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EC number: 603-923-2 | CAS number: 135590-91-9
- 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: dermal
Administrative data
- Endpoint:
- short-term repeated dose toxicity: dermal
- Type of information:
- experimental study
- Adequacy of study:
- key study
- 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 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
- Deviations:
- yes
- Remarks:
- occlusive dressing, extended program of histopathology
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)
- Deviations:
- yes
- Remarks:
- occlusive dressing, extended program of histopathology
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- diethyl 1-(2,4-dichlorophenyl)-5-methyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylate
- EC Number:
- 603-923-2
- Cas Number:
- 135590-91-9
- Molecular formula:
- C16H18Cl2N2O4
- IUPAC Name:
- diethyl 1-(2,4-dichlorophenyl)-5-methyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylate
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Hoechst AG, Kastengrund, SPF breeding colony
- Age at study initiation: approx. 8 weeks
- Weight at study initiation: males 190 ± 2.4 g; females 181 ± 2.6 g
- Housing: in Makrolon cages (Type 3) on soft wood granulate, one animal per cage
- Diet (e.g. ad libitum): Altromin 1324 pelleted rat diet (Altromin GmbH, Lage/ Lippe), ad libitum, except for the period in which the animals were kept in diuresis cages
- Water (e.g. ad libitum): tap water in plastic bottles, ad libitum, except for the period in which the animals were kept in diuresis cages
- Acclimation period: 8 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 23
- Humidity (%): 25 - 75
- Air changes (per hr): approx. 12 per hour
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Type of coverage:
- occlusive
- Vehicle:
- polyethylene glycol
- Details on exposure:
- TEST SITE
- Area of exposure: dorsal
- % coverage: 10
- Type of wrap if used: occlusive bandage (3-layer cellulose bandage, aluminium foil, Fixomull-Stretch and Elastoplast from Beiersdorf/Hamburg)
- Time intervals for shavings or clipplings: At the start of the study and subsequently at least once weekly with an electric clipper
REMOVAL OF TEST SUBSTANCE
- Washing (if done): with warm water
- Time after start of exposure: 6 hours
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100, 300, 1000 mg/kg
- Concentration (if solution): 50, 150, 500 mg/ml
- Constant volume or concentration used: yes
VEHICLE
- Justification for use and choice of vehicle (if other than water): handling at dosing
- Amount(s) applied (volume or weight with unit): 2 ml/kg
USE OF RESTRAINERS FOR PREVENTING INGESTION: yes, occlusive dressing - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Immediatly after preparation and once more at last day of use for application, the active ingredient contents and homogeneity of all formulations
were examined by an analytical laboratory. According to report of 23 October 1991, the homogeneity and stability of the test substance preparations were guaranteed for a period of 18 days and the actually administered test substance concentrations corresponded in high degree to the nominal concentrations. - Duration of treatment / exposure:
- 29 days
- Frequency of treatment:
- 6 h/day, 5 days/week
Doses / concentrationsopen allclose all
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 5 (additionally 5 males and females in control and high dose recovery groups)
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The selection of dosages was based on the results of an acute dermal toxicity study in rats, which yielded a LD50-value of > 4000 mg/kg body weight (Report No. 90.0451).
- Post-exposure recovery period in satellite groups: 15 days
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations included: behaviour, general health condition (clinical signs), mortality
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly for neurological disturbances, damage to the oral mucosa, and impairment of dental growth.
DERMAL IRRITATION (if dermal study): Yes, based on scores of OECD 404
- Time schedule for examinations: prior to each application
BODY WEIGHT: Yes
- Time schedule for examinations: at start of the study and then twice weekly
FOOD CONSUMPTION: Yes, at the start of the study and then twice weekly (same days as body weight)
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data
WATER CONSUMPTION: Yes
- Time schedule for examinations: once weekly for a period of 16 hours
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: weekly for opacity of the refracting media of the eyes
- Dose groups that were examined: all
HAEMATOLOGY: Yes
- Time schedule for collection of blood: one day after the last application (recovery groups at the end of the 2-week recovery period)
- Anaesthetic used for blood collection: Yes (Nembutal), at retrobulbar venous plexus
- Animals fasted: No data
- How many animals: all (a few parameters only for control and high dose group)
- Parameters examined: erythrocytes, haemoglobin, haematocrit, MCV, MCH, MCHC, leucocytes, thrombocytes, differential blood count, reticulocytes*, Heinz bodies*, coagulation time, thromboplastin time, activated partial thromboplastin time, thrombin time, methaemoglobin* (*only performed for control and high dose group)
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: one day after the last application (recovery groups at the end of the 2-week recovery period): after blood sampling from the retrobulbar venous plexus for haematological examination, the animals were killed by opening of the vena cava cranial is under
Nembutal anaesthesia (50 mg/kg body weight, i.p.) and exsanguinated.
- Animals fasted: No data
- How many animals: all
- Parameters examined: sodium, potassium, inorganic phosphorus, uric acid, total bilirubin, creatinine, serum glucose, urea nitrogen, calcium, chloride, ASAT, ALAT, alkaline phosphatase, gamma-GT, LDH, cholesterol, triglycerides, total lipids, total protein, electrophoresis
URINALYSIS: Yes
- Time schedule for collection of urine: in all main groups during the night (about 16 hours) before day 25 of the study. The urine of the recovery animals was not collected, since no effects were observed in the animals of the main groups.
- Metabolism cages used for collection of urine: Yes, individual diuresis cages
- Animals fasted: Yes
- Parameters examined: appearance, colour, pH value, haemoglobin, protein, glucose, ketone bodies, bilirubin, urobilinogen, nitrite, ascorbic acid, sediment (performed only for control and high dose group), volume of urine
NEUROBEHAVIOURAL EXAMINATION: No
OTHER: - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (skin, orifices, eyes, teeth, oral mucosa and internal organs)
HISTOPATHOLOGY: Yes, of control and high dose animals (heart, uterus/ovaries, lungs, adrenals, liver, pituitary, kidneys, thyroid (both lobes), spleen, bone marrow (femur), brain, sternum, both testes, skin (treated & untreated, approx. 2 x 2 cm), seminal vesicle, prostate gland, special macroscopic abnormalities); slides of treated skin, liver, kidneys, testes and macroscopic lesions were read of animals from intermediate groups - Other examinations:
- ORGAN WEIGHTS
The absolute weights of the following organs were determined and the relative weights per 100 g body weight calculated: heart, brain, lungs, testes/ovaries, liver, adrenals, kidneys, pituitary, spleen, thyroid - Statistics:
- The following data were evaluated statistically at the level of significance p < 0.05:
body weights at the designated measurement times, haematology parameters (except diff. blood count and methaemoglobin), clinical chemistry parameters (except gamma-GT), urinalysis (pH value, volume), absolute organ weights, relative organ weights.
Evaluation was performed by PHARMA DEVELOPMENT INFORMATIC with the aid of a program package for evaluating toxicological studies. The statistical methods used in each case were given on the computer printouts.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Dermal irritation:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY
Behaviour and general health condition remained normal throughout the study in all of the treated groups. There were no indications of any neurological disturbances, impairment of dental growth or changes in the oral mucosa which might have been attributed to administration of the test substance. There were no deaths at any time during the study.
BODY WEIGHT AND WEIGHT GAIN
The test substance had no effect on body weight gains in animals of either sex in any of the treatment groups.
FOOD CONSUMPTION
The test substance had no effect on the food consumption of animals of either sex in any of the treatment groups.
WATER CONSUMPTION
Water consumption was variable. No effects could be observed as a result of treatment with the test substance.
OPHTHALMOSCOPIC EXAMINATION
There were no indications of opacity of the refracting media of the eyes.
HAEMATOLOGY
At the end of the treatment period slight decreases in erythrocyte counts, haemoglobin content and haematocrit value in the females from the highest dose group. This finding might be related to the test substance and indicative of a marginal anaemia. This effect could not be observed at the end of the recovery period. Additional correlates indicative of haematoxicity could not established by clinical biochemistry or pathology. No other changes attributable to the test substance could be detected.
CLINICAL CHEMISTRY
Statistical analysis revealed only a decrease in total bilirubin in the females of the highest dose group at the end of treatment. This effect showed a dose-dependency and was therefore considered to be related to the treatment with the test compound. No other changes were noted at the end of treatment.
Evaluation of the serum electrophoresis data gave no convincing evidence of substance-related changes at the end of treatment. Only a marginal increase in globulines was noted in the females treated at 300 and 1000 mg/kg body weight. However, no biological significance could be assigned to this change.
URINALYSIS
The urinary status of all animals remained unaffected by dermal treatment with the test substance. There was no evidence of any damage to the renal system. The urine of the large majority of animals in all groups was clear and yellow in colour. At the end of the treatment period, the group mean pH values varied between 6.7 and 6.9 in the males and between 6.2 and 6.8 in the females. The group mean urinary volume varied between 6.1 and 7.4 ml in the males and between 2.8 and 4.3 ml/16h in the females. Examination of the urine for protein, glucose, haemoglobin, bilirubin, urobilinogen, ascorbic acid, nitrite and ketone bodies gave no indication of substance-related changes; the same applies to the examination of urinary sediments in the
control and high-dose animals at the end of the treatment period.
ORGAN WEIGHTS
Statistical analysis of the absolute and relative organ weights indicated no changes in any of the treated groups as compared with the control group.
GROSS PATHOLOGY
Neither topically nor systemically any adverse reaction attributable to the test compound administered was to be found at morphological investigation of skin and internal organs.
HISTOPATHOLOGY: NON-NEOPLASTIC
Neither topically nor systemically any adverse reaction attributable to the test compound administered was to be found at microscopical investigation of skin and internal organs.
OTHER FINDINGS
The test substance proved to be non-irrating to the skin and histopathology indicated also no changes attributable to the test compound.
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- systemic toxicity
- Effect level:
- 300 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no adverse effect observed
- Key result
- Dose descriptor:
- LOAEL
- Remarks:
- sytemic toxicity
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical biochemistry
- haematology
Target system / organ toxicity
- Key result
- Critical effects observed:
- not specified
Any other information on results incl. tables
Haematology parameters:
|
Dose level (mg/kg bw/d) |
|||||||
|
males |
females |
||||||
Parameter |
0 |
100 |
300 |
1000 |
0 |
100 |
300 |
1000 |
Erythrocytes (10e12/L) |
6.65 |
6.79 |
7.08 |
6.76 |
6.85 |
6.32 |
6.64 |
6.10* |
Hb (g/L) |
131 |
137 |
139 |
137 |
131 |
130 |
128 |
125 |
Haematocrit |
0.40 |
0.41 |
0.42 |
0.41 |
0.42 |
0.40 |
0.40 |
0.38 |
MCH (10e-12g) |
20 |
20 |
20 |
20 |
19 |
21* |
19 |
21* |
MCHC (g/L) |
327 |
333 |
331 |
336 |
314 |
327* |
321 |
330* |
* p<= 0.05
Conclusion:
Based on the results of this repeated-dose dermal toxicity study (21 treatments in 29 days) with Hoe 107892 00 ZC94 0001 in the Wistar rat, the NO OBSERVABLE ADVERSE EFFECT LEVEL (NOAEL) for systemic toxicity is considered to be 300 mg/kg bw/day.
Repeated dermal treatment with 1000 mg/kg body weight caused a marginal anaemia and a decrease in total bilirubin in the female rat.
Under the conditions of this study, the test substance in the form of a suspension in PEG 400 proved to be non-irritating to the treated skin.
Applicant's summary and conclusion
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