In the terms of reference VKM was requested to consider possible health risk for operators related to the properties of the active substance spirotetramat and the product Movento 100 SC ; in particular the relevance of the effects of spirotetramat on thyroid hormones, brain, thymus and body weight observed in dogs, and the reproductive effects of spirotetramat observed in rats.
4.1.1 EFFECTS SEEN IN DOG STUDIES
VKM discussed the seriousness of the effects in studies with dogs and concluded that thyroid and thymus glands are target organs in the oral subchronic toxicity studies, and that effects could be observed from 19 mg/kg bw/day (600 ppm). Decreases in circulating thyroid hormone levels were detected in three studies, and should be considered as toxicologically relevant. Furthermore, it cannot be excluded that the observed brain dilatation could be treatment-related. Higher doses of spirotetramat also induced decreased body weights.
Thyroid and thyroid hormones: A dose–related decrease in thyroid hormones (T4 and T3) were observed in three different studies with spirotetramat, 28-days, 90-days and 1-year, both in male and female dogs. The hormonal decreases were significant from 400 ppm, 150 ppm and 200 (600) ppm, respectively, in the three studies. The T4 and T3 levels were measured at various time-points during the studies, and the onset for significant reduction of T4 and/or T3 varied. The declines in circulating thyroid hormones were observed at lower concentrations than those needed for induced changes in thyroid weight and thyroid histopathology. Reduced thyroid follicular size was noted in two dogs at 1800 ppm (equal to 55 mg/kg bw/day). Thus, it cannot be excluded that the observed decline in thyroid hormones could be an early event in the development of hypothyroidism, and should therefore be considered as toxicologically relevant.
Brain: Brain dilatation was observed in the 1-year study, and describes a condition where a brain ventricle is identified to be larger than expected. Dilated brain was observed in males at 600 (mild) and 1800 ppm (moderate), and was noted in females, but only at 600 ppm
(moderate); mild axonal degeneration was also detected in one female dog at 1800 ppm. The notifier (BCS) claimed that with a persistent incidence of only one individual dog per dose group (spirotetramat study and historical controls) and since brain ventricle dilation also has been observed in other BCS dog studies, there should be valid reasons to conclude that the phenomenon represents a pre-existing condition, and thus not treatment-related. VKM concludes, however, that although brain ventricle dilation has been observed in other dog studies, it cannot be excluded that this serious response could be treatment-related.
Thymus and body weight: In addition to the thyroid, also the thymus gland is a target organ for spirotetramat in oral subchronic toxicity studies in dogs. Thymus involution was graded mild in one male at 600 ppm and moderate in one male at 1800 ppm. The thymus changes (decreased size and weight, atrophy and involution) were observed at high concentrations (600-6400 ppm) in all three dog studies (28-, 90- and 365 days). The effects on thymus should be considered toxicologically relevant.
In the subchronic toxicity studies (28 and 90-days), a decrease in body weight, body weight gain, and food consumption was observed at the highest treatment doses (from 2,500 ppm and
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higher). In the 1-year study there were no compound-related effects on body weights, even at the highest concentration (1800 ppm). Thus, doses of 2,500 ppm spirotetramat and higher seem to affect the dog body weight.
4.1.2 THE EFFECTS SEEN IN RAT STUDIES
Reproductive effects: In addition to testicular histopathology observed following subchronic and chronic exposure of male rats to spirotetramat, evidence of male reproductive toxicity was provided in the 2-generation reproductive toxicity study. Abnormal sperm cells were reported in F1-generation male rats treated with 6000 ppm (419 mg/kg bw/day) spirotetramat in the diet, and decreased reproductive performance was also observed in one of these males.
The findings were supported by a 1-generation range-finding study. Renal toxicity was observed in the F1-adults in the 2-, but not the 1-generation study, and offspring toxicity was observed to be limited to reduced body weights.
In an investigative study designed to explore the time of onset of testicular toxicity in rats, decreased epididymal sperm counts were recorded after more than 10 days treatment to 1000 mg/kg bw/day by gavage. Repeated dosing, therefore, seems necessary to produce male reproductive toxicity in rats. In a second investigative study of a spirotetramat metabolite, male rats were treated by gavage with the enol metabolite (formed by enzymatic cleavage of parent compound) for 21 days at a dose of 800 mg/kg bw/day. Spermatotoxicity, abnormal sperm, and Sertoli cell vacuolation were observed in the testis-epididymides of treated animals. Therefore, male reproductive toxicity in rats is likely due to the enol metabolite (or further oxidation products) of spirotetramat. The testicular toxicity was not observed in mice, probably due to the high conjugation of the enol metabolite with glucuronic acid
(approximately 30%). The notifier claimed that based on a metabolic similarity between mice and humans, it is likely that humans are also less sensitive to the enol metabolite toxicity than rats. However, VKM concludes that due to the low conjugation in human liver cells at high doses (only 2%), as well as the far lower conjugation in humans compared to mice, it cannot be assumed that humans are fundamentally different from rats with regard to sensitivity to spirotetramat. Thus, VKM concludes that the reproductive effect in rats could be relevant for humans.
Neurotoxicity: Clinical signs of toxicity and decreased motor activity were observed following one single dose of 200 mg/kg bw spirotetramat to rats.
4.1.3 ESTABLISHMENT OF REFERENCE VALUES
NOAEL
VKM concludes on a NOAEL of 5 mg/kg bw/day (200 ppm) for spirotetramat based on 1- year toxicity study in dogs, and is of the opinion that the test substance-related decrease in thyroid hormone levels, thymus involution and brain dilation is relevant for humans.
Furthermore, a NOAEL of 100 mg/kg bw/day based on the acute neurotoxicity study in rats is used to establish the ARfD value.
ADI
An ADI of 0.05 mg/kg bw/day is proposed for spirotetramat based on applying a 100-fold uncertainty factor on the NOAEL of 5 mg /kg bw/day in the 1- year toxicity study in dogs.
The uncertainty factor accounts for interspecies extrapolation (10X) and intraspecies variability (10X).
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AOEL
An AOEL of 0.05 mg/kg bw/day is proposed for spirotetramat based on the NOAEL of 5 mg /kg bw/day determined in the 1- year toxicity study in dogs.
ARfD
An ARfD of 1 mg/kg bw/day is proposed for spirotetramat based on NOAEL of 100 mg/kg bw/day in the acute neurotoxicity study in rats.
4.2 H
EALTH RISK CHARACTERIZATION 4.2.1 HEALTH RISK DUE TO HUMAN EXPOSUREVKM has based the risk characterization for operators on the summary from the Norwegian Food Safety Authority (section 5.5), and related this to the suggested AOEL value as indicated here in section 2.1.
4.2.1.1 Operator, worker and bystander exposure Operator exposure:
The AOEL for spirotetramat is not exceeded when applied in greenhouses, even if no
personal protective equipment (PPE) is used. On fruit trees in field there is a medium excess of AOEL without PPE, but no excess with PPE (Gloves during mixing and loading, and gloves, coveralls and sturdy footwear during application).
Worker and bystander exposure:
The AOEL is slightly exceeded for fruit trees, and thus the use of gloves is recommended.
4.2.2 HEALTH RISK DUE TO RESIDUES IN PRODUCTS FOR CONSUMPTION
Not included in the terms of reference.
4.3 E
NVIRONMENTAL FATE ASSESSMENTVKM was also asked to consider the fate and behaviour of Movento 100 SC and the active ingredient spirotetramat in the environment, and the ecotoxicological effects and risks related.
4.3.1 DEGRADATION IN SOIL
Spirotetramat degrades very quickly to spirotetramat-enol in soil (DT50: 0.1 – 0.3 days). The relevant metabolites are also degraded at high to medium rates. Spirotetramat and its
metabolites are not expected to accumulate in soil.
4.3.2 MOBILITY IN SOIL AND LEACHING TO GROUNDWATER
Sorption studies indicate medium sorption of spirotetramat to soil and moderate to low sorption of the main metabolites. Due to the rapid degradation in soil, no significant leaching of spirotetramat to groundwater is expected. Leaching models show concentrations of relevant metabolites below 0.001 µg/L for all FOCUS scenarios. Hence, VKM considers it unlikely that spirotetramat or any of its metabolites will reach concentrations above the threshold level of 0.1 μg/L when the formulation Movento 100 SC is applied according to the intended use.
4.3.3 SURFACE WATER CONCENTRATIONS
Surface water concentrations of spirotetramat and the relevant metabolites have been
calculated using FOCUS models, step 2. Additional calculations were performed including a 5 m buffer zone. VKM considers the calculated maximum PEC values as shown in section 3.3.2 to be relevant for aquatic risk assessment.
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4.4 E
NVIRONMENTAL RISK CHARACTERIZATIONThe risk characterization of the product’s ecotoxicological effects on terrestrial and aquatic organisms made by VKM is based on the summary from the Norwegian Food Safety Authority presented in section 3.3 and using the risk scale described in section 2.2.
4.4.1 EFFECTS AND RISKS TO TERRESTRIAL ORGANISMS
VKM concludes that the risk for toxic effects of spirotetramat to mammals, birds, earthworms, and soil microorganisms is minimal with the proposed application regime.
Extended laboratory studies with non-target arthropods Movento 100 SC showed effects above the trigger of 50% mortality for one species of predatory mites (T. pyri) at and above application doses of 42 g/ha, while the proposed application rate is 225 g/ha. Although a field study did not show any effects on the mite fauna, VKM considers that in-field effects on sensitive species of predatory mites in the fields cannot be excluded.
The acute contact and oral toxicity of spirotetramat to adult bees is low. Transient effects on honey-bee brood were observed under worst-case scenarios in some semi-field studies.
However, no adverse effects were observed in field studies and VKM concludes that the risk of adverse effects on bees is minimal providing that spirotetramat is not used on crops during flowering or when bees are actively foraging.
4.4.2 EFFECTS AND RISK TO AQUATIC ORGANISMS
VKM concludes that there is a minimal risk for toxic effects of spirotetramat to fish, aquatic plants, and algae with the proposed application regime. For invertebrates and sediment dwelling organisms, minimal risks are calculated provided that a 5 m buffer zone is used.
4.5 Q
UALITY OF THE SUBMITTED DOCUMENTATIONVKM is of the opinion that the documentation submitted to VKM is adequate as a basis for an evaluation of the active substance, the metabolites, and for the technical material.
5 Conclusion 5.1 H
EALTHVKM concludes that spirotetramat show toxic effects in dogs and rats that could be relevant for humans. Thyroid and thymus glands are target organs in the oral subchronic toxicity studies in dogs. Decreases in circulating thyroid hormone levels were detected in all three studies carried out with dogs (28-, 90-days and 1-year) and should be considered
toxicologically relevant. It cannot be excluded that the brain dilatation observed in the 1-year dog study is treatment-related.
Furthermore, VKM concludes that the reproductive effect observed in rats should be considered relevant for humans.
VKM proposes a NOAEL of 5 mg/kg bw/day for spirotetramat based on a 1- year toxicity study in dogs, and a NOAEL of 100 mg/kg bw/day based on the acute neurotoxicity study in rats.
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VKM proposes:
• ADI: 0.05 mg/kg bw/day.
• AOEL: 0.05 mg/kg bw/day.
• ARfD: 1 mg/kg bw/day.
Risk calculations show minimal risk if personal protective equipment is used.
5.2 E
NVIRONMENTVKM concludes that spirotetramat and its metabolites are not expected to accumulate in soil.
It is not expected that spirotetramat or any of its metabolites will reach concentrations in groundwater above the threshold level of 0.1 μg/L when the formulation Movento 100 SC is applied according to the intended use.
VKM concludes that use of Movento 100 SC with the active substance spirotetramat
according to the proposed application scheme in Norway represents a minimal risk of adverse effects on terrestrial mammals, birds, earthworms, and soil microorganisms. However, in-field effects on sensitive species of predatory mites in the crop cannot be excluded.
The risk of adverse effects on bees is minimal providing that spirotetramat is not used on crops during flowering or when bees are actively foraging.
For aquatic organisms in surface water, the risk is considered minimal, provided that a 5 m buffer zone to open water is used.
6 Documentation
The documentation submitted by the applicant in the process of application for registration of Movento 100 SC has been compiled and evaluated by The Norwegian Food Safety Authority (www.Mattilsynet.no).
In addition, VKM has performed a combined literature search in PubMed, TOXNET and Embase using the name of the active substance (spirotetramat). The resulting references has been considered by VKM and used in the risk assessment when relevant.
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