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EC number: 261-351-5 | CAS number: 58594-72-2
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data

Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1988-03-08 to 1988-04-15
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 988
- Report date:
- 1988
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 1-[2-(allyloxy)ethyl-2-(2,4-dichlorophenyl)-1H-imidazolium hydrogen sulphate
- EC Number:
- 261-351-5
- EC Name:
- 1-[2-(allyloxy)ethyl-2-(2,4-dichlorophenyl)-1H-imidazolium hydrogen sulphate
- Cas Number:
- 58594-72-2
- Molecular formula:
- C14H14Cl2N2O.H2O4S
- IUPAC Name:
- 1-[2-(2,4-DICHLOROPHENYL)-2-(PROP-2-EN-1-YLOXY)ETHYL]-1H-IMIDAZOLE SULFATE (1:1)
- Test material form:
- solid: particulate/powder
- Details on test material:
- - Product names: FUNGAFLOR® 75C / FUNGAFLOR® 75SP / FUNGAZIL® 750SP / FUNGAFLOR® 75PS / FUNGAZIL® 75SP / FUNGAFLOR® 750SP
- Reference number: JNJ-2634372-ABI / R027180 (product code)
- Physical state: solid
- Appearance: beige solid
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Janssen Pharmaceutica laboratories; lot ZR027180G1A631. Agroform 047701 was used (Imaezalil 498.6 g/L)
- Appearance: off-white to beige coloured powder
- Expiration date of the lot/batch: no data
- Purity test date: 1998-03-04
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature in closed containers
- Stability under test conditions: known
- Solubility and stability of the test substance in the solvent/vehicle: no data
FORM AS APPLIED IN THE TEST (if different from that of starting material) : given as a solution or a suspension
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- OFA.SD. (IOPS Caw)
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: IFFA CREDO , young and healthy virgin female rats
- Age at study initiation: 2-3 months ; sexually mature at the start of the study
- Weight at study initiation: 245.9 - 252.4 g
- Fasting period before study: no
- Housing: plastic cages with 6 females per cage (37x20x15 cm), and isolated as soon as sperm is observed until the end of pregnancy
- Diet (e.g. ad libitum): ad libitum, pelleted rat food, administered in self-raising hoppers
- Water (e.g. ad libitum): ad libitum, administered in drinking bottles
- Acclimation period: at least one week under test conditions
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +- 2°C
- Humidity (%): 50 +- 20 %
- Air changes (per hr): 9
- Photoperiod (hrs dark / hrs light): 12h/day
IN-LIFE DATES: no data
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test article i given orally by gavage as a solution or a suspension and 1mL per 100g body weight is given.
VEHICLE
- Justification for use and choice of vehicle (if other than water): not specified
- Concentration in vehicle: not specified
- Amount of vehicle (if gavage): 1ml/100 g bw
- Lot/batch no. (if required): not specified
- Purity: not specified - Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1F/2M
- Length of cohabitation: until sperm is observed
- No replacement of first male by another male with proven fertility after number of days of unsuccessful pairing
- Further matings after two unsuccessful attempts: no data
- Verification of same strain and source of both sexes: no
- Proof of pregnancy: sperm in vaginal smear referred to as day 1 of pregnancy
- Any other deviations from standard protocol: males are used for breeding and are not dosed - Duration of treatment / exposure:
- from day 6 to day 16 of the pregnancy
- Frequency of treatment:
- daily
- Duration of test:
- 22 days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 40 mg/kg bw/day (nominal)
- Dose / conc.:
- 80 mg/kg bw/day (nominal)
- Dose / conc.:
- 120 mg/kg bw/day (nominal)
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- control group
- No. of animals per sex per dose:
- 24 females per group, 4 groups
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale: Dose levels are determined following review of available data in pharmacology, kinetics and toxicity studies. Dose determination aims to include a surely toxic dose and a no-effect dose level.
- Rationale for animal assignment (if not random): random
- Justification for selection of the test system: The rat is selected following review of available data on toxicity, pharmacology and/or pharmacokinetics and also because of the possibility to compare the hereby recorded data with the accumulated control data of rats.
- Route of administration: this route of administration is chosen following review of available data on pharmacology and/or because this route is the intended route for therapeutic applications of the test article in man and/or animal.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations include examination of signs of waning health, abnormal behaviour or unusual appearance, occurence of untoward clinical effects and manifestations of toxic and pharmacological response, morbidity and mortality.
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: in the morning of days 1, 6, 17 and 22 of the presumed pregnancy. Body weights are also determined daily during the dosing period (day 6 through day 16) for adjustment of dose.
FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
- Individual records are made prior to, during and after dosing or respectively in the morning of day 6 (non-dosing period: day 1 through day 5), in the morning of day 17 (dosing period: day 6 through day 16) and in the morning of day 22 (non dosing period : day 17 through day 21).
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
POST-MORTEM EXAMINATIONS: Yes
- Prior to sacrifice, a complete physical examination is performed on all surviving rats
- Sacrifice on gestation day 22: all surviving females by decapitation
- autopsy is performed as soon as possible after death during the stud or after sacrifice at the end of the study and any macroscopic pathological changes are noted
ORGAN WEIGHT:
- after removing the uterus in toto, the weight of the uterus is recorded.
- Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included: Gravid uterus weight, Number of corpora lutea, Number of implantations, Number of resorptions, Number of live and dead fetuses, any abnormal condition
- in case a reduced litter size (0 to 3 fetuses) is noted, the Salewski technique is performed in order to discriminate between resorption and pseudopregnancy - Fetal examinations:
- - External examinations: Yes
- all per litter
- all live fetuses are individually weighed
- all live and dead fetuses are carefully examined for any external anomalies
- Soft tissue examinations: No
- Skeletal examinations: Radiographic examinations are carried out for all fetuses of all groups. Rat fetuses of each litter are randomized for dissection (half) and if indicated by the results of the radiographic examination for clearing and bone staining with alizarin (half).
- Head examinations: No
- Malformations or fetal anomalies encountered at the moment delivery by caeserean section or at each stage of dissection are noted - Statistics:
- Adult rat:
- mortality and pregnancy: Chi-square test
- body weight, bodyweight change and food consumption: Mann-Whitney U test
Litter data:
live fetuses, dead fetuses, resorbed fetuses, litter size, body weight, abnormalities: Mann-Whitney U test - Indices:
- no data
- Historical control data:
- no data
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- not specified
- Description (incidence and severity):
- No data on clinical signs is available
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- One female (n° 34-not pregnant of the 40 mg/kg dosed group) died for unknown reason on day 12. This animal did not show drug- or dose-related effects.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- There was an increase in weight among all dams of control as well as dams doses at 40, 80 and 120 mg/kg. Lower body weight was observed at 40, 80 and 120 mg/kg at the end of dosing period (day 17) and at 120 mg/kg at the end of post-dosing perdiod. In addition, body weight change was lower when compared to controls in the 80 and 120 mg/kg.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Food consumption significantly decreased during dosing in the three dosed groups compared to controls.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not specified
- Description (incidence and severity):
- No further data available
- Gross pathological findings:
- not specified
- Description (incidence and severity):
- No further data available
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not specified
Maternal developmental toxicity
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- No significant difference wasnoticed in the number of implantations between the various groups.
- Total litter losses by resorption:
- not specified
- Early or late resorptions:
- effects observed, treatment-related
- Description (incidence and severity):
- At 80 mg/kg resorption rate showed a tendency for increase (statistically not significant). At 120 mg/kg bw, this increase was statistically significant (p<0.01). At 120 mg/kg this finding resulted in a lower litter size (p<0.01) and a decreased number of live fetuses (p<0.01).
- Dead fetuses:
- effects observed, treatment-related
- Description (incidence and severity):
- At 120 mg/kg there was a decreased number of live fetuses (p<0.01)
- Changes in pregnancy duration:
- not specified
- Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- Althought somewhat fluctuating between groups, pregnancy rate was comparable between groups:
Control group: 24/24 or 100 %
40 mg/kg: 20/24 or 83%
80 mg/kg: 23/24 or 96%
120 mg/kg: 22/24 or 92% - Other effects:
- not specified
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- 40 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
Maternal abnormalities
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Mean weight was comparable between controls and the 40 mg/kg dosed group. At 80 and 120 mg/kg body weight of pups decreased (p<0.05 and p<0.001, respectively).
- Reduction in number of live offspring:
- effects observed, treatment-related
- Description (incidence and severity):
- Decreased number of live fetuses observed at 120 mg/kg bw.
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- Fetal sex ratios determined for the dosed groups were 0.84, 0.96 and 0.91 respectively whereas in the controls the ratio was 0.76 which is slightly lower value than normally expected.
- Changes in litter size and weights:
- effects observed, treatment-related
- Description (incidence and severity):
- Lower litter size at 120 mg/kg bw.
- Changes in postnatal survival:
- not specified
- External malformations:
- no effects observed
- Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Split vertebrae center, rudimentary 14th ribs and wavy ribs are skeletal variations revealed by the X-ray method and confirmed by the alizarin staining. These findings are reguarly encountered in rat fetuses.
- Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Coelosomia and macroglossia are visceral abnormalities that might occur spontaneously and are randomly distributed among control and dosed groups.
- Other effects:
- not specified
- Details on embryotoxic / teratogenic effects:
- It is concluded that no teratogenic effects were evidenced in this study.
Effect levels (fetuses)
open allclose all
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- 80 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- not specified
- Basis for effect level:
- reduction in number of live offspring
- fetal/pup body weight changes
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 40 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- not specified
- Basis for effect level:
- reduction in number of live offspring
- fetal/pup body weight changes
Fetal abnormalities
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
Litter data
Fetuses (number expressed as mean+/-SE) |
|||||
dosage groups | litter size | N | live | dead | resorbed |
control group | 13.9 | 24 | 13.8 +/-0.8 | 0.0 | 0.4 +/-0.1 |
40 mg/kg | 12.1 | 20 | 12.0 +/-1.1 | 0.1 +/-0.1 | 0.5 +/-0.2 |
80 mg/kg | 13.0 | 23 | 13.0 +/-0.9 | 0.0 | 2.0 +/-0.7 |
120 mg/kg | 11.2** | 22 | 11.1 +/-0.9** | 0.1 +/-0.1 | 3.7 +/-0.7*** |
N: the number of litters examined per group
**p<0.01; ***p<0.001
Body weight
Dosage groups | N | weight of pups (grams) |
Control | 24 | 5.6 +/-0.1 |
40 mg/kg | 20 | 5.5 +/-0.1 |
80 mg/kg | 22 | 5.2 +/-0.1* |
120 mg/kg | 22 | 4.6 +/-0.1*** |
N represents the number of litters examined per group
*p<0.05; ***p<0.001
Applicant's summary and conclusion
- Conclusions:
- The test substance, when administered orally to pregnant Sprague-Dawley rats from day 6 through day 16 of pregnancy at the dose of 40 mg/kg was slightly maternally toxic (decreased food consumption and body weight at the end of the dosing) but without any adverse effect on litter parameters. Dosing at 80 and 120 mg/kg also resulted in maternal toxicity (decreased food consumption, body weight at the end of dosing and body weight gain) and herwith associated, in slight to moderate embryonal resorption and decreased pup weight. No teratogenic effect was evidenced up to the dose of 120 mg/kg in rats.
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