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Diss Factsheets

Administrative data

Description of key information

NOAEL = 100 mg/kg/day for males or females (OECD 407, GLP, K rel. 1)

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

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:
1 November 1999 to 13 December 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
GLP study performed in accordance with OECD guideline 407 without deviations.
Data on range-finding study were included in this endpoint summary report.
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Qualifier:
according to guideline
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
Substance identity: Javanol
Appereance: Liquid
Species:
rat
Strain:
Wistar
Details on species / strain selection:
The study was conducted in Wistar HanIbm (SPF) rats because this species is recognized by the international guidelines as the recommended test system.
Sex:
male/female
Details on test animals or test system and environmental conditions:
Identification: Cage card and individual ear tattoo
Randomization: Computer-generated random algorithm
Acclimatization: Under test conditions after health examination. Only animals without any visible signs of illness were used for the study.
Husbandry conditions: standard laboratory conditions. Air-conditioned with 10-15 air changes per hour, and continuously monitored environment with a target range for temperature of 22 +/- 3°C and for relative humidity between 40-70%. 12 hours fluorescent light/12 hours dark, music during the light period.
Accomodation: In groups of 5 in Makrolon type-4 cages with wire mesh tops and standardized softwood bedding.
Diet: Pellet standard Provimi KLiba 3433 rat maintenance diet was available ad libitum. The feed batch was analyzed for contaminants.
Water: Community tap-water from Itingen was available ad libitum in water bottles.
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
PEG 300
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
The test article formulations were prepared weekly.
Javanol was weighted into a glass beaker on a tared Mettler balance and the vehicle added. The mixture were prepared using a ultrasonic water bath (40°C) and a magnetic stirrer and stored in a refrigerator (2-8°C)
Homogeneity of the test item in the vehicle was maintained during the daily administration period using a magnetic stirrer.

VEHICLE
Vehicle identity: PEG 300
Batch no. 395304/1 22099
Expiry date: May 2004
Storage conditions at room temperature (17-23°C) in original container
Safety precautions: Routine hygiennic procedures (gloves, goggles, face mask)

TREATMENT:
- dose levels:
Group 1: 0 mg/kg body weight (vehicle)
Group 2: 20 mg/kg body weight
Group 3: 100 mg/kg body weight
Group 4: 500 mg/kg body weight

- dose volume: 5 ml/kg body weight
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentration, honogeneity and stability (after 2 hours and 7 days) of the dose formulations were determined in samples taken during acclimatization. Concentration and homogeneity of the dose formulations were determined in samples taken during week 3 of the tretment. The analysis were performed according to a GC method.
Duration of treatment / exposure:
Range-finding study: 7 days
28-day study: 28 days
Frequency of treatment:
Once daily at a similar time until the day prior to necropsy
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Group 1 (vehicle)
Dose / conc.:
20 mg/kg bw/day (nominal)
Remarks:
Group 2
Dose / conc.:
100 mg/kg bw/day (nominal)
Remarks:
Group 3
Dose / conc.:
500 mg/kg bw/day (nominal)
Remarks:
Group 4
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
Rationale for dose level selection: Based upon the results of a non-GLP 5-day dose-range-finding study in which Javanol was administered by gavage to 2 rats per group and sex at 0, 200, 600, 1000 mg/kg/day . Animals showed clinical signs of reduced food consumption and reduced body weight development at 600 and 1000 mg/kg/day. Higher liver weights were noted at 600 and 1000 mg/kg/day; lower thymus weights at 200 and 600 mg/kg/day (females only) and 1000 mg/kg/day (both sexes); lower spleen weights 600 and 1000 mg/kg/day (females only).

- Fasting period before blood sampling for clinical biochemistry: Yes
Positive control:
None
Observations and examinations performed and frequency:
Mortality/viability: twice daily
General cageside observations: once before beginning of study, twice daily on days 1-3 and once daily on days 4-28
Detailed clinical observations: animals observed in their home cages, outside their home cages in a standard area and in the hand. These observations were performed in random sequence once before commencement of administration and once weekly (weeks 1-3) thereafter.
Food consumption: once during pretest period and weekly thereafter
Body weights: weekly during pretest, treatment and before necropsy
FOB: Irwin Screen Test during week 4, grip strength, locomotor activity monitored during week 4 for 60 minutes
Clinical Labs: hematology, clinical biochemistry (after 4 weeks)
Pathology: organ weights, gross and microscopic (after 4 weeks)
Sacrifice and pathology:
After 4 weeks, all animals were weighed and necropsied. Descriptions of all macroscopic abnormalities were recorded. Necropsies were performed by experienced prosectors supervised by an experienced veterinary pathologist. All animals were anesthetized by intraperitoneal injection of sodium pentobarbitone and killed by exsanguination. Samples of the following tissues and organs were collected and evaluated by the pathologists: adrenal glands, bone marrow, brain, cecum, colon, duodenum, epididymides, heart, illeum with peyer's patch, jejunum with peyer's patch, kidneys, liver, lungs, lymph nodes, ovaries, prostate, gland, rectum, sciatic nerve, seminal vesicle, spinal cord, spleen, stomach, testes, thymus, thyroid, trachea, urinary bladder, uterus, vagina, gross lesions.
Other examinations:
Absolute and relative organ weights: brain, heart, liver, thymus, kidneys, adrenals, spleen, testes, epididymides
Statistics:
Dunnett-test was applied for the comparison of treated groups and the control groups for each sex.
Steel-test was applied instead of Dunnett-test when the data could not be assumed to follow a normal distribution.
Student's T-Test was applied to locomotor activity and grip strength
Fisher's exact-test was applied to macroscopic findings
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Breathing noises in 1 male at 500 mg/kg/day and 1 male at 100 mg/kg/day and salivation in 1 female at 500 mg/kg/day on treatment days 14 and 15. No treatment-related clinical signs were evident in any animal during daily or weekly observations.
Mortality:
no mortality observed
Description (incidence):
All animals survived until scheduled necropsy.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The mean body weights and body weight gain of the test article-treated animals compared favorably with those of the controls.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
A test article-related decrease in the mean food consumption and the mean relative food consumption of the females treated with 500 mg/kg/day compared to control was observed throughout the treatment period. While the mean daily food consumption of the test-article treated males was unaffected.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Lower absolute reticulocyte count in the males treated with 500 mg/kg/day was considered incidental. Significant decrease in WBC in males at 20 mg/kg/day was not dose-dependent. Similarly, significant increase in hemoglobin at 20 mg/kg/day was not dose-dependent. Overall, no changes of toxicological significance observed in hematology in the test-article treated animals.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Test article-related changes in clinical biochemistry parameters included reductions in glucose levels at 100 mg/kg/day in males and in both sexes at 500 mg/kg/day. Females treated with 500 mg/kg/day also had increased levels of total cholesterol, triglycerides and phospholipids. Statistically significantly higher activity of gamma glutamyltransferase was seen in both sexes at 500 mg/kg/day. Calcium levels were higher in males and females at 500 mg/kg/day, and potassiuml evels were lower in males and females at 500 mg/kg/day. These changes were considered to be test-article related.

Total plasma bilirubin was reduced in females at 500 mg/kg/day but this difference was not of toxicological significance. All other differences to the control data were considered to be unrelated to the test article.
Urinalysis findings:
not specified
Behaviour (functional findings):
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related findings on functional observational battery (week 4). Males treated at 100 mg/kg/day were significantly more active during the forth measurement interval compared to controls and females at 50 mg/kg/day were signifcantly less active compared to control. In the absence of a similar finding in the animals at higher dose levels, the finding was considered incidental.
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
When compared with the controls, absolute liver weights were increased in both sexes treated with 500 mg/kg/day and in females at 100 mg/kg/day. Relative liver weights were higher in males at 500 mg/kg/day and in females at 20, 100 and 500 mg/kg/day. Since the changes in the female relative liver weights at 20 and 100 mg/kg/day were not accompanied by clinical biochemistry changes, these effects were considered adaptive. Those at 500 mg/kg/day for both sexes were accompanied by clinical biochemistry changes and therefore considered test-article related.

Relative and absolute kidney weights were significantly increased in males treated at 500 mg/kg/day and were considered test article related.

Mean thymus weights were statistically significantly lower in males treated with 100 and 500 mg/kg/day when compared with control values. These differences were considered to be test article related.

All other organ weights were considered to be unaffected.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
The only gross lesion which could be attributed to treatment with the test article consisted of enlarged liver in one male treated with 500 mg/kg/day. A morphologic correlate for this finding was not detected.
The remaining gross findings were considered to be within the range of spontaneous background alterations in rats of this strain and age. They consisted of incompletely collapsed lungs, renal pelvis dilation, cysts in the ovaries and discoloration/foci in several organs.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
In the kidneys of males treated at 500 mg/kg/d, there was an increase incidence and severity of tubular basophilia and this was accompanied by tubular mineralization at the corticomedullary junction. In one male rat a focal hyaline tubular cast was seen within a tubular cyst located at the corticomedullary junction. At 100 mg/kg/day, there was tubular basophilia in 2 males and tubular mineralization in one male. These findings were considered to be test article related.
Histopathological findings: neoplastic:
not specified
Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical biochemistry
histopathology: non-neoplastic
organ weights and organ / body weight ratios
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
100 mg/kg bw/day (nominal)
System:
other: renal
Organ:
kidney
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes
Conclusions:
Due to the uncertainty in the relevance of the kidney findings at 500 mg/kg/day, the NOAEL can be established at 100 mg/kg/day and 20 mg/kg/day was the no-observed-effect- level (NOEL).
Executive summary:

In a sub-acute toxicity study performed in accordance with the OECD guideline No. 407, under GLP, Javanol was administered daily to SPF-bred Wistar rats of both sexes at dose levels of 0, 20, 100 and 500 mg/kg body weight/day via oral gavage for 28-days. The above dose-levels were selected on the basis of a range finding study in which animals (2/sex/group) received the test material by oral gavage at dose-levels of 0 (PEG300), 200, 600 and 1000 mg/kg/day for 5 consecutive days. In this 5 -day study, there were clinical findings of ruffled fur in both sex at 1000 mg/kg/day and in females treated at 600 mg/kg/day. There was slight emaciation on treatment day 5 in 1 female treat with 600 mg/kg/day and 1 female treated with 1000 mg/kg/day. Mean food consumption was decreased in males and females at 600 mg/kg/day and 1000 mg/kg/day and mean body weight gain of males and females treated at 600 mg/kg/day and 1000 mg/kg/day were lower than controls and considered test article related. Changes in organ weights were noted in both sexes treated at 1000 mg/kg/day and females treated at 200 and 600 mg/kg/day. Liver weights were higher for both sexes treated at 600 and 1000 mg/kg/day. Thymus weights were reduced in both sexes at 1000 mg/kg/day and in females at 200 and 600 mg/kg/day and spleen weights in the females treated with 600 and 1000 mg/kg/day were slightly lower than controls. Macroscopic evaluation revealed renal pelvis dilation in one male treated at 200 mg/kg/day and one male treated at 600 mg/kg/day. A gray-white kidney focus was noted in one female treated with 1000 mg/kg/day. Based on these results the dose levels of 20, 100 and 500 were proposed for the definitive study.

In the definitive study, the groups comprised of 5 animals per sex which were sacrificed after 28 days of treatment. Clinical signs, outside cage observation, food consumption and body weights were recorded periodically during pretest and treatment periods. Functional observational battery, locomotor activity and grip strength were performed during week 4. At the end of the dosing period, blood samples were withdrawn for hematology and plasma chemistry analyses. All animals were killed, necropsied and examined post mortem. Histological examinations were performed on organs and tissues from all control and high dose animals, and all gross lesions from all animals. From the animals of the low and middle dose groups, kidneys were examined to establish a no-effect level.

Javanol presented no observable changes in mortality, clinical signs, grip strength, locomotor activity, body weight development and hematology parameters. Test article-related findings included a transient reduction of food consumption at 500 mg/kg/day (females only). Changes in metabolism were noted, characterized by reductions of plasma glucose at 100 mg/kg/day (males only) and 500 mg/kg/day (both sexes), changes in lipid metabolism at 500 mg/kg/d (females only), and increased activity of gamma glutamyltransferase at 500 mg/kg/d (both sexes). Minor changes in electrolyte homeostasis were evidenced by higher calcium levels at 500 mg/kg/d (both sexes), and lower potassium levels 500 mg/kg/d (both sexes). Changes in organ weights which were related to the treatment with the test article were noted in the liver at 500 mg/kg/d (increased in both sexes), in the kidney at 500 mg/kg/d (increased in males only) and in the thymus at 100 and 500 mg/kg/d (lower in males only). Microscopic changes, consisting of tubular basophilia and tubular mineralization at the corticomedullary junction, were noted in the kidneys of males at 100 and 500 mg/kg/d. This finding was accompanied by a hyaline tubular cast in a single male treated at 500 mg/kg/d. These findings, generally indicative of non-specific renal tubular damage, were considered to be test article related.

The oral administration of Javanol for 28 days at 100 mg/kg/day was associated with a statistically significant reduction in plasma glucose in males only, increases in absolute and relative liver weights in females only, and a decrease in absolute and relative thymus weight in males only. There were no corresponding macroscopic changes among animals in this treatment group and microscopic changes were confined to the kidney; grade 1 tubular basophilia in two males (1 male affected in the control group) and grade 1 tubular mineralization in one male. The mean severity of this effect was the same as that of controls; 1.0. Given the lack of microscopic changes in the liver and the low incidence and severity of microscopic kidney effects observed in the absence of kidney specific biochemical changes, these findings can be considered adaptive non-adverse changes that are not biologically significant. Additionally, in the OECD 421 study, rats exposed to Javanol for 28-days via oral gavage showed no kidney effects at 100 mg/kg/day or up to 250 mg/kg/day.

 

At 500 mg/kg/day, there are statistically significant increases in absolute and relative liver weights in males and females with corresponding changes in clinical biochemistry. However, no other than an enlarged liver in one male rat, there were no other liver related macro/microscopic changes. There was an increase in absolute and relative kidney weights in males as well as decreased absolute and relative thymus weights. No macroscopic kidney changes were observed. However, microscopic evaluation showed an increase in the incidence of tubular basophilia (1 control male versus 5 males in the high dose group) and tubular mineralization was observed in 4 males. Of the 5 males with tubular basophilia, 3 showed grade 1 change (defined as minimal/very few/very small) while 2 showed grade 2 changes (slight/few/small). While of the 4 males with tubular mineralization, 3 animals were classified as grade 1 and 1 animal classified as grade 2. The severity of the tubular basophilia effect was 1.0 in controls and 1.4 in the high dose group while the severity of tubular mineralization in the high dose was 1.3. Although renal tubular basophilia can be considered a marker of nephrotoxicity, given the low severity of the effects it is likely that this is an adaptive response and these basophilic tubules are regenerative and would disappear as the regenerating cell becomes a fully differentiated epithelium (Chennekatu et al., 1986). Also, these observed kidney changes may be male rat specific and related to alpha-2u-globin and therefore not relevant to humans.

 

Due to the uncertainty in the relevance of the kidney findings at 500 mg/kg/day, the NOAEL can be established at 100 mg/kg/day and 20 mg/kg/day was the no-observed-effect- level (NOEL).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Klimisch 1, OECD guideline and GLP study
System:
other: Renal
Organ:
kidney

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

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

Mode of Action Analysis / Human Relevance Framework

There is an uncertainty in the relevance of the kidney findings observed at 500 mg/kg bw/d (see description below).

No macroscopic kidney changes were observed.

And although renal tubular basophilia can be considered a marker of nephrotoxicity, given the low severity of the effects it is likely that this is an adaptive response and these basophilic tubules are regenerative and would disappear as the regenerating cell becomes a fully differentiated epithelium (Chennekatu et al., 1986). Also, these observed kidney changes may be male rat specific and related to alpha-2u-globin and therefore not relevant to humans.

Additional information

In a sub-acute toxicity study performed in accordance with the OECD guideline No. 407, under GLP, Javanol was administered daily to SPF-bred Wistar rats of both sexes at dose levels of 0, 20, 100 and 500 mg/kg body weight/day via oral gavage for 28-days. The above dose-levels were selected on the basis of a range finding study in which animals (2/sex/group) received the test material by oral gavage at dose-levels of 0 (PEG300), 200, 600 and 1000 mg/kg/day for 5 consecutive days. In this 5 -day study, there were clinical findings of ruffled fur in both sex at 1000 mg/kg/day and in females treated at 600 mg/kg/day. There was slight emaciation on treatment day 5 in 1 female treat with 600 mg/kg/day and 1 female treated with 1000 mg/kg/day. Mean food consumption was decreased in males and females at 600 mg/kg/day and 1000 mg/kg/day and mean body weight gain of males and females treated at 600 mg/kg/day and 1000 mg/kg/day were lower than controls and considered test article related. Changes in organ weights were noted in both sexes treated at 1000 mg/kg/day and females treated at 200 and 600 mg/kg/day. Liver weights were higher for both sexes treated at 600 and 1000 mg/kg/day. Thymus weights were reduced in both sexes at 1000 mg/kg/day and in females at 200 and 600 mg/kg/day and spleen weights in the females treated with 600 and 1000 mg/kg/day were slightly lower than controls. Macroscopic evaluation revealed renal pelvis dilation in one male treated at 200 mg/kg/day and one male treated at 600 mg/kg/day. A gray-white kidney focus was noted in one female treated with 1000 mg/kg/day. Based on these results the dose levels of 20, 100 and 500 were proposed for the definitive study.

In the definitive study, the groups comprised of 5 animals per sex which were sacrificed after 28 days of treatment. Clinical signs, outside cage observation, food consumption and body weights were recorded periodically during pretest and treatment periods. Functional observational battery, locomotor activity and grip strength were performed during week 4. At the end of the dosing period, blood samples were withdrawn for hematology and plasma chemistry analyses. All animals were killed, necropsied and examined post mortem. Histological examinations were performed on organs and tissues from all control and high dose animals, and all gross lesions from all animals. From the animals of the low and middle dose groups, kidneys were examined to establish a no-effect level.

Javanol presented no observable changes in mortality, clinical signs, grip strength, locomotor activity, body weight development and hematology parameters. Test article-related findings included a transient reduction of food consumption at 500 mg/kg/day (females only). Changes in metabolism were noted, characterized by reductions of plasma glucose at 100 mg/kg/day (males only) and 500 mg/kg/day (both sexes), changes in lipid metabolism at 500 mg/kg/d (females only), and increased activity of gamma glutamyltransferase at 500 mg/kg/d (both sexes). Minor changes in electrolyte homeostasis were evidenced by higher calcium levels at 500 mg/kg/d (both sexes), and lower potassium levels 500 mg/kg/d (both sexes). Changes in organ weights which were related to the treatment with the test article were noted in the liver at 500 mg/kg/d (increased in both sexes), in the kidney at 500 mg/kg/d (increased in males only) and in the thymus at 100 and 500 mg/kg/d (lower in males only). Microscopic changes, consisting of tubular basophilia and tubular mineralization at the corticomedullary junction, were noted in the kidneys of males at 100 and 500 mg/kg/d. This finding was accompanied by a hyaline tubular cast in a single male treated at 500 mg/kg/d. These findings, generally indicative of non-specific renal tubular damage, were considered to be test article related.

 

The oral administration of Javanol for 28 days at 100 mg/kg/day was associated with a statistically significant reduction in plasma glucose in males only, increases in absolute and relative liver weights in females only, and a decrease in absolute and relative thymus weight in males only. There were no corresponding macroscopic changes among animals in this treatment group and microscopic changes were confined to the kidney; grade 1 tubular basophilia in two males (1 male affected in the control group) and grade 1 tubular mineralization in one male. The mean severity of this effect was the same as that of controls; 1.0. Given the lack of microscopic changes in the liver and the low incidence and severity of microscopic kidney effects observed in the absence of kidney specific biochemical changes, these findings can be considered adaptive non-adverse changes that are not biologically significant. Additionally, in the OECD 421 study, rats exposed to Javanol for 28-days via oral gavage showed no kidney effects at 100 mg/kg/day or up to 250 mg/kg/day.

 

At 500 mg/kg/day, there are statistically significant increases in absolute and relative liver weights in males and females with corresponding changes in clinical biochemistry. However, no other than an enlarged liver in one male rat, there were no other liver related macro/microscopic changes. There was an increase in absolute and relative kidney weights in males as well as decreased absolute and relative thymus weights. No macroscopic kidney changes were observed. However, microscopic evaluation showed an increase in the incidence of tubular basophilia (1 control male versus 5 males in the high dose group) and tubular mineralization was observed in 4 males. Of the 5 males with tubular basophilia, 3 showed grade 1 change (defined as minimal/very few/very small) while 2 showed grade 2 changes (slight/few/small). While of the 4 males with tubular mineralization, 3 animals were classified as grade 1 and 1 animal classified as grade 2. The severity of the tubular basophilia effect was 1.0 in controls and 1.4 in the high dose group while the severity of tubular mineralization in the high dose was 1.3. Although renal tubular basophilia can be considered a marker of nephrotoxicity, given the low severity of the effects it is likely that this is an adaptive response and these basophilic tubules are regenerative and would disappear as the regenerating cell becomes a fully differentiated epithelium (Chennekatu et al., 1986). Also, these observed kidney changes may be male rat specific and related to alpha-2u-globin and therefore not relevant to humans.

Due to the uncertainty in the relevance of the kidney findings at 500 mg/kg/day, the NOAEL can be established at 100 mg/kg/day and 20 mg/kg/day was the no-observed-effect- level (NOEL).

Justification for classification or non-classification

Harmonised classification:

The test material has no harmonized classification for repeated dose toxicity according to the Regulation (EC) No. 1272/2008 (CLP).

 

Self-classification:

Based on the available information, no additional self-classification is proposed regarding the specific target organ toxicity after oral dose-repeated exposure according to the Regulation (EC) No. 1272/2008 (CLP) and to the GHS.

No information is available regarding the dermal and inhalation routes.