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EC number: 428-650-4 | CAS number: 153719-23-4
- 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:
- supporting study
- Study period:
- 06 Feb 1996 to 07 Mar 1996
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 996
- Report date:
- 1996
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
- Version / remarks:
- 1981
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)
- Version / remarks:
- 1984
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.9 (Repeated Dose (28 Days) Toxicity (Dermal))
- Version / remarks:
- 1992
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 3-(2-chloro-thiazol-5-ylmethyl)-5-methyl-[1,3,5]oxadiazinan-4-ylidene-N-nitroamine
- Cas Number:
- 153719-23-4
- Molecular formula:
- C8H10ClN5O3S
- IUPAC Name:
- 3-(2-chloro-thiazol-5-ylmethyl)-5-methyl-[1,3,5]oxadiazinan-4-ylidene-N-nitroamine
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- Tif: RAIf, SPF strain
- Sex:
- male/female
Results and discussion
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 250 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- body weight and weight gain
- histopathology: non-neoplastic
- Dose descriptor:
- NOAEL
- Effect level:
- 60 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- histopathology: non-neoplastic
Target system / organ toxicity
- Critical effects observed:
- no
Any other information on results incl. tables
Achieved doses
Concentration analysis results: The mean test substance concentrations were 101.4%, 102.3%, 105.9% and 102.1% of nominal for formulations prepared at concentrations of 1, 10, 100 and 500 mg/mL, respectively predose. During administration concentrations were 116.0%, 115.4%, 113.3% and 109.9% of nominal for dose formulations prepared 10, 30, 125 and 500 mg/mL, respectively.
Homogeneity results: The test substance was homogeneously distributed in the vehicle and varied between ‑2% to +3% of the mean concentrations.
Stability results: The test substance was stable in the vehicle at room temperature over a period of 7 hours, covering the period of dosing.
Mortality: There were no mortalities.
Clinical observations: There were no treatment-related clinical signs and no local irritation at the application sites.
Body weight and weight gain: Weight gain of males at 1000 mg/kg was retarded during the first 2 weeks of treatment but was unaffected by treatment at other dose levels and in females at 1000 mg/kg.
Table 1: Intergroup comparison of body weights and body weight gain (g) – selected time points
|
Dose level of the test substance (mg/kg bw/day) |
|||||||||
Males |
Females |
|||||||||
0 |
20 |
60 |
250 |
1000 |
0 |
20 |
60 |
250 |
1000 |
|
week 1 |
277.8 |
290.3 |
294.9*+ |
292.1 |
277.4 |
231.8 |
233.9 |
234.0 |
231.6 |
228.9 |
week 2 |
292.6 |
309.6* |
311.4* |
307.1 |
288.8 |
234.9 |
232.0 |
236.0 |
225.3 |
237.1 |
week 4 |
338.8 |
353.1 |
353.1 |
351.8 |
324.7 |
250.9 |
248.9 |
250.5 |
244.0 |
248.0 |
* p =< 0.05 (Wilcoxon), +/- p =< 0.01 |
Food consumption and compound intake: There were no treatment related effects on food consumption.
Haematology: There were no treatment-related effects on haematological profiles. All statistically significant values either showed no dose-relationship or recorded values were within historical ranges.
Clinical chemistry: Females at 250 and 1000 mg/kg had slightly raised plasma glucose levels and minimally raised alkaline phosphatase activities. Triglyceride levels were also slightly raised in females at 1000 mg/kg. Significantly elevated plasma K+ levels in all male groups are considered not to have been influenced by the test substance since control values were unusually low. Other differences from the controls in blood chemistry are considered not to be treatment related because they were too small to be of toxicological relevance (inorganic phosphate levels in males at 1000 mg/kg) or their occurrence showed no relationship to dose level.
Table 2: Intergroup comparison of treatment related clinical chemistry parameters
Parameter |
Dose level of the test substance (mg/kg bw/day) |
|||||||||
Male |
Female |
|||||||||
0 |
20 |
60 |
250 |
1000 |
0 |
20 |
60 |
250 |
1000 |
|
Glucose (mmol/L) |
7.528 |
7.786 |
7.886 |
7.592 |
6.622 |
6.390 |
6.126 |
6.159 |
9.592* |
9.739*+ |
Alk. phosphatase (u/L) |
171.5 |
140.0 |
144.7 |
155.2 |
135.6 |
108.3 |
95.42 |
95.62 |
174.5* |
139.8+ |
Triglycerides (mmol/L) |
0.501 |
0.623 |
0.688 |
0.708 |
0.516 |
0.515 |
0.506 |
0.438 |
0.700 |
1.091*+ |
*p < 0.05 (Wilcoxon);+positive trend (p < 0.01 Jonckheere) |
Sacrifice and pathology
Macroscopic findings: There were no treatment related macroscopic findings..
Organ weights: There were no treatment related effects on organ weights or ratios.
Microscopic findings: Morphological changes in the skin of the application site occurred at low incidence in both treated and control animals and are considered to have been induced by the treatment procedure rather than by the administration of the test substance. The liver, kidneys and adrenal glands were identified as target organs on the basis of histological findings. An increased incidence of minimal inflammatory cell infiltration and necrosis of single hepatocytes occurred in the liver of females at 250 and 1000 mg/kg. The elevated incidence of this lesion at 60 mg/kg is considered to fall within the limits of normal variation for this strain of rat. Effects on liver morphology were absent in the males. In the kidneys, minimal tubular hyaline change in males and minimal chronic tubular lesions in females were apparent at 1000 mg/kg. A single female at this dose level also showed minimal basophilic cell infiltration in the renal tubules. Lower dose levels were unaffected by these renal changes. In the adrenal glands, minimal inflammatory cell infiltration was evident in the cortex of females at 1000 mg/kg. No other groups were affected.
Table 3: Incidence of treatment-related histopathological findings
Organ/finding |
Dose level of the test substance (mg/kg bw/day) |
|||||||||
Male |
Female |
|||||||||
0 |
20 |
60 |
250 |
1000 |
0 |
20 |
60 |
250 |
1000 |
|
Adrenal glands: cortical fatty change inflammatory cell infiltration |
4 0 |
4 0 |
3 0 |
3 0 |
4 0 |
1 0 |
0 1 |
1 0 |
1 1 |
1 3 |
Kidneys: |
|
|
|
|
|
|
|
|
|
|
chronic progressive nephropathy |
0 |
0 |
0 |
0 |
1 |
0 |
1 |
0 |
0 |
0 |
glomerulosclerosis |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
chronic tubular lesion |
1 |
0 |
1 |
1 |
1 |
1 |
2 |
2 |
1 |
4 |
nephrocalcinosis |
1 |
0 |
0 |
1 |
0 |
3 |
5 |
5 |
5 |
5 |
renal tubular cast |
0 |
0 |
1 |
0 |
1 |
0 |
1 |
0 |
1 |
0 |
hyaline change |
1 |
2 |
1 |
1 |
3 |
0 |
0 |
0 |
0 |
0 |
calcification |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
basophilic proliferation |
2 |
2 |
0 |
2 |
1 |
0 |
0 |
0 |
0 |
1 |
Liver: |
|
|
|
|
|
|
|
|
|
|
inflammatory cell infiltration |
3 |
4 |
4 |
3 |
2 |
2 |
2 |
4 |
5 |
5 |
intrahepatic bile duct cholang/fibrosis |
1 |
0 |
0 |
1 |
1 |
0 |
0 |
0 |
0 |
0 |
extramedullary hematopoiesis |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
Kupffer cell hyperplasia |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
1 |
0 |
0 |
hepatocyte necrosis |
0 |
0 |
0 |
0 |
0 |
2 |
0 |
2 |
3 |
4 |
Applicant's summary and conclusion
- Conclusions:
- The no-observed-effect-level (NOEL) was 250 mg/kg (males) and 60 mg/kg (females) based on the occurrence of renal tubular hyaline change and minimal growth retardation at 1000 mg/kg (males) and histological changes in the liver at 250 mg/kg (females). In view of the low order of toxicity by the percutaneous route, a 90-day dermal study is not required.
- Executive summary:
In this repeated dose toxicity test, performed according to OECD 410 under GLP, groups of 5 male and 5 female Sprague-Dawley-derived rats (Tif: RAIf, SPF strain) were exposed dermally to the test material at dose levels of 0, 20, 60, 250 and 1000 mg/kg bw/day, by topical application under occlusive dressing for 6 hours/day, 5 days/week, for 4 weeks. The test substance was formulated as a suspension in aqueous 0.5% carboxymethylcellulose/0.1% Tween 80. Mortality and clinical signs were checked daily, individual body weights and food and water consumption were recorded weekly. Haematological and clinical chemistry investigations were performed on all animals towards the end of the treatment period. All animals were subjected to necropsy and post mortem examination, major organs were weighed and selected tissues examined histopathologically.
There were no mortalities, no clinical signs of an adverse reaction to treatment and no local irritation at the application site at any dose level. Weight gain of males at 1000 mg/kg was retarded during the first 2 weeks of treatment but was unaffected by treatment at other dose levels and in females at 1000 mg/kg. Food consumption was unaffected by treatment at all dose levels. There were no treatment related effects on haematology profiles. Females at 250 and 1000 mg/kg had slightly raised plasma glucose levels and minimally raised alkaline phosphatase activities. Triglyceride levels were also slightly raised in females at 1000 mg/kg. No macroscopic anomalies were detected at necropsy and all organ weights and ratios were unaffected by treatment. A treatment related increase in the incidence of minimal inflammatory cell infiltration and necrosis of single hepatocytes occurred in the liver of females at 250 and 1000 mg/kg. In the kidneys, minimal tubular hyaline change in males and minimal chronic tubular lesions in females were apparent at 1000 mg/kg. A single female at this dose level also showed minimal basophilic cell infiltration in the renal tubules. In the adrenal glands, minimal inflammatory cell infiltration was evident in the cortex of females at 1000 mg/kg.
The no-observed-effect-level (NOEL) was 250mg/kg (males) and 60mg/kg (females) based on the occurrence of renal tubular hyaline change and minimal growth retardation at 1000 mg/kg (males) and histological changes in the liver at 250 mg/kg (females). In view of the low order of toxicity by the percutaneous route, a 90-day dermal study is not required.
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