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Administrative data

Description of key information

In a sub-acute (28-d) oral study in rats a NOAEL (systemic effects) of 100 mg/kg bw/day was established based on an increase of liver weights and a reduction in ovary weights in the females and a suppression of body weight gain in males at 500 mg/kg bw/day. In a sub-chronic (90-d) inhalation toxicity study in rats a NOAEC (local effects) of 0.12 mg/m3 was established based on hyperplasia with or without inflammation (rhinitis) in the transitional epithelium in males at 0.55 mg/m3. In the same study, a NOAEC (systemic effects) of ≥2.03 mg/m3 (highest dose tested) was established.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
August 28, 1990 - August 12, 1991
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study meets the standards of the EC-method and was conducted according to GLP principles. However, deviations from the test guideline were noted, which affect the reliability of the study.
Qualifier:
according to
Guideline:
other: The Japanese Guidelines for Screening Toxicity Testings of Chemicals (1986)
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
no full histopathology was done
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan
- Age at study initiation: At the start of the exposure, the rats are 5 weeks old.
- Weight at study initiation: males: 157-188, females: 123-151
- Housing: Two rats of the same sex were housed in a polycarbonate cage with hard wood chip bedding
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5-7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25 °C
- Humidity (%): 40-70%
- Air changes (per hr): 12 changes/hour
- Photoperiod (hrs dark / hrs light): 12/12 hours
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
The test substance solutions were prepared by dissolving the test substance in the vehicle (olive oil) at desired concentrations using an ultra high speed homogenizer. The test substance solutions were prepared once a week and stored in the refridgerator until just before use. The stability of the test substance solutions for 7 days after preparation was confirmed by chemical analysis.

VEHICLE
- Amount of vehicle (if gavage): 1.0 ml per 100 g body weight in all rats
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The stability of the test substance solutions for 7 days after preparation was confirmed by chemical analysis. No results included in the report.
Duration of treatment / exposure:
28 days
Frequency of treatment:
Once a day in the morning
Dose / conc.:
15 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
Main study:
0 and 500 mg/kg bw/day : 12 (6 for 14-day recovery)
15 and 100 mg/kg bw/day: 6
Additional study:
0, 2, 10 mg/kg bw/day: 6 females
2 mg/kg bw/day: 6 female
10 mg/kg bw/day: 6 female
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: A 1-week preliminary study was performed at the doses of 60, 500 and 700 mg/kg bw/day. It was found that the substance produced toxic effects on animals of the 500 and 700 mg/kg bw/day dose groups. Suppressed body weight gains, thickening of the forestomach and decreased spleen weight.
- Rationale for animal assignment (if not random): so that the body weights in each group became almost the same
- Rationale for selecting satellite groups: to evaluate recovery. Satelite animals in the control and the top dose group
- Post-exposure recovery period in satellite groups: 14 days
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least once daily, and with palpation once a week

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each cage (two animals) determined and mean daily diet consumption calculated as g food/animal/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: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: just before necropsy
- Anaesthetic used for blood collection: Yes (pentobarbital)
- Animals fasted: No data
- How many animals: all
- Parameters were examined: erytrocyte count, Leucocyte count, platelet count, hemoglobin concentration, hematocrit, leucocyte count differential, reticulocyte count, prothrombin time, activated partial thromboplastin time, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: just before necropsy
- Animals fasted: No data
- How many animals: all
- Parameters were examined: total protein, albumin, A/G ratio, Glucose, triglyceride, total cholesterol, urea nitrogen, creatinine, calcium, inorganic phosphorus, GOT(AST), GTP(ALT, gamma-GTP, ALP, sodium, potassium, chloride.

URINALYSIS: Yes
- Time schedule for collection of urine: two days before necropsy
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters were examined: pH, occult blood, protein, glucose, ketone bodies, bilirubin, urobilinogen

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes , brain, pituitary, eyes(with Hardian glands), lungs, stomach, thyroids (with parathyroids), heart, liver, spleen, kidneys, adrenals, urinary bladder and bone marrow (femur), testes or ovaries. Of all organs removed at the end of treatment, the heart, liver, kidneys, adrenals, spleen and stomach from rats of both sexes of the control and high dose group and the kidneys from 1 male rat of the low dose group, were examined microscopically. The OECD guideline states that full histopathology should be done.
Statistics:
Barlett's test.
Anova and dunnett's multiplerange test or Kruskal-Wallis and Dunnet's type rank sum test.
Armitage's chi2test was used for urunary paper tests
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Almost all rats of both sexes of the 500 mg/kg bw/day dose group had salivation after administration continuously after 5 days of treatment (reversible). Although related to the substance, it was only slight and readily improved, disappearing after discontinuation. Some male rats also had soft faeces, reduced spontaneous movement and rales. These symptoms were transient and seemed to be slight.
Mortality:
no mortality observed
Description (incidence):
No death occurred during the periods of treatment and recovery.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight gains were suppressed in male rats of the 500 mg/kg bw/day dose group during treatment and recovery (up to 13% on day 7 and day 28).
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Decreased in rats of both sexes of the high dose group early in treatment, returned to normal or tended to increase thereafter, and thus considered only slight.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Starting at the 15 mg/kg bw/day dose group, the hematocrit values decreased in the female animals:
At 15 mg/kg bw/day: 5% decrease compared to control
At 100 mg/kg bw/day: 4.8% decrease compared to control
At 500 mg/kg bw/day: 6.4% decrease compared to control
These changes, although statistically significant, are not considered toxicologically relevant, since the decrease is not dose-dependent and only minor. The author of the report considers the effects to be related to the substance.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
At highest dose, increase in GPT in rats of both sexes, increase in GOT in males, decrease in glucose and increase in A/G ratio in female rats.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Presence of occult blood in male rats of high dose group and decreased protein in female rats of the high dose dose group. These effecst were not considered to be toxicologically relevant.
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant observations:
Female rats of 500 mg/kg bw/day dose group showed an increase of absolute (12%) and relative (7%) liver weights as well as a reduction in relative (14%) and absolute (18%) ovary weight, and decreased relative and absolute adrenal weight. The latter was also seen in the low dose groups (small change and not dose related). Male rats of 500 mg/kg bw/day dose group showed a statistically significant but very slight decrease in absolute liver weight only (2%).
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
In female rats of the high dose group, deposition of glycogen in the liver (6/6) was seen.
Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on an increase of liver weights and a reduction in ovary weights in the females and a suppression of body weight gain in males at 500 mg/kg bw/day.
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
500 mg/kg bw/day (actual dose received)
System:
hepatobiliary
Organ:
liver
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
500 mg/kg bw/day (actual dose received)
System:
female reproductive system
Organ:
ovary
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes

In the additional study with 0, 2 and 10 mg/kg bw/day dose groups, no mortality, no clinical signs, no effect on bodyweight and food consumption, neither on haematological parameters, organ weight and macroscopic examination were observed.

Based on the main study, the effects on organ weights at the highest dose tested and the decrease in body weight gain are considered toxicologically relevant. As all other effects, clinical signs, haematological and biochemical effects, are considered not relevant, the NOAEL is considered to be 100 mg/kg bw/day. Note: no microscopic examination of several organs was performed, therefore the organ weight effects although sometimes slight, are considered relevant.

Conclusions:
In a sub-acute oral study in rats a NOAEL (systemic effects) of 100 mg/kg bw/day was established based on an increase of liver weights and a reduction in ovary weights in the females and a suppression of body weight gain in males at 500 mg/kg bw/day.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
A reliable study was used.
System:
hepatobiliary
Organ:
liver

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
December 21, 1998 - June 29, 2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Conducted in accordance with OECD 413 and GLP principles.
Qualifier:
according to
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK)
- Age at study initiation: 6 weeks
- Weight at study initiation:
Group mean bodyweights (g): 258.6-260.6 (male) and 196.0-196.8 (female)
IN-LIFE DATES: From: June 14, 1999 To: September 14, 1999
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
The rats were housed 5 of the same sex to a cage in suspended stainless steel cages fitted with mesh front, back and floor with stainless steel sheet sides. Each cage was 35 cm wide, 53 com long and 25 cm high. Plastic trays lined with absorbent paper, were place below each cage to collect animal excreta. The paper was changed daily. Clean cages were introduced at intervals throughout the study. The rats were kept in a single room and, additionally, after the start of the exposure period, each group was positioned on an individual cage battery. Each battery was in a separate ventilated cabinet within the holding room to avoid the possibility of inhalation of the substance from the fur of rats in other groups. Exposure took place in the same room.

The rats were exposed to the control/test atmosphere in whole-body exposure chambers (internal volume: 0.75 m3)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
During the exposure (6 hours), samples were taken after 1, 3 and 5 hours.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
The vapour of the test substance was administered for 6 hours a day, 5 days a week for 13 consecutive weeks.
Dose / conc.:
0.12 mg/L air
Dose / conc.:
0.55 mg/m³ air
Dose / conc.:
2.03 mg/m³ air
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on the results of the acute inhalation study
- Rationale for animal assignment (if not random): such that the group mean bodyweights were approximately equalised
Positive control:
No
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
BODY WEIGHT: Yes, weekly
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, weekly
WATER CONSUMPTION: Yes
OPHTHALMOSCOPIC EXAMINATION: Yes, week 13
HAEMATOLOGY: Yes, prior to sacrifice
CLINICAL CHEMISTRY: Yes
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
During exposure, no treatment-related clinical signs were observed at 0, 0.12 and 0.55 ug/L. The highest dose group (2.03 ug/L) showed signs of irritation (some rubbing noses with paws and sneezing) starting from day 5 throughout the study. The highest dose group also showed to be less responsive to outside stimuli starting from day 22 throughout the study.
Mortality:
no mortality observed
Description (incidence):
There were no unscheduled deaths.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No treatment-related effects observed.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No treatment-related effects observed.
Food efficiency:
not examined
Description (incidence and severity):
No treatment-related effects observed.
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
No treatment-related effects observed.
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No treatment-related effects observed.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
For a small number of parameters the differences between control and the highest dose group attained a degree of statistical signifance:
HCt: 4.4%; RBC: 3.7% and MCHC: 2.4% (all 3 parameters in males only)
For the parameter LUC, the differences between control and dose groups 0.12 and 2.03 ug/L attained a degree of statistical signifance in the males:
0.12 ug/L: 47%; 0.55 ug/L: 13.9%; 2.03 ug/L: 36%
As the differences were not dose-related and inconsistent between the sexes, they are not considered as toxicological relevant.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant observations:
-In males at the highest dose group, the parameter Ca Total was 3% decreased compared to the control;
-In females at the highest dose group, the parameter Phos was 21.8% decreased compared to the control;
As the differences were small, not dose-related and inconsistent between the sexes, they are not considered as toxicological relevant.
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No statistically significant observations were done.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No treatment-related findings were seen at the terminal necropsy.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
No effects were seen in females at 0.12 and 0.55 ug/L and in males at 0.12 ug/L. Erosion (2/10)/hyperplasia (10/10) with (3/10) or without (7/10) inflammation (rhinitis) were detected in the transitional epithelium of male rats from the 2.03 ug/L dose group. Hyperplasia of the transitional epithelium was seen at a low incidence in male rats from the 0.55 ug/L dose group (2/10). Hyperplasia was detected in the respiratory epithelium of rats, of both sexes, from the 2.03 ug/L dose group (males: 7/10; females: 2/10), but only in male rats from the 0.55 ug/L dose group (2/10)
Histopathological findings: neoplastic:
not examined
Key result
Dose descriptor:
NOAEC
Remarks:
Systemic
Effect level:
>= 2.03 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse systemic effects seen at highest dose tested
Key result
Dose descriptor:
NOAEC
Remarks:
Local
Effect level:
>= 0.12 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male
Basis for effect level:
histopathology: non-neoplastic
Key result
Critical effects observed:
no

Evaluation:

-No systemic effects observed of toxicological relevance

-Local effects observed starting from 0.55 ug/L in males:

Erosion/hyperplasia with or without inflammation (rhinitis) were detected in the transitional epithelium of rats from the 2.03 ug/L dosage group. Hyperplasia of the transitional epithelium was seen at a low incidence in male rats from the 0.55 ug/L dosage groups. Hyperplasia was detected in the respiratory epithelium of rats, of both sexes, from the 2.03 ug/L dosage groups, but only in male rats from the 0.55 ug/L dosage group.

Conclusions:
In a sub-chronic (90-day) inhalation toxicity study in rats a NOAEC (local effects) of 0.12 mg/m3 was established based on hyperplasia with or without inflammation (rhinitis) in the transitional epithelium in males at 0.55 mg/m3. In the same study, a NOAEC (systemic effects) of ≥2.03 mg/m3 (highest dose tested) was established.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
2.03 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
A reliable study is used.

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
December 21, 1998 - June 29, 2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Conducted in accordance with OECD 413 and GLP principles.
Qualifier:
according to
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK)
- Age at study initiation: 6 weeks
- Weight at study initiation:
Group mean bodyweights (g): 258.6-260.6 (male) and 196.0-196.8 (female)
IN-LIFE DATES: From: June 14, 1999 To: September 14, 1999
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
The rats were housed 5 of the same sex to a cage in suspended stainless steel cages fitted with mesh front, back and floor with stainless steel sheet sides. Each cage was 35 cm wide, 53 com long and 25 cm high. Plastic trays lined with absorbent paper, were place below each cage to collect animal excreta. The paper was changed daily. Clean cages were introduced at intervals throughout the study. The rats were kept in a single room and, additionally, after the start of the exposure period, each group was positioned on an individual cage battery. Each battery was in a separate ventilated cabinet within the holding room to avoid the possibility of inhalation of the substance from the fur of rats in other groups. Exposure took place in the same room.

The rats were exposed to the control/test atmosphere in whole-body exposure chambers (internal volume: 0.75 m3)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
During the exposure (6 hours), samples were taken after 1, 3 and 5 hours.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
The vapour of the test substance was administered for 6 hours a day, 5 days a week for 13 consecutive weeks.
Dose / conc.:
0.12 mg/L air
Dose / conc.:
0.55 mg/m³ air
Dose / conc.:
2.03 mg/m³ air
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on the results of the acute inhalation study
- Rationale for animal assignment (if not random): such that the group mean bodyweights were approximately equalised
Positive control:
No
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
BODY WEIGHT: Yes, weekly
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, weekly
WATER CONSUMPTION: Yes
OPHTHALMOSCOPIC EXAMINATION: Yes, week 13
HAEMATOLOGY: Yes, prior to sacrifice
CLINICAL CHEMISTRY: Yes
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
During exposure, no treatment-related clinical signs were observed at 0, 0.12 and 0.55 ug/L. The highest dose group (2.03 ug/L) showed signs of irritation (some rubbing noses with paws and sneezing) starting from day 5 throughout the study. The highest dose group also showed to be less responsive to outside stimuli starting from day 22 throughout the study.
Mortality:
no mortality observed
Description (incidence):
There were no unscheduled deaths.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No treatment-related effects observed.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No treatment-related effects observed.
Food efficiency:
not examined
Description (incidence and severity):
No treatment-related effects observed.
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
No treatment-related effects observed.
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No treatment-related effects observed.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
For a small number of parameters the differences between control and the highest dose group attained a degree of statistical signifance:
HCt: 4.4%; RBC: 3.7% and MCHC: 2.4% (all 3 parameters in males only)
For the parameter LUC, the differences between control and dose groups 0.12 and 2.03 ug/L attained a degree of statistical signifance in the males:
0.12 ug/L: 47%; 0.55 ug/L: 13.9%; 2.03 ug/L: 36%
As the differences were not dose-related and inconsistent between the sexes, they are not considered as toxicological relevant.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant observations:
-In males at the highest dose group, the parameter Ca Total was 3% decreased compared to the control;
-In females at the highest dose group, the parameter Phos was 21.8% decreased compared to the control;
As the differences were small, not dose-related and inconsistent between the sexes, they are not considered as toxicological relevant.
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No statistically significant observations were done.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No treatment-related findings were seen at the terminal necropsy.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
No effects were seen in females at 0.12 and 0.55 ug/L and in males at 0.12 ug/L. Erosion (2/10)/hyperplasia (10/10) with (3/10) or without (7/10) inflammation (rhinitis) were detected in the transitional epithelium of male rats from the 2.03 ug/L dose group. Hyperplasia of the transitional epithelium was seen at a low incidence in male rats from the 0.55 ug/L dose group (2/10). Hyperplasia was detected in the respiratory epithelium of rats, of both sexes, from the 2.03 ug/L dose group (males: 7/10; females: 2/10), but only in male rats from the 0.55 ug/L dose group (2/10)
Histopathological findings: neoplastic:
not examined
Key result
Dose descriptor:
NOAEC
Remarks:
Systemic
Effect level:
>= 2.03 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse systemic effects seen at highest dose tested
Key result
Dose descriptor:
NOAEC
Remarks:
Local
Effect level:
>= 0.12 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male
Basis for effect level:
histopathology: non-neoplastic
Key result
Critical effects observed:
no

Evaluation:

-No systemic effects observed of toxicological relevance

-Local effects observed starting from 0.55 ug/L in males:

Erosion/hyperplasia with or without inflammation (rhinitis) were detected in the transitional epithelium of rats from the 2.03 ug/L dosage group. Hyperplasia of the transitional epithelium was seen at a low incidence in male rats from the 0.55 ug/L dosage groups. Hyperplasia was detected in the respiratory epithelium of rats, of both sexes, from the 2.03 ug/L dosage groups, but only in male rats from the 0.55 ug/L dosage group.

Conclusions:
In a sub-chronic (90-day) inhalation toxicity study in rats a NOAEC (local effects) of 0.12 mg/m3 was established based on hyperplasia with or without inflammation (rhinitis) in the transitional epithelium in males at 0.55 mg/m3. In the same study, a NOAEC (systemic effects) of ≥2.03 mg/m3 (highest dose tested) was established.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
0.12 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
A reliable study is used.

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

The following effects were seen on histopathology in the 90 days inhalation study:

-Erosion/hyperplasia with or without inflammation (rhinitis) were detected in the transitional epithelium of male rats from the 2.03 ug/L dose group. Hyperplasia of the transitional epithelium was seen at a low incidence in male rats from the 0.55 ug/L dose group.

-Hyperplasia was detected in the respiratory epithelium of rats, of both sexes, from the 2.03 ug/L dose group, but only in male rats from the 0.55 ug/L dose group.

As these effects were observed at a low concentration (0.55 mg/m3) which are a factor 100 lower compared to single toxicity, the effect should be considered to be a repeated dose effect distinct from the acute toxicity (ECHA Guidance on the Application of the CLP Criteria, version 28/08/2009, page 376 -377), and thus the substance should be classified with:

STOT RE Category 1: Causes damage to organs (respiratory tract), through prolonged or repeated exposure (inhalation), in accordance with the CLP Regulation