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EC number: 446-630-3 | CAS number: 181587-01-9
- 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
- Study period:
- 07 Oct 1999 - 05 Nov 1999
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 002
- Report date:
- 2002
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3200 (Repeated Dose Dermal Toxicity -21/28 Days)
- Version / remarks:
- 1998
- Deviations:
- no
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
- Version / remarks:
- Current version adopted in 1981
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- -
- EC Number:
- 446-630-3
- EC Name:
- -
- Cas Number:
- 181587-01-9
- Molecular formula:
- C13H9Cl2F3N4OS
- IUPAC Name:
- 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(ethanesulfinyl)-1H-pyrazole-3-carbonitrile
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Albino Rats (Outbred) VAF/Plus® CD® (Sprague-Dawley derived) [Crl:CD®(SD)IGS BR]
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Kingston, USA
- Age at study initiation: 8 weeks
- Weight at study initiation: 231–284 g (males) and 183–218 g (females)
- Housing: animals were housed individually in suspended, stainless steel wire mesh cages.
- Diet: certified Rodent Diet No. 5002 (PMI Feeds, Inc., St. Louis, Missouri), pelleted, ad libitum
- Water: water was available via an automated watering system (Elizabethtown Water Company, Westfield, USA).
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-28
- Humidity (%): 36-78
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Type of coverage:
- semiocclusive
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- TEST SITE
- Area of exposure: dorsal area
- % coverage: 10
- Type of wrap if used: the test substance was evenly spread over a saline-moistened gauze patch, which was placed on the skin and secured with gauze and Elastoplast®.
- Time intervals for shavings or clippings: approximately 24 h before initiation of dosing
REMOVAL OF TEST SUBSTANCE
- Washing: water and gauze were used to remove residual test substance.
- Time after start of exposure: 6 h
TEST MATERIAL
- Amount(s) applied:
10 mg/kg bw/day: 2.62-3.76 mg (m) and 2.03-2.55 mg (f)
20 mg/kg bw/day: 5.24-7.52 mg (m) and 4.06-5.1 mg (f)
500 mg/kg bw/day: 131-188 mg (m) and 101.5-127.5 mg (f)
2500 mg/kg bw/day: 655-940 mg (m) and 507.5-637.5 mg (f)
- Constant volume or concentration used: no
- For solids, paste formed: no
USE OF RESTRAINERS FOR PREVENTING INGESTION: no - Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- at least 28 days
- Frequency of treatment:
- daily, 7 days/week
Doses / concentrationsopen allclose all
- Dose / conc.:
- 10 mg/kg bw/day (nominal)
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- Dose / conc.:
- 250 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, sham-exposed
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: animals were observed, in their cages, for mortality and general appearance twice daily, once in the morning and once in the afternoon. Observations for signs of toxic or pharmacologic effects were made once daily. Any abnormal signs were recorded.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: each animal was removed from its cage and examined twice pre-test and once weekly during the study period.
- Clinical observations included: observations of general condition, skin and fur, eyes, nose, oral cavity, abdomen and external genitalia, occurrence of secretions and excretions, and autonomic activity, changes in gait, posture and response to handling as well as the presence of clonic or tonic movements, stereotypy or bizarre behaviour
DERMAL IRRITATION: Yes
- Time schedule for examinations: the treated skin was evaluated for irritation and scored pre-test, and prior to dosing for the first week (days 0, 1, 2, 3, 4, 5 and 6) and weekly thereafter during the treatment period and again just prior to necropsy.
BODY WEIGHT: Yes
- Time schedule for examinations: animals were weighed twice pre-test, weekly during the study and at termination.
FOOD CONSUMPTION:
- Food consumption for each group determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
FOOD EFFICIENCY:
- 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: No
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: ophthalmoscopic examinations were performed at Week -1 (pre-test) and Week 4.
- Dose groups that were examined: all
HAEMATOLOGY: Yes
- Time schedule for collection of blood: blood samples were obtained at study termination (Week 5) via retrobulbar venous plexus.
- Anaesthetic used for blood collection: Yes (light CO2/O2)
- Animals fasted: Yes
- How many animals: 100
- Parameters listed in Table 1 under “Any other information on materials and methods incl. tables” were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: blood samples were obtained from the aorta at necropsy (Week 5).
- Animals fasted: Yes
- How many animals: 100
- Parameters listed in Table 1 under “Any other information on materials and methods incl. tables” were examined.
URINALYSIS: Yes
- Time schedule for collection of urine: at Weeks 4 and 5
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes (at Week 5)
- Parameters listed in Table 1 under “Any other information on materials and methods incl. tables” were examined.
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: pre-test and at Week 4
- Dose groups that were examined: all
- Battery of functions tested: sensory activity / grip strength / motor activity - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see Table 2 under “Any other information on materials and methods incl. tables”)
HISTOPATHOLOGY: Yes (see Table 2 under “Any other information on materials and methods incl. tables”) - Statistics:
- The mean values of the following parameters comparing control and test substance-treated groups were analysed statistically: body weight, food consumption, terminal organ weights, organ/body and organ/brain weight ratios, clinical pathology and motor activity counts. Bartlett's test was performed to determine if groups had equal variances. If the variances were equal, parametric procedures were used; if not, nonparametric procedures were used. The parametric method was the standard one-way analysis of variance (ANOVA) using the F ratio to assess significance followed by Dunnett's or Williams test to determine which means were significantly different from the control. The nonparametric method was the Kruskal-Wallis test followed by Shirley's or Dunn's test or pairwise comparison with Bonferroni correction to determine which mean values significantly differed from control.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- All test and control animals survived and were free of significant clinical signs throughout the study.
- Dermal irritation:
- no effects observed
- Mortality:
- no mortality observed
- Description (incidence):
- All test and control animals survived until the end of the study.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Mean body weight values for the test groups were comparable to the control values throughout the study. At Week 1, mean body weight and body weight gain were statistically significantly decreased (-7.4%) in males of the 1000 mg/kg bw/day group compared to controls. Since body weight gain was also statistically significantly decreased in the pre-test period, as compared to the control value, the body weight effects in Week 1 could not be attributed solely to the test substance. Mean body weights for the 1000 mg/kg bw/day males during the remainder of the study were slightly lower than those of the control males, although the decreases were not statistically significant. In females, a slight, but statistically significant, increase in body weight gain in Week 1 was observed for the 250 and 1000 mg/kg bw/day groups, as compared to the controls. In subsequent weeks, body weight gains for these animals were comparable to the control values.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- The mean food consumption values for the test groups were generally comparable to, or slightly greater than, the control values throughout the study. At Week 1, the mean feed consumption values for the 1000 mg/kg bw/day males and females were statistically significantly decreased compared to the controls. In subsequent weeks, food consumption values of these animals were comparable to the control values.
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- There was no evidence for test substance-related ocular abnormalities at termination of the study.
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Mean haemoglobin concentration, haematocrit and erythrocyte counts were statistically significantly decreased for males and females at 250 and 1000 mg/kg bw/day. In females, haematocrit was also statistically significantly decreased at 50 mg/kg bw/day. The decreases appeared to be test substance-related, although the decreases were slight (less than 10%) and no compensatory increase in reticulocyte counts was noted at any dose level. Activated partial thromboplastin times were significantly and dose-dependently prolonged in males and females at 50, 250, and 1000 mg/kg bw/day. Statistically significant increases in prothrombin time were observed at 250 and 1000 mg/kg/day in males and at 1000 mg/kg bw/day in females. Platelet counts were generally increased in males and females at 50, 250 and 1000 mg/kg bw/day. However, only the increases in males at 50 mg/kg bw/day and in females at 250 and 1000 mg/kg bw/day were statistically significant. A few statistically significant decreases in the counts of leukocytes, absolute lymphocytes and eosinophils were noted at the high-dose group (1000 mg/kg bw/day) in females, but these slight changes were not considered to be biologically significant.
(see Table 3 under “Any other information on results incl. tables”) - Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Test substance-related changes in clinical chemistry parameters were observed in males and females at 250 and 1000 mg/kg/day (see Table 3 under “Any other information on results incl. tables”). In general, the affected parameters were those usually related to hepatic changes (e.g. gamma-glutamyl transferase, alanine aminotransferase, cholesterol). Only a few statistically significant changes in clinical chemistry parameters were noted at 50 mg/kg bw/day (decreased albumin/globulin ratio in males and decreased globulin values in females).
- Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- The urinalysis values of the test animals were comparable to control animal values, or within the range of normal variability.
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- No test substance-related effects on motor activity and no indications of neurological effects were observed at any dose group.
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- ≥ 50 mg/kg bw/day: increased abs. and rel. liver weight and liver/brain weight ratios; ≥ 250 mg/kg bw/day (f): increased abs. and rel. adrenal gland weight and adrenal/brain weight ratios
The mean liver weight and the mean liver/body weight and liver/brain weight ratios for the 50, 250, and 1000 mg/kg bw/day males and females were statistically significantly increased compared to control group values. The increases in liver weight values were dose-related and are consistent with the observed changes in clinical chemistry parameters indicative of hepatotoxicity. The mean adrenal weight and the mean adrenal/body weight and adrenal/brain weight ratios for the 250 and 1000 mg/kg bw/day females were also statistically significantly increased, as compared to control female values. These increases are consistent with histopathological changes in the adrenal cortex of females treated with the high-dose (1000 mg/kg bw/day). - Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- ≥ 50 mg/kg bw/day: brown discolouration and scattered tan foci in liver
A test article-related brown discolouration and scattered tan foci were found in males and females at 50, 250 and 1000 mg/kg bw/day. Other macroscopic findings involved sporadic incidences in control and test substance treated groups. These incidental findings were not considered to be test substance-related, since they were also observed in rats of this strain and age used in previous studies. - Neuropathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- ≥ 50 mg/kg bw/day: centrilobular hepatocellular hypertrophy and follicular cell hyperthrophy/hyperplasia in thyroid gland; ≥ 250 mg/kg bw/day (f): hypertrophy/hyperplasia in adrenal cortex (zona fasiculata)
Centrilobular hepatocellular hypertrophy was present in all males and females at 250 and 1000 mg/kg bw/day, and in males (3/10 ) and females (6/10) at 50 mg/kg bw/day. Follicular cell hypertrophy/hyperplasia in the thyroid gland was present in all males and females at 250 and 1000 mg/kg bw/day and in males (4/10) and females (3/10) at 50 mg/kg bw/day. In the adrenal cortex, hypertrophy/hyperplasia of the zona fasiculata was present in females at 250 mg/kg bw/day (1/10) and females at 1000 mg/kg bw/day (5/10). In liver, thyroid and adrenal gland, a dose-related increase in severity of histopathological effects was observed.
(see Table 4 under “Any other information on results incl. tables”) - Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- The skin at the site of the topical application of either the vehicle or the vehicle/test article combination had squamous cell hyperplasia, hyperkeratosis and/or hyperplasia of parafollicular sebaceous glands; all findings were of minimal severity. The liver of a number of rats, including controls, had lesions possibly associated with wrapping of the torso following dermal application of the test article (Parker and Gibson, 1995). These lesions were focal/multifocal, subcapsular, in various stages of development and minimal to slight in severity. The acute lesions consisted of coagulative necrosis, occasional haemorrhage and acute/subacute inflammation. Older lesions consisted of subacute/chronic inflammation and various stages of fibroplasia leading to focal fibrosis. These findings in the skin and liver were considered to be procedurally related rather than vehicle or test article-related. Other microscopic findings in the liver, thyroid and adrenal glands and in the other tissues and organs occurred with comparable incidence and severity in rats from the control and test article treatment groups. These incidental findings, not considered to be test article related, have been seen in rats of this strain and age used in other studies conducted in this facility.
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 10 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: overall effects
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- 50 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- haematology
- histopathology: non-neoplastic
- organ weights and organ / body weight ratios
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 50 mg/kg bw/day (nominal)
- System:
- other: hepatobiliary and endocrine system
- Organ:
- liver
- thyroid gland
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
Any other information on results incl. tables
Table 3. Changes in clinical chemistry parameters (data are presented as mean values ± SD)
Parameters |
Test substance [mg/kg bw/day] |
||||
0 |
10 |
50 |
250 |
1000 |
|
HGB [g/dL] |
|
||||
male |
16 ± 0.4 |
14.6 ± 3.4 |
15.8 ± 0.4 |
15.3 ± 0.5* |
14.8 ± 0.6** |
female |
15.5 ± 0.4 |
15.2 ± 0.5 |
14.9 ± 0.7 |
14.1 ± 0.7** |
14.2 ± 0.5** |
HCT [%] |
|
||||
male |
47.7 ± 1.2 |
46.9 ± 1.1 |
47.5 ± 1.4 |
45.4 ± 1.8** |
44.7 ± 2.1** |
female |
45.9 ± 1.4 |
44.9 ± 1.7 |
43.6 ± 1.8* |
42.1 ± 2.0** |
42.2 ± 1.6** |
RBC [10E+6/µL] |
|
||||
male |
8.64 ± 0.29 |
8.56 ± 0.36 |
8.50 ± 0.30 |
8.23 ± 0.43* |
8.21 ± 0.40* |
female |
8.30 ± 0.35 |
8.07 ± 0.31 |
7.94 ± 0.47 |
7.65 ± 0.31** |
7.68 ± 0.36** |
PLT [10E+3/µL] |
|
||||
male |
770 ± 183 |
763 ± 214 |
1017 ± 125* |
922 ± 235 |
937 ± 256 |
female |
821 ± 333 |
847 ± 282 |
950 ± 287 |
1312 ± 263** |
1255 ± 260** |
WBC [10E+3/µL] |
|
||||
male |
11.4 ± 2.9 |
12.9 ± 2.5 |
10.8 ± 2.7 |
9.9 ± 2.6 |
9.2 ± 1.5 |
female |
12.7 ± 3.1 |
12.8 ± 3.1 |
10.6 ± 2.9 |
9.6 ± 2.3 |
8.8 ± 2.6* |
PT [s] |
|
||||
male |
12.6 ± 0.8 |
12.5 ± 0.5 |
14.2 ± 1.5 |
18.8 ± 4.3* |
21.4 ± 4.9** |
female |
11.2 ± 0.4 |
11.2 ± 0.3 |
11.4 ± 0.5 |
11.8 ± 0.7 |
13.8 ± 1.9** |
APTT [s] |
|
||||
male |
18.9 ± 2.4 |
19.1 ± 1.5 |
22.2 ± 2.1* |
25.7 ± 3.8** |
27.9 ± 3.1** |
female |
13.9 ± 2.2 |
15.3 ± 1.1 |
17.2 ± 3.1* |
19.8 ± 2.5** |
22.8 ± 3.1** |
ANEU [10E+3/µL] |
|
||||
male |
1.46 ± 0.38 |
1.47 ± 0.24 |
1.28 ± 0.31 |
1.34 ± 0.37 |
1.02 ± 0.27* |
female |
1.54 ± 0.60 |
1.24 ± 0.67 |
1.75 ± 0.98 |
1.26 ± 0.65 |
1.04 ± 0.41 |
ALYM [10E+3/µL] |
|
||||
male |
9.41 ± 2.78 |
10.89 ± 2.44 |
9.00 ± 2.77 |
7.98 ± 2.54 |
7.85 ± 1.40 |
female |
10.48 ± 2.66 |
11.02 ± 2.80 |
8.33 ± 1.98 |
7.95 ± 1.83 |
7.39 ± 2.69* |
EOS [% WBC] |
|
||||
male |
1.8 ± 0.9 |
1.5 ± 0.9 |
1.5 ± 1.5 |
2.7 ± 2.2 |
1.4 ± 1.2 |
female |
2.0 ± 1.6 |
1.6 ± 1.0 |
1.1 ± 0.9 |
1.0 ± 0.8 |
0.5 ± 0.3** |
GGT [IU/L] |
|
||||
male |
0 ± 0 |
1 ± 1 |
1 ± 1 |
3 ± 1** |
10 ± 3** |
female |
1 ± 1 |
1 ± 1 |
2 ± 2 |
7 ± 2** |
15 ± 5** |
TP [g/dL] |
|
|
|
|
|
male |
6.1 ± 0.2 |
6.0 ± 0.4 |
6.3 ± 0.6 |
6.6 ± 0.3* |
6.9 ± 0.4** |
female |
6.2 ± 0.5 |
6.3 ± 0.4 |
6.6 ± 0.3 |
7.1 ± 0.4** |
7.4 ± 0.6** |
GLOB [g/dL] |
|
||||
male |
1.8 ± 0.2 |
1.8 ± 0.2 |
2.1 ± 0.3 |
2.4 ± 0.2** |
2.5 ± 0.3** |
female |
1.8 ± 0.4 |
1.8 ± 0.2 |
2.2 ± 0.3* |
2.5 ± 0.4** |
2.8 ± 0.3** |
A/G |
|
||||
male |
2.3 ± 0.3 |
2.3 ± 0.3 |
2.1 ± 0.2* |
1.8 ± 0.2** |
1.8 ± 0.2** |
female |
2.6 ± 0.6 |
2.6 ± 0.3 |
2.1 ± 0.4 |
1.9 ± 0.4** |
1.6 ± 0.3** |
CHOL [mg/dL] |
|
||||
male |
41 ± 017 |
47 ± 13 |
41 ± 12 |
57 ± 9 |
64 ± 18** |
female |
53 ± 11 |
50 ± 15 |
58 ± 12 |
84 ± 20* |
117 ± 40** |
GLUC [mg/dL] |
|
||||
male |
154 ± 26 |
143 ± 28 |
138 ± 23 |
121 ± 16** |
112 ± 12** |
female |
138 ± 23 |
142 ± 29 |
147 ± 29 |
146 ± 26 |
130 ± 24 |
ALT [IU/L] |
|
||||
male |
41 ± 10 |
41 ± 14 |
52 ± 22 |
50 ± 13 |
75 ± 25** |
female |
35 ± 11 |
58 ± 91 |
90 ± 169 |
50 ± 24 |
50 ± 17 |
ALKP [IU/L] |
|
||||
male |
162 ± 25 |
169 ± 21 |
166 ± 23 |
153 ± 29 |
124 ± 25** |
female |
98 ± 23 |
92 ± 11 |
82 ± 13 |
68 ± 15** |
71 ± 21** |
Cl- [mEq/L] |
|
||||
male |
100 ± 2 |
101 ± 2 |
101 ± 2 |
100 ± 1 |
101 ± 1 |
female |
104 ± 2 |
103 ± 2 |
103 ± 1 |
102 ± 2 |
101 ± 3* |
HGB = haemoglobin; HCT = haematocrit; RBC = erythrocyte count; PLT = platelet count; WBC = total leukocyte count; PT = prothrombin time; APTT = activated partial thromboplastin time; ANEU = absolute neutrophils; ALYM = absolute lymphocytes; EOS = eosinophil count; GGT = gamma-glutamyl transferase; TP = total protein; GLOB = globulin; A/G = albumin/globulin ratio; CHOL = cholesterol; GLUC = glucose; ALT = alanine aminotransferase; ALKP = alkaline phosphatase; SD = standard deviation
Statistical significance is indicated by *p < 0.05, **p < 0.01 and ***p < 0.001.
Table 4. Histopathological changes in liver, thyroid and adrenal gland
Liver: hepatocellular hypertrophy (centrilobular) |
||||||||||
|
Males |
Females |
||||||||
Dose [mg/kg bw/day] |
0 |
10 |
50 |
250 |
1000 |
0 |
10 |
50 |
250 |
1000 |
Number examined |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
Severity |
|
|||||||||
No abnormal diagnosis |
10 |
10 |
7 |
0 |
0 |
10 |
10 |
4 |
0 |
0 |
Minimal |
0 |
0 |
3 |
0 |
0 |
0 |
0 |
5 |
0 |
0 |
Slight |
0 |
0 |
0 |
9 |
0 |
0 |
0 |
1 |
5 |
3 |
Moderate |
0 |
0 |
0 |
1 |
10 |
0 |
0 |
0 |
5 |
7 |
Total findings |
0 |
0 |
3 |
10 |
10 |
0 |
0 |
6 |
10 |
10 |
Thyroid gland: follicular cell hypertrophy/hyperplasia |
||||||||||
|
Males |
Females |
||||||||
Dose [mg/kg bw/day] |
0 |
10 |
50 |
250 |
1000 |
0 |
10 |
50 |
250 |
1000 |
Number examined |
10 |
9 |
10 |
10 |
10 |
10 |
10 |
7 |
0 |
0 |
Severity |
|
|||||||||
No abnormal diagnosis |
10 |
9 |
6 |
0 |
0 |
10 |
10 |
7 |
0 |
0 |
Minimal |
0 |
0 |
4 |
0 |
0 |
0 |
0 |
3 |
0 |
0 |
Slight |
0 |
0 |
0 |
5 |
0 |
0 |
0 |
0 |
5 |
1 |
Moderate |
0 |
0 |
0 |
5 |
10 |
0 |
0 |
0 |
5 |
9 |
Total findings |
0 |
0 |
4 |
10 |
10 |
0 |
0 |
3 |
10 |
10 |
Adrenal cortex: zona fasiculata-hypertrophy/hyperplasia |
||||||||||
|
Males |
Females |
||||||||
Dose [mg/kg bw/day] |
0 |
10 |
50 |
250 |
1000 |
0 |
10 |
50 |
250 |
1000 |
Number examined |
10 |
0 |
0 |
0 |
10 |
10 |
10 |
10 |
10 |
10 |
Severity |
|
|||||||||
No abnormal diagnosis |
10 |
- |
- |
- |
10 |
10 |
10 |
10 |
9 |
5 |
Slight |
0 |
- |
- |
- |
0 |
0 |
0 |
0 |
1 |
5 |
Total findings |
0 |
- |
- |
- |
10 |
0 |
0 |
0 |
1 |
5 |
Applicant's summary and conclusion
- Conclusions:
- Sub-acute dermal administration of the test substance to rats resulted in increase in liver weight, the presence of centrilobular hepatocellular hypertrophy and follicular cell hypertrophy/hyperplasia in thyroid glands as well as changes in clinical chemistry parameters indicative of hepatotoxicity at 50 mg/kg bw/day. Based on these findings, the No Observed Adverse Effect Level (NOAEL) was found to be 10 mg/kg bw/day.
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