Absorption, Distribution and Excretion
... In rats, radiolabelled cyprodinil administered by gavage as a single dose of 0.5 or 100 mg/kg bw, or as repeated doses of 0.5 mg/kg bw per day for 14 days, was rapidly absorbed from the gastrointestinal tract and excreted. Approximately 75% (range, 71-85%) of an orally administered dose was absorbed over 48 hr. At a dose of 0.5 and 100 mg/kg bw, two plasma level maxima of radioactivity were observed at approximately 0.5-1 hr and 8-12 hr, probably caused by reabsorption of material excreted in the bile. Approximately 92-97% of the administered dose was eliminated within 48 hr in the urine (48-68%), feces (29-47%), and bile (accounting for up to 35.4% of the dose in cannulated rats), with elimination being almost complete by day 7. Seven days after single or repeated oral administration at the lower dose, total tissue residues accounted for 0.15-0.60% of the administered dose. ... Excretion, distribution and metabolite profiles were essentially independent of dose, pretreatment and site of radiolabel, although there were some quantitative sex-dependent differences in urinary metabolites.
After oral administration, CGA 219417 is rapidly absorbed and also rapidly and almost completely eliminated with urine and feces. ... Residues in tissues were generally low and there was no evidence for accumulation or retention of radioactivity.

---

Metabolism / Metabolites
In studies of metabolism in rats, ... cyprodinil was primarily metabolized by hydroxylation of the phenyl and pyrimidine rings and methyl group, and excreted mainly as glucuronide or sulfate conjugates in urine, feces and bile. Approximately 3-8% of the parent compound was detected in the feces. Excretion, distribution and metabolite profiles were essentially independent of dose, pretreatment and site of radiolabel, although there were some quantitative sex-dependent differences in urinary metabolites.
The metabolic pathways are independent of sex, pre-treatment or dose level administered.
In tomatoes, the metabolism of CGA 219417 proceeded mainly via hydroxylation of the 6-methyl group of the pyrimidine ring as well as hydroxylation of the phenyl & pyrimidine ring.

Toxicity Summary
IDENTIFICATION AND USE: Cyprodinil is a fine beige powder. It is used as a foliar fungicide in cereals, grapes, pome fruits, stone fruits, strawberries, and vegetables and as a seed dressing on barley; it controls a wide range of pathogens, including Pseudocercosporella herpotrichoides, Erysiphe spp., Pyrenophora teres, Rhynchosporium secalis, and Septoria nodorum. HUMAN EXPOSURE AND TOXICITY: Cyprodinil acts as an aryl hydrocarbon receptor activator, a potential endocrine disrupter, and an extracellular signal-regulated kinase disrupter. Weak androgen receptor binding was shown for cyprodinil. Cyprodinil was genotoxic for HepG2 cells at concentrations 20 uM. ANIMAL STUDIES: In a 28 day gavage study in rats, the LOEL is 100 mg/kg bw/day for rats, based on increased liver weights and abnormalities in liver morphology. In a two-generation reproduction study in rats, the LOEL for maternal systemic toxicity is 4000 (about 326 mg/kg/day) based on lower body weights in the F0 females during the pre-mating period. The NOEL for maternal systemic toxicity is 1000 ppm (about 81 mg/kg/day). The LOEL for reproductive/developmental toxicity is 4000 ppm (about 326 mg/kg/day) based on decreased pup weights (F1 and F2). The NOEL for reproductive toxicity is 1000 ppm (about 81 mg/kg/day). In an 18-month carcinogenicity study in mice, the LOEL is 2000 ppm (males- 212.4 mg/kg/day) based on a dose-related increase in the incidence of focal and multifocal hyperplasia of the exocrine pancreas in males. The NOEL is 150 ppm (males- 16.1 mg/kg/day). This study was tested to adequate levels based on signs of toxicity in males at 2000 ppm and females at 5000 ppm. There was no indication of carcinogenic potential at any dose level. ECOTOXICITY STUDIES: In plants, cyprodinil promoted a copious increase in exudate secretion and caused the most severe collapse of stigmatic cells of all the fungicides evaluated.

---

Toxicity Data
LC50 (rat) > 1,200 mg/m3/4h

---

Interactions
... A previous study identified the seven most common pesticide mixtures to which the French population was exposed through food consumption in 2006. The aim of this study was to investigate if the seven mixtures are potentially cytotoxic and genotoxic and if so, whether compounds in a same mixture have a combined effect. The cytotoxicity and genotoxicity of the seven mixtures were investigated with a new assay (gamma-H2AX) using four human cell lines (ACHN, SH-SY5Y, LS-174T, and HepG2). Mixtures were tested at equimolar concentrations and also at concentrations reflecting their actual proportion in the diet. Irrespective of the cell line tested, parallel cytotoxicity of the seven mixtures was observed. Only one mixture was genotoxic for the HepG2 cells at concentrations = 3 uM in equimolar proportion and at 30 uM in actual proportion. Caspase 3/7 activity, the comet assay, and reactive oxygen species production were also investigated using the same mixture and HepG2 cells. Our results suggest that pesticide metabolites from the mixture generated by HepG2 cells were responsible for the observed damage to DNA. Among the five compounds in the genotoxic mixture, only fludioxonil and cyprodinil were genotoxic for HepG2 cells alone at concentrations = 4 and 20 uM, respectively. Our data suggest a combined genotoxic effect of the mixture at low concentrations with a significantly higher effect of the mixture of pesticides than would be expected from the response to the individual compounds.

---

Non-Human Toxicity Values
LD50 Rat oral >2000 mg/kg
LD50 Rat percutaneous >2000 mg/kg
LC50 Rat inhalation >1200 mg/cu m/4 hr

[1]. Possible methionine biosynthesis inhibition by pyrimidinamine fungicides. Pestic. Sci. 42(3),163-166 (1994).

[2]. Widely used pesticides with previously unknown endocrine activity revealed as in vitro antiandrogens. Environ Health Perspect. 2011 Jun;119(6):794-800.

Cyprodinil is a member of the class of aminopyrimidine that is N-phenylpyrimidin-2-amine carrying additional cyclopropyl and methyl substituents at positions 4 and 6 respectively. A broad spectrum fungicide used to control a range of pathogens including Tapesia yallundae, Botrytis spp., Alternaria spp. and Rhynchospium secalis. Whilst it is a recognised irritant no serious human health concerns have been identified. It is moderately toxic to birds as well as most aquatic organisms and earthworms, but it is not considered toxic to honeybees. It has a role as an aryl hydrocarbon receptor agonist, an environmental contaminant, a xenobiotic and an antifungal agrochemical. It is an aminopyrimidine, a secondary amino compound, a member of cyclopropanes and an anilinopyrimidine fungicide.
Cyprodinil is a fungicide that acts by inhibition of germ tube elongation and hyphal mycelia. Cyprodinil is applied to the foliage of almonds, grapes, stone fruit crops, and pome fruit crops to control plant diseases.

C14H15N3

225.29

225.126

121552-61-2

Cyprodinil-d5;1773496-67-5;Cyprodinil-13C6;1773496-63-1

86367

White to off-white solid powder

1.2±0.1 g/cm3

406.0±48.0 °C at 760 mmHg

68 - 70ºC

199.3±29.6 °C

0.0±0.9 mmHg at 25°C

1.659

4

1

3

3

17

246

0

HAORKNGNJCEJBX-UHFFFAOYSA-N

InChI=1S/C14H15N3/c1-10-9-13(11-7-8-11)17-14(15-10)16-12-5-3-2-4-6-12/h2-6,9,11H,7-8H2,1H3,(H,15,16,17)

4-cyclopropyl-6-methyl-N-phenylpyrimidin-2-amine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 100 mg/mL (443.87 mM)

Solubility in Formulation 1: 2.5 mg/mL (11.10 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 2.5 mg/mL (11.10 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

 (Please use freshly prepared in vivo formulations for optimal results.)