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EC number: 259-627-5 | CAS number: 55406-53-6
- 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:
- sub-chronic toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1994-11-11
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 994
- Report date:
- 1994
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
- Version / remarks:
- 1981
- Deviations:
- yes
- Remarks:
- adrenals were not weighed
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 3-iodo-2-propynyl butylcarbamate
- EC Number:
- 259-627-5
- EC Name:
- 3-iodo-2-propynyl butylcarbamate
- Cas Number:
- 55406-53-6
- Molecular formula:
- C8H12INO2
- IUPAC Name:
- 3-iodoprop-2-yn-1-yl butylcarbamate
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 2DR-293-TSI
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River (UK) Ltd
- Age at study initiation: 8 - 9 weeks
- Weight at study initiation: Group mean weight first delivery: males: 268 - 273 g; females: 188 - 193 g; second delivery: males: 312 g; females: 219 g
- Housing: individually
- Diet: ad libitum
- Water:ad libitum
DETAILS OF FOOD AND WATER QUALITY: There was no information available to indicate that any non-nutrient substance likely to influence the effect of the test substance could reasonably be expected to be present in the diet or in the drinking water.
ENVIRONMENTAL CONDITIONS
- Temperature: 15.5 - 23.5°C
- Humidity: 25 - 54 %
- Photoperiod: 12 / 12 hrs dark / hrs light
Administration / exposure
- Route of administration:
- inhalation: dust
- Type of inhalation exposure:
- whole body
- Vehicle:
- air
- Mass median aerodynamic diameter (MMAD):
- > 1.55 - < 3.5 µm
- Remarks on MMAD:
- Examination of the data indicates that the test aerosol did not contain a normal distribution of particle sizes. The test aerosols consisted of at least 2 populations of particles, one with a median aerodynamic diameter of between approximately 1.55 and 3.5 µm and one with median aerodynamic diameter less than 0.5 µm. Size distributions of this type cannot be described by a single mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD).
67.5 to 83.1 % of the population of particles is considered to be less than 6 µm in aerodynamic diameter in each dose group, respectively. These particles are considered to be respirable to the rat. - Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: exposure chambers were of stainless steel and glass construction, approx. 0.75 m^3 internal volume
- System of generating particulates/aerosols: Wright dust feed mechanism (WDFM)
TEST ATMOSPHERE
- Brief description of analytical method used: Samples of each test atmosphere were withdrawn through 37 mm diameter glass microfibre filters (Type GF/A, Whatman International Ltd, Maidstone, Kent, England) supported in an open-face holder, at a rate of 10 litres per minute. The total volume sampled was measured using an in-line wet-type gas meter (Model DM3D Alexander Wright and Co (Westminster) Ltd). The test substance deposited on the filters was extracted into acetonitrile and the resultant solutions were analysed by an HPLC method.
VEHICLE: air - Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 6 h
- Frequency of treatment:
- 5 days a week
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/m³ air
- Remarks:
- control
- Dose / conc.:
- 0.25 mg/m³ air
- Remarks:
- analytical: 0.30 mg/m^3
- Dose / conc.:
- 1.25 mg/m³ air
- Remarks:
- analytical: 1.16 mg/m^3
- Dose / conc.:
- 6.25 mg/m³ air
- Remarks:
- analytical: 6.70 mg/m^3
- Dose / conc.:
- 0.25 mg/m³ air
- Remarks:
- analytical: 0.23 mg/m^3 (repeat low dose)
- No. of animals per sex per dose:
- Main groups: 10
Satellite groups: 5 - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Rationale for animal assignment: random
- Post-exposure recovery period in satellite groups: no - Positive control:
- not applicable
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: during each exposure period and at least twice daily
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: for allocation to groups and weekly, starting one week before exposures commenced until the end of the study
FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
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
WATER CONSUMPTION AND COMPOUND INTAKE: No
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to treatment and during week 13 of exposure
- Dose groups that were examined: all
HAEMATOLOGY: Yes
- Time schedule for collection of blood: during week 13
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: all animals of the main groups
- Parameters examined: packed cell volume (PCV), haemoglobin concentration, erythrocyte count, total and differential white cell count, platelet count, mean corpuscular haemoglobin concentration (MCHC), mean corpuscular volume (MCV), reticulocyte count, cell morphology, prothrombin time
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: during week 13
- Animals fasted: Not specified
- How many animals: all animals of the main groups
- Parameters examined: sodium, potassium, calcium, inorganic phosphorus, chloride, glucose, cholesterol, urea nitrogen, bilirubin, creatinine, total protein, albumin, globulin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), gamma glutamyl transpeptidase (gGT)
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
IMMUNOLOGY: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, all animals
ORGAN WEIGHTS: Yes, all animals: liver, kidneys, testes with epididymides main groups: brain
HISTOPATHOLOGY: Yes
- tissues examined:
control and high dosed groups: adrenals, aorta, caecum, colon, duodenum, eyes, gross abnormalities, heart, ileum, jejunum, lymph nodes, mammary gland, nasal passages, oesophagus, pancreas, pituitary, prostate, rectum, salivary gland, sciatic nerve, seminal vesicles, skeletal muscle, skin, spinal cord, spleen, stomach, sternum with marrow, testes with epididymides, thymus, thyroids with parathyroids, trachea, urinary bladder, uterus
all rats: kidneys, liver, lungs (all lobes and bronchi)
control, low, repeat low, and high dosed groups: larynx
main groups only: brain (medullary cerebellar and cortical sections) - Other examinations:
- Plasma and erythrocyte cholinesterase activity was determined in the animals of the satellite groups after 2 and 13 weeks. Brain cholinesterase activity was determined in the satellite groups after terminal sacrifice. For determination of cholinesterase activity the method of Ellman was used.
- Statistics:
- Bartlett’s test: heterogeneity of variance between treatment when the relative frequency of data does not exceed 75%. One-way analysis of variance: for data not showing statistically significant heterogeneity using Bartlett’s test. Kruskal-Wallis analysis for data with significant heterogeneity of variance. Student’s t-test and Williams test for a dose-related response. Analysis of covariance it appropriate. Fischer’s Exact Test for histopathological incidences.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- During the first three exposures, closed/half closed eyes were seen in the high dosed rats. Red ears were noted following exposures 3, 4, and 5. These effects were considered to be attributable to the irritating potential of the test substance and not of toxicological relevance. There were no other treatment-related signs noted. Clinical signs attributable to cholinesterase inhibition were also not noted.
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- Two male and two female rats of the low dose groups were sacrificed during week 10 on study following the period of overdosing. There were no deaths attributable to treatment with the test substance.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Mean group body weight and body weight gain were comparable between control and treated dose groups.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Mean group food consumption was comparable between control and treated dose groups.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- Ophthalmoscopy was comparable between controls and treated groups.
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The following statistically significant differences from concurrent control values were observed:
In the high dosed females a greater erythrocyte count, higher PCV, lower MCHC and lower reticulocyte count when compared to controls were observed. In all treated male groups MCV was lower when compared to concurrent controls.
All the above differences were either of low magnitude, not dose-related or inconsistent between sexes. Thus, these changes are not considered to be of toxicological relevance.
Values for haematological parameters of the repeat low dose group were also similar to the controls. - Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The following statistically significant changes in cholinesterase activity determination were noted:
During week 2 a statistically significant lower plasma cholinesterase activity (-21.7%) in high dosed males when compared to concurrent controls and a statistically significant lower erythrocyte cholinesterase activity (-38.9%) in high dosed females when compared to concurrent controls was observed. During week 13 plasma cholinesterase activity in high dosed males was statistically significant lower (-18.2%) when compared to concurrent controls. Brain cholinesterase activity in the mid dosed females (-24.6%) and in males and females of the high dose group was statistically significantly reduced (-16.8% and –35.3%, respectively) when compared to concurrent controls.
Plasma cholinesterase activity is considered to be only a marker of exposure and should not be considered to be of toxicological relevance.
Erythrocyte cholinesterase activity was statistically significant reduced in the high dosed females after two weeks. After 13 weeks of treatment, however, there was no statistically significant difference to concurrent control in erythrocyte cholinesterase activity noted. In the absence of time consistency, reduced erythrocyte cholinesterase activity in the high dose females was not considered to be of toxicological relevance.
At termination, brain cholinesterase activity was statistically significantly reduced in the mid dosed females (-25% lower than concurrent control) as well as in the high dosed males and females (-17% and 36% lower than concurrent control, respectively). However, the trigger of 20% reduction is not reached when females brain cholinesterase activities are compared to the historical control mean. At 1.16 mg/m3, the measured mean brain cholinesterase activity is 10.5% lower than historical control mean, at 6.7 mg/m3 12.3%. A clear dose-response relationship is further not observable.
However, when control brain cholinesterase activities are compared to the historical control data given in the report, one notes that activities show a great variability. Males concurrent control brain cholinesterase activity is 9% lower when compared to historical control mean. In females the concurrent mean control values exceeds the historical mean (+19%).
By inspection of individual data, one can see that the lowest concurrent control value (5.03 µmol/g/min for males and 4.74 µmol/g/min in females) is always comparable to the lowest figure of the treated animals (4.35 µmol/g/min for males and 4.2 µmol/g/min for females).
It is therefore concluded, that brain cholinesterase activity was not adversely affected during the course of the study up to and including the high dose animals and is within the normal biological variation.
The following statistically significant changes in further clinical chemistry parameters were noted: During week 13, higher albumin levels in the high dosed females when compared to controls were observed. ALT activity in the low dosed females and in males and females of the mid and high dosed groups was elevated when compared to concurrent controls.
Changes in albumin and glucose parameters were not considered to be related to treatment because they were inconsistent between sexes, of low magnitude, and/or without a dose response relationship. The increases in ALT activity were within the expected range for rats of this age and strain. In the absence of any histopathological findings in liver, the increase in ALT was not considered to be of toxicological importance.
Clinical chemistry parameters of the repeat low dose group were well within the expected range for animals of this age and strain. - Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- Absolute and adjusted organ weights were comparable to control values.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There were no changes in macroscopic pathology noted in which could be attributed to test item administration.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Treatment-related histopathological changes were noted larynx and lungs:
In lungs, macrophage aggregates were observed in a slightly higher incidence in the high dosed males when compared to control males. In all treated females and in the low and mid dosed males, the incidence in macrophage aggregates in lungs was comparable to the concurrent control.
Histopathological findings in the larynx were necrosis in the ventral cartilage, epithelial hyperplasia in ventral region, and squamous metaplasia in ventrolateral region in all animals of the high dose group.
In addition, epithelial hyperplasia over the arytenoid projections in all high dosed males and a proportion of the high dosed females was noted. Epithelial ulceration in the ventral region was observed in low incidence in the high dosed males. In some of the high dosed males and females, additionally, atrophy of submucosal glands was noted.
Similar findings (epithelial hyperplasia and/or necrosis of the ventral cartilage) were observed in low incidence in the initial low dosed animals at terminal sacrifice. This was not observed in the animals of this dose group sacrificed during the course of the study. Furthermore, no histopathological lesions were observed in the repeat low dose group.
In conclusion, histopathological lesions in the larynx observed in the initial low dosed animals are not considered to be related to test item treatment due to the lack of a dose-response relationship and thus are considered to be incidental.
The larynx is often damaged during inhalation studies especially in the high dosed animals due to its morphology. Especially the ventral cartilage – a small U-shaped cartilage - is affected. The ventral cartilage lies immediately beneath the thin surface squamous epithelium. The damage of the epithelium normally results in necrosis of the underlying cartilage. Subsequently the epithelium of the cartilage undergoes reparative hyperplasia but the necrotic appearance of the cartilage persists after the epithelium has repaired.
The test item is known to be an irritating substance. The histopathological changes of the larynx in the high dosed animals may thus be associated with the intrinsic irritating properties of the test item.
It should further be considered during evaluation that rats respire obligatory through their nose whereas human tend to respire also through the mouth. The anatomical differences in the nasal passages as well as in the larynx should also be taken into account. For these reasons, histopathological changes seen in larynx are not considered to be of relevance for human exposed to the test item via air.
There were no histopathological changes noted in the other organs. - Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- no effects observed
Effect levels
open allclose all
- Key result
- Dose descriptor:
- LOAEC
- Effect level:
- 6.7 mg/m³ air (analytical)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- histopathology: non-neoplastic
- Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 1.16 mg/m³ air (analytical)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- histopathology: non-neoplastic
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 0.007 mg/L air (analytical)
- System:
- respiratory system: upper respiratory tract
- Organ:
- larynx
- Treatment related:
- yes
- Dose response relationship:
- yes
Any other information on results incl. tables
Table 1 Cholinesterase activity determination
Parameter |
unit |
time [week] |
Dose level [mg/m3] |
|||||
0 |
0.3 |
0.23 |
1.16 |
6.7 |
||||
controls |
historical |
|||||||
Males |
|
|
|
|
|
|
|
|
plasma ChE |
µmol/mL/min |
2 |
0.46 |
0.47 |
0.46 |
0.40 |
0.40 |
0.36** |
RBC ChE |
µmol/mL/min |
|
1.41 |
2.03 |
1.37 |
2.83 |
1.52 |
1.59 |
plasma ChE |
µmol/mL/min |
13 |
0.44 |
0.47 |
0.42 |
0.42 |
0.44 |
0.36** |
RBC ChE |
µmol/mL/min |
|
1.68 |
2.03 |
1.74 |
1.37 |
1.54 |
1.07 |
brain ChE |
µmol/g/min |
14 |
5.77 |
6.31 |
5.02 |
7.17 |
5.05 |
4.80* |
Females |
|
|
|
|
|
|
|
|
plasma ChE |
µmol/mL/min |
2 |
0.83 |
1.30 |
0.79 |
1.01 |
0.88 |
0.73 |
RBC ChE |
µmol/mL/min |
|
1.62 |
1.64 |
1.46 |
1.67 |
1.46 |
0.99* |
plasma ChE |
µmol/mL/min |
13 |
1.27 |
1.30 |
1.46 |
1.36 |
1.28 |
1.29 |
RBC ChE |
µmol/mL/min |
|
1.90 |
1.64 |
1.59 |
1.22 |
2.03 |
2.00 |
brain ChE |
µmol/g/min |
14 |
6.59 |
5.55 |
6.38 |
7.21 |
4.97* |
4.87* |
* p < 0.05 compared with control values (William’s test)
** p < 0.01 compared with control values (William’s test)
1 Values in parenthesis indicate the percentage change from concurrent control
2 Values in parenthesis indicate the percentage change from historical control
Table 2 Results of 90-day inhalation toxicity study in rats
Parameter |
Dose level [mg/m3] |
dose-response +/- |
||||||||||
0 |
0.3 |
0.23 |
1.16 |
6.7 |
||||||||
m |
f |
m |
f |
m |
f |
m |
f |
m |
f |
m |
f |
|
number of animals examined |
15 |
15 |
15 |
15 |
15 |
15 |
15 |
15 |
15 |
15 |
15 |
15 |
Mortality |
0 |
0 |
21) |
21) |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
clinical signs |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
body weight |
|
|
ne |
ne |
ne |
ne |
ne |
ne |
ne |
ne |
- |
- |
food consumption |
|
|
ne |
ne |
ne |
ne |
ne |
ne |
ne |
ne |
- |
- |
clinical chemistry |
|
|
ne |
ne |
ne |
ne |
ne |
ne |
ne |
ne |
- |
- |
haematology |
|
|
ne |
ne |
ne |
ne |
ne |
ne |
ne |
ne |
- |
- |
cholinesterase activities |
|
|
ne |
ne |
ne |
ne |
ne |
ne |
ne |
ne |
- |
- |
Larynx |
|
|
|
|
|
|
|
|
|
|
|
|
weight |
nd |
nd |
nd |
nd |
nd |
nd |
nd |
nd |
nd |
nd |
|
|
gross pathology |
ne |
ne |
ne |
ne |
ne |
ne |
ne |
ne |
ne |
ne |
- |
- |
microscopic pathology |
152) |
15 |
13 |
13 |
15 |
15 |
15 |
15 |
15 |
15 |
|
|
necrosis of the ventral cartilage |
0 |
0 |
2 |
0 |
0 |
0 |
nd |
nd |
15 |
15 |
+ |
+ |
epithelial hyperplasia in ventral region |
0 |
0 |
4 |
7 |
0 |
0 |
nd |
nd |
15 |
15 |
+ |
+ |
epithelial hyperplasia over arytenoid |
0 |
0 |
0 |
1 |
0 |
0 |
nd |
nd |
15 |
5 |
+ |
+ |
squamous metaplasia in ventrolateral region |
0 |
0 |
0 |
0 |
0 |
0 |
nd |
nd |
15 |
15 |
+ |
+ |
epithelial ulceration in ventral region |
0 |
0 |
0 |
0 |
0 |
0 |
nd |
nd |
4 |
1 |
+ |
- |
atrophy of submucosal glands |
0 |
0 |
0 |
0 |
0 |
0 |
nd |
nd |
3 |
6 |
+ |
+ |
Lungs |
|
|
|
|
|
|
|
|
|
|
|
|
weight |
|
|
ne |
ne |
ne |
ne |
ne |
ne |
ne |
ne |
- |
- |
gross pathology |
|
|
ne |
ne |
ne |
ne |
ne |
ne |
ne |
ne |
- |
- |
microscopic pathology |
152) |
15 |
13 |
13 |
15 |
15 |
15 |
15 |
15 |
15 |
|
|
aggregates of macrophages |
4 |
1 |
3 |
1 |
1 |
0 |
3 |
3 |
7 |
2 |
+ |
- |
1) sacrificed due to overdosing
2) number of animals examined at terminal sacrifice
3) Please note: the low dosing regime was repeated due to overdosing of the original low dose. However, no concurrent control was used
Abbreviations:
ne no effects
nd not determined
na not applicable (no concurrent control)
Applicant's summary and conclusion
- Conclusions:
- Based on the results and under the conditions of this study a NOAEC is considered to be 1.16 mg/m^3 based on larynx effects.
- Executive summary:
Treatment of Crl:CD BR rats over 90 days with the test item via the inhalation route at doses of 0, 0.23, 0.3, 1.16, and 6.7 mg/m3 did not influence the survival, the body weight development, or the food consumption of all treated animals. Ophthalmoscopical examination did not show any treatment-related effects on the eyes of the treated rats. There were no treatment-related effects on haematological and clinical chemistry parameters noted.
There were no changes in organ weights noted. Histopathological examination of the organs showed no changes in treated animals when compared to controls except for larynx and lungs of the high dosed animals. In lungs an increased incidence in the aggregation of macrophages was noted in the high dosed males (7 of 15 animals compared to 4 of 15 animals in the concurrent control).
RBC and brain cholinesterase activities were within the normal biological variation.
Histopathological findings in the larynx of the high dose group were necrosis in the ventral cartilage, epithelial hyperplasia in ventral region, and squamous metaplasia in ventrolateral region in all animals. In addition, epithelial hyperplasia over the arytenoid projections in all high dosed males and in 5 of the 15 high dosed females was noted. Epithelial ulceration in the ventral region was observed in low incidence in the high dosed males (4 of 15 animals). In some of the high dosed males and females, additionally, atrophy of submucosal glands was noted (3 and 6 animals of 15, respectively).
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