Using existing knowledge for the risk evaluation of crop protection products in order to guide exposure driven data generation strategies and minimise unnecessary animal testing

Figures & data

Table 1. Use scenarios for exposure prediction and risk evaluation.

Crop use scenario	Max dose product & application method	Max no. of apps	Min treatment interval	Latest time of application	Product
Fungicide used on soya bean rust & white mould in USA 41% g/L SC	Asian rust − 2.5 − 3.0 fl oz/A (0.078–0.094 lbs a.i./A). Minimum 2 gpa for aerial application, minimum of 10 gpa by ground sprayer White mould − 3.0–5.0 fl oz/A (0.094–0.156 lbs a.i./A). Minimum of 5 gpa for aerial application minimum of 10 gpa by ground sprayer	3	10–21 days	21 days pre-harvest	Proline^® 480 SC Fungicide – Prothioconazole
Insecticide used on sweetcorn against earworm, rootworm, beetles, cutworm on in the USA Product − 90% w/w SP in water soluble bags	0.25–0.5 lbs a.i./A. Mechanical ground overhead sprinkler or aerial application only; hand-held not allowed. Low volume aerial spray at minimum of 1gpa	28 Do not apply more than 7 lbs a.i./A/crop	1 day	0 days ears 3 days forage 21 days stover	Annihilate^TM SP Insecticide – Methomyl
Non-selective pre- and post-emergence herbicide use on cotton in USA 33.6% (3.2 lb ai per gal)	Ground application: low pressure boom mounted sprayer, minimum of 10 gpa or 20–40 gpa under heavy weed pressure Aerial – minimum of 3 gpa. Pre-emergence − 1.3–2.1 fl oz/A Post emergence − 2.6–3.8 fl oz/A	None stated Do not exceed 5.1 fl oz/A/y	7 days	60 days pre-harvest	DuPont^TM Staple® LX – Pyrithiobac sodium
Fungicide on winter and spring wheat in EU Product − 250 g/L SC (circa 23.1% w/w)	1 L/ha At least 200 L/ha Horizontal boom sprayer	2 Max dose applied must be <500 g a.s./ha/year	14 days	GS71 – before water ripe stage	Amistar^® – Azoxystrobin

SC: suspension concentrate; fl oz: fluid ounces; lb a.i./A: pounds active ingredient per acre; gpa: gallons per acre; fl oz/A: fluid ounces per acre; lb a.i./A: pounds active ingredient per acre; SP: soluble powder; g/L: grams per litre; L/ha: litres per hectare; g a.s./ha/year: kilograms active substance per hectare per year; GS71: growth stage 71.

Table 2. Use scenarios evaluated for SDHI fungicides.

Crop use scenario	Max dose product & application method	Max no. of apps	Min treatment interval	Latest time of application	Product
SDHI Fungicide use on stone fruit for Blossom blight, Brown rot in the USA 400 g/L SC	12.5 fl oz (0.326 lb. a.i. /A) Spray volume will usually be 100–200 gallons per acre.	3 (37.5 fl oz/A/year (0.978 lb. a.i./A/year)	14 days	1 day pre-harvest interval	ISK Biosciences Isofetamid 400 SC Fungicide
SDHI Fungicide use on Canola for Sclerotinia stem rot in the USA 40 g/L SC	10.25–12 fl oz (0.267–0.312 lb. a.i./A) Spray volume 50–100 gallons per acre for dilute sprays and 5–10 gallons per acre for aerial sprays. For aerial apply in a minimum of 5 gallons of water per acre.	2 (24 fl oz/A/year (0.63 lb. a.i./A/year)	7 days	First treatment at 20–40% flowering (BBCH 62–64); if required second treatment near end of flowering (BBCH 67–69)	ISK Biosciences Isofetamid 400 SC Fungicide
SDHI Fungicide use on wheat in the EU 62.5 g/l SC	100–300 L/ha 0.0417- 0.125 kg a.s./ha/L 0.125 kg a.s./ha	2	21 days	35 days pre-harvest interval	Fluxapyroxad 62.5 g/l SC In combination with epoxiconazole 62.5 g/l SC BASF Adexar^®

SDHI: Succinate Dehydrogenase Inhibitors; g/L: grams per litre; SC: suspension concentrate; fl oz: fluid ounces; lb a.i./A: pound active ingredient per acre; fl oz/A/year: fluid ounces per acre per year; lb. a.i./A/year: pounds active ingredient per acre per year; BBCH: Biologische Bundesanstalt,Bundessortenamt and Chemical Industry; L/ha: litres per hectare; kg a.s./h/L: kg active substance per hectare per litre; kg a.s./ha: kilograms active substance per hectare.

Table 3. Proposed approach to judge the acceptability of risk based on comparison of predicted exposure with the reference dose range distribution.

Exposure estimate	Judgement on acceptability of risk
Exposure below 5^th percentile of reference dose range	High likelihood to pose no unacceptable risk
Exposure 5–25^th percentile of reference dose range	Likely to pose no unacceptable risk
Exposure within 25^th–50^th percentile of reference dose range	Reasonably likely to pose no unacceptable risk – refine
Exposure within 50^th–75^th percentile of reference dose range	Risk potentially unacceptable – refine
Exposure >75^th percentile of reference dose range	Risk likely to be unacceptable – refine
Exposure >95^th percentile of reference dose range	Risk highly likely to be unacceptable – refine

Green = low risk as reference dose is lower than exposure; Orange = moderate risk as reference dose is approaching exposure; Red = high risk as reference dose is greater than exposure.

Figure 1. Outline of approach to exposure and hazard prediction for risk evaluation. POD: point of departure; RfD: reference dose; GAP: good agricultural practice; MOA: mode of action.

Table 4. Range of Acute Reference Dose (aPAD or ARfD) Values from US EPA, JMPR and the EU.

	US EPA aPAD (mg/kg bw/day)	JMPR ARfD (mg/kg bw/day)	EU ARfD (mg/kg bw/day)
Fungicides
n	36	26	51
Minimum	0.01	0.05	0.004
5^th Percentile	0.02	0.053	0.02
25^th Percentile	0.095	0.1	0.05
50^th Percentile	0.2	0.3	0.18
75^th Percentile	0.54	0.58	0.3
95^th Percentile	2	0.95	0.83
Maximum	2.5	3.0	1.8
Insecticides
n	34	36	48
Minimum	0.00032	0.0003	0.001
5^th Percentile	0.0007	0.003	0.0034
25^th Percentile	0.0019	0.02	0.012
50^th Percentile	0.006	0.05	0.043
75^th Percentile	0.095	0.2	0.15
95^th Percentile	1.0	1.0	1.0
Maximum	2.0	2.0	2.0
Herbicides
n	14	7	30
Minimum	0.03	0.08	0.01
5^th Percentile	0.037	0.15	0.023
25^th Percentile	0.063	0.4	0.068
50^th Percentile	0.27	0.5	0.3
75^th Percentile	0.5	0.75	0.5
95^th Percentile	1.0	1.7	1.0
Maximum	1.0	2.0	2.0
SDHI
n	8	5	10
Minimum	0.1	0.1	0.1
5^th Percentile	0.17	0.12	0.15
25^th Percentile	0.3	0.2	0.23
50^th Percentile	0.4	0.3	0.4
75^th Percentile	1.06	0.5	0.5
95^th Percentile	2.06	0.9	0.9
Maximum	2.5	1.0	1.0

ARfD: acute reference dose; aPAD: acute population adjusted dose; n: number; SDHI: Succinate Dehydrogenase Inhibitors.

Table 5. Range of chronic reference dose (cPAD or ADI) values from US EPA, JMPR and the EU.

	US EPA cPAD (mg/kg bw/day)	JMPR ADI (mg/kg bw/day)	EU ADI (mg/kg bw/day)
Fungicides
n	59	39	73
Minimum	0.0004	0.004	0.002
5^th Percentile	0.0049	0.0059	0.0052
25^th Percentile	0.018	0.025	0.015
50^th Percentile	0.055	0.06	0.04
75^th Percentile	0.265	0.16	0.1
95^th Percentile	0.79	0.46	1.0
Maximum	2.5	1.0	10
Insecticides
n	52	48	62
Minimum	0.00012	0.0005	0.0005
5^th Percentile	0.00028	0.0024	0.001
25^th Percentile	0.0025	0.01	0.01
50^th Percentile	0.013	0.02	0.017
75^th Percentile	0.03	0.053	0.034
95^th Percentile	0.089	0.23	0.1
Maximum	1.58	2.0	1.56
Herbicides
n	32	11	47
Minimum	0.0032	0.0007	0.0004
5^th Percentile	0.005	0.005	0.003
25^th Percentile	0.025	0.03	0.01
50^th Percentile	0.1	0.09	0.07
75^th Percentile	0.28	0.2	0.13
95^th Percentile	1.1	0.7	0.44
Maximum	1.25	0.9	2.0
SDHI
n	15	10	13
Minimum	0.01	0.02	0.008
5^th Percentile	0.01	0.02	0.0152
25^th Percentile	0.03	0.043	0.02
50^th Percentile	0.092	0.055	0.04
75^th Percentile	0.27	0.0975	0.09
95^th Percentile	0.58	0.1055	0.11
Maximum	0.77	0.11	0.12

ADI: acceptable daily intake; cPAD: chronic population adjusted dose; n: number; SDHI: Succinate Dehydrogenase Inhibitors.

Table 6. Range of occupational reference values from US EPA and the EU.

	EPA OEL Inhalation (mg/kg bw/day)	EPA OEL Dermal (mg/kg bw/day)	EU AOEL Systemic (mg/kg bw/day)
Fungicides
n	50	29	73
Minimum	0.000052	0.004	0.001
5^th Percentile	0.00072	0.0056	0.0058
25^th Percentile	0.01	0.016	0.02
50^th Percentile	0.06	0.13	0.05
75^th Percentile	0.36	0.31	0.15
95^th Percentile	1.43	2.8	1.0
Maximum	4	4	5.0
Insecticides
n	51	31	61
Minimum	0.000013	0.00016	0.0003
5^th Percentile	0.0001	0.0018	0.001
25^th Percentile	0.0018	0.00945	0.0075
50^th Percentile	0.015	0.033	0.016
75^th Percentile	0.066	0.09	0.036
95^th Percentile	0.34	0.98	0.1
Maximum	0.87	5.0	0.36
Herbicides
n	29	11	47
Minimum	0.0033	0.005	0.0006
5^th Percentile	0.005	0.006	0.005
25^th Percentile	0.021	0.032	0.02
50^th Percentile	0.12	0.3	0.1
75^th Percentile	0.75	0.363	0.17
95^th Percentile	1.44	1.39	0.42
Maximum	2.0	1.59	0.8
SDHI
n	13	6	13
Minimum	0.0145	0.129	0.04
5^th Percentile	0.0188	0.151	0.04
25^th Percentile	0.055	0.229	0.05
50^th Percentile	0.129	0.31	0.1
75^th Percentile	0.36	0.69	0.13
95^th Percentile	0.78	2.45	0.392
Maximum	0.8	3	0.56

OEL: occupational exposure limit; AOEL: acceptable occupational exposure level; n: number; SDHI: Succinate Dehydrogenase Inhibitors

Table 7. Basis for acute reference doses (ARfD) set by US EPA and EU commission for SDHI fungicides.

Active substance	EU ARfD	EU UF	EU NOAEL	EU LOAEL	Study type	US ARfD	US aPAD	US UF	US NOAEL	US LOAEL	Study type
Benzovindiflupyr	0.1	100	10	30	Acute neurotoxicity	0.1	0.1	100	10	30	Acute neurotoxicity
Bixafen	0.2	100	20	75	Rat and rabbit developmental toxicity; maternal and developmental	2.5	2.5	100	250	1000	Acute neurotoxicity
Carboxin	Not required – no acute endpoint					Not required – no acute endpoint
Fluopyram	0.5	100	50	2000	Acute neurotoxicity	0.5	0.5	100	50	100	Acute neurotoxicity
Flutolanil	0.5	100	50	125	Acute neurotoxicity	Not required – no acute endpoint
Fluxapyroxad	Not required – no acute endpoint					Not required – no acute endpoint
Inpyrfluxam	Not required – no acute endpoint					0.3	0.3	100	30	100	Acute neurotoxicity
Isofetamid	1.0	100	100	300	Rabbit developmental toxicity, maternal and offspring	Not required – no acute endpoint
Isopyrazam	0.2	100	20	75	Rat developmental toxicity; maternal	0.3	0.3	100	30	100	Clinical signs 90 day dog
Penflufen	0.5	100	50	100	Acute neurotoxicity	0.5	0.5	100	50	100	Acute neurotoxicity
Penthiopyrad	0.75	100	75	225	Rabbit developmental toxicity; maternal	1.25	1.25	100	125	500	Acute neurotoxicity
Pydiflumetofen	0.3	100	30	100	Developmental toxicity study in rats, maternal	1.0	1.0	100	100	300	Acute neurotoxicity
Sedaxane	0.3	100	30	250	Acute neurotoxicity	0.3	0.3	100	30	250	Acute neurotoxicity

aRfD: acute reference dose; SDHI: Succinate Dehydrogenase Inhibitors; UF: uncertainty factors; NOAEL: no observed adverse effect level; LOAEL: lowest observed adverse effect concentration; aPAD: acute population adjusted dose.

Table 8. Basis for chronic reference doses (ADI/cPAD) set by US EPA and EU commission for SDHI fungicides.

Active substance	EU ADI	EU UF	EU NOAEL	EU LOAEL	EU Effects at LOAEL	US cRfD	US cPAD	US UF	US NOAEL	US LOAEL	US Effects at LOAEL
Benzovindiflupyr	0.05	100	4.9	27.4	2 year rat study – bwt and liver	0.082	0.082	100	8.2	19.4	2‐Gen repro in rat -↓ bwt and food consumption, liver, pars distalis of the pituitary, delayed PPS
Bixafen	0.02	100	2	12.1	2 year rat –↑liver wt and CL hypertrophy, thyroid colloid alteration	0.03	0.03	100	2.8	17.4	2 year rat – thyroid follicular cell hypertrophy & alteration colloid
Boscalid	0.04	100	4.4	22	2 year rat – liver with clin chem and haemo changes	0.218	0.218	100	21.8	57	2 year rat – and 1-year dog studies, based on liver and thyroid effects.
Carboxin	0.008	100	0.82	8.7	2 year rat – kidney and bone	0.01	0.01	100	1	9	2 year rat – ↓ bwt, kidney
Fluopyram	0.012	100	1.2	8.6	2 year rat – liver, thyroid kidney, eye	0.012	0.012	100	1.2	6	2 year rat – thyroid, liver
Flutolanil	0.09	100	8.7	87	2 year rat – spleen	0.5	0.5	100	50	250	2-year dog – GIT
Fluxapyroxad	0.02	100	2.1	11	2 year rat – liver, incisor whitening	0.02	0.02	100	2.1	11	2 year rat – liver
Inpyrfluxam	Not evaluated					0.3	0.26	100	26	86	2‐Gen repro in rat – thyroid and ↓ pup weights
Isofetamid	0.02	100	1.57	5.34	1 year study in dogs – ↓ bwt	0.77	0.77	100	76.6	679	2‐Gen repro in rat – liver, thyroid & spleen
Isopyrazam	0.03	200	None	5.5	2 year rat – liver & ↓ bwt	0.055	0.055	100	5.5	27.6	2 year rat – ↓bwt liver and bile duct
Oxycarboxin	Not evaluated					0.01	0.01	100	1	9	2 year rat – ↓bwt clin chem & kidney
Penflufen	0.04	100	4	79	2 year rat- liver and thyroid	0.38	0.38	100	38	357	1 year dog – ↓bwt liver, thyroid and adrenal
Penthiopyrad	0.1	100	11	54	2‐Gen repro in rat – ↓bwt, liver thyroid and adrenal	0.27	0.27	100	27	83	2 year rat – ↓bwt, liver, thyroid & adrenal
Pydiflumetofen	0.09	100	9.2	45	18 month mouse – liver	0.092	0.092	100	9.2	45.4	18 month mouse – liver
Sedaxane	0.11	100	11	67	2 year rat – ↓bwt, liver & thyroid	0.11	0.11	100	11	67	2 year rat – ↓hind limb grip strength, liver and thyroid

ADI: Acceptable Daily Intake; SDHI: Succinate Dehydrogenase Inhibitors; UF: uncertainty factors; NOAEL: no observed adverse effect level; LOAEL: lowest observed adverse effect concentration; cRfD: chronic reference dose; cPAD: chronic population adjusted dose; Bwt: body weight; wt: weight; CL: centrilobular; haemo: haematology; GIT: gastrointestinal tract; GEN: generation; repro: reproductive; clin chem: clinical chemistry; PPS preputial separation.

Table 9. Summary of range of exposure estimates for use scenario in USA – most sensitive population for acute and chronic dietary exposure estimates based on surrogate compounds.

Use scenario	Exposure duration	Exposure just from tolerance (mg/kg/day)	Exposure from estimated drinking water concentrations (mg/kg/day)	Dietary exposure from tolerance + EDWCs (mg/kg/day)	Dietary exposure (EPA Aggregate: All food + EDWC) (mg/kg/day)
Fungicide on soya bean	Acute	0.000184 − 0.001843	0.001908–0.056591	0.002271–0.057466	0.009120–0.269743
	Chronic	0.000099–0.000993	0.000353–0.015245	0.000544–0.015691	0.00036–0.027728
Insecticide on sweet corn	Acute	0.000062–0.000310	0.000155–0.204459	0.000375–0.204431	0.001938–0.029784
	Chronic	0.000008–0.000040	0.000020–0.015623	0.000040–0.015625	0.000214–0.12812
Herbicide on cotton	Acute	0.000003–0.000602	0.000027–0.090911	0.000606–0.090861	0.001215–0.009345
	Chronic	0.000001- 0.000238	0.000011–0.010717	0.000242–0.032681	0.000558–0.023934
SDHI on stone fruit	Acute	0.006711–0.026843	0.003843–0.242795	0.007897–0.245468	0.008803–0.257324
	Chronic	0.000834–0.004172	0.000120–0.073812	0.002029–0.077149	0.000983–0.079019
SDHI on canola	Acute	0.000020–0.000650	0.000650–0.024097	0.006927–0.024110	0.008135–0.255856
	Chronic	0.000007–0.000223	0.000223–0.052604	0.002651–0.052638	0.008007–0.126264

EDWC: Estimated Drinking Water Concentration; SDHI: Succinate Dehydrogenase Inhibitors.

Table 10. Acute and chronic exposure estimates for EU use scenario on wheat.

Active substance	Acute risk assessment		Chronic risk assessment
	Exposure (mg/kg bw/day)	Most sensitive population	Exposure (mg/kg bw/day)	Critical diet
Azoxystrobin	n/a (not acutely toxic)	n/a (not acutely toxic)	0.00058	GEMS/Food G06
Dimoxystrobin	0.00072	UK child 4–6 years	0.00036	GEMS/Food G06
Fluoxastrobin	0.00029	UK child 4–6 years	0.00014	GEMS/Food G06
Penthiopyrad	0.00029	UK child 4–6 years	0.00014	GEMS/Food G06
Prothioconazole	0.00029	UK child 4–6 years	0.00014	GEMS/Food G06
Pyraclostrobin	0.00029	UK child 4–6 years	0.00014	GEMS/Food G06
Trifloxystrobin	0.00043	UK child 4–6 years	0.00022	GEMS/Food G06
Exposure range (mg/kg bw/day)	0.00029–0.00072		0.00014–0.00058

Table 11. Acute and chronic exposure estimates for EU use scenario for SDHI on wheat.

Active substance	Acute risk assessment		Chronic risk assessment
	Exposure (mg/kg bw/day)	Most sensitive population	Exposure (mg/kg bw/day)	Critical diet
Bixafen	0.00029	UK child 4–6 years	0.00014	GEMS/Food G06
Cyproconazole	0.00014	UK child 4–6 years	0.000072	GEMS/Food G06
Epoxiconazole	0.00058	UK child 4–6 years	0.00029	GEMS/Food G06
Famoxadone	0.00029	UK child 4–6 years	0.00014	GEMS/Food G06
Fluopyram	0.00014	UK child 4–6 years	0.000072	GEMS/Food G06
Flutriafol	0.00029	UK child 4–6 years	0.00014	GEMS/Food G06
Fluxapyroxad	0.00043	UK child 4–6 years	0.00022	GEMS/Food G06
Isopyrazam	0.00053	UK child 4–6 years	0.00026	GEMS/Food G06
Kresoxim-methyl	n/a (not acutely toxic)	n/a (not acutely toxic)	0.00087	GEMS/Food G06
Metrafenone	n/a (not acutely toxic)	n/a (not acutely toxic)	0.000072	GEMS/Food G06
Exposure range (mg/kg bw/day)	0.00014–0.00058		0.000072–0.00087

SDHI: Succinate Dehydrogenase Inhibitors.

Table 12. Occupational exposure estimates for USA use scenarios.

Scenario	Application rate (lb ai/A)	Area treated or amount handled per day (Acres)	Unit exposure		^aExposure (mg/kg bw/day)
			Dermal (Single Layer, Gloves)	Inhalation (No Respirator)	Dermal	Inhalation
Fungicide on soya bean – aerial
Mixing/Loading	0.094	350	37.6	0.219	0.0155	0.00009
Applicator	0.094	350	2.08	0.0049	0.00086	0.000002
Flagger	0.094	350	12	0.35	0.0049	0.00014
Fungicide on soya bean – ground boom
Mixing/Loading Liquids	0.094	200	37.6	0.219	0.0088	0.0000515
Applicator	0.094	200	16.1	0.34	0.0038	0.00008
Insecticide on sweet corn – aerial
Mixing/Loading	0.500	350	37.6	0.219	0.0823	0.000479
Applicator	0.500	350	2.08	0.0049	0.0046	0.0000107
Flagger	0.500	350	12	0.35	0.0263	0.00077
Insecticide on sweet corn – airblast
Mixing/Loading	0.500	200	37.6	0.219	0.0470	0.0002738
Applicator	0.500	200	1590	4.71	1.9875	0.00589
Herbicide on cotton – aerial
Mixing/Loading	0.095	350	37.6	0.219	0.0156	0.000091
Applicator	0.095	350	2.08	0.0049	0.0009	0.0000020
Flagger	0.095	350	12	0.35	0.0050	0.00015
Herbicide on cotton – ground boom
Mixing/Loading	0.095	200	37.6	0.219	0.0089	0.0000520
Applicator	0.095	200	16.1	0.34	0.0038	0.00008

lb ai/A: pounds active ingredient per acre.

^aDermal absorption was assumed to be 100% and body weight assumed to be 80 kg.

Table 13. Acute and long-term occupational exposure estimates for EU fungicide use scenario on wheat.

Application method	Exposed group	PPE	Systemic exposure (mg/kg bw/day)
Acute exposure
Field crop sprayer	Operator	No	0.0086
Field crop sprayer	Operator	Yes	0.0015
Field crop sprayer	Bystander child	No	0.0011
Field crop sprayer	Bystander adult	No	0.0002
Long-term exposure
Field crop sprayer	Operator	No	0.0021
Field crop sprayer	Operator	Yes	0.0003
Field crop sprayer	Worker	No	0.0003
Field crop sprayer	Worker	Yes	*Estimate not available
Field crop sprayer	Resident child	No	0.0018
Field crop sprayer	Resident adult	No	0.0004

PPE: Personal Protective Equipment.

*Mechanically harvested crop.

Figure 2. Risk21 plots for fungicide USA use scenario on soya bean for acute and chronic exposure. (a) Soya bean alone at tolerance, (b) EDWC, (c) tolerance plus EDWC, and (d) US EPA aggregate assessment for surrogate substance including all crops on the label and EDWC. Line denotes median reference dose value, toxicity values are 5th and 75th percentile from the aPAD/cPAD range, respectively. Exposure values are for the most sensitive population and worst case surrogate compound for acute or chronic exposures, respectively. Blue box refers to acute duration assessment and black box refers to chronic duration assessment.

Figure 3. Risk21 plots for insecticide USA use scenario on sweet corn for acute and chronic exposure. (a) Sweet corn alone at tolerance, (b) EDWC, (c) tolerance plus EDWC, and (d) US EPA aggregate assessment for surrogate substance including all crops on the label and EDWC. Line denotes median reference dose value, toxicity values are 5th and 75th percentile from the aPAD/cPAD range, respectively. Exposure values are for the most sensitive population and worst case surrogate compound for acute or chronic exposures, respectively. Blue box refers to acute duration assessment and black box refers to chronic duration assessment.

Figure 4. Risk21 plots for herbicide USA use scenario on cotton for acute and chronic exposure. (a) Cotton alone at tolerance, (b) EDWC, (c) tolerance plus EDWC, and (d) US EPA aggregate assessment for surrogate substance including all crops on the label and EDWC. Line denotes median reference dose value, toxicity values are 5th and 75th percentile from the aPAD/cPAD range, respectively. Exposure values are for the most sensitive population and worst case surrogate compound for acute or chronic exposures, respectively. Blue box refers to acute duration assessment and black box refers to chronic duration assessment.

Figure 5. Risk21 plots for SDHI USA use scenario on stone fruit for acute and chronic exposure. (a) Stone fruit alone at tolerance, (b) EDWC, (c) tolerance plus EDWC, and (d) US EPA aggregate assessment for surrogate substance including all crops on the label and EDWC. Line denotes median reference dose value, toxicity values are 5th and 75th percentile from the aPAD/cPAD range, respectively. Exposure values are for the most sensitive population and worst case surrogate compound for acute or chronic exposures, respectively. Blue box refers to acute duration assessment and black box refers to chronic duration assessment.

Figure 6. Risk21 plots for EU use scenarios on wheat. (a) Fungicide on wheat acute dietary exposure (b) fungicide on wheat chronic dietary exposure (c) SDHI on wheat acute dietary exposure (d) SDHI on wheat chronic dietary exposure. Line denotes median reference dose value, toxicity values are 5^th and 75^th percentile from the aRfD/ADI range, respectively. Exposure values are for the most sensitive population and worst case surrogate compound for acute and chronic exposures, respectively. Blue box represents acute duration exposure and black box represents chronic duration exposure.

Figure 7. Risk21 plots for US occupational exposure via inhalation and dermal routes of exposure. (a) Fungicide use scenario, (b) Insecticides use scenario, (c) Herbicide use scenario, and (d) USA SDHI scenario. Line denotes median calculated occupational exposure level (OEL) reference dose value, toxicity values are 5th and 75th percentile from the range of derived dermal and inhalation occupational reference dose ranges for the USA. Exposure values were derived from the most conservative (highest potential for) exposure for inhalation and dermal exposures. Magenta box represents inhalation exposures and dark blue box represents dermal exposures.

Table 14. Judgement on acceptability of risk: acute exposure for USA use scenarios.

	Exposure at tolerance (mg/kg/day)	Exposure from estimated drinking water concentrations (mg/kg/day)	Dietary exposure from tolerance + EDWCs mg/kg/day)	Dietary exposure (EPA Aggregate: All food + EDWC) (mg/kg/day)
Fungicide on soya bean
Maximum acute exposure value	0.001843	0.056591	0.057466	0.269743
Comparison to aPAD percentile	<5^th percentile (0.02)	5^th–25^th Percentile (0.02–0.095)	5^th–25^th Percentile (0.02–0.095)	50^th–75^th Percentile 0.2–0.54)
Judgement on risk	High likelihood of no unacceptable risk	Likely to pose no unacceptable risk	Likely to pose no unacceptable risk	Risk potentially unacceptable – refine
Insecticide on sweet corn
Maximum acute exposure value	0.000310	0.204459	0.204431	0.029784
Comparison to aPAD percentile	<5^th percentile (<0.00032)	>75^thpercentile (>0.095)	>75^thpercentile (>0.095)	>75^thpercentile (>0.095)
Judgement on risk	High likelihood of no unacceptable risk	Risk likely to be unacceptable – refine	Risk likely to be unacceptable – refine	Risk likely to be unacceptable – refine
Herbicide on cotton
Maximum acute exposure value	0.000602	0.090911	0.090861	0.009345
Comparison to US EPA aPAD percentile	<5^th percentile (<0.03)	25^th–50^th percentile (0.063–0.27)	25^th–50^th percentile (0.063–0.27)	<5^th percentile (<0.03)
Judgement on risk	High likelihood of no unacceptable risk	Reasonably likely to pose no unacceptable risk – refine	Reasonably likely to pose no unacceptable risk – refine	High likelihood of no unacceptable risk
SDHI on stone fruit
Maximum acute exposure value	0.006711	0.242795	0.245468	0.257324
Comparison to aPAD percentile	<5^th percentile (<0.17)	5^th–25^th percentile (0.17–0.3)	5^th–25^th percentile (0.17–0.3)	5^th–25^th percentile (0.17–0.3)
Judgement on risk	High likelihood of no unacceptable risk	Likely to pose no unacceptable risk	Likely to pose no unacceptable risk	Likely to pose no unacceptable risk
SDHI on canola
Maximum acute exposure value	0.000650	0.024097	0.024110	0.255856
Comparison to aPAD percentile	<5^th percentile (<0.17)	<5^th percentile (<0.17)	<5^th percentile (<0.17)	5^th–25^th percentile (0.17–0.3)
Judgement on risk	High likelihood of no unacceptable risk	High likelihood of no unacceptable risk	High likelihood of no unacceptable risk	Likely to pose no unacceptable risk

Green = low risk as reference dose is lower than exposure; Orange = moderate risk as reference dose is approaching exposure; Red = high risk as reference dose is greater than exposure.

Table 15. Judgement on acceptability of risk: chronic exposure for USA use scenarios.

	Exposure at tolerance (mg/kg/day)	Exposure from Estimated Drinking Water Concentrations (mg/kg/day)	Dietary exposure from tolerance + EDWCs (mg/kg/day)	Dietary Exposure (EPA Aggregate: All food + EDWC) (mg/kg/day)
Fungicide on soya bean
Maximum chronic exposure value	0.000993	0.015245	0.015691	0.027728
Comparison to cPAD percentile	<5^th percentile <0.0049	5^th–25^th percentile 0.0049–0.018	5^th–25^th percentile 0.0049–0.018	25^th–50^th percentile 0.018–0.055
Judgement on risk	High likelihood of no unacceptable risk	Likely to pose no unacceptable risk	Likely to pose no unacceptable risk	Reasonably likely to pose no unacceptable risk – refine
Insecticide on sweet corn
Maximum chronic exposure value	0.000040	0.015623	0.015625	0.12812
Comparison to cPAD percentile	<5^th percentile <0.00012	50^th–75^th percentile 0.013–0.03	50^th–75^th percentile 0.013–0.03	>95^th percentile >0.089
Judgement on risk	High likelihood of no unacceptable risk	Risk potentially unacceptable – refine	Risk potentially unacceptable – refine	Risk highly likely to be unacceptable – refine
Herbicide on cotton
Maximum chronic exposure value	0.000001	0.010717	0.032681	0.023934
Comparison to cPAD percentile	<5^th percentile <0.0032	5^th–25^th percentile 0.005–0.025	25^th–50^th percentile 0.025–0.1	5^th–25^th percentile 0.005–0.025
Judgement on risk	High likelihood of no unacceptable risk	Likely to pose no unacceptable risk	Reasonably likely to pose no unacceptable risk – refine	Likely to pose no unacceptable risk
SDHI on stone fruit
Maximum chronic exposure value	0.004172	0.073812	0.077149	0.079019
Comparison to cPAD Percentile	<5^th percentile 0.01	25^th–50^th percentile 0.03–0.092	25^th–50^th percentile 0.03–0.092	25^th–50^th percentile 0.03–0.092
Judgement on risk	High likelihood of no unacceptable risk	Reasonably likely to pose no unacceptable risk – refine	Reasonably likely to pose no unacceptable risk – refine	Reasonably likely to pose no unacceptable risk – refine
SDHI on canola
Maximum chronic exposure value	0.000223	0.052604	0.052638	0.126264
Comparison to cPAD percentile	<5^th percentile 0.01	25^th–50^th percentile 0.03–0.092	25^th–50^th percentile 0.03–0.092	50^th–75^th percentile 0.092–0.27
Judgement on risk	High likelihood of no unacceptable risk	Reasonably likely to pose no unacceptable risk – refine	Reasonably likely to pose no unacceptable risk – refine	Risk potentially unacceptable – refine

Green = low risk as reference dose is lower than exposure; Orange = moderate risk as reference dose is approaching exposure; Red = high risk as reference dose is greater than exposure.

Table 16. Judgement on acceptability of risk: fungicides and SDHI use scenarios for the EU acute and chronic exposure.

	Fungicide on wheat		SDHI on wheat
	Acute	Chronic	Acute	Chronic
Maximum exposure value	0.00072	0.00058	0.00058	0.00087
EU ARfD or ADI Percentile	<5^th percentile <0.02	<5^thpercentile <0.0052	<5^th percentile 0.15	<5^th percentile <0.0152
Judgement on risk	likelihood of no unacceptable risk	Likely to pose no unacceptable risk	Likely to pose no unacceptable risk	Likely to pose no unacceptable risk

Green = low risk as reference dose is lower than exposure; Orange = moderate risk as reference dose is approaching exposure; Red = high risk as reference dose is greater than exposure.

Figure 8. Risk21 plots for acute (a) and long-term operator (b) with and without PPE exposures for EU fungicide use scenario on wheat. Line denotes median reference value, toxicity values are 5^th and 75^th percentile from the range of systemic AOELs for fungicides in the EU.