DATA EVALUATION RECORD OXAMYL/ 103801 NON GUIDELINE STUDY STUDY TYPE: ASCENDING ORAL TOXICITY STUDY IN HUMANS MRID 44912301 Prepared for Health Effects Division Office of Pesticide Programs U. S. Environmental Protection Agency 1801 Bell Street Arlington, VA 22202 Prepared by Toxicology and Hazard Assessment Group Life Sciences Division Oak Ridge National Laboratory Oak Ridge, TN 37831 Task Order No. 74 2005 Primary Reviewer: Judith H. Moyer, Ph. D., D. A. B. T. Signature: Date: Secondary Reviewers: Signature: Sylvia Milanez, Ph. D., D. A. B. T. Date: Robert H. Ross, M. S., Group Leader Signature: Date: Quality Assurance: Lee Ann Wilson, M. A. Signature: Date:

Disclaimer This review may have been altered subsequent to the contractors' signatures above.

Oak Ridge National Laboratory managed and operated by UT Battelle, LLC., for the U. S. Department of Energy under Contract No. DE AC05 00OR22725. EPA Reviewer: Elissa Reaves, Ph. D. Signature: Reregistration Branch 2, Health Effects Division ( 7509C) Date EPA Secondary Reviewer: Anna Lowit, Ph. D. Signature: Reregistration Branch 2, Health Effects Division ( 7509C) Date Template version 11/ 01 TXR#: 0052872 DATA EVALUATION RECORD STUDY TYPE: Ascending Oral Toxicity  Humans, non guideline.

PC CODE: 103801 DP BARCODE: 308714 TEST MATERIAL ( PURITY): Ethanimidothioic acid, 2( dimethylamino) N{[( methlamino) carbonyl] oxy}] 2 oxo, methyl ester ( 97.6%)

SYNONYMS: Oxamyl technical, DPX D1410 Technical, Methyl 2( dimethylamino) N [( methylamino) carbonyl) oxy) 2 oxo ethanimidothioate, Methyl N', N' dimethyl N[( methyl carbonyl) oxythiooxaminidate CITATION: McFarlane, P., Freestone, S. ( 1999) A randomized double blind ascending oral dose study with oxamyl. Inveresk Clinical Research, Riccarton, Edinburgh, EH14 4AP, Scotland. Laboratory Project ID: HLO 1998 01505, August 10, 1999. MRID 44912301. Unpublished.

SPONSOR: E. I. du Pont de Nemours and Company, Newark, Delaware 19714 0050 EXECUTIVE SUMMARY: In a non guideline, ascending acute oral toxicity study ( MRID 44912301), 40 healthy human male volunteers, aged 19  39 years, were each given a single oral dose of oxamyl technical ( approximately 97.6% a. i., batch #: DPX D140 196) in a gelatin capsule at doses of 0, 0.005, 0.015, 0.03, 0.06, 0.09, or 0.15 a. i. mg/ kg bw. Volunteers were admitted to the clinic the afternoon prior to the morning dosing. The volunteers were fasted for 9 hours prior to breakfast. Study volunteers were dosed approximately 5 minutes following a " standard" breakfast, and observed for two nights and one follow up visit 7 (" 2) days post dose. All volunteers remained under close medical and nursing supervision throughout the study. The study was conducted as a double blind ascending dose escalation clinical trial, and each male was treated at one of nine dosing sessions. Volunteers received a complete screening physical examination, testing for Hepatitis B, C, and HIV infection, and drug screening of urine within 14 days of study commencement. Blood pressure and heart rate were measured at screening ( within 14 days prior to dosing), 16 hours pre dose ( admission), 30 minutes pre dose, and 1, 2, 3, 4, 8 , and 24 hours post dose. Oral temperature was recorded at screening, 16 hours and 30 minutes pre dose, and 2, 4, and 24 hours post dose. A 12 lead ECG was obtained at screening, 30 minutes pre dose, and 30 minutes, 1, 2, and 24 hours post dose. Hematology and clinical chemistry testing was performed at screening, 30 minutes pre dose, and 24 hours post dose. Urinalysis was conducted at screening and 24 hours post dose. Pupillometry was performed 16 hours and 30 minutes pre dose, and 1, 2, 3, 4, 8, and 24 hours post dose. Saliva was collected and quantified by weight 16 hours and 30 minutes pre dose, and 1, 2, 3, 4, 8, and 24 hours postdose Plasma and red blood cell cholinesterase activity were assayed at screening, and 2 days, 16 hours, and 30 minutes pre dose, and at 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, and 24 hours post dose, and at 7 (" 2) days post dose. Clinical signs were reported by a total of 7 individuals from both the placebo ( 3 volunteers) and oxamyl dose groups ( 4 volunteers). These clinical observations did not correspond with peak ChE inhibition and were therefore not considered to be treatment related. Clinical observations from the placebo volunteers included bleeding gums, headache, fever, tremor, muscular pains, and right sided groin pain. Symptoms reported by the two volunteers in the 0.015 mg/ kg dose group included headache ( pre dose), brief nausea ( 57 minutes post dose to 61 minutes), and abdominal pain ( 46 hours post dose to 46.5 hours post dose). Examination of the volunteer with the brief nausea revealed no inhibition of cholinesterase activity or effects on pupil size or salivation and so was deemed unlikely related to the test compound. An earache was noted by one volunteer ( 46 hours post dose to 46.5 hours post dose) of the 0.03 mg/ kg dose group. At 0.15 mg/ kg, one volunteer experienced a headache ( 6 hours 50 minutes lasting 15 hours 15 minutes) and increased generalized sweating ( 10 hours 50 minutes lasting 3 hours 55 minutes). Both of these symptoms were considered possibly related to study compound but further investigation revealed the time course of symptoms were not consistent with the cholinesterase activity inhibition observed. Therefore, the adverse events were not likely to be truly related to the test compound.

The mean percent change in plasma cholinesterase activity was statistically decreased compared to placebo in the high dose ( 0.15 mg/ kg) beginning at the first time point ( 14%, 15 min) until 3 hours post dosing ( 8%), with peak inhibition at 45 minutes post dosing ( 43%, p< 0.001). Plasma cholinesterase activity returned to baseline by 6 hours post dosing. For the group exposed to 0.09 mg/ kg, plasma cholinesterase activity was significantly inhibited starting at 75 minutes post dosing ( 12% peak, p= 0.026) until 2 hours post dosing ( 10%, p= 0.039) with recovery at 3 hours post dosing. Within the 0.06 mg/ kg dose group, the maximum plasma cholinesterase inhibition was  7% at 75 minutes post dosing ( non statistical, p= 0.22). Plasma cholinesterase activity was similar to placebo in the 0.005, 0.015 and 0.03 mg/ kg dose groups at all time points. However, when the linear trend was tested for dose at each time point, the test was significant for every time point except at 4, 8, 12, and 24 hours, and 7 days post dosing. The inclusion or exclusion of outlying values did not alter the results for plasma cholinesterase activity.

The mean RBC cholinesterase activity of the high dose group ( 0.15 mg/ kg) was inhibited significantly beginning at 30 minutes ( 23%, p< 0.001) with peak inhibition at 45 and 60 minutes ( 28% and  27%, respectively with p< 0.001 for both) until 2 hours post dosing ( 8%, p= 0.011) and recovery to baseline by 3 hours post dosing. For the 0.09 mg/ kg dose group, the mean RBC cholinesterase activity was significantly decreased only at 30 minutes ( 7%, p= 0.016) with recovery following at 45 minutes post dosing. RBC cholinesterase activity was statistically similar to placebo at all time points in the 0.005, 0.015, 0.03, and 0.06 mg/ kg dose groups. Analysis of a linear trend for RBC cholinesterase activity by dose at varying time points indicated significance from 30 minutes until 105 minutes post dosing.

Saliva weight when examined with outliers was increased in the two highest dose groups at 1 hour post dosing compared to the placebo group. A linear trend was observed for saliva weight ( change from baseline), which increased with increasing dose and was only significant ( p= 0.002) at the 1 hour time point. The significance of saliva weight and dose was not achieved at any other time point during the study.

There were no significant decreases in minimum pupil size and recovery pupil size relative to baseline between any dose level and placebo, at any of the time points. Significant increases in recovery pupil size were observed at 2,4, 8 and 24 hour post dosing in the 0.005 mg/ kg group when compared to placebo. However, increases in pupil size are contrary to the expected response to cholinergic stimulation by the test substance.

Under the conditions of this ascending oral dose study in humans, 0.09 mg/ kg/ day represents a level where 7 12% plasma and RBC ChE inhibition was observed. Three of 5 volunteers at this dose ( 0.09 mg/ kg/ day) exhibited greater than 20% plasma ChE inhibition. Therefore, 0.06 mg/ kg/ day is considered the NOAEL.

The Agency generated BMD and BMDL estimates based on the RBC ChE data from this study. The resulting RBC BMD10 is 0.083 mg/ kg with BMDL10 of 0.069 mg/ kg.

COMPLIANCE: Signed and dated Good Clinical Practice Compliance, Quality Assurance, and No Data Confidentiality statements were provided. The study was conducted in accordance with the Declaration of Helsinki, 1964, as amended by the 29th Medical World Assembly in Tokyo ( 1975), the 35th Medical World Assembly in Venice, 1983, 41st Medical World Assembly in Hong Kong, 1989, and the 48th General Assembly, Somerset West, Republic of South Africa, October 1996.

I. MATERIALS AND METHODS A. MATERIALS: 1. Test Material: Oxamyl technical Description: White solid; " appeared to be stable" under study conditions. Analyses were conducted to assess the accuracy, homogeneity and stability of the preparation prior to the initiation of dosing Lot/ Batch #: Batch No. DPX D1410 196 Purity: Approx. 97.6% a. i., approx. 2.25% inerts. . CAS # of TGAI: 23135 22 0 Chemical structure:

2. Vehicle and/ or positive control: Oxamyl technical was administered in a gelatin capsule as an oxamyl/ lactose blend. Placebo was lactose administered in a matching capsule.

3. Volunteers: Species: Human ( Male) Strain: N. A. Age/ weight at dosing: Age: 19  39 years; Weight: 60.8  95.5 kg Source: Volunteers recruited and screened for inclusion in the study by Inveresk Clinical Research clinical staff. Housing: Admitted to clinic the afternoon prior to morning dosing, and discharged approx. 24 hours post dose. Diet: " Standard" breakfast approx. 5 minutes before dosing; fasted until approx. 3 hours post dose and then allowed decaffeinated fluids; and a light lunch approx. 4 hours post dosing. Water: Water consumption not specified. Environmental conditions: Temperature: Humidity: Air changes: Photoperiod: Not specified Not specified Not specified Not specified Acclimation period: Volunteers admitted to clinic the afternoon before dosing the next a. m.

B. STUDY DESIGN and METHODS:

1. Study dates: Start: September 28, 1998, End: not given 2. Volunteer population: Forty volunteers were assigned to the test groups noted in Table 1, and were admitted to the clinic the afternoon before the study. All volunteers were healthy white males; thirty four were non smokers and six were previous smokers. Four volunteers were non drinkers, and 36 reported the regular consumption of approximately 1 to 20 " units" of alcohol/ week ( 1 unit = 1 glass wine or beer, or measure of spirit).

3. Blinding: The study design was double blind and placebo controlled, with the exception of Session 1 in which both volunteers received placebo. Dose escalation was not to occur if there were clinically significant symptoms/ signs of carbamate toxicity or if any volunteer had $ 40% inhibition of RBC cholinesterase at a single time point or $ 25% inhibition at 2 consecutive time points. If there were associated symptoms/ signs of carbamate toxicity, no further administration of that particular dose would occur. The allocation of the test substance or placebo was randomized and based on the randomization code generated by the Statistics Department of Inveresk Research. A copy of the randomization code was held by the ICR phamacist where it was required for dispensing purposes and by the Regulatory Affairs Department at Inveresk Research. Sealed disclosure envelopes were also provided to ICR. In the event of an emergency requiring identification of the drug administered to a volunteer, the Study Director could request that the envelope be opened.

4. Experimental Design: Approximately 5 minutes after the completion of a " standard" breakfast, the volunteers were given a single dose of an oxamyl/ lactose blend ( Batch No. DPX D140 196) or placebo in a gelatin capsule while sitting, with 150 mL water. The dosing schedule is presented in Table 1. Based on available animal data, the starting dose ( 0.005 mg/ kg bw) was predicted to have no detectable effects on humans. The volunteers remained seated or recumbent until approximately 3 hours post dosing, when they were allowed to be ambulant and have decaffeinated fluids. A light lunch was provided approximately 4 hours post dosing. Volunteers were discharged about 24 hours postdosing with their agreement to return within 7 (") days for follow up evaluation of wellbeing any outstanding adverse events, and for measurement of plasma and red blood cell ( RBC) cholinesterase activity. TABLE 1. Study design Doses Administered ( mg/ kg bw) and number of volunteers Session Numbers 0 ( Placebo) 0.005 0.015 0.03 0.06 0.09 0.15 1 2 2 1 1 3 1 4 1 4 1 4 1 5 1 4 1 6 1 4 1 7 1 4 8 1 1 9 1 4 Total Volunteers 10 5 5 5 5 5 5 Data obtained from p. 20, MRID 44912301.

5. Clinical evaluation: Volunteers received a complete screening physical examination, testing for Hepatitis B, C, and HIV infection, and drug screening of urine within 14 days of study commencement. Blood pressure and heart rate were measured at screening ( within 14 days prior to dosing), 16 hours pre dose ( admission), 30 minutes pre dose, and 1, 2, 3, 4, 8 , and 24 hours post dose. Oral temperature was recorded at screening, 16 hours and 30 minutes pre dose, and 2, 4, and 24 hours post dose. A 12 lead ECG was obtained at screening, 30 minutes pre dose, and 30 minutes post dose, and 1, 2, and 24 hours post dose. Hematology and clinical chemistry testing was performed at screening, 30 minutes pre dose, and 24 hours post dose. Urinalysis was conducted at screening and 24 hours post dose. Pupillometry was performed 16 hours and 30 minutes pre dose, and 1, 2, 3, 4, 8, and 24 hours post dose using the optical unit ( pupilscan, hand held electronic pupillometer). Saliva was collected and quantified by weight 16 hours and 30 minutes pre dose, and 1, 2, 3, 4, 8, and 24 hours post dose by having the volunteers place 2 sterilin treated, weighed dental rolls opposite the 2nd molar on the upper cheek pouch on both sides for 5 minutes. The dental rolls were then replaced in the sterilin and the pre and post collection weights were used to determine the salivary weight. Plasma and red blood cell cholinesterase activity were assayed at screening, and 2 days, 16 hours, and 30 minutes pre dose, and at 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, and 24 hours post dose, and at 7 (" 2) days post dose. Plasma and red cell fraction ( except screening and post study samples) were separated and immediately snap frozen in liquid nitrogen. The collected plasma and red cell samples were assayed for cholinesterase activity according to the method of Ellman ( 1961) adapted as a clinical chemistry kit and analyzed on a Hitachi clinical chemistry analyzer ( IR/ SOP/ CLC/ 043).

6. Statistics: The SAS ( v6.07) statistical package was used to perform statistical analyses. The parameters evaluated included the mean, standard deviation, minimum, maximum, and number at each timepoint for pupillometry ( initial, minimum, recovery, and change from initial to minimum), vital signs, saliva collection, and plasma and RBC cholinesterase activity. These parameters were analyzed and summarized by dose level and timepoint. The percentage change from baseline at each time point was calculated on an individual basis and tabulated by dose level. Baseline was defined as the mean of all available pre dose values ( for that individual) ( screening, 2 days, 16 hours, or 30 minutes pre dose).

A repeated measures analysis of variance ( ANOVA)  including terms for dose level, timepoint, and dose level by timepoint interaction  were used to analyze the percentage change from baseline in RBC and plasma cholinesterase activity, pupillometry, and saliva collection. At each timepoint, a test for linear trend with dose was performed using a linear contrast. Using the error variance from the ANOVA, pairwise comparisons between placebo and each dose level were carried out at each timepoint using the Student's ` t' test. If the test for linear trend was significant at the 5% level, then the pairwise comparisons at that timepoint were not adjusted for multiple comparisons. If the test for linear trend was not significant at the 5% level, a Bonferroni adjustment was applied to the pairwise comparisons at that timepoint ( i. e., each comparison was tested at the 0.83% significance level). Treatment group LSMeans ( i. e., means adjusted for any imbalance in the model) were presented together with the significance level of the ` t' tests and the test for linear trend.

Normality of distribution was examined using a Shapiro Wilk test, while homogeneity of variance was assessed by plotting the residuals against the predicted values for the model. If there was significant non normality that could not be resolved by transforming the data, the data were analyzed excluding outliers. If the omission of outliers had no effect on the conclusions, the results of the full data set only were reported.

Descriptive statistical methods were used to summarize demographic data, ECG, urinalysis, and adverse events by dose level and, where appropriate, by timepoint. Adverse events were summarized under each dose level by tabulating the frequency of reports of each unique event, and were coded using the WHO Adverse Reaction Terminology ( 1997).

II. RESULTS:

A. CLINICAL FINDINGS:

1. Clinical observations: A total of 13 clinical effects were reported by a total of 7 study volunteers. No clinical signs were reported for the 0.005, 0.06 or 0.09 mg/ kg dose groups. Three placebo volunteers reported clinical signs that included bleeding gums; secondary to trauma, headache, fever, tremor " feeling shaky", muscular pains, and discomfort in right groin; and slightly enlarged inguinal nodes on the right side were noted. In the 0.015 mg/ kg group, clinical signs were reported for 3 volunteers and included nausea ( 4 minutes) and headache; pre dose, and abdominal pain; 46 hours postdose for 30 minutes. An earache was reported by one volunteer in the 0.03 mg/ kg group. Headache, sweating and epistaxis ( nosebleed) were reported in the 0.15 mg/ kg dose group by one volunteer. The sweating began 10 hours 50 minutes post dose and lasted for 3 hours and 55 minutes. The nose bleed began 22 hours and 50 minutes post dose. All reported clinical signs in all volunteers were gone by the post study visit. The symptoms reported by the volunteers typically do not correspond with the peak ChE inhibition and fall outside the time of ChE recovery. Therefore, the clinical observations are not considered to be treatment related.

2. Vital signs and ECG: No dose group had changes in vital signs or ECGs. 3. Cholinesterase inhibition: see Tables 2 and 3.

Individual cholinesterase: Four of the 5 volunteers of the high dose ( 0.15 mg/ kg) group demonstrated a greater than  40% inhibition of plasma cholinesterase activity from that individuals baseline ( baseline consisted of the mean of screening,  2 days,  16 hours, and  30 minutes pre dosing). One of these 4 volunteers also has greater than  40% RBC ChE inhibition. The first volunteer had  46%,  45%, and  42% plasma cholinesterase activity at 60, 75, and 90 minutes post dosing. The corresponding peak RBC ChE inhibition occurred at 60 minutes ( 43%). The second volunteer also displayed inhibited plasma cholinesterase activity at 30 ( 54%), 45 ( 58%), 60 ( 49%), and 75 ( 39%) minutes postdosing Peak RBC ChE inhibition of  38% occurred at 45 minutes post dosing. Plasma cholinesterase inhibition occurred beginning at 30 minutes ( 61%) in the third volunteer until 60 minutes ( 40%) post dosing. A maximum of  34% RBC ChE inhibition occurred at 45 minutes post dosing. Plasma cholinesterase inhibition for the fourth volunteer occurred at 45 minutes post dosing only ( 41%) with peak RBC ChE inhibition of  35% at 45 minutes post dosing.

Three of the 5 volunteers of the 0.09 mg/ kg dose group exhibited a  20% or greater inhibition of plasma cholinesterase activity beginning at 45 minutes post dosing. These 3 volunteers of the 0.09 mg/ kg dose group exhibited  23% plasma ( 7% RBC at 45 minutes),  21% plasma ( 18% RBC at 30 minutes), and  20% plasma ( 15% RBC at 120 minutes) cholinesterase inhibition at 45, 75, and 120 minutes post dosing, respectively.

Plasma cholinesterase: Statistical analysis of the group mean by time point was not performed. Instead, statistical analysis was performed on the percent change from baseline ( average of values at screening,  2 days,  16 hr, and  30 min). The mean percent change in plasma cholinesterase activity was statistically decreased compared to placebo in the high dose ( 0.15 mg/ kg) beginning at the first time point ( 14%, 15 min) until 3 hours post dosing ( 8%), with peak inhibition at 45 minutes post dosing ( 43%, p< 0.001). Plasma cholinesterase activity returned to baseline by 6 hours post dosing. For the group exposed to 0.09 mg/ kg, plasma cholinesterase activity was significantly inhibited starting at 75 minutes post dosing ( 12% peak, p= 0.026) until 2 hours post dosing ( 10%, p= 0.039) with recovery at 3 hours post dosing. Maximum plasma ChE inhibition varied among volunteers with a maximum of  23% at 45 minutes until approximately 2 hours ( 20%) post dosing. Within the 0.06 mg/ kg dose group, the maximum plasma cholinesterase inhibition was  7% at 75 minutes post dosing ( non statistical, p= 0.22). Plasma cholinesterase activity was similar to placebo in the 0.005, 0.015 and 0.03 mg/ kg dose groups at all time points. However, when the linear trend was tested for dose at each time point, the test was significant for every time point except at 4, 8, 12, and 24 hours, and 7 days post dosing. The inclusion or exclusion of outlying values did not alter the results for plasma cholinesterase activity.

Red blood cell ( RBC) cholinesterase: As with plasma cholinesterase activity, RBC cholinesterase activity was analyzed as the percent change from baseline compared to placebo at varying time points post dosing. The mean RBC cholinesterase activity of the high dose group ( 0.15 mg/ kg) was inhibited significantly beginning at 30 minutes ( 23%, p< 0.001) with peak inhibition at 45 and 60 minutes ( 28% and  27%, respectively with p< 0.001 for both) until 2 hours post dosing ( 8%, p= 0.011) and recovery to baseline by 3 hours post dosing. For the 0.09 mg/ kg dose group, the mean RBC cholinesterase activity was significantly decreased only at 30 minutes ( 7%, p= 0.016) with recovery following at 45 minutes post dosing. Volunteer variation of RBC ChE activity at this dose at 30 minutes ranged from + 8% to  18%. RBC cholinesterase activity was statistically similar to placebo at all time points in the 0.005, 0.015, 0.03, and 0.06 mg/ kg dose groups. Analysis of a linear trend for RBC cholinesterase activity by dose at varying time points indicated significance from 30 minutes until 105 minutes post dosing.

Table 2. Plasma and RBC cholinesterase activity change from baseline (%) over time in volunteers receiving oxamyl ( outlying values included) Dosage Group ( mg/ kg bw) Time 0 0.005 0.015 0.03 0.06 0.09 0.15 Plasma cholinesterase ( mean " SD)

15 mins postdose  1.3 " 6.3  3.0 " 7.7 2.7 " 11.5 0.4 " 2.1  2.4 " 1.7  4.1 " 8.6  14.1*" 12.0 30 mins postdose  4.7 " 4.8  4.8 " 6.2 0.1 " 8.0 2.0 " 1.6  5.4 " 3.5  5.6 " 9.1  35.9**" 21.9 45 mins postdose  7.3 " 7.4  4.6 " 5.3 0.1 " 8.7 0.5 " 2.3  2.1 " 14.7 1.2 " 17.7  43.4**" 14.7 1 h postdose  1.7 " 5.7 1.3 " 7.0 0.7 " 7.4  1.2 " 4.8  5.6 " 4.8  6.2 " 8.4  40.4**" 7.2 1 h 15 mins postdose  1.5 " 5.4  0.4 " 6.9 3.6 " 8.2  0.3 " 3.3  7.1 " 4.8  11.6* " 8.2  35.9**" 6.0 1 h 30 mins postdose  3.3 " 4.7  2.6 " 6.4 3.4 " 8.1  2.2 " 5.9  4.1 " 4.9  10.1 " 6.4  30.2**" 7.5 1 h 45 mins postdose  4.0 " 5.1  1.3 " 6.7 3.0 " 10.3  0.8 " 4.5  3.9 " 4.2  9.5 " 4.5  25.3**" 4.6 2 h postdose  1.0 " 4.4 1.9 " 5.7 2.8 " 7.3  2.1 " 2.1  5.7 " 3.3  10.2* " 6.0  20.9**" 4.8 3 h postdose 0.4 " 5.7 3.2 " 5.1 6.6 " 5.3 5.4 " 2.3  3.3 " 5.4 1.3 " 5.9  8.0 " 5.8 4 h postdose  1.0 " 5.3 0.9 " 4.1 7.4 " 7.3 3.5 " 4.8  1.0 " 4.5 1.4 " 3.5  1.7 " 2.7 6 h postdose  4.4 " 5.0  11.7 " 7.0 3.9 " 15.5 0.9 " 4.9  4.5 " 3.3  1.7 " 4.6 5.8 " 26.0 8 h postdose  3.7 " 5.3  8.5 " 5.1 10.8 " 16.4 2.0 " 4.5  2.4 " 4.9 0.8 " 4.8 2.5 " 24.8 12 h postdose  5.5 " 6.7  13.0 " 3.7 2.6 " 16.2 1.8 " 7.3  4.0 " 2.3  2.2 " 5.1 1.6 " 16.8 RBC cholinesterase ( mean " SD)

15 mins postdose 4.9 " 10.6 2.0 " 7.6  0.4 " 10.8 4.8 " 14.6  1.3 " 7.2 1.0 " 8.9  2.3 " 16.6 30 mins postdose 7.8 " 11.2 11.6 " 4.8 1.5 " 8.5 5.5 " 10.9  2.4 " 7.8  7.3*" 8.3  23.2**" 13.8 45 mins postdose 6.5 " 10.8  0.2 " 6.2  4.8 " 16.0 3.0 " 13.8  4.3 " 8.2 0.2 " 12.2  27.9**" 12.7 1 h postdose 9.4 " 10.3 4.9 " 8.1 3.0 " 3.9 1.9 " 16.3 5.9 " 11.1  0.3 " 7.5  27.1**" 10.1 1 h 15 mins postdose 5.5 " 10.3 2.5 " 12.4 1.0 " 9.9 7.3 " 11.3 1.6 " 14.0  0.7 " 7.2  16.8**" 15.0 1 h 30 mins postdose 11.1 " 8.8 3.2 " 9.9 2.9 " 6.6 6.0 " 11.1 4.5 " 9.0 1.8 " 6.2  15.9**" 9.3 1 h 45 mins postdose 4.5 " 14.7 2.1 " 11.0 2.5 " 9.5  0.1 " 10.5 1.9 " 4.1  1.1 " 5.8  9.2*" 7.2 2 h postdose 7.9 " 9.7 0.3 " 2.8  2.3 " 7.3  0.5 " 5.4  2.8 " 12.6  2.1 " 7.8  8.0 " 9.7 3 h postdose 10.3 " 10.9 9.2 " 9.5  3.7 " 9.5 7.8 " 13.4 3.2 " 11.6  0.2 " 14.0  0.4 " 6.8 4 h postdose 12.4 " 10.4 8.4 " 11.5 9.6 " 8.2  0.5 " 5.2 2.3 " 7.2 3.0 " 13.4 3.7 " 11.0 6 h postdose 3.5 " 13.8 10.6" 10.7 4.8 " 12.9 6.5 " 7.5 5.1 " 5.2 21.3*" 14.0 10.9 " 6.6 Data obtained from pp. 415 416, and 419 420, MRID 44912301. * Statistically significant at p < 0.05, compared with controls. ** Statistically significant at p # 0.001, compared with controls. mins = minutes, h = hours Table 3. Mean values for Plasma and RBC cholinesterase activity in all volunteers receiving oxamyl ( outlying values included)

Dosage Group ( mg/ kg bw) Time 0 0.005 0.015 0.03 0.06 0.09 0.15 Plasma cholinesterase screening 5013" 648.9 5306" 817 5082" 1008 5314" 842 5125" 804 5014" 552 4682" 837 Day  2 5685" 671.5 6541" 929 5221" 784 6153" 1409 6137" 1000 5301" 586 5158" 935  16 h 5473" 603.9 6379" 1017 5460" 1030 5664" 1412 5787" 900 5142" 412 4945" 920  30 mins 5346" 593.6 6117" 1259 5388" 844 5943" 964 5809" 951 5297" 791 4871" 777 15 mins postdose 5321" 767.4 5902" 934 5455" 1367 5776" 1055 5571" 812 4978" 605 4158*" 465 30 mins postdose 5130" 639.4 5799" 954 5320" 1175 5881" 1151 5396" 830 4894" 496 3140**" 1153 45 mins postdose 4981" 646.0 5825" 1050 5308" 1135 5785" 1091 5527" 758 5233" 878 2758**" 739 1 h postdose 5287" 651.3 6180" 1088 5355" 1192 5677" 1047 5385" 833 4859" 448 2913**" 566 1 h 15 mins postdose 5307" 703.7 6051" 894 5484" 1082 5737" 1059 5303" 843 4574*" 285 3138**" 567 1 h 30 mins postdose 5208" 682.6 5919" 914 5475" 1057 5609" 981 5466" 818 4658" 386 3431**" 743 1 h 45 mins postdose 5174" 676.5 6014" 1025 5450" 1105 5708" 1082 5480" 838 4692" 301 3673**" 705 2 h postdose 5325" 579.8 5988" 1105 5440" 1040 5650" 1114 5380" 796 4667*" 533 3890**" 758 3 h postdose 5402" 640.4 6282" 971 5628" 916 6057" 1053 5518" 919 5268" 602 4513" 793 4 h postdose 5337" 725.4 6151" 1023 5680" 1063 5951" 1096 5663" 974 5268" 446 4822" 787 6 h postdose 5149" 665.0 5340" 580 5462" 1060 5793" 1016 5462" 939 5110" 521 5105" 1122 8 h postdose 5189" 688.0 5555" 759 5809" 1018 5878" 1190 5591" 1079 5242" 535 4941" 979 12 h postdose 5080" 634.9 5278" 663 5361" 889 5867" 1227 5500" 966 5082" 503 4938" 812 24 h postdose 5301" 744.9 5738" 840 5713" 840 6276" 1111 5996" 1010 5355" 457 4568" 484 post study 5672" 640.8 5978" 1000 5450" 767 6038" 1179 5838" 722 5292" 542 5180" 975 RBC cholinesterase screening 8433" 1539 8898" 943 9808" 1242 9457" 1007 9006" 633 7870" 901 8557" 585 Day  2 12063" 928 12380" 1105 12143" 1114 11866" 601 12194" 1179 11349" 1344 11863" 1065  16 h 11501" 1200 12839" 1419 12127" 1023 11776" 991 12570" 784 11092" 587 11299" 850  30 mins 11457" 868 12534" 1148 11714" 655 12599" 619 12246" 699 11437" 2026 10686" 1644 15 mins postdose 11402" 1430 11887" 890 11397" 1346 11959" 1547 11324" 501 10512" 1238 10346" 1822 30 mins postdose 11698" 1336 13009" 862 11645" 1442 12061" 1458 11198" 602 9618*" 713 8125**" 1477 45 mins postdose 11551" 1303 11656" 1157 10887" 1861 11766" 1654 11015" 1144 10407" 1249 7605**" 1043 1 h postdose 11878" 1358 12250" 1379 11781" 596 11642" 1898 12178" 1286 10354" 767 7695**" 874 1 h 15 mins postdose 11458" 1328 11914" 1197 11606" 1785 12298" 1816 11655" 1372 10309" 655 8753**" 1079 1 h 30 mins postdose 12088" 1448 12028" 1261 11760" 571 12095" 1230 12015" 1027 10612" 1244 8881**" 640 1 h 45 mins postdose 11286" 1239 11911" 1469 11748" 1426 11418" 1314 11719" 663 10270" 649 9599*" 444 2 h postdose 11703" 1121 11931" 981 11170" 865 11380" 941 11191" 1699 10174" 909 9713*" 731 3 h postdose 11946" 1130 12758" 1481 11056" 1580 12309" 1493 11901" 1685 10321" 967 10530" 217 4 h postdose 12211" 1394 12628" 1309 12573" 1528 11363" 747 11757" 904 10649" 869 10956" 873 6 h postdose 11187" 1231 12910" 1618 11986" 1565 12164" 906 12102" 984 12536" 436 11723" 320 8 h postdose 11850" 1876 11047" 974 12679" 1865 12826" 1170 11050" 1159 11947" 1502 11570" 773 12 h postdose 12056" 1323 12628" 1687 11337" 1063 11641" 1152 11764" 753 12066" 1145 12056" 997 24 h postdose 11639" 1418 11710" 1218 12906" 1605 12131" 1406 12275" 471 11574" 1002 11809" 1638 post study 12333" 1887 13120" 865 13368" 1274 12984" 1386 12775" 1379 12296" 1463 12690" 1534 Data obtained from pp. 419 420, and 435 447, MRID 44912301. * Statistically significant at p < 0.05, compared with controls. ** Statistically significant at p # 0.001, compared with controls. mins = minutes, h = hours 4. Pupillometry:

With Outliers: When all outlying values were included, the percent change of the mean initial pupil size from baseline ( 30 minutes pre dose) compared to placebo was decreased in the 0.06 and 0.09 mg/ kg dose groups one hour post dose ( 14.6%, p= 0.4 and  17.7% , p= 0.77, respectively). The 0.06 mg/ kg group mean initial pupil size returned to + 2.6% of baseline by 4 hours post dose, and the 0.09 mg/ kg group returned to + 1.9% of baseline at 8 hours post dose. The high dose group mean pupil size ( initial) was reduced the most at 3 hours post dose ( 10.7% of baseline, p= 0.42); subsequent values did not show a gradual increase over time. None of these reductions were statistically significant.

Without Outliers: When the outlying values were included however, the test for distributional assumption of normality ( Shapiro Wilk test) was not satisfied. As a result, the pupillometry data were re analyzed without outliers. Approximately 75% of the outliers were found in the 0.005 mg/ kg dose level. When the outlying values were excluded, a linear trend ( Bonferroni adjustment) was apparent at every time point.

There were no significant decreases in minimum pupil size and recovery pupil size relative to baseline between any dose level and placebo, at any of the time points. Significant increases in recovery pupil size were observed at 2,4, 8 and 24 hour postdosing in the 0.005 mg/ kg group when compared to placebo.

5. Increased salivation: Saliva weight ( including outliers) was increased in the 0.09 and 0.15 mg/ kg groups ( 97.6%, p= 0.19; and 160.7%, p= 0.01, change from baseline at  30 minutes) at 1 hour post dose when compared to the placebo group. A linear trend with increasing dose was only significant ( p= 0.002) at the 1 hour time point; percentage change from baseline saliva collection increased with dose. At subsequent time points during the study, neither the mean saliva weight nor the trend with dose were significant.

B. CLINICAL CHEMISTRY: 1. Hematology, clinical chemistry, and urinalysis: No treatment related effects were found at any test dose.

III. DISCUSSION AND CONCLUSIONS:

A. INVESTIGATORS' CONCLUSIONS:

The study authors concluded that the 0.005, 0.015, 0.03, and 0.06 mg/ kg dose groups had no treatment related and biologically relevant inhibition in RBC or plasma cholinesterase activity, increase in salivary secretion, decrease in pupil size, or effect on ECGs, vital signs, body temperature, clinical chemistry, urinalysis, or clinical signs.

" The 0.9 mg/ kg dose group did not have any statistically significant increases in salivary secretion. There were no compound related effect on ECGs, vital signs, body temperature, hematology, clinical chemistry, urinalysis, or clinical signs at any timepoint. Plasma cholinesterase activity was decreased at the 1 hour 15 minute ( 11.6% from baseline), 1 hour 30 minutes ( 10.1% from baseline), and 2 hours ( 10.2 from baseline) timepoint, and RBC cholinesterase activity was statistically decreased at 30 minutes ( 7.3%). Although these depressions were statistically significant, they were not considered to be adverse since they were relatively small in magnitude ( less than 20%) and similar to depressions in plasma and RBC cholinesterase that occurred in individual volunteers within the placebo group during the course of the study. A statistically significant decrease in initial pupil size occurred at the 1 hour timepoint. This was not of clinical significance as minimum and recovery pupil sizes for that timepoint were not significantly decreased and there were no adverse effects on blood cholinesterase."

" The 0.15 mg/ kg dose group had no compound related effects on ECG, vital signs, body temperature, hematology, clinical chemistry, urinalysis or clinical signs at any timepoint. At the 1 hour assessment, there was a statistically significant decrease in initial pupil size and a statistically significant increase in saliva collected. In addition, statistically significant depressions in plasma cholinesterase activity were present at all time points up to and including 3 hours post dosing and statistically significant depressions in RBC cholinesterase activity was observed from 30 minutes up to and including 1 hour 45 minutes. The period of maximum depression occurred at 45 and 60 minutes for plasma cholinesterase and from 30 to 60 minutes for RBC cholinesterase. Plasma and RBC cholinesterase activities returned to baseline within 4 and 3 hours following administration of the test substance, respectively." B. EPA CONCLUSIONS:

No dose group had changes in respiratory rate, ECGs, vital signs, hematology, clinical chemistry, urinalysis, or clinical signs. There were no significant decreases in minimum and recovery pupil sizes in any dose group compared to placebo. Plasma and RBC cholinesterase activity typically returned to normal by 3 hours post dosing in all groups. In the high dose ( 0.15 mg/ kg) plasma and RBC cholinesterase activity both peaked ( 43% and 28%, respectively) at 45 minutes post dosing with recovery by 3 to 4 hours postdosing Plasma cholinesterase inhibition peaked at 75 minutes ( 12%) and recovered by 3 hours post dosing in the 0.09 mg/ kg dose group. RBC cholinesterase inhibition was statistically decreased ( 7%) at 30 minutes only. No differences in plasma or RBC cholinesterase activities were observed in the other dose groups compared to control. Under the conditions of this ascending oral dose study in humans, 0.09 mg/ kg/ day represents a level where 7 12% plasma and RBC ChE inhibition was observed. Three of 5 volunteers at this dose ( 0.09 mg/ kg/ day) exhibited greater than 20% plasma ChE inhibition. Therefore, 0.06 mg/ kg/ day is considered the NOAEL.

Additionally, the Agency used the RBC ChE inhibition time course data for input into the Agency's BMDS model. The BMD10 is 0.083 mg/ kg and BMDL10 of 0.069 mg/ kg. The BMD and BMDL were considered for the NMC carbamate cumulative risk assessment for refinement of the interspecies extrapolation factor for oxamyl.

C. DEFICIENCIES:

There were no study deficiencies identified that would have affected the outcome and conclusions of this study.


[Federal Register Volume 88, Number 139 (Friday, July 21, 2023)]
[Notices]
[Pages 47232-47233]
[FR Doc No: 2023-15450]

=======================================================================
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DEPARTMENT OF TRANSPORTATION

Federal Aviation Administration

Notice of Intent To Rule on a Land Release Request at Malden
Regional Airport & Industrial Park (MAW), Malden, MO

AGENCY: Federal Aviation Administration (FAA), DOT.

ACTION: Notice of request to release of airport land.

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SUMMARY: The FAA proposes to rule and invites public comment on the
request to release and sell a 1.42 acre parcel of federally obligated
airport property at the Malden Regional Airport & Industrial Park
(MAW), Malden, Missouri.

DATES: Comments must be received on or before August 21, 2023.

ADDRESSES: Comments on this application may be mailed or delivered to
the FAA at the following address: Amy J. Walter, Airports Land
Specialist, Federal Aviation Administration, Airports Division, ACE-
620G, 901 Locust, Room 364, Kansas City, MO 64106.
    In addition, one copy of any comments submitted to the FAA must be
mailed or delivered to: David Blalock, Airport Manager, City of Malden
Regional Airport & Industrial Park, 3077 Mitchell Drive, P.O. Box 411,
Malden, MO 63863-0411,<PHONE_NUMBER>.

FOR FURTHER INFORMATION CONTACT: Amy J. Walter, Airports Land
Specialist, Federal Aviation Administration, Airports Division, ACE-
620G, 901 Locust, Room 364, Kansas City, MO 64106,<PHONE_NUMBER>,
[email protected]. The request to release property may be reviewed, by
appointment, in person at this same location.

SUPPLEMENTARY INFORMATION: The FAA invites public comment on the
request to release a 1.42 acre parcel of airport property at the Malden
Regional Airport & Industrial Park (MAW) under the provisions of 49
U.S.C. 47107(h)(2). This is a Surplus Property Airport. The City of
Malden requested a release from the FAA to sell a 1.42 acre parcel to
Kenneth W. Huey for commercial development. The FAA determined this

request to release and sell property at the Malden Regional Airport &
Industrial Park (MAW) submitted by the Sponsor meets the procedural
requirements of the FAA and the release and sale of the property does
not and will not impact future aviation needs at the airport. The FAA
may approve the request, in whole or in part, no sooner than thirty
days after the publication of this notice.
    The following is a brief overview of the request:
    The Malden Regional Airport & Industrial Park (MAW) is proposing
the release from obligations and sale of a 1.42 acre parcel of airport
property. The release of land is necessary to comply with Federal
Aviation Administration Grant Assurances that do not allow federally
acquired airport property to be used for non-aviation purposes. The
sale of the subject property will result in the land at the Malden
Regional Airport & Industrial Park (MAW) being changed from
aeronautical to non-aeronautical use and release the lands from the
conditions of the Airport Improvement Program Grant Agreement Grant
Assurances in order to sell the land. In accordance with 49 U.S.C.
47107(c)(2)(B)(i) and (iii), the airport will receive fair market value
for the property, which will be subsequently reinvested in another
eligible airport improvement project for general aviation use.
    Any person may inspect, by appointment, the request in person at
the FAA office listed above under FOR FURTHER INFORMATION CONTACT. In
addition, any person may request an appointment to inspect the
application, notice and other documents determined by the FAA to be
related to the application in person at the Malden City Hall.

    Issued in Kansas City, MO, on July 17, 2023.
James A. Johnson,
Director, FAA Central Region, Airports Division.
[FR Doc. 2023-15450 Filed 7-20-23; 8:45 am]
BILLING CODE 4910-13-P


[Federal Register Volume 87, Number 70 (Tuesday, April 12, 2022)]
[Rules and Regulations]
[Pages 21554-21556]
[FR Doc No: 2022-07836]

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DEPARTMENT OF COMMERCE

Bureau of Industry and Security

15 CFR Part 746

[Docket No.<PHONE_NUMBER>]
RIN 0694-AI81

Additions to the List of Countries Excluded From Certain License
Requirements Under the Export Administration Regulations (EAR)

AGENCY: Bureau of Industry and Security, Department of Commerce.

ACTION: Final rule.

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SUMMARY: In response to the Russian Federation's (Russia's) further
invasion of Ukraine and to protect U.S. national security and foreign
policy interests, the Department of Commerce established highly
restrictive license requirements and policies for certain transactions
involving Russia and Belarus under the Export Administration
Regulations (EAR). To recognize partner countries implementing
substantially similar export controls on Russia and Belarus, the
Department of Commerce published a list of countries excluded from
certain U.S. export controls related to foreign-produced items. In this
rule, the Department of Commerce adds Iceland, Liechtenstein, Norway,
and Switzerland to the list of excluded countries.

DATES: This rule is effective April 8, 2022.

FOR FURTHER INFORMATION CONTACT: For questions on this final rule,
contact Eileen Albanese, Director, Office of National Security and
Technology Transfer Controls, Bureau of Industry and Security,
Department of Commerce, Phone:<PHONE_NUMBER>, Fax: (202)<PHONE_NUMBER>,
Email: [email protected]. For emails, include ``Russia'' in the subject
line.

SUPPLEMENTARY INFORMATION:

Background

    In response to Russia's February 2022 invasion of Ukraine and
Belarus's substantial enabling of Russia's invasion, the Bureau of
Industry and Security (BIS) imposed extensive export controls on Russia
and Belarus under the Export Administration Regulations (15 CFR parts
730-774) (EAR) by implementing the final rule, Implementation of
Sanctions Against Russia Under the Export Administration Regulations
(EAR), effective February 24, 2022 (``Russia rule''),\1\ and four
subsequent final rules published in March 2022: Imposition of Sanctions
Against Belarus Under the Export Administration Regulations (EAR),
effective March 2, 2022 (``Belarus rule''); \2\ Expansion of Sanctions
Against the Russian Industry Sector Under the Export Administration
Regulations (EAR) (``Industry Sector rule''); \3\ Further Imposition of
Sanctions Against Russia with the Addition of Certain Entities to the
Entity List (``Russia Entity List rule''); \4\ and Imposition of
Sanctions on `Luxury Goods' Destined for Russia and Belarus and for
Russian and Belarusian Oligarchs and Malign Actors Under the Export
Administration Regulations (``Luxury Goods rule'').\5\ As described in
the Russia rule's preamble, as well as in the other March 2022 rules,
Russia's invasion of Ukraine and Belarus's enabling of such invasion
flagrantly violate international law, are contrary to U.S. national
security and foreign policy interests, and undermine global order,
peace, and security. Accordingly, BIS has imposed stringent export
controls on Russia and Belarus.
---------------------------------------------------------------------------

    \1\ 87 FR 12226 (March 3, 2022).
    \2\ 87 FR 13048 (March 8, 2022).
    \3\ 87 FR 12856 (March 8, 2022).
    \4\ 87 FR 13141 (March 9, 2022).
    \5\ 87 FR 14785 (March 16, 2022).
---------------------------------------------------------------------------

    Also in March 2022, BIS published Addition to the List of Countries
Excluded from Certain License Requirements under the Export
Administration Regulations (``South Korea exclusion rule''),\6\ which
added South Korea to the list of countries in supplement no. 3 to part
746 of the EAR that are excluded from certain Sec.  746.8 license
requirements that pertain to items destined for Russia or Belarus. The
countries listed in supplement no. 3 to part 746 have committed to
implementing substantially similar export controls on Belarus and
Russia under their domestic laws. Pursuant to Sec.  746.8(a)(5) of the
EAR, countries that have made such a commitment receive full or partial
exclusions, as appropriate, from the FDP rules' license requirements
set forth under Sec.  746.8(a)(2) and (3). Similarly, the license
requirements in Sec.  746.8(a)(1) are not used to determine controlled
U.S.-content under the EAR's de minimis rules, as set forth in
supplement no. 2 to part 734 of the EAR, provided the

criteria in Sec.  746.8(a)(5)(i) and (ii) are met.
---------------------------------------------------------------------------

    \6\ 87 FR 13627 (March 10, 2022).
---------------------------------------------------------------------------

    Iceland, Liechtenstein, Norway, and Switzerland have adopted and
implemented substantially similar measures to those imposed by BIS
through U.S. export controls on Russia and Belarus. In recognition of
their substantial alignment with U.S. controls, BIS adds the four
countries to supplement no. 3 to part 746 in this rule with the
designation of ``full.''

Export Control Reform Act of 2018

    On August 13, 2018, the President signed into law the John S.
McCain National Defense Authorization Act for Fiscal Year 2019, which
included the Export Control Reform Act of 2018 (ECRA) (codified, as
amended, at 50 U.S.C. 4801-4852). ECRA provides the legal basis for
BIS's principal authorities and serves as the authority under which BIS
issues this rule.

Rulemaking Requirements

    1. This final rule is not a ``significant regulatory action''
because it ``pertain[s]'' to a ``military or foreign affairs function
of the United States'' under sec. 3(d)(2) of Executive Order 12866.
    2. Notwithstanding any other provision of law, no person is
required to respond to, nor shall any person be subject to a penalty
for failure to comply with, a collection of information subject to the
requirements of the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et
seq.) (PRA), unless that collection of information displays a currently
valid Office of Management and Budget (OMB) Control Number. This rule
involves the following OMB-approved collections of information subject
to the PRA: 0694-0088, ``Multi-Purpose Application,'' which carries a
burden hour estimate of 29.6 minutes for a manual or electronic
submission; 0694-0096 ``Five Year Records Retention Period,'' which
carries a burden hour estimate of less than 1 minute; and 0607-0152
``Automated Export System (AES) Program,'' which carries a burden hour
estimate of 3 minutes per electronic submission. BIS anticipates this
rule will result in a slight decrease in the number of estimated
license applications because this rule provides relief from the burden
of the new Russia rule and Belarus rule requirements that would
otherwise pertain to items produced in, exported or reexported from
Iceland, Liechtenstein, Norway, or Switzerland, or transferred (in-
country) in either country. Thus, this rule does not create a
substantive change to OMB Control Numbers 0694-0088, 0694-0096, or
0607-0152.
    3. This rule does not contain policies with federalism implications
as that term is defined in Executive Order 13132.
    4. Pursuant to section 1762 of the Export Control Reform Act of
2018 (50 U.S.C. 4821) (ECRA), this action is exempt from the
Administrative Procedure Act (APA) (5 U.S.C. 553) requirements for
notice of proposed rulemaking, opportunity for public participation,
and delay in effective date. While section 1762 of ECRA provides
sufficient authority for such an exemption, this action is also
independently exempt from these APA requirements because it involves a
military or foreign affairs function of the United States (5. U.S.C.
553(a)(1)).
    5. Because a notice of proposed rulemaking and an opportunity for
public comment are not required to be given for this rule by 5 U.S.C.
553, or by any other law, the analytical requirements of the Regulatory
Flexibility Act, 5 U.S.C. 601, et seq., are not applicable.
Accordingly, no regulatory flexibility analysis is required, and none
has been prepared.

List of Subjects in 15 CFR Part 746

    Exports, Reporting and recordkeeping requirements.

    For the reasons stated in the preamble, part 746 of the Export
Administration Regulations (15 CFR parts 730 through 774) is amended as
follows:

PART 746--EMBARGOES AND OTHER SPECIAL CONTROLS

0
1. The authority citation for 15 CFR part 746 continues to read as
follows:

    Authority:  50 U.S.C. 4801-4852; 50 U.S.C. 4601 et seq.; 50
U.S.C. 1701 et seq.; 22 U.S.C. 287c; Sec 1503, Pub. L. 108-11, 117
Stat. 559; 22 U.S.C. 2151 note; 22 U.S.C. 6004; 22 U.S.C. 7201 et
seq.; 22 U.S.C. 7210; E.O. 12854, 58 FR 36587, 3 CFR, 1993 Comp., p.
614; E.O. 12918, 59 FR 28205, 3 CFR, 1994 Comp., p. 899; E.O. 13222,
66 FR 44025, 3 CFR, 2001 Comp., p. 783; E.O. 13338, 69 FR 26751, 3
CFR, 2004 Comp., p 168; Presidential Determination 2003-23, 68 FR
26459, 3 CFR, 2004 Comp., p. 320; Presidential Determination 2007-7,
72 FR 1899, 3 CFR, 2006 Comp., p. 325; Notice of May 6, 2021, 86 FR
26793 (May 10, 2021).

0
2. Supplement no. 3 to part 746 is amended by adding entries for
``Iceland,'' ``Liechtenstein,'' ``Norway,'' and ``Switzerland'' to the
table in alphabetical order to read as follows:

Supplement No. 3 to Part 746--Countries Excluded From Certain License
Requirements of Sec.  746.8

* * * * *

------------------------------------------------------------------------
                                                      Federal Register
            Country                   Scope               citation
------------------------------------------------------------------------

                              * * * * * * *
Iceland.......................  Full.............  87 FR [INSERT FR PAGE
                                                    NUMBER AND April 12,
                                                    2022].

                              * * * * * * *
Liechtenstein.................  Full.............  87 FR [INSERT FR PAGE
                                                    NUMBER AND April 12,
                                                    2022].

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Norway........................  Full.............  87 FR [INSERT FR PAGE
                                                    NUMBER AND April 12,
                                                    2022].

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Switzerland...................  Full.............  87 FR [INSERT FR PAGE
                                                    NUMBER AND April 12,
                                                    2022].

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Matthew S. Borman,
Deputy Assistant Secretary for Export Administration.
[FR Doc. 2022-07836 Filed 4-8-22; 8:45 am]
BILLING CODE 3510-33-P


   Federal Food, Drug, and Cosmetic Act (FFDCA) Considerations for 1-Octanol

                    Docket ID Number: EPA-HQ-OPP-2014-0353
                             Date: March 13, 2015

Section 408(c)(2)(A)(i) of FFDCA allows the U.S. Environmental Protection Agency (EPA or the Agency) to establish an exemption from the requirement for a tolerance (the legal limit for a pesticide chemical residue in or on a food) only if the EPA determines that the exemption is "safe." Section 408(c)(2)(A)(ii) of FFDCA defines "safe" to mean that "there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposures for which there is reliable information." This includes exposure through drinking water and in residential settings but does not include occupational exposure. Pursuant to FFDCA section 408(c)(2)(B), in establishing or maintaining in effect an exemption from the requirement of a tolerance, the EPA must take into account the factors set forth in FFDCA section 408(b)(2)(C), which require the EPA to give special consideration to exposure of infants and children to the pesticide chemical residue in establishing a tolerance exemption, and to "ensure that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to the pesticide chemical residue...." Additionally, FFDCA section 408(b)(2)(D) requires that the EPA consider "available information concerning the cumulative effects of [a particular pesticide's] . . . residues and other substances that have a common mechanism of toxicity."
The EPA performs a number of analyses to determine the risks from aggregate exposure to pesticide residues. First, the EPA determines the toxicity of pesticides. Second, the EPA examines exposure to the pesticide through food, drinking water, and through other exposures that occur as a result of pesticide use in residential settings.
I.  Summary of Petitioned-for Tolerance Exemption
In the Federal Register of August 1, 2014 (79 FR 44729) (FRL-9911-67), EPA issued a notice pursuant to FFDCA section 408(d)(3), 21 U.S.C. 346a(d)(3), announcing the filing of a pesticide tolerance petition (PP 3F8195) by D-I-1-4, Inc., a division of 1,4-Group, Inc. (the Petitioner), P.O. Box 860, Meridian, ID 83360. The petition requested that 40 CFR part 180 be amended by establishing an exemption from the requirement of a tolerance for residues of 1-octanol, applied post-harvest to stored potatoes and other sprouting root and tuber crops. The notice referenced a summary of the petition prepared by the Petitioner, which is available in Docket ID Number EPA-HQ-OPP-2014-0353 via http://www.regulations.gov.
II. Toxicological Profile
Consistent with section 408(b)(2)(D) of FFDCA, the EPA reviewed the available scientific data and other relevant information on 1-octanol, and considered its validity, completeness, and reliability, as well as the relationship of this information to human risk. The EPA also considered available information concerning the variability of the sensitivities of major identifiable subgroups of consumers, including infants and children.
A.  Overview of 1-Octanol

1-Octanol, or octyl alcohol, is a linear saturated aliphatic alcohol containing eight carbons. It is classified as a biochemical pesticide and functions as a plant growth regulator (PGR) by inhibiting sprout growth on stored potatoes and other sprouting root and tuber crops when applied after harvesting.

There is a significant history of human dietary exposure to 1-octanol. 1-Octanol occurs naturally in the essential oils of green tea, grapefruit, California orange, bitter orange, Turkish rose and Bulgarian rose. 1-Octanol has also been identified as a component of fried bacon, roasted filberts, raw and roasted earth almonds, mutton, chicken, pork, raw beef, frankfurters, nectarines, apple juice, common guava, Gruyere cheese and in foods processed from cassava root. The amount of 1-octanol has been quantified in some foods: fermented soybean curds were found to contain 164.8 to 337.1 micrograms per kilogram (ug/kg) of 1-octanol, and duck meat and duck fat were found to contain 1-octanol as a volatile component at 8.88 parts per billion (ppb) and 12.69 ppb, respectively (Ref 1). 1-Octanol is approved by the FDA for use as a direct food additive under 21 CFR § 172.230 in microcapsules for flavoring substances and under 21 CFR § 172.515 as a synthetic flavoring substance and adjuvant.

EPA has already determined under the FFDCA that there is a reasonable certainty that no harm will result from aggregate exposures to 1-octanol, when 1-octanol is used as an inert ingredient (specifically as a solvent or co-solvent) in pesticide products applied to food.  40 CFR § 180.910.  In addition, 1-octanol has been registered for use as an active ingredient to control tobacco sucker and as an inert ingredient for nonfood and fragrance uses (Ref`2).

Based on the data submitted in support of this petition (summarized in Unit II. B., below) and the comprehensive risk assessment conducted by the Agency (Ref. 1, below), EPA concludes that there is a reasonable certainty of no harm from aggregate exposures to 1-octanol, including the consumption of food treated with this active ingredient in accordance with label directions and good agricultural practices. EPA has made this determination because available toxicology data indicate that the active ingredient is of low acute toxicity and is not a developmental toxicant, a mutagen, or toxic via repeat oral exposure.

B.  Biochemical Pesticide Toxicology Data Requirements

All applicable mammalian toxicology data requirements supporting the request for an exemption from the requirement of a tolerance for residues of 1-octanol when used post-harvest to root and tuber crops have been fulfilled with data submitted by the petitioner. The following is a summary of EPA's review of the toxicity profile of this biochemical:

Acute Toxicity: Acute toxicity studies on 1-octanol (99% pure), confirm a low toxicity profile. The acute toxicity data show virtual nontoxicity for all routes of exposure, with the exception of eye irritation (MRID 48964402; Ref. 1, and references therein).

1.	The acute oral median lethal dose (LD50) in rats was greater than 5,000 milligrams per kilogram (mg/kg) bodyweight in one study and equal to 4,135 mg/kg bodyweight in a second study. The LD50 in mouse was 1,800 mg/kg bodyweight. 1-Octanol is classified as Toxicity Category III for acute oral toxicity.

2.	The acute dermal LD50 in rabbit was greater than 5,000 mg/kg body weight. 1-Octanol is classified as Toxicity Category IV for acute dermal toxicity.

 3.	The acute inhalation median lethal concentration (LC50) in rats was greater than 6.4 milligrams per liter (mg/L) after 1-hour exposure (no deaths occurred) and greater than 5.6 mg/L after 4-hour exposure (3 rats dying within two days of exposure). 1-Octanol is classified as Toxicity Category IV for acute inhalation toxicity.

4.	For primary eye irritation, EPA has classified 1-octanol as irritating because the available data indicate that 1-octanol is "irritating" or "an irritant," but information regarding the degree of severity is unavailable. Because specific data on the eye irritation severity of 1-octanol is unavailable and data on similar substances indicate varying levels of irritation from moderate to severe, a toxicity category II classification is appropriate at this time.

 5.	A skin irritation study on rabbits indicates that 1-octanol is slightly irritating. 1-Octanol is classified as Toxicity Category IV for primary skin irritation.
 6.	Data indicate that 1-octanol is not a dermal sensitizer.

Mutagenicity: Information on 1-octanol mutagenicity testing is contained in MRID 49458902. In an Ames assay, five strains of Salmonella typhimurium were exposed to 2,000 nanoliters per plate (nl/plate) of 1-octanol with or without metabolic activation; 1-octanol was not considered mutagenic in the assay. In a mouse lymphoma assay (L5178Y TK+/-), cells were exposed to 100 micrograms per milliliter (ug/ml) 1-octanol with or without metabolic activation; again, 1-octanol was not considered mutagenic in the assay.

Subchronic Toxicity:

1. 90-day oral data requirement is required to be addressed for uses of a pesticide on foods. In MRID 48964402, data were cited from the open scientific literature to satisfy the data requirement. The study has been reviewed and cited by the World Health Organization's (WHO) International Programme on Chemical Safety in its assessment of 1-octanol as a food additive. The study is also cited in the National Library of Medicine's (NLM) Hazardous Substances Database (HSDB) for 1-octanol. Mice were administered the chemical via gavage at a dose of 179 mg/kg body weight for 30 days. No adverse effects were reported.

2. The 90-day dermal data requirement is conditionally required to support uses involving purposeful application to the human skin or uses that would result in prolonged dermal exposure and if data from a 90-day oral study are not required or the active ingredient is known or expected to be metabolized differently by the dermal route of exposure than by the oral route and the metabolite is of toxicological concern. The Agency has waived this data requirement at this time. Purposeful application and prolonged exposure to the human skin is not anticipated based on the use pattern of the proposed product; 1-octanol is intended to be applied inside crop storage facilities through ventilation systems from outside of the facility. Per label instructions, buildings are sealed until fully ventilated and early reentry requirements include the use of appropriate PPE which includes coveralls over long-sleeved shirt, long pants, shoes plus socks, chemical resistant gloves, face-sealing goggles and a respirator. During use of the pesticide, applicators and handlers are required to wear appropriate PPE (long-sleeved shirt, long pants, shoes, socks, gloves and protective eyewear. These PPE requirements mitigate the potential for repeated dermal exposure. Additionally, prolonged dermal exposure is also not anticipated as 1-octanol is a volatile chemical that is expected to degrade rapidly once introduced into the environment. The chemical has an estimated half-life of 3.5 minutes and is not likely to remain on skin if exposure occurs (Ref. 1).

3. 90-day inhalation data requirement is conditionally required if there is a likelihood of significant levels of repeated inhalation exposure to the pesticide as a gas, vapor or aerosol. The Agency has waived this data requirement at this time. Significant inhalation exposure is not anticipated based on the use pattern: 1-octanol is intended to be applied inside crop storage facilities through ventilation systems from outside of the facility. Per label instructions, buildings are sealed until fully ventilated and early reentry requirements include the use of a respirator. Additionally, prolonged inhalation exposure is also not anticipated as 1-octanol is a volatile chemical that is expected to degrade rapidly once introduced into the environment (Ref. 1).

Developmental Toxicity: No adverse effects (maternal or developmental) were observed in a developmental toxicity study where pregnant rats were exposed to 100 mg/m[3] 1-octanol (the maximum achievable vapor) for seven hours per day on gestation days 1-19. No developmental toxicity occurred in a study were pregnant rats were dosed via gavage with a blend of 55% decanol and 40.7% octanol at 0, 125, 375 and 1,000 mg/kg/day on gestation days 6-16. Increased salivation was observed in dams at the highest dose. The Agency does not consider this to be an adverse effect because the effect occurs at a very high dose, much higher dose than the level at which humans are likely to be exposed, given the half-life of this substance and the classification of the pesticide: a plant growth regulator intended for use before long-term storage. The maternal no observed adverse effect level (NOAEL) = 375 mg/kg/day and the maternal lowest observed adverse effect level (LOAEL) = 1,000 mg/kg/day.

III.  Aggregate Exposure

In examining aggregate exposure, FFDCA section 408 directs the EPA to consider available information concerning exposures from the pesticide residue in food and all other non-occupational exposures, including drinking water from ground water or surface water and exposure through pesticide use in gardens, lawns, or buildings (residential and other indoor uses).

Food Exposure: The proposed use patterns may results in dietary exposure to 1-octanol, however, dietary exposure as a result of the application of 1-octanol to post-harvest potatoes and other root tubers is expected to be insignificant.  Some dietary exposure is expected from the use of 1-octanol as an inert ingredient in pesticide formulations. Some dietary exposure to 1-octanol might occur through other nonpesticidal sources as a result of its natural presence in other foods or from its use as a food additive and flavoring substance. Should exposure occur, however, minimal to no risk is expected for the general population, including infants and children, due to the low toxicity of 1-octanol (Ref 1).

Drinking Water Exposure:  No significant exposure via drinking water is expected from its use as an active ingredient in this pesticide as 1-octanol is applied indoors only.

Other Non-occupational Exposure: Other non-occupational exposure to 1-octanol from pesticidal use may occur in tobacco products from its use on tobacco or in or on other food and non-food commodities, as a result of its use as a pesticide inert ingredient. However, minimal to no risk is expected for the general population, including infants and children, due to the low toxicity of this chemical.

IV.  Cumulative Effects from Substances with a Common Mechanism of Toxicity

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the EPA consider "available information concerning the cumulative effects of [a particular pesticide's] . . . residues and other substances that have a common mechanism of toxicity."

The EPA has not found 1-octanol to share a common mechanism of toxicity with any other substances, and 1-octanol does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, the EPA has assumed that 1-octanol does not have a common mechanism of toxicity with other substances. Following from this, the EPA concludes that there are no cumulative effects associated with 1-octanol that need to be considered. For information regarding the EPA's efforts to determine chemicals that have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the EPA's website at http://www.epa.gov/pesticides/cumulative.

V.  Determination of Safety for the United States Population, Infants and Children

FFDCA section 408(b)(2)(C) provides that, in considering the establishment of a tolerance or tolerance exemption for a pesticide chemical residue, the EPA shall assess the available information about consumption patterns among infants and children, special susceptibility of infants and children to pesticide chemical residues, and the cumulative effects on infants and children of the residues and other substances with a common mechanism of toxicity. In addition, FFDCA section 408(b)(2)(C) provides that the EPA shall apply an additional tenfold (10X) margin of safety for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the completeness of the database on toxicity and exposure, unless the EPA determines that a different margin of safety will be safe for infants and children. This additional margin of safety is commonly referred to as the Food Quality Protection Act Safety Factor. In applying this provision, the EPA either retains the default value of 10X, or uses a different additional or no safety factor when reliable data are available to support a different additional or no safety factor.

Because there are no threshold effects associated with this biochemical, an additional margin of safety for infants and children is not necessary.

EPA has determined that there are no foreseeable dietary risks to the U.S. population, including infants and children, from the use of 1-octanol as a pesticide (plant growth regulator) on root and tuber vegetables when label instructions and good agricultural practices are followed. The available data and information indicate that the chemical is of low toxicity and not a developmental toxicant. Therefore, EPA concludes that there is a reasonable certainty that no harm will result to the U.S. population, including infants and children, from aggregate exposure to the residues of 1-octanol when it is used as labeled and in accordance with good agricultural practices. Such exposure includes all anticipated dietary exposures and all other exposures for which there is reliable information. EPA has arrived at this conclusion because the data and information available on 1-octanol do not demonstrate significant toxic potential to mammals, including infants and children.

VI.  Conclusions
EPA concludes that there is a reasonable certainty that no harm will result to the U.S. population, including infants and children, from aggregate exposure to residues of 1-octanol. Therefore, an exemption is established for residues of the biochemical pesticide 1-octanol when used on root and tuber vegetables in accordance with label directions and good agricultural practices.

VII.  References

1. EPA (2015a) Science Review in Support of the Registration of 1,4Zap Technical, Containing 99.0%
   1-Octanol as its Active Ingredient. February 23, 2015.

2. EPA (2015a) Inert Use Information. Inert Finder. Pesticides. US EPA. U.S. Environmental Protection
      Agency. Available at: http://iaspub.epa.gov/apex/pesticides/f?p=101:1: (Accessed January 13, 2015).