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Diss Factsheets

Administrative data

Description of key information

OECD TG No. 413, GLP, reliability 1, rat: NOAEC > 5200 ppm


Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
other information
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Secondary literature (However, peer-reviewed data (EU RAR))
Principles of method if other than guideline:
Summarized overview of further data
Critical effects observed:
no
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
subchronic
Species:
other: rat and mouse

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:
not specified
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
in accordance with GLP
Reason / purpose for cross-reference:
reference to other study
Qualifier:
according to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Version / remarks:
2009
GLP compliance:
yes
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: 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
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

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
Dose / conc.:
0 ppm
Dose / conc.:
500 ppm (nominal)
Remarks:
analytical concentration: 501.30 ± 9.54 ppm
Dose / conc.:
1 600 ppm (nominal)
Remarks:
analytical concentration: 1605.43 ± 66.55 ppm
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
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.
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.
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
Critical effects observed:
no
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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
5 200 ppm
Study duration:
subchronic
Experimental exposure time per week (hours/week):
30
Species:
rat
Quality of whole database:
The quality of the whole database is high: Guideline study according to GLP

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:
not specified
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
in accordance with GLP
Reason / purpose for cross-reference:
reference to other study
Qualifier:
according to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Version / remarks:
2009
GLP compliance:
yes
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: 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
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

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
Dose / conc.:
0 ppm
Dose / conc.:
500 ppm (nominal)
Remarks:
analytical concentration: 501.30 ± 9.54 ppm
Dose / conc.:
1 600 ppm (nominal)
Remarks:
analytical concentration: 1605.43 ± 66.55 ppm
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
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.
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.
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
Critical effects observed:
no
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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
5 200 ppm
Study duration:
subchronic
Species:
rat
Quality of whole database:
The quality of the whole database is high: Guideline study according to GLP

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

NON HUMAN DATA


ORAL


Only a few data are available. The available data is regarded to be insufficient for a toxicological assessment and is furthermore not appropriate to be used as a basis for the derivation of a NOAEL.


DERMAL


This information is not available


 


INHALATION


In several reliable studies the sub-acute and sub-chronic toxicity of the test item after inhalation was investigated in rat and mice.


Long-term inhalation studies


A sub-chronic inhalation toxicity study (Kim et al., 2021) conforming to the OECD TG 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 examined. 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 ppm.


Furthermore, a reliable supportive study according to OECD TG No. 413 and in accordance with GLP was performed with B6C3F1 mice (Cho et al. 2020). Ten mice of each sex were exposed for 6 h/d at 5 d/week for 13 weeks at concentrations of 0, 500, 1600, or 5200 ppm for 90 days in whole-body inhalation chambers. No effects on food consumption, body weight, organ weight, clinical signs, hematology and biochemistry parameters, or gross or histological features even at the maximum concentration were observed. Therefore, the NOAEC was defined as more than 5200 ppm for male and female mice under study conditions.


In another reliable supporting 13-week inhalation toxicity study in Wistar (WU)-rats (OECD TG No. 413, GLP, 2004) a NOEC has been reported. Due to confidentiality issues no details are given in the CSR. Further details are be contained in the robust study summary (see IUC6 section 7-5-2, endpoint study record "Sup.OECD413.confidential").


short-term inhalation studies


A reliable 4-week repeated inhalation toxicity study according to OECD TG No. 412 (GLP not specified) was performed with F344 rats (Kim et al. 2020). 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/day, 5 days/week, for 4 weeks in a whole-body inhalation chamber system. No adverse toxicity was detected and the no-observed-adverse-effect concentration of was over 1600 ppm.


Further, the toxicity of the vaporized test substance was evaluated in a study performed according to OECD 412 and GLP in B6C3F1 mice (Cho et al. 2020). Five mice of each sex were exposed for 6 h/d at 5 d/week for 4 weeks at concentrations of 0, 100, 400, 1600 ppm in whole-body inhalation chambers. No effects on food consumption, body weight, organ weight, clinical signs, hematology and biochemistry parameters, or gross or histological features even at the maximum concentration were observed. Therefore, the NOAEC was defined as more than 1600 ppm for mice under study conditions.


Supportingly, a sub-acute inhalation toxicity study, similar to OECD TG No. 412, was conducted with Sprague-Dawley rats for 6 hours/day for 9 exposures during a 2-week period (UCC, 1992). Target concentrations were 0 (control), 100, 500, and 1000 ppm. An additional 5 animals per sex of the control and 1000 ppm groups were exposed to the same exposure regimen and held for 4 weeks after the final exposure to determine the reversibility of any observed toxic effects. For systemic effects a NOAEC of 1000 ppm is stated. Regarding local effects a LOEC of 500 ppm is given for male animals and a LOEC of 1000 ppm is given for female animals. 



 



HUMAN DATA


No human information is available.

Justification for classification or non-classification

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. Due to the absence of significant toxic effects in rodents for vapor doses up to 5200 ppm, the substance is not classified for repeated dose toxicity under Regulation (EC) No. 1272/2008, as amended for the fourteenth time in Regulation (EC) No. 2020/217.