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EC number: 406-850-2 | CAS number: 133855-98-8 BAS 480 F
- 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- Jan 1989 - Jan 1991
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 992
- Report date:
- 1992
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 452 (Chronic Toxicity Studies)
- Qualifier:
- according to guideline
- Guideline:
- other: Pesticide Assessment Guidelines, Subdivisoin F, § 83-1, pages 107-117 NTIS, Nov. 1982 and revised edition, Nov. 1984
- Qualifier:
- according to guideline
- Guideline:
- other: Testing Guidelines for Toxicology Studies (Japan/MAFF, 1985)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- (2RS,3RS)-3-(2-chlorophenyl)-2-(4-fluorophenyl)-[(1H-1,2,4-triazol-1-yl)methyl]oxirane
- EC Number:
- 406-850-2
- EC Name:
- (2RS,3RS)-3-(2-chlorophenyl)-2-(4-fluorophenyl)-[(1H-1,2,4-triazol-1-yl)methyl]oxirane
- Cas Number:
- 133855-98-8
- Molecular formula:
- C17 H13 Cl F N3 O
- IUPAC Name:
- 1-{[(2R,3R)-3-(2-chlorophenyl)-2-(4-fluorophenyl)oxiran-2-yl]methyl}-1H-1,2,4-triazole
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on species / strain selection:
- not specified
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Dr. Karl Thomae GmbH, Biberach, Germany
- Age at study initiation: 35 days
- Weight at study initiation: 189 g males (175 - 202 g); 148 g females (132 - 161 g)
- Fasting period: 16-20 h before sacrifice
- Housing: single
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 6 days
DETAILS OF FOOD AND WATER QUALITY: The food used in the study was assayed for chemical as well as for microbiological contaminants. The drinking water is regularly assayed for chemical contaminants by the municipal authorities.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: January 26 (administration period began) 1989 To: January 24, 1991 (last day of sacrifice)
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- other: diet
- Details on oral exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): regular intervals
- Mixing appropriate amounts with (Type of food): Kliba maintenance diet rat/mouse/hamster 343 meal
- Storage temperature of food: not specified
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The analysis of the test substance in the food was carried out using HPLC.
- Duration of treatment / exposure:
- 24 months
- Frequency of treatment:
- continous
Doses / concentrationsopen allclose all
- Dose / conc.:
- 30 ppm
- Remarks:
- males: 1 mg/kg bw/day, females: 2 mg/kg bw/day, all animals: 2 mg/kg bw/day
- Dose / conc.:
- 150 ppm
- Remarks:
- males: 6 mg/kg bw/day, females: 9 mg/kg bw/day, all animals: 8 mg/kg bw/day
- Dose / conc.:
- 750 ppm
- Remarks:
- males: 32 mg/kg bw/day, females: 44 mg/kg bw/day, all animals: 38 mg/kg bw/day
- Dose / conc.:
- 1 500 ppm
- Remarks:
- males: 67 mg/kg bw/day, females: 89 mg/kg bw/day, all animals: 78 mg/kg bw/day
- No. of animals per sex per dose:
- 20
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale:
The selection of doses was based on the following studies: A 4-week study in rats via diet with concentrations of 4000 ppm, 1000 ppm, and 250 ppm, the first 3-month feeding study in rats via diet using 800 ppm, 270 ppm, 90 ppm, and 30 ppm, a second 3-month feeding study in rats using 2000 ppm, 1500 ppm, 1000 ppm, and 500 ppm.
- Rationale for animal assignment (if not random): random
- Fasting period before blood sampling for clinical biochemistry: not fasted - Positive control:
- not included
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at leat once daily
- Cage side observations checked: state of health
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once a week
BODY WEIGHT: Yes
- Time schedule for examinations: Once a week during the first 14 weeks. Thereafter, at 4-week intervals and at the end of the study
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Time schedule: Once a week during the first 14 weeks. Thereafter, at 4-week intervals and at the end of the study
FOOD EFFICIENCY: Yes
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: before start and end of study
- Dose groups that were examined: both sexes from control and maximum dose
HAEMATOLOGY: Yes
- Time schedule for collection of blood: after about 3, 6, 12, 18 and 24months after the start of the study.
- Anaesthetic used for blood collection: No
- Animals fasted: No
- How many animals: all animals
- Parameters checked: Leukocyte count (WBC), erythrocyte count (RBC), hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelets count (PLT), differential blood count, reticulocytes (RETI), thromboplastin time (Hepato Quick's test)
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after about 3, 6, 12, 18 and 24months after the start of the study.
- Animals fasted: No
- How many animals: all animals
- Parameters checked: Alanine aminotransferase, aspartate aminotrasferase, alkaline phosphatase, serum-gamma-glutamyltransferase, sodium, potassium, chloride, inorganic phosphate, calcium, urea, creatinine, glucose, total bilirubin, total protein, albumin, globulins, triglycerides, cholesterol
URINALYSIS: Yes
- Time schedule for collection of urine: after about 3, 6, 12, 18 and 24months after the start of the study.
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No
- Parameters checked: appearance, nitrite, pH, protein, glucose, ketones, urobilinogen, bilirubin, blood, sediment
NEUROBEHAVIOURAL EXAMINATION: No
IMMUNOLOGY: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
- Complete necropsies were performed on all rats.
- Terminal body weight, weights of adrenal glands, brain, liver, kidneys, and testees were determined from all animals which survived to scheduled necrospy
HISTOPATHOLOGY: Yes
- Adrenal glands, aorta, bone (sternum, femur including femorotibial joint), bone marrow (sternum, femur), brain, cecum, coagulation glands, colon, duodenum, epididymides, esophagus, eyes, female mammary gland, heart, jejunum, kidneys, liver, lungs, lymph node (mandibular, mesenteric), ovaries, pancreas, parathyroid glands, pituitary gland, prostate gland, rectum, salivary glands (mandibular, sublingual), sciatic nerve, seminal vesicles, skeletal muscle, skin, spinal cord (cervical, thoracic, lumbar), spleen, stomach, testes, thymus, thyroid gland, trachea, urinary bladder, uterus, and all organs or tissues with macroscopic abnormalities. - Statistics:
- ANOVA, Dunnett's test
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Description (incidence):
- The mortality rate of the male and female animals was not affected by admnistration of the test substance.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- - 1500 ppm: Retarded body weight gain in the males and at the end of the study reduced body weight in the males of about 9% and in the females of about 9%
- 750 ppm: In males, during the second half of the study body weights turned to comparable values to control and at the end of the study did not show statistically significance or biological relevance - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- - 1500 ppm: Reduced food consumption in males of about 12% and in females of about 7% at the end of the study
- 750 ppm: In males, slight decrease in food consumptionoccurred until the 86th week and then became comparable to the control group until the end of the study, where no biologically evident deviation was noted. - Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The remainders of the pupillary mambrane are incomplete involution of vessels, which are evident for the nutrition of the eye during the normal embryonic development. They have no influence on the general development, general state and the normal life span of the affected animals. Due to this, this finding is without any pathological or substance-related relevance.
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- - 1500 ppm: Decrease in mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), platelets, and alkaline phosphatase in both sexes. Decrease in mean corpuscular hemoglobin concentration (MCHC) and thromboplastin time in females. These changes are assessed to be substance related and are due to a slight hemotoxic potential of the test substance.
- 750 ppm: Decrease in platelets in both sexes. Decrease in mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), thromboplastin time, and alkaline phosphatase in females
- 150 ppm: Decrease in platelets in males - Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- - 1500 ppm: Increase in gamma-glutamyltransferase in both sexes. Increase in urobilinogen in the urine of both sexes. Increase in albumin in males. Increase in cholesterol, total protein and globuline in females. Decrease in triglyceride concentration in both sexes.
- 750 ppm: Increase in gamma-glutamyltransferase and albumin in males. Increase in cholesterol and globulins in females. Decrease in triglycerides in females.
- 150 ppm: Decrease in triglycerides in females, increase in cholesterol in females - Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- - 1500 ppm: Discoloration of the urine specimens in females. Increased urobilinogen levels in both sexes, which suggestes a liver dysfunction
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- - 1500 ppm: Increased absolute and relative liver weights in both sexes.
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- As compared with controls, the incidences of ovarian cysts and thickening of the cervix were higher in groups 150, 750, and 1500 ppm. However, there was no clear dose relationship. In males, the incidence of testicular masses was remarkably lower in all treated groups.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- - 1500 ppm: Increase in incidence and severity of hepatocellular hypertrophy in both sexes
- 750 ppm: Increase in incidence and severity of hepatocellular hypertrophy in both sexes - Histopathological findings: neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- All neoplastic lesions recorded in this study were considered to be of a spontaneous nature.
Males: slight increase of hepatocellular carcinoma at 1500 ppm; females: slight increase of ovarian tumours (granulosa) in all doses; but the changes to the control groups were not statistically significant. - Details on results:
- The slight decrease in food consumption until the 86th week and the slight retardation of the body weight gain in the males dosed 750 ppm is probably induced by the test substance, but both changes improved during the further course of the study and at the end of the study these parameters were comparable to the respective controls. Thus, these changes were assessed as signs of minor or no toxicological relevance.
At histopathological examination, non-neoplastic treatment-related findings of toxicological significance were recorded in the liver in the form of hepatocellular hypertrophy. As compared with controls, the incidence and severity of hypertrophy were increased in males and
females of groups 750 and 1500 ppm.
Further, as compared with controls delayed age-related involution of the female gonads and less advanced age related lesions in adrenal glands, heart, kidneys and uterus/cervix were recorded in males and females of dose groups 750 and/or 1500 ppm, respectively.
All other histopathological findings recorded in this study were considered to be incidental.
It is concluded from this study, that the long-term administration of the test article did not result in oncogenic effects in rats when given via the feed at nominal concentrations of 30, 150, 750, and 1,500 ppm. All neoplastic lesions recorded in this study were considered to be of a spontaneous nature. Malignant hepatocellular neoplasms were recorded at a higher incidence in males of the dose group 1500 ppm. This difference, however, did not prove to be statistically significant. The combined incidence of benign plus malignant hepatocellular
neoplasms across the groups in males was 6, 2, 3, 4, 9, in females 0, 1, 1, 0, 0 for control, 30 ppm, 150ppm, 750 ppm, 1500 ppm, respectively. Theca-granulosa cell tumors were more frequently recorded in treated groups at an incidence of 0, 0, 1, 3, 3. This difference did not prove to be statistically significant. The administration of the test article did not cause any nonneoplastic histopathologic lesions at concentrations of 30 ppm and 150 ppm.
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- 30 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- histopathology: non-neoplastic
- organ weights and organ / body weight ratios
Target system / organ toxicity
open allclose all
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 750 ppm
- System:
- hepatobiliary
- Organ:
- liver
- Treatment related:
- yes
- Dose response relationship:
- yes
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 750 ppm
- System:
- haematopoietic
- Organ:
- blood
- Treatment related:
- yes
- Dose response relationship:
- yes
Any other information on results incl. tables
Table 1: Neoplastic lesions on the liver
|
|
Group 0 |
Group 1 |
Group 2 |
Group 3 |
Group 4 |
Liver -adenoma Males |
n N |
6 20 |
2 20 |
1 20 |
3 20 |
5 20 |
Liver – carcinoma Males |
n N |
0 20 |
0 20 |
2 20 |
1 20 |
4 20 |
Ovaries – theca-granulosa cell tumor |
n N |
0 20 |
0 20 |
1 20 |
3 20 |
3 20 |
N = number of animals examined; n = number of animals affected
Table 2: Absolute weights, summary
|
|
Group 0 |
Group 1 |
Group 2 |
Group 3 |
Group 4 |
Kidneys |
M N |
4.239 17 |
4.296 14 |
4.141 13 |
3.866* 19 |
3.813* 16 |
Liver |
M N |
19.906 17 |
19.819 14 |
20.537 13 |
20.547 19 |
25.566* 16 |
Testes |
M N |
5.069 17 |
3.802* 14 |
4.073 13 |
4.113 19 |
3.808* 16 |
M = Mean number in g, N = number of animals examined, p = <= 0.05
Applicant's summary and conclusion
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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