Flutolanil is an existing active substance, included in Annex I of Directive 91/414/EEC. The final List of Endpoints presented below is taken from the EFSA Scientific Report on flutolanil (2008) 126; 1-63 (d.d. 20 March 2008). Where relevant, some additional remarks/information are given in italics.
Absorption, distribution, excretion and metabolism in mammals (Annex IIA, point 5.1) Rate and extent of oral absorption 70%; based on urinary excretion within 24h
Distribution Uniformly distributed
Potential for accumulation No evidence for accumulation
Rate and extent of excretion >95% excreted within 72 h via urine (70%) and faeces (26%)
Metabolism in animals Extensively metabolised; excreted as metabolites (mainly M-4) in urine and as unchanged flutolanil in faeces
Toxicologically relevant compounds (animals and plants)
Flutolanil and metabolites (M2 and M4)
Toxicologically relevant compounds (environment)
Flutolanil
Acute toxicity (Annex IIA, point 5.2)
Rat LD50 oral > 10,000 mg/kg bw
Rat LD50 dermal > 5,000 mg/kg bw
Rat LC50 inhalation > 5.98 mg/l air /4 h (whole body)
Skin irritation Non-irritant
Eye irritation Non-irritant
Skin sensitisation Non-sensitizing (M&K)
Short term toxicity (Annex IIA, point 5.3)
Target / critical effect Increased weight of liver (rat, dog) and thyroid/parathyroid (rat) and histopathological alterations in liver (dog)
Relevant oral NOAEL 299 mg/kg bw/d (90-d rat) 80 mg/kg bw/d (90-d dog) 680 mg/kg bw/d (90-d mouse) Relevant dermal NOAEL >1000 mg/kg bw/day (21-d rat) Relevant inhalation NOAEL No data available - not required
Genotoxicity (Annex IIA, point 5.4) No genotoxic potential 1
1 The genotoxic potential of flutolanil was investigated in six in vitro studies (Ames test, DNA repair test (Rec-assay), mammalian cytogenetic test in Chinese hamster lung cells, mammalian cytogenetic test in human lymphocytes, forward mutation test in mouse lymphoma cells and UDS test in rat hepatocytes) and in one in vivo study (micronucleus test in mouse bone marrow).
Long term toxicity and carcinogenicity (Annex IIA, point 5.5)
Target/critical effect Histological changes in spleen (rat);
Histological alterations in liver (male mouse) Clinical signs (emesis, salivation, excretion of soft faeces) (dog)
Relevant NOAEL 8.7 mg/kg bw/d (2-yr rat),
32 mg/kg bw/day (79-wk mouse), 50 mg/kg bw/d (2-yr dog)
Carcinogenicity No carcinogenic potential
Reproductive toxicity (Annex IIA, point 5.6) Reproduction toxicity
Reproduction target / critical effect Parental: increased liver weight
Reproduction and offspring: no effect up to the highest dose
Relevant parental NOAEL 157 mg/kg bw/day Relevant reproductive NOAEL 1614 mg/kg bw/day Relevant offspring NOAEL 1614 mg/kg bw/day
Developmental toxicity
Developmental target / critical effect Maternal: no effect up to the highest dose (rat and rabbit)
Foetal: no effect up to the highest dose (rat and rabbit)
Relevant maternal NOAEL >1000 mg/kg bw/d (rat and rabbit) Relevant developmental NOAEL >1000 mg/kg bw/d (rat and rabbit)
Neurotoxicity (Annex IIA, point 5.7)
Acute neurotoxicity No data available - not required Repeated neurotoxicity No data available - not required Delayed neurotoxicity No data available - not required Other toxicological studies (Annex IIA, point 5.8)
Mechanism studies No data available - not required
Studies performed on metabolites or impurities
No data available - not required
Medical data (Annex IIA, point 5.9)
No evidence of adverse effects to workers of manufacturing plants, agricultural workers and consumers
Summary (Annex IIA, point 5.10) Value Study Safety
bw/d
AOEL 0.56 mg/kg
bw/d
90-d dog study 100*
ARfD (acute reference dose) Not allocated, not necessary
*Corrected for oral absorption 70%
Dermal absorption (Annex IIIA, point 7.3)
SC formulation (461 g/L) In vitro study with human skin:2 Concentrate: 0.5%
Spray dilution (10%): 5%
2 See 4.2 Dermal absorption
Local effects
Flutolanil does not produce local effects, neither after a single nor repeated exposure.
Data requirements active substance
No additional data requirements are identified.
4.1 Toxicity of the formulated product (IIIA 7.1)
The formulation Symphonie does not need to be classified on the basis of its acute oral (LD50 rat >2000 mg/kg bw), dermal (LD50 rat >2000 mg/kg bw), and inhalation toxicology (LC50 rat >
5.13 mg/L).
The formulation Symphonie is considered irritating to eyes and needs to be classified as R36
‘Irritating to eyes’.
The formulation Symphonie is considered not irritating to skin.
No studies on sensitization with Symphonie have been submitted and the classification and labelling of the formulation has been prepared based on the calculation method described in Annex II of Directive 1999/45/EC.
4.1.1 Data requirements formulated product No additional data requirements are identified.
4.2 Dermal absorption (IIIA 7.3)
See List of Endpoints. In the in vitro dermal absorption study with human skin only the concentrate of the formulation Monarch was tested. After an exposure of 24 h, the amount of flutolanil in the receptor fluid was below the limit of quantification (<0.06%). 0.35% of the dose was found in epidermis. A rounded value of 0.5% was derived for the concentrate. The formulation Monarch can be diluted max. 10 fold, but there are no dermal absorption data available for the 10-fold dilution. This was discussed in the expert meeting (PRAPeR 24, June 2007) and it was proposed to use as worst case 5% for the 10-fold dilution. The Dutch expert did not agree, because the dermal depot is not saturated after exposure to the concentrate, nothing went through the skin and it is therefore not expected that dermal absorption of a 10-fold dilution will be significantly different compared to the concentrate.
However, the majority of the experts agreed to set a very conservative value of 5% for the 10-fold dilution, and this value will be used for the current risk assessment.
The tested formulation of Monarch contained 460 g/L flutolanil, which is considerably lower compared to Symphonie (60 g/L). As this is comparable to the 10% dilution stated in the LoEP the dermal absorption value of 5% can be used for Symphonie.
4.3 Available toxicological data relating to non-active substances (IIIA 7.4)
The available toxicological data relating to non-active substances will be taken into account in the classification and labelling of Symphonie.
4.4 Exposure/risk assessments 4.4.1 Operator exposure/risk
According to the Dutch Plant Protection Products and Biocides Regulations the risk assessment is performed according to a tiered approach. There are four possible tiers:
Tier 1: Risk assessment using the EU-AOEL without the use of PPE Tier 2: Risk assessment using the NL-AOEL without the use of PPE
Tier 3: Refinement of the risk assessment using new dermal absorption data Tier 4: Prescription of PPE
Tier 1
Calculation of the EU-AOEL / Tolerable Limit Value (TLV)
For flutolanil no TLV has been set. The AOEL will be used for the risk assessment.
Since the formulation is applied once during the period March-April, a semi-chronic exposure duration is applicable for the operator (including contract workers). A semi-chronic AOEL is therefore derived.
Since flutolanil is included in Annex I of 91/414/EEC, the semi-chronic EU-AOEL of 0.56 mg/kg bw/day (= 39.2 mg/day for a 70-kg operator), based on the 90-day study in dog is used for the risk assessment (see List of Endpoints).
Exposure/risk
The models currently available for estimating operator exposure are not designed for seed treatment of potatoes. The applicant made reference to two exposure studies using similar formulation types (Stevens and Davis, 1981 and Jackson, 1995). During EPCO 14 it was concluded that the study by Steven and Davis is less suited to estimate operator exposure during dust applications in potatoes as it was performed under US specific conditions.
The study by Jackson 1995, which has been evaluated in the DAR for tolclofos-methyl, is suited to estimate operator exposure to flutolanil during dust applications of Symphonie in ware, starch and seed potatoes. The study was conducted at eight sites. At two of the sites, separate subjects conducted the loading and application tasks, while at the remaining six sites, a single subject completed both loading and application tasks. On average, subjects treated 7.8 tonnes of potatoes with 19.7 kg of Rizolex during a mean trial period of 414 minutes (6.9 hr). The average application rate of Rizolex was 253 g as/tonne. Study subjects wore the label-required personal protective clothing (coveralls), gloves, and respiratory equipment when loading the hopper and handling contaminated surfaces. Potential dermal exposures were assessed by sampling and analysing outer and inner clothing. Potential inhalation exposures were assessed using sampling pumps located in the breathing zone.
Potential dermal exposures and inhalation exposures to the active substance are summarised in the tables below.
Table 1: Dermal exposures to tolclofos-methyl assessed using outer clothing and cap
Based on the exposure study the average dermal exposure for the unprotected worker is 2.06 mg/kg bw/day. The average inhalation exposure is 0.025 mg/kg bw. However, based on the relatively low number of operators in the study, the highest measured exposures will be used for the risk assessment as a worst case (site 3: 0.106 and 4.51 mg/kg bw/d for
respiratory and dermal exposure respectively during loading and 0.005 and 0.427 mg/kg bw/d respectively for application tasks).
These values should be adjusted for a dermal absorption value of 5.0% and the difference in application rate between Rizolex and Symphonie (253 g/tonne and 90 g/tonne, respectively).
This leads to the following exposure values: ((4.51 * 0.05) + 0.106) * (90/253) = 0.12 mg/kg bw/day for the exposure during loading and (( 0.427 * 0.05) + 0.005) * (90/253) = 0.009 mg/kg bw/day. The combined exposure for the operator is 0.13 mg/kg bw, 23% of the AOEL.
Since the EU-AOEL is not exceeded without the use of PPE, a higher tier assessment is not required.
4.4.2 Bystander exposure/risk
The bystander exposure is only a fraction of the operator exposure. Based on the low risk-index for the operator, no exposure calculations are performed for bystanders.
4.4.3 Worker exposure/risk
Shortly after application it is not necessary to perform any re-entry activities, including crop inspection tasks. Therefore no worker exposure is calculated.
Furthermore, Symphonie is a fungicide that is applied to potato tubers during the planting process only. After application the treated tubers fall to the ground and will be directly covered with soil. Therefore workers re-entering the treated field are not at risk to come into contact with Symphonie.
4.4.4 Re-entry
See 4.4.3 Worker exposure/risk.
Activity Trial
site/operator
Overall conclusion of the exposure/risk assessments of operator, bystander, and worker
The product complies with the Uniform Principles.
Operator exposure
Based on the risk assessment, it can be concluded that no adverse health effects are
expected for the unprotected operator after dermal and respiratory exposure to flutolanil as a result of the application of Symphonie in ware, starch and seed potatoes.
Bystander exposure
The bystander exposure is only a fraction of the operator exposure. Based on the low risk-index for the operator, no adverse health effects to bystanders are expected.
Worker exposure
Shortly after application it is not necessary to perform any re-entry activities including crop inspection tasks. Therefore, no adverse health effects to workers are expected.
4.5 Appropriate mammalian toxicology and operator exposure end-points relating to the product and approved uses
See List of Endpoints.
4.6 Data requirements
Based on this evaluation, no additional data requirements are identified.
4.7 Combination toxicology
Symphonie contains only one active substance and it is not described that it should be used in combination with other formulations.