthly reports required pursuant to Rule 605 of
Regulation NMS, available to the public in a uniform, readily
accessible, and usable electronic format. The proposed amendment to
include EDGA and EDGX as participants in the Joint-SRO Plan will
contribute to the maintenance of fair and orderly markets and remove
impediments to and perfect the mechanisms of a national market system
by facilitating the uniform public disclosure of order execution
information by all market centers.
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    \4\ In approving this proposed Joint-SRO Plan amendment, the
Commission has considered the proposal's impact on efficiency,
competition, and capital formation. 15 U.S.C. 78c(f).
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    The Commission finds good cause to grant temporary effectiveness to
the proposed Joint-SRO Plan amendment, for 120 days, until August 9,
2010. The Commission believes that it is necessary and appropriate in
the public interest, for the maintenance of fair and orderly markets,
to remove impediments to, and perfect mechanisms of, a national market
system to allow EDGA and EDGX to become participants in the Joint-SRO
Plan. On March 12, 2010, the Commission granted the application of EDGA
and EDGX for registration as national securities exchanges.\5\ One of
the conditions to operations of EDGA and EDGX is participation in
national market system plans, including the Joint-SRO Plan.\6\ As a
Plan participant, each of EDGA and EDGX would have timely information
on the Plan procedures as they are formulated and modified by the
participants. The Commission finds, therefore, that granting temporary
effectiveness of the proposed Joint-SRO Plan amendment is appropriate
and consistent with Section 11A of the Act.\7\
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    \5\ See Securities Exchange Act Release No. 61698 (March 12,
2010), 75 FR 13151 (March 22, 2010).
    \6\ Id.
    \7\ 15 U.S.C. 78k-1.
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IV. Conclusion

    It is therefore ordered, pursuant to Section 11A of the Act \8\ and
Rule 608 of Regulation NMS,\9\ that the proposed Joint-SRO Plan
amendment is approved for 120 days, through August 9, 2010.
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    \8\ 15 U.S.C. 78k-1.
    \9\ 17 CFR 242.608.

    For the Commission, by the Division of Trading and Markets,
pursuant to delegated authority.\10\
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    \10\ 17 CFR 200.30-3(a)(29).
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Florence E. Harmon,
Deputy Secretary.
[FR Doc. 2010-8152 Filed 4-8-10; 8:45 am]
BILLING CODE 8011-01-P


[Federal Register Volume 85, Number 93 (Wednesday, May 13, 2020)]
[Notices]
[Page 28619]
[FR Doc No: 2020-10258]

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DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Project No. 2837-000]

Erie Boulevard Hydropower, L.P.; Notice of Authorization for
Continued Project Operation

    On March 29, 2018, Erie Boulevard Hydropower, L.P., licensee for
the Granby Hydroelectric Project, filed an Application for a New
License pursuant to the Federal Power Act (FPA) and the Commission's
regulations thereunder. The Granby Hydroelectric Project is on the
Oswego River in the town of Fulton in Oswego County, New York.
    The license for Project No. 2837 was issued for a period ending
March 31, 2020. Section 15(a)(1) of the FPA, 16 U.S.C. 808(a)(1),
requires the Commission, at the expiration of a license term, to issue
from year-to-year an annual license to the then licensee under the
terms and conditions of the prior license until a new license is
issued, or the project is otherwise disposed of as provided in section
15 or any other applicable section of the FPA. If the project's prior
license waived the applicability of section 15 of the FPA, then, based
on section 9(b) of the Administrative Procedure Act, 5 U.S.C. 558(c),
and as set forth at 18 CFR 16.21(a), if the licensee of such project
has filed an application for a subsequent license, the licensee may
continue to operate the project in accordance with the terms and
conditions of the license after the minor or minor part license
expires, until the Commission acts on its application. If the licensee
of such a project has not filed an application for a subsequent
license, then it may be required, pursuant to 18 CFR 16.21(b), to
continue project operations until the Commission issues someone else a
license for the project or otherwise orders disposition of the project.
    If the project is subject to section 15 of the FPA, notice is
hereby given that an annual license for Project No. 2837 is issued to
Erie Boulevard Hydropower, L.P., for a period effective April 1, 2020
through March 31, 2021, or until the issuance of a new license for the
project or other disposition under the FPA, whichever comes first. If
issuance of a new license (or other disposition) does not take place on
or before March 31, 2021, notice is hereby given that, pursuant to 18
CFR 16.18(c), an annual license under section 15(a)(1) of the FPA is
renewed automatically without further order or notice by the
Commission, unless the Commission orders otherwise.
    If the project is not subject to section 15 of the FPA, notice is
hereby given that the Erie Boulevard Hydropower, L.P., is authorized to
continue operation of the Granby Hydroelectric Project, until such time
as the Commission acts on its application for a subsequent license.

    Dated: May 7, 2020.
 Kimberly D. Bose,
 Secretary.
[FR Doc. 2020-10258 Filed 5-12-20; 8:45 am]
BILLING CODE 6717-01-P