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Description of key information

The key physicochemical characteristics of the powder imazalil sulphate are: a moderate molecular weight (395.26 g/mol), a reported mean particle size of 128.317 µm (Dv,50), very high water solubility (5656 g/L at 20°C; Bates, 2002), moderate partition coefficient (log Kow 3.31) and very low volatility (vapour pressure <1E-8 mPa at 20-25°C).

Based on its molecular weight is < 500 g/mol its log Kow value between -1 and 4, and its high water solubility, dissolution of the substance into the gastrointestinal fluids and absorption through passive diffusion oral absorption is expected.

No key repeated dose and reproductive toxicity study is available for imazalil sulphate instead reliable data from the supporting substance imazalil base was used. Based on the results of the study, the no-effect level for imazalil base was 5 mg/kg bw/day. No major abnormalities were observed at the next higher level of 400 ppm. The test substance is therefore classified as STOT RE 2 according to the CLP Regulation. Reproductive toxicity of imazalil was evaluated in a full two-generation study in rats. Reduced offspring survival was considered adverse only for the high dose group. Based on the physicochemical properties and the results of the toxicity studies, the oral absorption factor is set to 50%.

Imazalil sulphate is a highly water-soluble powder and is lipophilic (logKow>0) implying that the product has the potential to be subsequently absorbed directly across the respiratory tract epithelium through passive diffusion. An acute inhalation toxicity study (OECD 403, Weniger, 2000) performed on Sprague-Dawley resulted in signs of damages to the respiratory system. However, these signs were not life threatening and no further abnormalities were observed. The respiratory absorption factor is set at 100%.

The dermal absorption factoris set to 50% based on the fact that the substance is a solid, its water solubility is high and its log Kow is moderate. Furthermore, a harmonised classification is available for Imazalil sulphate (Index numbers 613 -043 -01 -8 and 613-043 -00 -0) as Skin sens 1 (H317).

Key value for chemical safety assessment

Absorption rate - oral (%):
50
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information

Imazalil sulphate (CAS 58594-72-2) is a beige powder with a characteristic odour. Its molecular weight is 395.26 g/mol and the reported mean particle size is 128.317 µm (Dv,50). Imazalil sulphate has a very high water solubility (5656 g/L at 20°C; Bates, 2002), a moderate partition coefficient (log Kow of 3.31), and a very low volatility (vapour pressure of <1E-8 mPa at 20-25°C). The dissociation constant (pKa) is 6.54 ± 0.03 at 25°C (Bates, 2002) which implies that at ca. pH 6.5, 50% of imazalil sulfate is dissociated. The pH of a solution of imazalil sulfate 75 SP (1%) in water is experimentally determined to be 1.92 (de Ryckel, 2017) which is very acidic. In addition, the acidity of Imazalil sulfate was determined to be 23.214% w/w as H2SO4(De Ryckel, 2017) which agrees with the theoretical concentration of sulfuric acid in the product (i.e. 25%). 

Imazalil sulfate is the (sulfate) salt of the active substance imazalil, a derivative of imidazole. An ethyl group is attached to one of the nitrogen atoms of the imidazole functional group with an allyloxy and dichlorophenyl as substituents on the second carbon which is achiral center. The substance is therefore considered to be a racemic mixture of its two enantiomers (R and S). Due to the fact that the substance is a (sulfate) salt, its water solubility is very high. The base (imazalil) on the other hand has a limited solubility and will form an oily layer in water.

No toxicokinetic data (animal or human studies) are available on this substance. The data present in this dossier are based on physicochemical and toxicological parameters and will allow a qualitative assessment of the toxicokinetic behaviour of Imazalil sulphate.

Absorption

Oral/GI absorption:

Imazalil sulphate is considered favorable for absorption since its molecular weight is < 500 g/mol, its log Pow value is between -1 and 4 and its water solubility is high which leads to dissolution of the substance into the gastrointestinal fluids and absorption through passive diffusion. The lipophilic character of the substance makes it more readily dissolve in the gastrointestinal tract (predominantly in the small intestine) and be absorbed in the bloodstream more quickly. 

In an acute oral toxicity study (OECD 425; Merrill 2013), conducted with female Sprague-Dawley rats, the following doses of imazalil sulfate were administered 174 mg/kg, 550 mg/kg and 2000 mg/kg. 

The animals were observed for mortality, signs of gross toxicity, and behavior changes. Mortality was observed for females dosed at 550 mg/kg and 2000 mg/kg. Clinical signs were observed at 174 mg/kg and 550 mg/kg dose levels and included hypoactive and exhibited hunched posture, irregular respiration, reduced fecal volume and nasal discharge, hypoactivity, gasping and/or writhing. At 2000 mg/kg there were no clinical signs noted prior to death.

Necropsy was performed on survivors and revealed no gross abnormalities at 174 mg/kg dose Level. At 550 mg/kg and 2000 mg/kg , distention of the stomach and intestines was observed.

The acute oral LD50 of the test item is then estimated to be 550 mg/kg of body weight (the one dose with partial response) in female rats and the substance is classified as acute oral toxicant Category 4 under GHS.

No reliable, key repeated dose and reproductive toxicity study is available for imazalil sulphate. Therefore, reliable data from the supporting substance imazalil base was used.

The repeated dose oral toxicity (EU method B33, Til, 1983) was conducted with imazalil administrated daily for 6 months to wistar rat at the dose level groups of 1.25, 5 and 20 mg/kg bw/day. No mortality and no effects were observed at clinical signs, histopatology and urinalysis. However, organ weight findings showed in the top-dose group statistically significant increases in the relative weight of the kidneys in males, and in the absolute and relative weights of the kidneys and liver in females. The absolute weight of the thymus and the relative weight of the lungs were slightly, though significantly increased in females of the top-dose group as well. Based on the results of the study, the no-effect level for imazalil base was 5 mg/kg bw/day. No major abnormalities were observed at the next higher level of 400 ppm. The test substance is therefore classified as STOT RE 2 according to the CLP Regulation.

Reproductive toxicity of imazalil was evaluated in a full two-generation study in rats at nominal doses of 0, 5, 20 and 80 mg/kg bw/d (Dirkx et al., 1992b, K2). The highest dose caused parental toxicity as reduced body weight and body weight gain, increased incidence of pilo-erection, as well as vacuolisation of hepatocytes in P1 males was observed. At this dose, females also showed a reduced gestation rate and an increased duration of gestation. Reproductive toxicity manifested at 80 mg/kg bw/d with a slightly reduced number of implantations, a reduced number of live pups and an increased number of stillborn pups. Reduced offspring survival was considered adverse only for the high dose group. Hence, the NOAEL for parental and reproductive toxicity was identical with 20 mg/kg bw/d (nominal).

Based on the physicochemical properties and the results of the toxicity studies, the oral absorption factoris set to 50%, the default for the oral route of exposure.

Respiratory absorption:

Given its low volatility, the availability of imazalil sulphate for inhalation as a vapour is limited. Based on the fact that its mean particle size is larger than 100 µm, the solid particles have no or very limited potential to be inhaled (no presence of inhalable or respirable particles).

Imazalil sulphate can diffuse/dissolve into the mucus lining the respiratory tract, since it is a highly water soluble powder. Its lipophilic character (logKow>0) implies that the product has the potential to be subsequently absorbed directly across the respiratory tract epithelium through passive diffusion.

In an acute inhalation toxicity study (OECD 403, Weniger, 2000), the inhalative exposure of imazalil sulphate to Sprague-Dawley rats at the concentration of 0.66 mg/l lead to signs of general malaise and to signs of damages to the respiratory system. None of these signs were life threatening and the animals recovered within a few days. At terminal necropsy, no abnormal findings were noted. The LC50 (inhalative), four hour exposure of test item for male and female rats is therefore >0.66 mg/l.

Based on the physicochemical properties, the respiratory absorption factor is set to 100%.

Dermal absorption:

Imazalil sulphate is a solid substance and therefore not readily taken up by the skin in comparison to liquid products. The product will have to dissolve into the surface moisture of the skin before uptake can take place and based on its high water solubility (5656 g/L), dissolution into the surface moisture is expected to be high. However, in order to cross the skin, a compound must first penetrate into the stratum corneum (non-viable layer of corneocytes forming a complex lipid membrane) and may subsequently reach the viable epidermis, the dermis and the vascular network. It is expected that the penetration of imazalil sulphate into the lipid rich environment of the stratum corneum will be favoured to a small extent due to the moderate lipophilic character (log Kow 3.31) of the substance resulting in a low to moderate dermal absorption. Considering, its high water solubility again, dermal uptake is expected to be moderate to high. It is soluble enough in water to partition from the stratum corneum into the epidermis (water solubility >1000 g.L-1).

In an acute dermal toxicity study (PSL P322, Moore, 1998), performed on male and female New Zealand albino rabbits showed that a single exposure to 2000 mg/kg of bodyweight of imazalil sulphate leads to mortality for 1 male presenting Toxic signs prior to death included irregular respiration, hypoactivity and prone posture. The surviving rabbits exhibited similar clinical signs, as well as reduced food consumption and reduced fecal volume, but recovered by Day 8. Dermal irritation (eschar and/or erythema and edema) was also noted at the dose site of all animals. The gross necropsy of the decedent revealed discoloration of the lungs and injected veins of the intestines. No gross abnormalities were noted for the animals necropsied at the conclusion of the study. Based on these results, the dermal LD50 of the test item is set to be greater than 2000 mg/kg of bodyweight.

No repeated dose dermal toxicity study is available for imazalil sulphate. Therefore, reliable data from the supporting substance imazalil base was used. Imazalil base was given to New Zealand white rabbits for 4 consecutive days a daily dose of 63, 250 and 1000 mg/kg by dermal application (Teuns, 1993). No dermal irritation was observed at 63 mg/kg whereas slight erythema was noted at 250 and 100 mg/kg. After 4 days, severe skin lesions were seen at 250 and 1000 mg/kg; also a moderate hepatotoxicity of the liver was observed at the dose levels. 

As a result, the dermal absorption factor is set to 50%.

Furthermore, a harmonised classification is available for Imazalil sulphate (Index numbers 613 -043 -01 -8 and 613-043-00-0) as Skin sens 1 (H317).

Distribution

The high water solubility and moderate molecular weight predict that imazalil sulphate will probably distribute through the body due to diffusion through aqueous channels and pores. Since the substance is lipophilic (logKow>0), the substance is likely to distribute into cells leading to a higher intracellular concentration in comparison to the extracellular concentration particularly in fatty tissues.

Accumulation

The substance is only low to moderately lipophilic it is not expected to accumulate within the adipose tissue or the stratum corneum.

Metabolism

Information on the toxicokinetics of imazalil sulphate is available in the “Proposal for harmonized classification and labelling of Imazalil” submitted by BAuA, Federal Institute for Occupational Safety and Health, Dortmund, Germany (May, 2012). In this document,the toxicokinetics of imazalil sulphate salt was assessed in male and female Wistar rats with the active substance radioactively labeled at position 2 of its enoxyethyl moiety (Mannens et al., 1993) and compared between single oral low dose (1.25 mg/kg bw), high dose (20 mg/kg bw), and repeated (14 d) low dose application following a protocol similar to OECD TG 417. Metabolism was extensive for all dosing schemes, with more than 25 metabolites detected. Major metabolites included M3 (5.9-12.6 %), M4 (4.4-7.7 %), M8 (3.9-7.6 %), M10 (1.9-12 %) and M11 (0.4-1.2 %). M10 was identified as the product resulting from epoxidation of imazalil at its propenyl moiety and consecutive epoxide hydratation. M10 was apparently further oxidized at the propanediole moiety to form the corresponding carboxylic acid isomers M3A (fraction A of M3) and M4. Conjugation of M3A and M4 with alanine resulted in fraction B of M3 (M3B).

Excretion

Given its high water solubility, a possible route of excretion of Imazalil sulphate from the systemic circulation is the urine.The toxicokinetics of imazalil sulphate salt was assessed in male and female Wistar rats with the active substance radioactively labelled at position 2 of its enoxyethyl moiety (Mannens et al., 1993). Excretion of radioactivity in the rat amounted to 50 % or more within 1 day, suggesting an elimination half-life of less than 24 h. The amount of radioactivity excreted in the urine of rats was slightly higher than that found in faeces (46-60 % vs. 32-48 %), and the amount excreted with faeces by females was slightly lower than by male animals (-7.5 %). Residual radioactivity 96 h after administration of 14C-imazalil sulphate amounted to 0.8 - 1.2 % and was mainly found in liver (0.5 %) and carcass (0.4 %).

References

Proposal for harmonized classification and labelling of Imazalil, BAuA, Federal Institute for Occupational Safety and Health, Dortmund, Germany (May, 2012),https://echa.europa.eu/documents/10162/5b641b8f-d687-a4cb-f38d-084251cbd959