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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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- 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 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- 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:
- rabbit
- Strain:
- Himalayan
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Hoechst breeding colony
- Age at study initiation: about 6 - 10 months
- Weight at study initiation: mean body weight of 2639 ± 152 g
- Housing: individual metal-barred cages on wire-mesh floors
- Diet (e.g. ad libitum): ERKA 6000 standard diet in the form of pellets 4 mm in diameter (manufactured by Robert Koch OHG, Hamm/Westphalia), ad libitum; also 40-50 g autoclaved hay daily.
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: at least 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.5-23.5
- Humidity (%): 43-62
- Air changes (per hr): 16-20
- Photoperiod (hrs dark / hrs light): 10/14
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: starch mucilage
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Suspended freshly each day in starch mucilage (20 g potato starch per litre distilled water)
VEHICLE
- Justification for use and choice of vehicle (if other than water): handling at dosing
- Concentration in vehicle: 8, 20, 50 g/L
- Amount of vehicle (if gavage): 5 mL/kg bw - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The stability and homogeneity of the suspensions were guaranteed for a period of at least 4 hours (statements from the Analytical Laboratory, dated 24 August 1990 and 06 February 1991).
- Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: during the morning hours, not further specified
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- Any other deviations from standard protocol: Those females with sperm in the vaginal smear were mated again after about 6 hours in case the first mating had not been successful. - Duration of treatment / exposure:
- GD 6-18
- Frequency of treatment:
- once daily
- Duration of test:
- until GD29
Doses / concentrationsopen allclose all
- Dose / conc.:
- 40 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 250 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 15 - 16 mated females
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Preliminary range finder study with groups of 2-4 mated Himalayan rabbits administered doses of 200, 320 or 500 mg/kg once daily from the 6th to the 18th day after mating.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations included: behaviour, general health condition
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: prior to first treatment, once weekly (body weight gains) in the first 3 weeks, GD 19 and GD 29
FOOD CONSUMPTION: Yes, same intervals as body weight
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/100 g body weight/day: Yes
WATER CONSUMPTION: Yes
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 29
- Organs examined: gall-bladder, heart, intestines, kidney, liver, spleen, ovary, uterus; (heart, liver, kidneys and spleen were weighed) - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: live and dead foetuses, placentae, placental weights, diameter of conceptuses under resorption, crown/rump length, foetal weight, sex, survival rate after 24h incubator - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter (brain, eyes, heart and both kidneys)
- Skeletal examinations: Yes: all per litter
- Head examinations: No - Statistics:
- Comparisons with the control group of body weights and organ weights: standard MANOVA with sequentially rejective multiple comparisons, and relative food consumption by means of the nonparametric linear model of PURI & SEN (1985) with sequentially rejective multiple comparisons.
The Mantel-Haenszel test with sequentially rejective multiple comparisons (MANTEL & HAENSZEL, 1959) was used for analysing implants, corpora lutea, survival rates, ratios of live and dead foetuses, and conceptuses under resorption. The foetal weights, crown-rump lengths and placental weights were evaluated by means of a multivariate variance analysis corrected for litter effects. With each of these methods the probability of error for each group of parameters was 5%.
The findings at autopsy and at the examinations of organ cross-sections and skeletons were evaluated for foetuses and litters separately by the exact Fisher test. This tested whether the relative incidences of these findings in the dose groups differed from those in the control. For comparing the data with historical controls, ranges of normal variation for groups were calculated. These were drawn up in such a way as to include with a probability of 95 % at least 75 of the values for a group of control animals. The parallelipiped method of WALD (1943) was employed for body weight gains and food consumption among the dams and for mean foetal weights, crown-rump lengths and placental weights per litter. Comparisons of corpora lutea, implants and survival rates were performed with univariate normal ranges by the method of WILKS (1942). For the ratios of live and dead foetuses and of conceptuses under resorption, normal ranges were determined by the triangular method of ROSENKRANZ (1988). - Historical control data:
- A group of animals of a given size is normal with respect to a parameter, if at least 75 % of the values lie within the ranges of the historical control groups.
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
One dam in the 250 mg/kg group aborted during the night from days 22 to 23 of gravidity. Four dams had vaginal haemorrhages, which pointed to an abortion - the first on day 16, the second on day 20, the third on day 23, and the fourth during the night from days 16 to 17 of gravidity. One
other dam delivered prematurely on day 27 of gravidity. In addition to these findings, a decrease or absence of excrement was observed on one or several days between days 11 and 27, involving one dam from the 40 mg/kg group, two dams in the 100 mg/kg group and about half of the dams in the 250 mg/kg group. One dam in the 250 mg/kg group had soft excrement on days 19 and 23 of gravidity. The dams in this group which were killed intercurrently due to abortions had shown marked reductions in food consumption during the one or two weeks prior to killing. The considerably lower
food consumption was matched by reduced quantities of excrement. Lower food consumption was accompanied by reduced water consumption. In the 250 mg/kg group almost all the dams showed generally slight, but in several cases also more marked, body weight losses during the 1st week of treatment.
Effect levels (maternal animals)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- maternal toxicity
- Effect level:
- 100 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: no adverse effect observed
- Key result
- Dose descriptor:
- LOAEL
- Remarks:
- maternal toxicity
- Effect level:
- 250 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- clinical signs
- food consumption and compound intake
- pre and post implantation loss
- water consumption and compound intake
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
One dam in the 250 mg/kg group had only empty implantation sites in the uterus. There were also five dams in the 250 mg/kg group which had aborted with clinical signs. The animal killed on day 16 of gravidity had 3 empty implantation sites in addition to 6 conceptuses under resorption. Two dams had only conceptuses under resorption in the uterus: 7 in the one which was killed on day 17 of gravidity (having aborted in the night from days 16 to 17) , and 8 in the one which was killed on day 23. The animal killed on day 20 of gravidity had 3 conceptuses under resorption and also 5 dead foetuses, 3 of them severely stunted.
There was no evidence for teratogenic effects.
Effect levels (fetuses)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- embryotoxicity
- Effect level:
- 100 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: no adverse effects observed
- Key result
- Dose descriptor:
- LOAEL
- Remarks:
- embryotoxicity
- Effect level:
- 250 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- reduction in number of live offspring
- changes in litter size and weights
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- teratogenicity
- Effect level:
- >= 250 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: no adverse effects observed
- Remarks on result:
- other:
- Remarks:
- highest dose tested
Overall developmental toxicity
- Key result
- Developmental effects observed:
- not specified
Any other information on results incl. tables
Selected maternal parameters:
|
Dose (mg/kg bw) |
|||
Parameter |
0 |
40 |
100 |
250 |
Dams with live foetuses |
13 |
14 |
15 |
8 |
Number of live foetuses (total) |
86 |
82 |
84 |
46 |
Conclusion:
Based on the results of this study, the NOAEL for maternal toxicity and embryotoxicity in the rabbit was 100 mg/kg bw/day Hoe 107892. No teratogenic effect was observed at any dose level tested.
5/6 abortions observed in the high dose group occurred in dams which demonstrated the most severe characteristics of reduced food and water consumption, body weight loss, and reduced defecation in this group.
It is widely known that food deprivation of does during the phase of organogenesis has significant effects on the development of their offspring and the dams themselves, manifesting as reduced body weight gain or even loss, reduced water consumption and increased number of abortions. Publications are available demonstrating this phenomenon: Petrere, J.A. et al. (1993). Fundam. Appl. Toxicol. 21: 517-522; Matsuzawa, T. et al. (1981). Toxicology 22: 255-259.
Therefore, abortions and embryotoxicity observed in this study have to be considered as secondary effects due to maternal toxicity, induced by reduced food uptake and body weight loss of the dams during the phase of organogenesis.
Applicant's summary and conclusion
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