Propan-1-ol

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

not specified

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

in accordance with GLP

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

not specified

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

according to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

Version / remarks:

2009

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source (i.e. manufacturer or supplier) of test material: Duksan Pure Chemicals
(Ansan, Korea)
- Purity: 99.9%

FORM AS APPLIED IN THE TEST (if different from that of starting material)
The test material was converted to a vapor by a LVG-04-A liquid vapor generator

FORM AS APPLIED IN THE TEST (if different from that of starting material)
- vapor

Species:

rat

Strain:

Fischer 344

Remarks:

SPF

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Japan SLC Inc. (Tokyo, Japan)
- Females (if applicable) nulliparous and non-pregnant: not specified
- Age at study initiation: 6 weeks
- Fasting period before study: not specified
- Housing: individually in a multi-compartment stainless steel wire mesh cage (W240 × L1200 × H200 mm) in the
WITC-14 M whole-body inhalation chamber (HCT, Icheon, Korea).
- Diet (e.g. ad libitum): 18 % protein Rodent Diet 2918C, Envigo RMS Inc., IN, USA, ad libitum
- Water (e.g. ad libitum): water, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 50 ± 20 %
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

clean air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: WITC-14 M whole-body inhalation chamber (HCT, Icheon, Korea).
- Method of conditioning air: LVG-04-A liquid vapor generator (HCT); vapors were diluted by regulating clean air flow through the liquid reservoir container of the test item in the generating system
- Air change rate: During the exposure period, the test material in the liquid reservoir was replaced weekly

TEST ATMOSPHERE
- Brief description of analytical method used: gAn IRGAS Fourier-transform infrared
spectrometer (Lab Frontier, Anyang, Korea) to determine the concentration of the test material in the inhalation chambers
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:

yes

Remarks:

IRGAS Fourier-transform infrared spectrometer (Lab Frontier, Anyang, Korea)

Details on analytical verification of doses or concentrations:

Analytical chamber concentrations were measured at least three times each exposure day

Duration of treatment / exposure:

6 h/day, 5 days/week, for 4 weeks

Frequency of treatment:

once daily

Dose / conc.:

0 ppm

Dose / conc.:

100 ppm (nominal)

Remarks:

analytical concentration 100.11 ± 5.10 ppm

Dose / conc.:

400 ppm (nominal)

Remarks:

analytical concentration 403.19 ± 12.31 ppm

Dose / conc.:

1 600 ppm (nominal)

Remarks:

analytical concentration 1598.08 ± 139.58 ppm

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: doses were selected based on a previous report of an acute toxicity study with 3936 ppm for 4h in rats.
- Fasting period before blood sampling for clinical biochemistry: yes, overnight

Positive control:

no

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Not specified

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: twice/week

FOOD CONSUMPTION: 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

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 4 weeks
- Anaesthetic used for blood collection: Yes, isoflurane (Il-sung Pharm, Seoul, Korea).
- Animals fasted: Yes
- How many animals: all
- Parameters checked: total red blood cell count, hematocrit (HCT), hemoglobin concentration, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration (MCHC), platelet count, reticulocyte (RET) count, total white blood cell count, differential white blood cell count (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), activated partial thromboplastin time (APTT), and prothrombin time

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after 4 weeks
- Animals fasted: Yes
- How many animals: all
- Parameters checked: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase (ALP), total protein, albumin, triglyceride,
total cholesterol (TCHO), total bilirubin, blood urea nitrogen, creatinine, creatinine phosphokinase, sodium, and potassium,

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No

BRONCHOALVEOLAR LAVAGE FLUID (BALF): No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
All rats underwent a complete necropsy that involved examining the external body surfaces and all orifices, as well as
the cranial, thoracic, and abdominal cavities and their contents. The following organs were trimmed and weighed: adrenal glands, brain, heart, kidneys, liver, lung, spleen, testes, thymus, epididymides, ovaries, and uterus.

HISTOPATHOLOGY: Yes, male and female rats of the control (0 ppm) and high dose (1600 ppm) groups
bone marrow, esophagus, femur, stifle joint, larynx, lymph nodes (tracheobronchial and mesenteric), nasopharyngeal
tissue, ovaries, seminal vesicles, spinal cord (cervical, lumbar, and thoracic), stomach, thyroid, trachea, urinary bladder, eye/optic nerves and testes

Statistics:

Data were assumed to be normally distributed and analyzed by a one-way analysis of variance. Dunnett’s multiple comparison test was used as the post hoc test.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

A relatively high standard deviation and unstable mean body weight were observed during the study period. This was considered to be caused by the stress of housing in stainless steel wire mesh cages during the exposure period, resulting in individual differences between animals.

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

No significant changes were noted in the hematology results between the control and different dose groups in female rats. However, in male rats, the MCHC was increased (p < 0.05) in the low (100 ppm) dose group, and APTT was increased (p < 0.05) in the middle (400 ppm) and high (1600 ppm)
dose groups. On the other hand, RETs were decreased (p < 0.05) in the middle dose group.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

increased TCHO (p < 0.05) in males in the low and middle dose groups, and increased
sodium (p < 0.05) and chloride (p < 0.05) in the middle and high dose groups. In addition, decreased ALP (p < 0.05) was observed in males in the middle dose group. In females,
decreased potassium (p < 0.05) in the middle dose group was the only change observed

Endocrine findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

A significant decrease in the absolute testes weight (p < 0.05) in males at the low (100 ppm) dose compared to the male control group was observed. The relative liver weight was significantly decreased (p < 0.05) in males at the low dose compared to male controls. Other organ weights did not show significant changes in either sex

Gross pathological findings:

not specified

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Mononuclear cell infiltration in heart, liver, and lung, metaplasia, macrophage aggregates in lung bronchi, and intracytoplasmic hyaline inclusions in the trachea were observed in male and female rats. In addition, tubule basophilia in the kidney and submucosal gland dilation in the trachea were observed in male rats, and focal nephropathy in the kidney was observed in female rats.

These findings are considered to be unrelated to the treatment incidental or spontaneous because they are observed commonly in similar aged rats as background lesions, and the frequency was similar to the results in control animals

Dose descriptor:

NOAEC

Effect level:

> 1 600

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other:

Critical effects observed:

no

Conclusions:

There were no adverse effects in F344 rats following repeated inhalation exposure of the test material as a vapor during a 4-week period. The study findings suggest that the NOAEC is over 1600 ppm.

Executive summary:

A 4-week repeated inhalation toxicity study according to OECD 412 (GLP not specified) was performed with F344 male and female rats. Concentrations of 0, 100, 400, and 1600 ppm were selected for the control, low, middle, and high dose groups. The rats (5/sex and dose) were exposed to the vapor 6 h a day, 5 days per week, for 4 weeks in a whole-body inhalation chamber system.

No mortality or clinical signs related to this exposure were observed. Furthermore, there were no significant changes in body weight or food consumption during the 4-week exposure period. The hematology results revealed increased MCHC, APTT, and decreased RETs. However, there was no dose–response relationship, and changes in other related hematological markers were not observed. The blood biochemistry results showed increased TCHO, sodium, and chloride, and decreased ALP and potassium. Again, there was no dose–response to these changes that remained within the normal range. The changes of absolute testes weight and relative liver weight did not occur in a dose–response manner, and there were no histopathological findings related to the test substance.

Therefore, the no-observed-adverse-effect concentration of was over 1600 ppm.

 

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2021

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

Version / remarks:

2009

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Propan-1-ol

EC Number:

200-746-9

EC Name:

Propan-1-ol

Cas Number:

71-23-8

Molecular formula:

C3H8O

IUPAC Name:

propan-1-ol

Test material form:

liquid

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source (i.e. manufacturer or supplier) of test material: REAGENTS DUKSAN
(Ansan, Korea)
- Purity: 99.9%

FORM AS APPLIED IN THE TEST (if different from that of starting material)
The test material was generated by vaporization, using a liquid vapor generator (LVG-04-A, HCT Co., Icheon, Korea)

FORM AS APPLIED IN THE TEST (if different from that of starting material)
- vapor

Test animals

Species:

rat

Strain:

Fischer 344

Remarks:

SPF

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Japan SLC Inc. (Tokyo, Japan)
- Females (if applicable) nulliparous and non-pregnant: not specified
- Age at study initiation: 6 weeks
- Weight at study initiation: males 141–173 g, females 108–134 g
- Fasting period before study: not specified
- Housing: poly-sulfone solid bottom cages (up to three animals of the same sex) with stainless steel grid tops during acclimation period; whole-body inhalation chambers (1.4 m3, WITC-14 M, HCT Co., Icheon, Korea) with individual multi-compartment stainless steel wire mesh cages (W240 × L1200 × H200 mm) during exposure period
- Diet (e.g. ad libitum): 18 % protein Rodent Diet 2918C, Envigo RMS Inc., IN, USA, ad libitum
- Water (e.g. ad libitum): filtered water, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 50 ± 20 %
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: whole-body inhalation chambers (1.4 m3, WITC-14 M, HCT Co., Icheon, Korea)
- Method of conditioning air: liquid vapor generator (LVG-04-A, HCT Co., Icheon, Korea), the test material was introduced into the chambers by regulating the airflow through the liquid reservoir container in the vapor generator
- Air change rate: During the exposure period, the test material in the liquid reservoir was replaced weekly

TEST ATMOSPHERE
- Brief description of analytical method used: gas chromatography (Model No. TRACE1310, Thermo Scientific, MA,
USA) was used to analyze its concentration of the test material in the inhalation chambers.
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:

yes

Remarks:

The chamber concentration was measured at least three times on each exposure day.

Details on analytical verification of doses or concentrations:

gas chromatography (Model No. TRACE1310, Thermo Scientific, MA, USA)

Duration of treatment / exposure:

6h/day, 5 days/week for 13 weeks

Frequency of treatment:

once daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 ppm

Doses / concentrations 2

Dose / conc.:

500 ppm (nominal)

Remarks:

analytical concentration: 501.30 ± 9.54 ppm

Doses / concentrations 3

Dose / conc.:

1 600 ppm (nominal)

Remarks:

analytical concentration: 1605.43 ± 66.55 ppm

Doses / concentrations 4

Dose / conc.:

5 200 ppm (nominal)

Remarks:

analytical concentration: 5202.19 ± 102.74 ppm

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Concentrations for low- and middle-exposure groups were selected based on a previously
conducted 28-day study, in which no toxic effects were observed at 100 ppm, 400 ppm, or 1600 ppm, while the high-exposure concentration selected was 5200 ppm, which allowed technically stable exposure and analysis
- Fasting period before blood sampling for clinical biochemistry: yes, fasted overnight

Positive control:

no

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Not specified

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: before and after exposure on the day of exposure, once on the day without exposure

BODY WEIGHT: Yes
- Time schedule for examinations: on the first day of exposure, twice per week in the first 4 weeks, once per week for the remainder of the study, and at the time of euthanasia

FOOD CONSUMPTION:
- Food consumption for each animal 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

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: once after exposure period
- Anaesthetic used for blood collection: Yes, isoflurane (Il-sung Pharm, Seoul, Korea)
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked: white blood cell (WBC) count, red blood cell (RBC) count, hemoglobin (HGB) concentration, hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelet (PLT) count, reticulocyte (RET) count, differential WBC count (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), activated partial thromboplastin time (APTT), and prothrombin time (PT);

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: once after exposure period
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked: Blood biochemical parameters, including sodium (Na), potassium (K), chloride (Cl), total protein (TP), albumin (ALB), creatinine (CREA), blood urea nitrogen (BUN), glucose (GLU), calcium (Ca), inorganic phosphorus (IP), total bilirubin (TBIL), total cholesterol (TCHO), triglyceride (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and albumin/globulin (A/G) ratio

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No

BRONCHOALVEOLAR LAVAGE FLUID (BALF):No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
external body surfaces, all orifices, and the cranial, thoracic, and abdominal cavities and their contents.
organ weigths: adrenal glands, brain, heart, kidneys, liver, lungs, spleen, testes, thymus,
epididymides, ovaries, and uterus

HISTOPATHOLOGY: Yes
adrenal glands, aorta, bone marrow, brain, cecum, colon, duodenum, epididymides, esophagus, femur, Harderian
glands, heart, ileum, jejunum, kidneys, larynx, liver, lung, lymph nodes (tracheobronchial and mesenteric), mammary glands, nasal cavity, ovaries, pancreas, pituitary, prostate, rectum, salivary glands (submandibular,
sublingual, and parotid), sciatic nerve, seminal vesicles, skeletal muscle, skin, spinal cord, spleen, sternum, stifle joint, stomach, teeth, thymus, thyroid, tongue, trachea, urinary bladder, uterus, vagina, eyes and testes

Statistics:

The data obtained during the study period were expressed as mean ± standard deviation (SD). Levene’s test was used to test for the homogeneity of group variances, and one-way analysis of variance (ANOVA) was used to compare the means of the groups. If Levene’s test was significant,
then Kruskal–Wallis non-parametric ANOVA was applied. Dunnett’s test or Dunn rank sum test was used following ANOVA as the post hoc test.

Results and discussion

Results of examinations

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

one case of soft stools in a male control from day 37 to day 40 after exposure

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Significant (p < 0.05, p < 0.01) decrease in the mean body weight was observed in the male high dose group from day 44 after exposure.
Considering that there was no correlation with the test substance in other test parameters, it was inferred that it was not an adverse effect.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

A significant (p < 0.01) decrease in food consumption was observed in the male high dose group from day 29 after exposure. In the male low dose group, a significant (p < 0.05 or p < 0.01) decrease in food consumption was observed on days 29, 71, and 85 after exposure, and in the male middle dose group, a significant (p < 0.05, or p < 0.01) decrease was observed on days 29, 64, and 71 after exposure. In the female middle dose group, a significant (p < 0.05) decrease in food consumption was observed on day 22 after exposure

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

RBC and HCT counts were significantly (p < 0.05) elevated in the male middle dose group compared to the male control group, while APTT level was significantly increased (p < 0.01) in the male low and high dose groups. PT was significantly increased (p < 0.01) in the female high dose group compared to the female control group. No significant changes were observed in other hematological parameters in the male and female rats. An increase in APTT and PT in rats was not considered to be correlated to the test substance because the changes were minor.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

BUN levels in the male low and middle dose groups were significantly (p < 0.05 or p < 0.01) elevated, and A/G ratio in the male low and high dose groups was significantly (p < 0.01) increased. Additionally, ALP levels in male middle and high dose groups were significantly (p <0.05 or p < 0.01) elevated; however, TBIL levels in all male exposure groups were significantly (p < 0.01) decreased, compared to the male control group. Na levels in female low and high dose groups were significantly (p < 0.05 or p < 0.01) increased, and Cl levels in all female exposure groups were significantly (p < 0.01) elevated. ALB, TP, TG, and Ca levels in the female high dose group were significantly (p < 0.05 or p < 0.01) decreased; however, ALP level in the female high dose group was significantly (P < 0.05) increased compared to the female control group. No significant changes were observed in other blood biochemical parameters in male and female rats.

The fluctuations in BUN levels and A/G ratio, were small and not dose-related. However, a decrease in TBIL level was observed in all the test groups, which seems to be related to the effect of the test substance. An increase in ALP level was observed in a dose-dependent manner, but no changes in related parameters, organs, and supporting histopathological findings were observed. In female rats, the blood biochemistry results indicated that the changes were only marginally significant, with no changes in related parameters. Likewise, changes in ALP levels were similar to those in males, with no accompanying changes in organs and histopathological findings.

Endocrine findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

In the male high dose group, the absolute weight of the epididymides and spleen were significantly (p < 0.01) decreased compared to the male control group. In the female middle dose group, the relative weights of the kidneys were significantly (P < 0.05) increased compared to the female control group.
The changes in the epididymis, spleen, and kidney weights were small, and no histopathological findings related to the test substance were observed.

Gross pathological findings:

not specified

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Microscopic findings such as granuloma of the epididymides; mononuclear cell infiltration of the heart, kidney, liver, lung, and pancreas; mineralization; tubular basophilia and dilation of the kidney; alveolar macrophage aggregates in the lung; pigmentation of the tracheobronchial lymph node; atrophy of the pancreas; cyst in the pituitary gland; basophilic cytoplasmic changes in the salivary gland; hematopoiesis of the spleen; cyst in thyroids; and hemorrhage in the ovary were observed in the control and high dose groups of male and female rats. Although some lesions were observed, they were considered incidental or spontaneous because they were of minimal or mild severity and were commonly observed in similar-aged rats as background lesions.

Some microscopic findings observed in the epididymis, heart, kidney, liver, lung, pancreas, tracheobronchial lymph node, pituitary gland, salivary gland, spleen, thyroids and ovary were considered incidental or spontaneous lesions.

Histopathological findings: neoplastic:

no effects observed

Details on results:

Respiratory tract irritation and hepatotoxicity were not observed after inhalation exposure.

Effect levels

Key result

Dose descriptor:

NOAEC

Effect level:

> 5 200 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other:

Remarks on result:

other: No adverse systemic toxicity up to and including the highest tested dose

Target system / organ toxicity

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

In a 13-week inhalation toxicity study in rats a NOAEC above 5200 ppm was determined due to the abscence of adverse toxicity.

Executive summary:

A subchronic inhalation toxicity study conforming to the OECD Test Guide No. 413 and in accordance with GLP was performed with Fischer 344 rats. The dosage concentrations in this study were 0, 500, 1600, and 5200 ppm for the control, low, middle, and high dose groups, respectively, based on reference values from previous studies. In this study, 80 (40 male and 40 female) rats were exposed to vapors of the test substance for 13 weeks (6 h a day, 5 days per week) in a whole-body inhalation chamber system. Clinical signs, mean body weight changes, food consumption, hematology, blood biochemistry, necropsy, organ weight, and histopathological findings were observed. The exposure concentrations in chambers were 501.30 ± 9.54 ppm, 1605.43 ± 66.55 ppm, and 5202.19 ± 102.74 ppm for the low, middle, and high dose groups, respectively.

No mortality and test substance-related clinical signs were observed during the study period. In the high dose group of males, a decrease in mean body weight and food consumption was observed, which could be attributed to the test substance. In respect to hematological parameters, the red blood cell count and hematocrit counts were significantly (p < 0.05) elevated in the male middle dose group compared to the male control group. The increase in activated partial thromboplastin time and prothrombin time in rats was not considered to be correlated to the test substance because the changes were minor. The blood biochemistry results in males revealed fluctuations in blood urea nitrogen levels and albumin/globulin ratio, that were small and not dose-related. However, a decrease in total bilirubin level was observed in all the test groups, which seems to be related to the effect of the test substance. An increase in alkaline phosphatase level was observed in a dose-dependent manner, but no changes in related parameters, organs, and supporting histopathological findings were observed. In female rats, the blood biochemistry results indicated that the changes were only marginally significant, with no changes in related parameters. Changes in alkaline phosphatase levels were similar to those in males, with no accompanying changes in organs and histopathological findings. The changes in the epididymis, spleen, and kidney weights were small and no histopathological findings related to the test substance were observed. Moreover, some microscopic findings in the examined organs were considered incidental or spontaneous lesions. Respiratory tract irritation and hepatotoxicity were not observed after inhalation exposure.

Based on the absence of adverse systemic effects the NOAEC (no observed adverse effect concentration) was determined to be greater than 5202.19 ppm.