4.19 Pyrethrins (063)

RESIDUE AND ANALYTICAL ASPECTS

Pyrethrins were evaluated for residues in the Periodic Review Programme of the 2000 JMPR, which concluded that the existing CXL of 1 mg/kg Po for tree nuts should be withdrawn because no information was submitted. The 34^th Session of the CCPR decided to maintain the CXL for tree nuts for 4 years, as the Government of Australia had indicated its intention to submit new residue data to the JMPR.

The 2005 JMPR received reports of studies on analytical methods and supervised residue trials and information on GAP for tree nuts. Reports were supplied by the government of Australia. The formulation used for trials contains not only pyrethrins but piperonyl butoxide. There is no residue information for piperonyl butoxide and a CXL for piperonyl butoxide in tree nuts has not been established.

Method of analysis

The sample was extracted with acetone and water. Extracts were assessed by HPLC with a fluorescence detector at 223nm. The limit of quantification (LOQ) was 0.2mg/kg for almond and 0.5mg/kg for macadamia nuts. This method was considered acceptable for supervised trials.

Definition of the residue

The Meeting agreed that the residue definition for enforcement purposes for plant commodities and for consideration of dietary intake should be total pyrethrins, calculated as the sum of pyrethrin 1, pyrethrin 2, cinerin 1, cinerin 2, jasmolin 1 and jasmolin 2, determined after calibration with World Standard pyrethrum extract. The Meeting agreed that the residues are fat-soluble.

Definition of the residue for compliance with MRLs and estimation of dietary intake: total pyrethrins, calculated as the sum of pyrethrin 1, pyrethrin 2, cinerin 1, cinerin 2, jasmolin 1 and jasmolin 2, determined after calibration with World Standard pyrethrum extract.

Results of supervised trials on crops

Tree nuts

The current Australian label indicates that a gas formulation of pyrethrins may be applied to stored tree nuts in food storage area. The application rate of pyrethrins for tree nuts is either 0.067 g ai/100m³ (for flying insects) or 0.2 g ai/100m³ (for crawling insects). However the frequency of applications is not described on the label. It is determined by the situation in which the products are being applied. Three supervised trials each were conducted for stored almond and macadamia nuts according to the maximum application rate based on the Australia GAP (0.2 g ai/100m³). The number of applications to almond or macadamia nuts was 3 or 4 respectively. The residues of pyrethrins were below the respective LOQ's, < 0.2 mg/kg in almond and < 0.5 mg/kg in macadamia nuts.

The Meeting estimated a maximum residue level of 0.5 * mg/kg, an STMR of 0.2 mg/kg and an HR of 0.5 mg/kg for post-harvest use of pyrethrins on tree nuts and recommended withdrawal of the existing CXL for tree nuts of 1 mg/kg Po.

DIETARY RISK ASSESSMENT

Long-term intake

The International Estimated Daily Intakes (IEDI) of pyrethrins, based on the STMRs estimated by the 2000, 2003 and 2005 JMPR for 12 commodities, for the five GEMS/Food regional diets was 1% of the maximum ADI of 0.04 mg/kg bw (Annex 3). The Meeting concluded that the long-term intake of residues of pyrethrins, resulting from the uses considered by the JMPR, is unlikely to present a public health concern.

Short-term intake

The International Estimated Short Term Intake (IESTI) for pyrethrins was calculated for tree nuts for which the maximum residue level was estimated by the current JMPR (Annex 4).

The IESTI represented 1% of the ARfD (0.2 mg/kg bw) for the general population and 0% of the ARfD for children. The Meeting concluded that the short-term intake of residues of pyrethrins, resulting from the uses considered by the JMPR, is unlikely to present a public health concern.

4.20 Sulfuryl fluoride (218)

TOXICOLOGY

Sulfuryl fluoride (O₂SF₂) is a gas used as a fumigant for the control of a range of insect pests. It has been used for structural fumigation since the early 1960s. In the USA it is approved for "food uses" (grain, dried fruit and tree nuts), while in the United Kingdom, Germany and Italy the structures being fumigated must be emptied of food items. Sulfuryl fluoride is thought to inhibit the glycolysis and fatty acid cycles via the release of fluoride ions, thereby depriving the insect of energy necessary for survival.

Sulfuryl fluoride has not been evaluated previously by the JMPR.

All the critical studies contained statements of compliance with GLP.

Biochemical aspects

In rats exposed to [³⁵S]-labelled sulfuryl fluoride at 30 or 300 ppm by inhalation, the radiolabel was rapidly absorbed, achieving maximum concentrations in both plasma and erythrocytes near the end of the 4-h exposure period. Once absorbed, the radiolabel was rapidly excreted, primarily via the urine. The radiolabel was rapidly cleared from the plasma and erythrocytes with initial half-lives of approximately 2.5 h after exposure at 30 ppm and 1-2.5 h after exposure at 300 ppm, but the terminal half-life of radioactivity was approximately 2.5-fold longer in erythrocytes than in plasma. The identification of fluorosulfate and sulfate in blood and urine suggests that sulfuryl fluoride is rapidly hydrolysed to fluorosulfate, with the release of fluoride, followed by further hydrolysis to sulfate and release of the remaining fluoride. This is supported by the observation of increases in fluoride in blood and urine after exposure of rats to sulfuryl fluoride. Seven days after exposure, radioactivity was widely distributed with significant concentrations remaining in tissues at the site of first exposure to the gas.

Toxicological data

The primary concern of the Meeting was the risk assessment for dietary exposures to sulfuryl fluoride. Sulfuryl fluoride is a gas and routine tests for toxicity via the oral and dermal routes are difficult to perform. All the critical studies involved exposures by inhalation (for about 6 h/day, 5 days/week) and it was necessary to convert these to systemic doses in order to derive health-based guidance values. To convert from concentrations in air to a systemic dose in mg/kg bw per day, account was taken of the respiratory rates and volumes of the animals^[13], the duration of exposure (h/day and days/week) and the proportion (10%) of the inspired dose that was absorbed based on a toxicokinetic study.

In assessing the effects of sulfuryl fluoride, the Meeting focused on effects related to systemic exposures rather than local effects linked with sulfuryl fluoride gas. In foodstuffs exposed to sulfuryl fluoride the predominant residue is fluoride ion, although some residues of sulfuryl fluoride have been detected in certain fumigated products. The data indicated that some toxic effects observed after exposure to sulfuryl fluoride (e.g. renal toxicity) were consistent with the toxicity of fluoride. The Meeting concluded that the "slight" dental fluorosis seen in some studies was not an adverse finding. Although no studies on fluoride were submitted the Meeting was aware of a number of recent expert evaluations of exposure to and toxicity attributable to fluoride.

Sulfuryl fluoride was found to be moderately acutely toxic when administered by the oral route (LD₅₀ of approximately 100 mg/kg bw; sulfuryl fluoride bubbled into corn oil), but the Meeting noted that the results of this study were difficult to interpret owing to the very high volume of corn oil administered (40 mL/kg bw). A standard study of dermal toxicity could not be performed, but whole-body (excluding head) exposure did not indicate any significant toxicity after exposure via the dermal route. Sulfuryl fluoride gas administered via inhalation has been extensively investigated in several studies of acute toxicity in rats and mice and was found to have low to moderate toxicity. All studies in rats and one of two studies in mice reported 4-h LC₅₀ values of > 2 mg/L (about 500 ppm). Exposure of humans to sulfuryl fluoride gas at high concentrations within enclosed structural fumigation areas has resulted in death. No tests for skin and eye irritation or studies of skin sensitization have been conducted. However, whole-body exposures and experience in humans over a period of 40 years of use indicate that sulfuryl fluoride is not a significant irritant, nor a skin sensitizer. Mechanistic studies on "time to acute incapacitation" have revealed an approximately linear relationship between concentration and duration of exposure.

In a 1959 study in which rats were fed for 66 days with diets previously exposed to sulfuryl fluoride, the NOAEL was 2.5 mg of total fluoride/kg bw per day on the basis of reduced body-weight gain and evidence of fluorosis, but the details reported were limited and relatively few end-points were investigated. Sulfuryl fluoride has been studied in short-term studies of toxicity in rats, dogs, mice and rabbits exposed by inhalation; in most experiments, the exposure period was 6 h/day, 5 days/week. In 14-day studies of exposure by inhalation, the lowest NOAEC was 30 ppm (approximately equivalent to systemic exposure at 4.1 mg/kg bw per day) in mice on the basis of brain vacuolation, while the NOAEC in dogs was 100 ppm (approximately equivalent to systemic exposure at 2.9 mg/kg bw per day) on the basis of tremors and tetany, but no evidence of brain lesions. The NOAEC was also 30 ppm in 90-day studies in mice (approximately equivalent to systemic exposure at 4.1 mg/kg bw per day), and in rabbits (approximately equivalent to systemic exposure at 1.4 mg/kg bw per day). In these studies the LOAEC was 100 ppm on the basis of vacuolation in the brain. Local effects on the respiratory tract were seen in many of the studies of administration via inhalation, but the Meeting considered that these were not relevant to dietary intakes. In a 1-year study in dogs exposed by inhalation, the NOAEC was 80 ppm (approximately equivalent to systemic exposure at 2.3 mg/kg bw per day) on the basis of deaths and general toxicity (including brain vacuolation) at 150 ppm. A higher concentration of 200 ppm was not tolerated by the dogs beyond approximately 9 months, when primarily respiratory effects were associated with a terminal decline in health status. Slight dental fluorosis was the most sensitive effect in the 13-week study in rats and the 1-year study in dogs, but the Meeting concluded that this was not an adverse finding. Although no specific investigations were performed on other end-points associated with excess exposure to fluoride, e.g. bone density, the Meeting concluded that the NOAELs used for risk assessment provided adequate protection for the bone effects of fluoride, as such effects are considered to be at least threefold less sensitive than dental fluorosis, on the basis of human observations.

In rats, the principal effects of long-term exposure by inhalation were reduced survival, brain vacuolation, chronic progressive glomerular nephrosis and associated lesions such as fibrous osteodystrophy in both sexes exposed at 80 ppm (approximately equivalent to 5.6 mg/kg bw per day). These latter findings are consistent with toxicity attributable to fluoride ions. In mice, the principal effects were reduced survival and slight vacuolation in the cerebrum. In rats, the NOAEC was 20 ppm (approximately equivalent to 1.4 mg/kg bw per day). In mice, the NOAEC was 20 ppm (approximately equivalent to 3.0 mg/kg bw per day). Sulfuryl fluoride was not tumourigenic or carcinogenic in rats or mice at concentrations of up to 80 ppm, the highest concentration tested (approximately equivalent to 5.6 and 12 mg/kg bw per day, respectively).

Sulfuryl fluoride showed no genotoxic potential in tests in vitro for bacterial cell mutation or unscheduled DNA synthesis in mammalian cells. The results of tests for mutagenicity and clastogenicity in mammalian cells in vitro (mouse lymphoma Tk^+/- and rat lymphocytes) were positive, consistent with the database on genotoxicity of the fluoride ion. A test for micronucleus formation in vivo gave negative results. The Meeting noted that sulfuryl fluoride is a highly reactive compound and dietary exposures would be predominantly to fluoride ion. It is generally recognized that fluoride does not represent a genotoxic risk to humans in vivo.

The Meeting concluded that consumption of foodstuffs treated with sulfuryl fluoride would not present a genotoxic risk to humans.

In view of the negative results obtained in studies of genotoxicity in vivo and the absence of carcinogenicity in mice and rats, the Meeting concluded that sulfuryl fluoride is unlikely to pose a carcinogenic risk to humans.

In a two-generation study of reproduction, no effect on reproductive parameters was observed in rats exposed by inhalation to sulfuryl fluoride at concentrations of up to 150 ppm, the highest concentration tested (approximately equivalent to 11 mg/kg bw per day). At 150 ppm, parental toxicity comprised reduced body weights and brain vacuolation; the NOAEC was 20 ppm. Reduced body-weight gain in F₁ and F₂ pups during the lactation period was noted at 150 ppm and was the only effect in offspring. The NOAEC in offspring was 20 ppm (approximately equivalent to 1.4 mg/kg bw per day). Sulfuryl fluoride has been tested for developmental effects in both rats and rabbits and found not to be teratogenic in either species. Pregnant rabbits were somewhat more sensitive to sulfuryl fluoride than were pregnant rats. In rats, there were no adverse effects on dams or offspring exposed to sulfuryl fluoride at concentrations of up to 225 ppm, the highest concentration tested (approximately equivalent to 16 mg/kg bw per day). In rabbits, however, there was slight toxicity to dams and offspring at 225 ppm, which was manifested as reduced body weights and lower fetal weights. The lowest relevant NOAEC for developmental toxicity was 75 ppm (approximately equivalent to 4.3 mg/kg bw per day) in rabbits.

Three studies specifically investigated the neurotoxicity of sulfuryl fluoride: a study of acute toxicity in rats exposed via inhalation, a 13-week study in rats exposed via inhalation and a 1-year in rats exposed via inhalation (a satellite group of the long-term/carcinogenicity study). The 13-week study was conducted first and comprised comprehensive electrophysiological tests, a functional observational battery (FOB) and histological examination of the peripheral and central nervous system. It demonstrated that the most sensitive indicator of effects on the nervous system after 13 weeks was a change in evoked potentials (visual, auditory and somatosensory). At a dietary concentration of 100 ppm and greater, visual and somatosensory evoked potentials were significantly slower in exposed female rats and auditory brainstem responses were possibly slower in exposed males relative to controls. Only at 300 ppm were histological effects evident, in the form of mild vacuolation in the brain (specifically, white fibre tracts of the caudate putamen). The NOAEC in the 13-week study was 30 ppm (approximately equivalent to 2.2 mg/kg bw per day) on the basis of alterations in evoked potentials at 100 ppm in females.

On the basis of the findings in the 13-week study of neurotoxicity, a study of acute neurotoxicity (two 6 h exposures in 30 h) in female rats was performed. This included extensive neurophysiological and behavioural investigations, including evoked potentials, but there were no investigations of brain histopathology. The Meeting considered that the absence of investigations of brain histopathology was not crucial as the brain lesions did not appear to be an acute effect, being absent in dogs or rats after 2 weeks, but were present at lower exposures in the 13-week studies. No adverse effects were produced at 300 ppm (approximately equivalent to 31 mg/kg bw per day), the highest concentration tested. The 1-year study of neurotoxicity in male and female F344 rats included a FOB, motor activity tests, fore- and hindlimb grip strength, hindlimb landing foot splay and neurohistopathology with perfusion fixation. These animals were a satellite group of the long-term/carcinogenicity study and no general histopathological examinations were performed as these were covered by other segments of the study. There were no effects on the nervous system at 80 ppm (approximately equivalent to 5.6 mg/kg bw per day), the highest concentration tested.

Sulfuryl fluoride has been used as a structural fumigant for more than 40 years. Health surveillance examinations in manufacturing plants have revealed no significant sulfuryl fluoride-related health problems among employees. Thirteen deaths have been reported in humans who gained access to buildings during fumigation, but the lethal concentration has not been determined. More than 300 incidents of non-lethal adverse effects associated with exposure to sulfuryl fluoride have been reported in the USA. Symptoms included irritation of eyes and respiratory tract, headache, nausea, fever and diarrhoea; some of these might be attributable to exposure to chloropicrin used as a sensory marker. Two epidemiological investigations of sulfuryl fluoride and methyl bromide fumigators have reported a small number of findings in the cohorts exposed to sulfuryl fluoride. Some of these findings appear to be related to physical activities associated with the fumigation process. Others present no clear pattern that can be attributed to the use of sulfuryl fluoride. In neither study was there any biomonitoring to assess exposure.

The Meeting concluded that the existing database on sulfuryl fluoride was adequate to characterize the potential hazards to fetuses, infants and children.

Toxicological evaluation

The Meeting established an ADI for sulfuryl fluoride of 0-0.01 mg/kg bw based on a NOAEC of 20 ppm (approximately equivalent to systemic exposure at 1.4 mg/kg bw per day) in both a 24-month study in rats exposed to sulfuryl fluoride by inhalation, on the basis of effects on the kidney, brain, bone and survival at 80 ppm, and the two-generation study of reproductive toxicity in rats exposed to sulfuryl fluoride by inhalation, on the basis of effects on the brain and body weight at 150 ppm, with a 100-fold safety factor. The Meeting noted that some of the end-points in the long-term study in rats, such as kidney toxicity, were consistent with the data on fluoride toxicity. The Meeting considered that the slight dental fluorosis seen at the toxicological NOAEC was not an adverse effect.

The Meeting noted that the residue resulting from sulfuryl fluoride fumigation of foodstuffs was primarily fluoride. The critical studies of toxicity with sulfuryl fluoride used inhalation exposures and while this would result in a significant systemic dose of fluoride, it was impossible to separate reliably the effects attributable to systemic exposure to fluoride with those attributable to gaseous sulfuryl fluoride. The Meeting did not receive any studies on fluoride that would enable it to derive reference values for fluoride. The Meeting concluded that the dietary intake of fluoride associated with the use of sulfuryl fluoride as a fumigant should be included in an overall assessment of fluoride from all sources. Upper levels for fluoride intakes have been proposed by a number of organizations^[14].

The Meeting established an ARfD of 0.3 mg/kg bw for sulfuryl fluoride based on a NOAEC of 300 ppm (approximately equivalent systemic exposure at 31 mg/kg bw per day) the highest concentration tested in a study of acute neurotoxicity in rats exposed to sulfuryl fluoride by inhalation, and a 100-fold safety factor. The Meeting noted that there was no clear evidence for acute systemic toxicity associated with sulfuryl fluoride. However, as the acute oral LD₅₀ was reported to be about 100 mg/kg bw, the Meeting agreed on the need to derive an ARfD. The Meeting concluded that the only appropriate study for deriving the ARfD was the study of acute neurotoxicity, although this was likely to result in a conservative assessment and was probably not relevant to intakes of fluoride ion as such from sulfuryl fluoride-treated commodities. The Meeting considered that the critical end-point of brain vacuolation, which had not been evaluated in this study, was not an acute effect based on its absence in the 2-week studies in dogs and rats.

A toxicological monograph was prepared.

Levels relevant to risk assessment

^a Highest concentration tested

Estimate of acceptable daily intake for humans

0-0.01 mg/kg bw

Estimate of acute reference dose

0.3 mg/kg bw

Information that would be useful for the continued evaluation of the compound

Studies with sulfuryl fluoride administered orally

Results from epidemiological, occupational health and other such observational studies of human exposures

Critical end-points for setting guidance values for exposure to sulfuryl fluoride

^a Highest concentration tested

RESIDUE AND ANALYTICAL ASPECTS

Sulfuryl fluoride is a post-harvest and structural fumigant for controlling a wide range of insect pests. Sulfuryl fluoride penetrates the insect's body through inhalation in actively respiring life stages or diffusion into the egg. It is a non-specific target poison acting by disrupting the glycolysis and citric acid cycles, thereby depriving the insect of the necessary energy for survival. Upon sulfuryl fluoride entering a target organism it is broken down to the insecticidally active fluoride anion which then inhibits the insect's metabolism. It is being evaluated for the first time by the 2005 JMPR.

Animal metabolism

No adequate animal metabolism study for sulfuryl fluoride was available.

Degradation in stored products

The metabolism/degradation of ³⁵S-labelled sulfuryl fluoride was studied after fumigation of a variety of food items.

Wheat flour was fumigated with ³⁵S- sulfuryl fluoride at 32 mg/L in a fumigation chamber under reduced pressure for 92 h at room temperature. The insoluble flour residue remaining after 80% ethanol extraction retained 24% of the radioactivity. Radiolabeled residues were characterized as anionic, and some of the radiolabeled residue was characterized as amino acids or soluble polypeptides. Sulfate is formed as a result of conventional hydrolysis of sulfuryl fluoride. This reaction proceeds stepwise, first to fluorosulfonic acid and then to the sulfate anion. An additional product of the breakdown of sulfuryl fluoride is inorganic fluoride.

Seven food items contained in open cups were fumigated with sulfuryl fluoride at 36 and 360 mg/L for 20 h in a chamber of 4.2 m³ volume. The food items included unbleached enriched wheat flour, dry dog food, non-fat dry milk, vegetable cooking oil, dried beef, Red Delicious Washington apples and snack cakes. Fluoride and sulfate residue levels were analysed at 1, 8, and 15 days after the treatment for both fumigation concentrations.

After the exposure to sulfuryl fluoride at 36 mg/L, fluoride residues found on the seven commodities ranged from approximately nil (for vegetable oil) to 170 mg/kg (for dried beef) at day one; 215 mg/kg (for dried beef) at day eight; and 216 (for dried beef) at day fifteen. Sulfate residues found on the seven commodities were up to 106 mg/kg at day one, 160 mg/kg at day eight and 189 mg/kg at day fifteen.

After exposure to sulfuryl fluoride at 360 mg/L, fluoride residues found on the seven commodities were up to 1300 mg/kg in dried beef at day one, 1200 mg/kg at day eight and 1200 mg/kg at day fifteen.

Any unreacted sulfuryl fluoride present in the matrix degrades to fluoride and sulfate as the terminal residues.

Environmental fate

Sulfuryl fluoride is a structural fumigant used only for post-harvest treatment. Since there are no uses on agriculture crops, an environmental fate study is not applicable.

Methods of analysis

The Meeting received separate methods for the analysis of sulfuryl fluoride and fluoride anion. It was concluded that adequate analytical methods exist both for the monitoring/enforcement of MRLs and for data gathering in fumigation facilities.

Gas chromatography with electron capture detection is suitable for the determination of sulfuryl fluoride residues in dried fruits, tree nuts, maize, wheat and rice commodities. A limit of quantification (LOQ) of 0.008 mg/kg was typically achieved.

The method for the analysis of fluoride anion uses aqueous extraction followed by use of a fluoride selective electrode. This method is suitable for the determination of fluoride in cereal grains, dried fruits and tree nuts. An LOQ of 0.2-2.4 mg/kg was typically achieved for fluoride ion.

No analytical methods were developed for animal tissue matrices.

Stability of pesticide residues in stored analytical samples

Residues of fluoride in maize, wheat grain, raisin, walnut, and maize meal are considered to be stable when stored at room temperature for at least 35 days, and when stored frozen at approximately -20 °C for at least 138 days. The exception is for wheat flour, which is stable for at least 104 days. No data on storage stability for sulfuryl fluoride was provided.

Definition of the residue

The degradation of sulfuryl fluoride results in the formation of sulfate and inorganic fluoride. Sulfate residues resulting from the degradation of sulfuryl fluoride are insignificant in comparison to naturally occurring levels.

Residue data revealed that sulfuryl fluoride could be present in a commodity following the 24 h aeration period. The measured levels of sulfuryl fluoride in small grains, grain process fractions, and in dried fruit were extremely low, except for maize oil. The sulfuryl fluoride retained on tree nuts was higher, but declined rapidly with time. With the possible presence of sulfuryl fluoride on a commodity following the 24 h aeration, sulfuryl fluoride was considered as suitable for monitoring purposes. Fluoride is ubiquitous in the environment and is not suitable as a residue for enforcement purposes.

Adequate analytical methods exist for the determination of fluoride and sulfuryl fluoride.

The Meeting concluded that the residue definition for monitoring/enforcement is "sulfuryl fluoride", and for dietary intake considerations "sulfuryl fluoride and fluoride ion" measured separately.

Results of the supervised trials on crops

Fumigation treatments in the supervised trials for cereals, dried fruits and tree nuts summarized in the following paragraphs represent a wide range of treatment rates, calculated as the product of fumigant Concentration (C) × Exposure Time (T) or CTP with either single or multiple applications, and residues determined at different PFIs (Post-Fumigation Intervals). Based on the maximum cumulative CTP of 1500 (or 1500 gram-hours per cubic metre given as g·h/m³ or mg·h/L), and the consideration of allowing a ± 25% GAP variation, residues generated from a single application at ± 25 GAP (1125-1875 CTP, or 1,125-1,875 mg·h/L or g·h/m³) will be used for MRL estimation and dietary risk assessment. Since sulfuryl fluoride (SF) residues are rapidly degraded to F^- (fluoride ion) after 24 h and the latter is stable in treated commodities, the Meeting decided that SF residues collected from 1 day PFI, and F^- residues collected at all PFIs would be used for MRL, STMR and HR estimations.

Cereals

The USA GAP specifies that for stored product pests a particular plant will be fumigated on a schedule from three times per year to once every few years at the maximum cumulative CTP of 1500 g h/m³, and the maximum cumulative CTP for vacuum fumigation of 200 g h/m³. In practice, stored cereal grains are likely to receive only one fumigation treatment. Sulfuryl fluoride residues reported in the following paragraphs were all from 1-day PFI, and were analysed immediately; fluoride residues were the highest residues from each sample irrespective of the PFI.

Barley

In trials matching USA GAP conducted in the USA, England, Germany, and Italy the sulfuryl fluoride (SF) residues were < 0.008 (4) mg/kg. Fluoride ion (F^-) residues in ranked order were: 2.8, 2.8, 3.1, 6.5, 7.1, 8.0, 10, 12, 18, 18, and 21 mg/kg.

Maize

In trials matching USA GAP conducted in the USA the SF residues were: < 0.008 (7), 0.02(2), and 0.03 mg/kg. F^- residues in ranked order were: 0.8, 0.9, 1.0, 1.2, 1.3, 1.4(4), 1.5, 1.6, 1.7, 1.9 and 2.3(3) mg/kg.

Oat

In seven trials matching USA GAP conducted in the USA, SF residues were < 0.008 (4) mg/kg. F^- residues in ranked order were: 7.0, 7.4, 7.5, 8.3, 9.2, 12, and 14 mg/kg.

Rice

In 19 trials matching USA GAP conducted in the USA, England, Italy, and Germany SF residues were < 0.008 (8) mg/kg. F^- residues were: 1.8, 2.0, 2.0, 2.0, 2.2, 2.2, 2.2, 2.4, 2.8, 3.6, 5.5, 6.2, 7.0, 7.3, 7.6, 7.9, 8.4, 11, and 15 mg/kg.

Wheat

In 52 trials matching USA GAP conducted in the USA, England, Italy, and Germany, SF residues in ranked order, were: < 0.008 (13), 0.01(3) and 0.03(2) mg/kg. F^- residues in ranked order were: 1.5, 1.8, 1.9(2), 2.0(3), 2.1(2), 2.2(2), 2.4, 2.6, 2.7, 2.9(2), 3.3, 3.4, 3.8, 3.9(2), 4.2, 4.5, 4.7, 4.8(3), 4.9, 5.0, 5.7, 5.8, 5.9, 6.1, 6.2, 9.2(2), 12 and 14(2) mg/kg.

The Meeting noted that maize, rice, and wheat along with barley and oats represent major commercial cereal grain commodities. Since residues of sulfuryl fluoride and fluoride ion among the five cereal commodities are comparable (< 0.008-0.03 mg/kg for sulfuryl fluoride, and 0.8-21 mg/kg for fluoride ion), a group MRL and STMR may be estimated for cereal grains. Overall, a total of 44 SF residues in ranked order, were: < 0.008 (36), 0.01(3), 0.02(2) and 0.03(3) mg/kg. A total of 92 F^- residues in ranked order were: 0.8, 0.9, 1.0, 1.2, 1.3, 1.4(4), 1.5(2), 1.6, 1.7, 1.8(2), 1.9(3), 2.0(6), 2.1(2), 2.2(5), 2.3(3), 2.4(2), 2.6, 2.7, 2.8(3), 2.9(2), 3.1, 3.3, 3.4, 3.6, 3.8, 3.9(2), 4.2, 4.5, 4.7, 4.8(2), 4.8, 4.9, 5.0, 5.5, 5.7, 5.8, 5.9, 6.1, 6.2(2), 6.5, 7.0(2), 7.1, 7.3, 7.4, 7.5, 7.6, 7.9, 8.0, 8.3, 8.4, 9.2(3), 10, 11, 12(3), 14(3), 15, 18(2) and 21 mg/kg.

The Meeting estimated a maximum residue level of 0.05 mg/kg, an HR of 0.03 mg/kg, and an STMR of 0.008 mg/kg for sulfuryl fluoride; and estimated an HR of 21 mg/kg and an STMR of 3.5 mg/kg for fluoride ion for cereal grains.

Cereal grain milling fractions and milled cereal products

Maize flour

In trials matching USA GAP conducted in the USA, England, Germany, and Italy the SF residues were < 0.008 (2) mg/kg. F^- residues in ranked order were: 14, 19(2), 24, 37, 56 and 70 mg/kg.

Maize meal

Two trials were conducted in the USA at higher than USA GAP rate. SF residues were < 0.008 mg/kg; F^- residues were 5.6 and 6.3 mg/kg.

Rice bran

Two trials were conducted in the USA at higher than USA GAP rate. SF residues were < 0.008 mg/kg; F^- residues were 24.2 and 28.5 mg/kg.

Rice polished

Two trials were conducted in the USA at higher than USA GAP rate. SF residues were < 0.008 mg/kg; F^- residues were 1.5 and 1.6 mg/kg.

Wheat bran

In four trials matching USA GAP conducted in the USA the SF residues were < 0.008 mg/kg (4). F^- residues in ranked order were 34, 36 and 37(2) mg/kg.

Wheat flour

In 32 trials matching USA GAP conducted in the USA, England, Germany, and Italy, SF residues in ranked order were all < 0.008 (10) mg/kg. F^- residues in ranked order were: 15, 16, 19, 21, 22, 26, 26, 28, 29, 33, 34(2), 35, 37(2), 38(2), 40, 41, 43(2), 45, 51 and 55 mg/kg.

Wheat germ

In 20 trials matching USA GAP conducted in the USA, SF residues were all < 0.008 (10) mg/kg. F^- residues were: 17, 19, 42, 44, 54, 55, 59(3), 66, 72, 73, 82, 83, 84 (2) 88, 90 and 104 mg/kg.

Residue data was insufficient for estimating maximum residue levels and STMRs for rice bran, rice polished, maize starch, maize meal, maize grits, and rice bran individually. However, group MRLs and STMRs may be estimated for the members of the Codex commodity group's cereal grain milling fractions and milled cereal products, utilizing the data from rice bran and rice polished trials for milled cereal products; and maize flour, maize meal, wheat bran, wheat flour and wheat germ trials for cereal grain milling fractions.

Overall, a total of 30 SF residues in ranked order, were: < 0.008 (29) and 0.06 mg/kg. A total of 58 F^- residues in ranked order were: 3.9, 5.4, 5.6, 14, 15, 16, 17, 19(4), 21, 22, 24(2), 26(2), 28, 29, 33, 34(3), 35, 36, 37(5), 38(2), 40, 41, 42, 43(2), 44, 45, 51, 54, 55(2), 56, 59(3), 66, 70, 72, 73, 82, 83, 84(2), 88, 90.3 and 104 mg/kg. The Meeting estimated maximum residue levels of 0.1 mg/kg, HRs of 0.06 mg/kg, and STMRs of 0.008 mg/kg for sulfuryl fluoride in cereal grain milling fractions and milled cereal products; and estimated an HR of 104 mg/kg and a STMR of 37 mg/kg for fluoride in both cereal grain milling fractions and milled cereal products.

Dried Fruits

For fumigation of stored dried fruits and tree nuts commodities the US EPA specifies that the maximum cumulative CTP is 1500 g h/m³ and the maximum cumulative CTP for vacuum fumigation is 200 g h/m³. In practice, stored dried fruits can be treated as many as four times with fumigation at a maximum cumulative CTP of 1500 g h/m³. Sulfuryl fluoride residues reported in the following paragraphs were all from a 1 day PFI, analysed immediately after sample collection; F^- residues were the highest residues from each sample.

Dates

In two trials matching USA GAP conducted in the USA, SF residues were 0.007(2) mg/kg. F^- residues were not detected (< 2.4 mg/kg).

Figs

In two trials matching USA GAP conducted in the USA, SF residues were 0.03 and 0.04 mg/kg. F^- residues were < 2.4(2) mg/kg.

Dried plum

In two trials matching USA GAP conducted in the USA, SF residues were not detected (< 0.0042 mg/kg). F^- residues were also not detected (< 2.4 mg/kg LOQ).

Raisin

Eight post-harvest fumigation trials conducted in the USA were all at above GAP rates. SF residues were not detected (< 0.0042 mg/kg) (4) mg/kg. F^- residues were below the LOQ: < 2.2 mg/kg (2) and < 2.4(2) mg/kg.

Data was insufficient to estimate maximum residue levels or STMRs on each commodity individually; however, since residues of sulfuryl fluoride and fluoride ion on each commodity from limited fumigation trials are comparable and consistent (< 0.0042-0.04 mg/kg for sulfuryl fluoride, and < 2.2-< 2.4 mg/kg for fluoride ion), a crop group MRL and STMR may be estimated. SF residues from the four dried fruits were < 0.004 (6), 0.007(2), 0.03 and 0.04 mg/kg. F^- residues were: < 2.2(2) and < 2.4 (8) mg/kg. The Meeting estimated an MRL of 0.06 mg/kg, an HR of 0.04 mg/kg, and an STMR of 0.004 mg/kg for sulfuryl fluoride; and estimated an HR of 2.4 mg/kg and an STMR of 2.4 mg/kg for fluoride ion in dried fruits.

Tree Nuts

For fumigation of stored dried fruits and tree nuts commodities the US EPA specifies that the maximum cumulative CTP is 1500 g h/m³ and the maximum cumulative CTP for vacuum fumigation is 200 g h/m³. In practical terms, stored tree nuts can receive as many as four fumigation treatments at a maximum cumulative CTP of 1500 g h/m³. Sulfuryl fluoride residues reported in the following paragraphs were all from a 1 day PFI, analysed immediately after sample collection; fluoride ion residues were the highest residues from each sample.

Almonds

In four trials matching USA GAP conducted in the USA, SF residues were 0.01, 0.02, 0.03, 0.04 mg/kg. F^- residues were: < 2.4(2), 4.3 and 5.0 mg/kg.

Pecans

In four trials matching USA GAP conducted in the USA, SF residues were: 1.1, 1.2, 2.3 and 2.5 mg/kg. F^- residues were < 2.4(2), 8.0 and 9.1 mg/kg.

Pistachios

In four trials matching USA GAP conducted in the USA, SF residues were: 0.01, 0.02, 0.27, 0.29 mg/kg. F^- residues were < 2.4(2) and 4.1(2) mg/kg.

Walnuts

In two trials at above USA GAP conducted in the USA, SF residues were 0.58 and 0.63 mg/kg. F^- residues were < 2.4(2) mg/kg.

Since residues of sulfuryl fluoride and fluoride ion on the four commodities tested are comparable (0.01-2.5 mg/kg for sulfuryl fluoride, and < 2.4-9.1 mg/kg for fluoride ion), a crop group MRL and STMR may be estimated. Overall, SF residues from the four tree nuts commodities, in ranked order, were 0.01(2), 0.02(2), 0.03, 0.04, 0.27, 0.29, 0.58, 0.63, 1.1, 1.2, 2.3 and 2.5 mg/kg. F^- residues from the four tree nuts commodities, in ranked order, were: < 2.4 (8), 4.1)2), 4.3, 5.0, 8.0 and 9.1 mg/kg. The Meeting estimated a maximum residue level of 3.0 mg/kg, an HR of 2.5 mg/kg and an STMR of 0.28 mg/kg for sulfuryl fluoride; and estimated an HR of 9.1 mg/kg and an STMR of 2.4 mg/kg for fluoride for tree nuts except coconuts.

Fate of residues in storage and processing

In storage

Sulfuryl fluoride rapidly degrades to fluoride under typical GAP conditions. No significant decline in the residue of fluoride was observed for the maize grain and wheat grain for 138 days, raisin and walnut for 141 days, and maize meal for 140 days of storage after treatment with sulfuryl fluoride. At present, sulfuryl fluoride is only registered for use on stored (i.e. post-harvest) food commodities. Sulfuryl fluoride is unstable and readily desorbs from the commodity or degrades under storage conditions, yielding fluoride and sulfate as the terminal residues.

In processing

Post-harvest fumigation on whole grain wheat and kernel maize was conducted to determine the fate of incurred residues of sulfuryl fluoride during the processing of the grain. Whole grain wheat and kernel maize were fumigated at 1787 mg·h/L and 1565 mg·h/L, respectively. The fumigated grain samples were then processed, and the control and treated processed samples, wheat flour, shorts, bran, middlings, impurities and germ, and maize flour, meal, grits, oil impurities, oil wet and starch (wet) were analysed. The LOQs were 0.6 mg/kg (fluoride) for whole wheat grain and maize grain; 0.3 mg/kg for wheat flour, shorts, middlings and impurities, maize meal, grits and oil; and 0.8 mg/kg for wheat germ and bran, and maize impurities; 0.4 mg/kg for maize starch; and 0.5 mg/kg for maize flour.

The processing of sulfuryl fluoride-fumigated whole grain wheat, containing fluoride ion at a concentration of 1.19 mg/kg, yielded flour, shorts, bran, middlings, impurities and germ containing fluoride at concentrations of 0.45, 1.50, 3.05, 0.72, 1.07, and 5.74 mg/kg, respectively. The elevated fluoride ion levels in wheat germ and wheat bran indicate that fluoride ion selectively accumulates in those grain fractions. The processing of fumigated whole grain maize, containing fluoride ion at a concentration of 1.76 mg/kg, produced flour, meal, grits and impurities containing fluoride ion at concentrations of 1.29, 1.37, 0.83, and 9.67 mg/kg, respectively. Thus, the maize impurities were the only fraction where it appears that fluoride ion concentrates.

Supervised fumigation trials conducted in food storage facilities on processed cereal grain commodities resulted in higher fluoride residues than those from processing studies, where the whole grains were fumigated and then processed. As a consequence, the higher residues values (HR) are derived from direct treatment rather than from the processing of the raw agricultural products, viz grains.

Farm animal feeding studies

No animal feeding studies were submitted.

Farm animal dietary burden

The Meeting considered the dietary burden for fluoride resulting from feeding treated commodities to dairy cattle and poultry. No animal dietary burden for sulfuryl fluoride could be estimated since no data was submitted.

Estimated maximum dietary burden of farm animals

Estimated median dietary burden of farm animals

The calculated dietary burden for estimation of maximum residue level was 28.9 ppm for beef cattle, 30.7 ppm for dairy cattle and 28.5 ppm for poultry. The calculated dietary burden of fluoride for estimation of STMR level was 21.1 ppm for beef cattle, 24.2 ppm for dairy cattle and 15.6 ppm for poultry. No recommendation for maximum residues level in animals could be made since adequate feeding studies were not submitted.

DIETARY RISK ASSESSMENT

Long-term intake

The evaluation of sulfuryl fluoride resulted in recommendations for MRLs and STMR values for raw and processed commodities. Data on consumption were available for 18 food commodities and were used to calculate dietary intake. The results are shown in Annex 3.

The IEDIs in the five GEMS/Food regional diets, based on estimated STMRs were 1% of the maximum ADI of 0.01 mg/kg bw. The Meeting concluded that the long-term intake of residues of sulfuryl fluoride from uses that have been considered by the JMPR is unlikely to present a public health concern.

The Meeting concluded that the dietary intake of fluoride associated with the use of sulfuryl fluoride as a fumigant (range of 7-15 mg/person/day across the five GEMS/Food regional diets) should be included in an overall assessment of fluoride from all sources. Upper levels for fluoride intakes have been proposed by a number of organizations. The dietary risk assessment for fluoride from fumigant use needs to be considered in light of the overall exposure to fluoride from other sources and FAO and WHO are requested to further investigate how this issue can be addressed at an international level.

Short-term intake

The IESTI of sulfuryl fluoride calculated on the basis of the recommendations made by the JMPR represented 0-3% of the ARfD (0.3 mg/kg bw) for children and 0-5% for the general population. The Meeting concluded that the short-term intake of residues of sulfuryl fluoride on commodities that have been considered by the JMPR is unlikely to present a public health concern.