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EC number: 619-020-1 | CAS number: 94361-06-5
- 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: inhalation
Administrative data
- Endpoint:
- short-term repeated dose toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 28 Oct 1987 to 27 Nov 1987
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 987
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
- Version / remarks:
- 1981
- Deviations:
- yes
- Remarks:
- 1) Number of animals sacrificed after 16 days, 3 males and 3 females instead of 5 males and 5 females. 2) Number of animals for recovery 2 males and 2 females instead of 5 males and 5 females. Such deviations did not effect the integrity of the study.
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- 2-(4-chloro-phenyl)-3-cyclopropyl-1-[1,2,4]triazol-1-yl-butan-2-ol
- Cas Number:
- 94361-06-5
- Molecular formula:
- C15H18ClN3O
- IUPAC Name:
- 2-(4-chloro-phenyl)-3-cyclopropyl-1-[1,2,4]triazol-1-yl-butan-2-ol
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Remarks:
- SPF
- Sex:
- male/female
Administration / exposure
- Route of administration:
- inhalation: aerosol
- Type of inhalation exposure:
- nose only
- Vehicle:
- air
- Details on inhalation exposure:
- Mean airflow in the exposure chambers was 1.4 L/min/animal
- Duration of treatment / exposure:
- 16 days
- Frequency of treatment:
- Exposed for 6 hours a day, 5 days a week for a total of 2 weeks (12 exposures). Recovery duration after the last exposure was 15 days.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0.01 mg/L air (nominal)
- Remarks:
- Group 2, low
- Dose / conc.:
- 0.1 mg/L air (nominal)
- Remarks:
- Group 3, mid
- Dose / conc.:
- 1 mg/L air (nominal)
- Remarks:
- Group 4, high
- No. of animals per sex per dose:
- 5
- Control animals:
- yes
Results and discussion
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- 0.01 mg/L air (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- food consumption and compound intake
- haematology
- histopathology: non-neoplastic
- Remarks on result:
- other: Equivalent to an actual dose of 0.017 mg/L, and equivalent to 4.9 mg/kg bw/day (6 hours exposure per day; 0.8 L air/kg/min)
Target system / organ toxicity
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 0.1 mg/L air (nominal)
- System:
- other: Respiratory, hepatobiliary and immune system
- Organ:
- liver
- lungs
- spleen
- Treatment related:
- yes
- Dose response relationship:
- yes
Any other information on results incl. tables
ANALYTICAL VERIFICATION OF TEST SUBSTANCE
Gravimetric determination of the aerosol concentrations revealed means of 0.017 mg/L (low dose), 0.099 mg/L (mid dose) and 1.026 mg/L (high dose).
Particle size determinations showed comparable distributions over time and dose. As a mean of all determinations 90 % of the particles were found to be smaller than 3.0 μm.
MORTALITY
Three females of the high dose group were found dead after the second exposure. Exposure of this group was stopped thereafter. The remaining animals had to be sacrificed on day 3 or day 6 for human reasons. No other deaths were observed.
CLINICAL SIGNS
With all high dose animals’ slight hunched posture, laboured respiration, ruffled fur and weakness were observed. Ventral recumbence was observed in females only. In mid dose animals slight squealing, howling and crying was noted in one male and three females. The same symptoms were observed in 1 male and 2 females of the low dose group.
BODY WEIGHT AND FOOD CONDUMPTION
From day 1 to 16 there was a slight increase in food consumption in the males and a decrease in food consumption in the females. Over the same period there was a slight increase in body weight gain in males and a decrease in body weight gain in females. Mid-dose females showed a slightly reduced body weight gain throughout the study and reduced body weight at the end of the study (156.4 g versus 177.5 g in the control group).
HAEMATOLOGY
Analysis of WBCs revealed a dose dependent increase in both males and females after 3 weeks.
Table 1. 16-day inhalation rat – affected haematology parameters.
parameter | control | 0.01 mg/L | 0.1 mg/L | control | 0.01 mg/L | 0.1 mg/L |
| males | females | ||||
WBC week 3 | 8.6 | 9.7 | 11.3 | 6.3 | 6.3 | 7.4 |
recovery |
|
| 10.2 |
|
| 7.7 |
CLINICAL CHEMISTRY
Bilirubin levels were slightly reduced in male animals of the low and mid dose group. LDH and ALP activities were slightly lower in mid dose male (not statistically significant). In female animals, effects were only seen in the mid dose group, being related to liver toxicity, i.e. a slight to moderate increase of ASAT and ALAT levels and high LDH activity. None of these effects were statistically significant. After recovery they were all returned to normal levels.
Table 2. 16-day inhalation rat - affected parameters of clinical chemistry.
parameter | control | 0.01 mg/L | 0.1 mg/L | control | 0.01 mg/L | 0.1 mg/L |
| males | females | ||||
bilirubin week 3 | 9.2 | 7.3* | 7.6* | 8.0 | 8.5 | 9.1 |
recovery |
|
| 10.7 |
|
| 12.0 |
LDH week 3 | 204 | 181 | 157 | 158 | 190 | 373 |
recovery |
|
| 160 |
|
| 75 |
ALP week 3 | 173 | 170 | 146 | 75.0 | 62.8 | 64.6 |
recovery |
|
| 114 |
|
| 62.6 |
ASAT week 3 | 87.6 | 80.8 | 81.5 | 76.5 | 72.1 | 86.9 |
recovery |
|
| 67.7 |
|
| 58.4 |
ALAT week 3 | 66.6 | 64.9 | 65.6 | 43.0 | 42.0 | 61.3 |
recovery |
|
| 44.6 |
|
| 38.1 |
*) P<0.05
ORGAN WEIGHTS
In male animals there was a statistically significant increase in absolute liver and kidney weights in the low and the mid dose group and in relative liver and kidney weights in the mid dose group. In female animals there was only a slight increase of the relative liver weight in the mid dose group. Recovery data indicates reversibility of these effects.
Table 3. 16-day inhalation rat - affected organ weights.
parameter | control | 0.01 mg/L | 0.1 mg/L | control | 0.01 mg/L | 0.1 mg/L | |
| males | females | |||||
carcass | week 3 | 227 | 237 | 243 | 178 | 167 | 156* |
| recovery |
|
| 286 |
|
| 189 |
Liver | absolute week 3 | 6.27 | 6.90* | 7.85** | 5.53 | 5.08 | 5.73 |
| recovery |
|
| 7.86 |
|
| 5.59 |
| relative to bw week 3 | 2.76 | 2.92 | 3.23** | 3.11 | 3.05 | 3.66** |
| recovery |
|
| 2.75 |
|
| 2.95 |
kidney | absolute week 3 | 1.50 | 1.64* | 1.75** | 1.19 | 1.12 | 1.06 |
| recovery |
|
| 1.78 |
|
| 1.23 |
| relative to bw week 3 | 0.66 | 0.69 | 0.72** | 0.67 | 0.67 | 0.68 |
| recovery |
|
| 0.62 |
|
| 0.65 |
*) P<0.05 **) P<0.01
MACROSCOPIC AND HISTOPATHOLOGY
No macroscopic findings were recorded.
For Histopathology, treatment-related findings were recorded in the respiratory tract, liver and spleen. In high dose animals (including intercurrent deaths), one male showed myonecrosis, slight squamous metaplasia of nasal epithelium was recorded in 2 females. The lungs were severely affected at the high dose with one male and 4 females showing signs of haemorrhage, 2 males and one female showing infiltration of macrophages, 3 males displaying perivascular cuffing and mineral deposition. Two females showed clear signs of thrombosis and emphysema.
Slight or moderate hepatocellular hypertrophy occurred in 4 males and 2 females at the high-dose, with minimal to marked fatty change of liver cells was recorded in 5 males and 4 females. Minimal or slight vacuolation of macrophages in the splenic pulp was recorded in 2 males and 2 females, and slight to moderate depletion of lymphocytes was evident in the spleen of 4 females treated at the high-dose.
Hepatocellular hypertrophy was also recorded in 2 males and 1 female of the middose group and one male of the low-dose group. At the end of the recovery period, hepatocellular hypertrophy was not recorded in the two males and two females of the 0.1 mg/L recovery group. Haemosiderosis was recorded in the spleen of 3 females.
Table 4. 16-day inhalation rat - histopathological findings of intercurrently died animals.
parameter | control | 1 mg/L | control | 1 mg/L |
| male |
| female |
|
Nasal epithelium |
|
|
|
|
Squamous metaplasia |
|
|
| 2/5 |
Liver |
|
|
|
|
Hepatocellular hypertrophy |
| 4/5 |
|
|
Fatty change | 1/5 | 5/5 | 1/5 | 4/5 |
Spleen |
|
|
|
|
Vacuolation of macrophages |
| 2/5 |
| 2/5 |
Depletion of lymphocytes |
|
|
| 4/5 |
Table 5. 16-day inhalation rat - histopathological findings of survivors.
parameter | control | 0.01 mg/L | 0.1 mg/L | control | 0.01 mg/L | 0.1 mg/L |
| male |
|
| female |
|
|
Liver |
|
|
|
|
|
|
Hepatocellular hypertrophy week 3 |
| 1/3 | 2/3 |
|
| 1/3 |
Spleen |
|
|
|
|
|
|
Haemosiderosis |
| 0/3 | 0/3 |
| 0/3 | 3/3 |
Recovery |
|
|
|
|
| 1/3 |
Applicant's summary and conclusion
- Conclusions:
- The aerosol concentration of 1 mg/L caused substantial mortality in male and female rats. The liver, the respiratory tract and the spleen were the target organs at this excessive level. At lower concentrations the liver is indicated as target organ, since changes in liver weights were accompanied by slight changes in liver enzymes and hepatocellular hypertrophy. There were also changes in the weight of the kidney but these were not associated with any changes in clinical chemistry and only slight mineralisation observed histopathologically. Histopathological examination revealed effects at the highest dose and haemosiderosis in the females at the mid-dose. Since the weak effects observed at the lowest concentration represent the kind of effects from which the animals recovered completely at the higher concentration of 0.1 mg/L, this nominal concentration of 0.01 mg/L corresponding to an achieved concentration of 0.017 mg/L is considered to represent the NOAEL of the study, equivalent to 4.9 mg/kg bw/day (6 hours exposure per day; 0.8 L air/kg/min).
- Executive summary:
In this 16-day inhalation toxicity study conducted according to OECD TG 412 following GLP, the test substance was administered via inhalation on five days per week to SPF-bred Wister rats in a nose-only exposure system. The study was comprised of four groups, each containing 5 male and female rats who recieved a nominal dose level of 0, 0.01, 0.1 or 1.0 mg/L air. Mean airflow in the exposure chambers was 1.4 L/min/animal. Recovery duration after the last exposure was 15 days. Aerosol concentration was determined gravimetrically using glass fibre filters once pre-test and daily thereafter during exposure periods. Particle size distribution was determined at least once daily in the high dose and in one of the lower doses using a stage cascade impactor. The animals were observed twice daily for mortality and once for clinical signs of toxicity. Food consumption was recorded weekly and individual body weights were recorded twice during the acclimatisation period and weekly thereafter. Blood samples for haematology and clinical chemistry were collected from all animals of the control and low dose groups and from 3 males and 3 females of the mid dose group on day 17 and from 2 males and 2 females of the mid dose group following the 15 day recovery period. At treatment termination or after recovery period, animals were sacrificed and subjected to a detailed necropsy.
Three females of the high dose group were found dead after the second exposure. Exposure of this group was stopped thereafter. The remaining animals had to be sacrificed on day 3 or day 6 for human reasons. No other deaths were observed. With all high dose animals’ slight hunched posture, laboured respiration, ruffled fur and weakness were observed. Ventral recumbence was observed in females only. In mid dose animals slight squealing, howling and crying was noted in one male and three females. The same symptoms were observed in 1 male and 2 females of the low dose group. From day 1 to 16 there was a slight increase in food consumption in the males and a decrease in food consumption in the females. Over the same period there was a slight increase in body weight gain in males and a decrease in body weight gain in females. Mid-dose females showed a slightly reduced body weight gain throughout the study and reduced body weight at the end of the study (156.4 g versus 177.5 g in the control group). Analysis of WBCs revealed a dose dependent increase in both males and females after 3 weeks. Bilirubin levels were slightly reduced in male animals of the low and mid dose group. LDH and ALP activities were slightly lower in mid dose male (not statistically significant). In female animals, effects were only seen in the mid dose group, being related to liver toxicity, i.e. a slight to moderate increase of ASAT and ALAT levels and high LDH activity. None of these effects were statistically significant. After recovery they were all returned to normal levels. In male animals there was a statistically significant increase in absolute liver and kidney weights in the low and the mid dose group and in relative liver and kidney weights in the mid dose group. In female animals there was only a slight increase of the relative liver weight in the mid dose group. Recovery data indicates reversibility of these effects. No macroscopic findings were recorded. For Histopathology, treatment-related findings were recorded in the respiratory tract, liver and spleen. In high dose animals (including intercurrent deaths), one male showed myonecrosis, slight squamous metaplasia of nasal epithelium was recorded in 2 females. The lungs were severely affected at the high dose with one male and 4 females showing signs of haemorrhage, 2 males and one female showing infiltration of macrophages, 3 males displaying perivascular cuffing and mineral deposition. Two females showed clear signs of thrombosis and emphysema. Slight or moderate hepatocellular hypertrophy occurred in 4 males and 2 females at the high-dose, with minimal to marked fatty change of liver cells was recorded in 5 males and 4 females. Minimal or slight vacuolation of macrophages in the splenic pulp was recorded in 2 males and 2 females, and slight to moderate depletion of lymphocytes was evident in the spleen of 4 females treated at the high-dose. Hepatocellular hypertrophy was also recorded in 2 males and 1 female of the middose group and one male of the low-dose group. At the end of the recovery period, hepatocellular hypertrophy was not recorded in the two males and two females of the 0.1 mg/L recovery group. Haemosiderosis was recorded in the spleen of 3 females.
Since the weak effects observed at the lowest concentration represent the kind of effects from which the animals recovered completely at the higher concentration of 0.1 mg/L, this nominal concentration of 0.01 mg/L corresponding to an achieved concentration of 0.017 mg/L is considered to represent the NOAEL of the study, equivalent to 4.9 mg/kg bw/day (6 hours exposure per day; 0.8 L air/kg/min).
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