Octadecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate

Endpoint summary

Description of key information

The test article was administered to dogs in a daily diet over a period of 90 days (CIBA-GEIGY 1981). Due to the non-reversible increase in liver weight at higher dose levels, the NOAEL is considered to be 34 mg/kg bw/day. In a chronic feeding study with rats, the test article caused increase in liver and thyroid weight (Ciba-Geigy 1974a), Due to these results, the NOAEL is considered to be 64 mg/kg bw/day in males and 81 mg/kg bw in females, respectively.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline without GLP, acceptable with restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 409 (Repeated Dose 90-Day Oral Toxicity Study in Non-Rodents)

Deviations:

yes

Remarks:

6 animals per dose group instead of 8; homogeneity of the test substance formulation was not determined, organ weights were limitedly determined. 28-day recovery period included

GLP compliance:

no

Limit test:

no

Species:

dog

Strain:

Beagle

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: WIGA, Sulzfeld/Germany
- Age at study initiation: 26-35 weeks
- Weight at study initiation: males 8.6-12.6 Kgs; females 7.6-12.2 kgs
- Housing: 2 per each kennel
- Diet : Pelleted standard diet (Nafag, No. 941) 350 g/day/animal
- Water (e.g. ad libitum): tap water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): floor temperature: approx. 23; room temperature: 20±3
- Photoperiod (hrs dark / hrs light): 10/14

Route of administration:

other: oral diet (pellets)

Vehicle:

polyethylene glycol

Details on oral exposure:

DIET PREPARATION
- The test substance was weighed and diluted with PAG 400 into an Erlenmeyer flask on a Mettler balance (Type PC 4400). The pulverized dog food was then homogenously mixed with the appropriate concentrations of the compound and about 10 % of water was added before pelleting to ensure the necessary pellet quality. The pellets were subsequently air-dried.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

- Method: liquid chromatography with UV-detection at 280 nm
- Sampling times: pre-test, week 4 and 9

Duration of treatment / exposure:

91 days

Frequency of treatment:

once (350 g)/day, 7 days a week

Remarks:

Doses / Concentrations:
1000, 3000 and 10000 ppm
Basis:
nominal in diet

Remarks:

Doses / Concentrations:
31.5, 92.2 and 295.4 mg/kg bw/day in males and 34.5, 97.2 and 335.7 mg/kg bw/day in females
Basis:
actual ingested

No. of animals per sex per dose:

6 (five plus 1 for recovery group)

Control animals:

yes, concurrent no treatment

Details on study design:

- Post-exposure recovery period in satellite groups: 28 days (1 animal per sex and dose group)

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: mortality, signs of local and systemic toxicity

BODY WEIGHT: Yes
- Time schedule for examinations: daily

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated : 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: Yes

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pretest, at week 13, and 17 (recovery period, test week 4)
- Dose groups that were examined: all

HAEMATOLOGY: Yes
- Time schedule for collection of blood: week 1, 4, 8 and 12, and at recovery period test week 1
- Anaesthetic used for blood collection: No
- Animals fasted: No
- How many animals: all
- Parameters checked: Haemoglobin (Hb), Erythrocytes (RBC), Haematocrit (PCV), Mean Corpuscular Volume (MCV), Mean Corpuscular Haemoglobin (MCH), Reticulocytes, Thrombocytes, Prothrombin Time, Partial Thromboplastin Time, Thrombin Time, Leucocytes (WBC), Differential Count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: week 1, 4, 8 and 12, and at recovery period test week 1
- Animals fasted: No
- How many animals: all
- Parameters checked: Glucose, Urea (urea-N), Total Bilirubin, Total protein, Protein Electrophoresis, Asp. Aminotransferase (GOT), Ala. Aminotransferase (GPT), Lactate Dehydrogenase (LDH), Alkaline Phosphatase (AP), G-Glutamyl transpeptidose (G-GTP), Cholesterol, Creatine Kinase (CK), Creatinine, Elektrolytes (Na, K, Cl, Ca, P)

URINALYSIS: Yes
- Time schedule for collection of urine: week 1, 4, 8 and 12, and at recovery period test week 1
- Metabolism cages used for collection of urine: No, obtained by catheterization
- Animals fasted: No
- Parameters checked: color, specific gravity, pH, protein, glucose, ketone, blood, bilirubin, urobilinogen, urine sediment

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: monthly
- Dose groups that were examined: all
- Battery of functions tested: sensory activity (simple noise test: calling the dog)

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

For both, the following organs were examined: Brain, spinal cord, eye, pituitary, salivary gland, heart, thymus, thyroid, lungs, trachea, spleen, bone (with marrow), lymph nodes, aorta, urinary bladder, oesophagus, stomach, small and large intestine, adrenal glands, pancreas, liver, kidneys, ovaries/testes, prostate/uterus, skin, skeletal muscle, sciatic nerve, gall bladder and mammary gland.

Other examinations:

The following organs were weighed: heart, liver, kidneys, adrenals, thyroid, gonads, brain and pituitary.

Statistics:

For each time point and parameter a uni-variate statistical analysis was conducted. Each treated group was compared to the control group in respect of dispersion and displacement (Y. Lepage, Biometrika, 58: pp. 213-217, 1971). In addition a trend test was applied considering all groups (H.R. Jonckheere, Biometrika, 41: pp. 133-145, 1954).

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

no effects observed

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

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY:
No animal died during the experiment.
A slight to moderate diarrhea was observed practically during the whole administration period in the control and all treated groups. Towards the end of the administration period this finding was less frequent and during the recovery period with very few exceptions no diarrhea was observed.
While sampling urine during week 4 a modulated vagina was observed in dogs 38, 42 and 45. This finding was no more observed at later stages.

BODY WEIGHT AND WEIGHT GAIN:
The body-weight gain was similar in all animals.

FOOD CONSUMPTION:
The food consumption of all animals was comparable.

FOOD EFFICIENCY:
The mean food conversion was similar in all animals.

OPHTHALMOSCOPIC EXAMINATION:
No findings related to the compound administration were recorded.

HAEMATOLOGY:
The values were generally unremarkable and comparable to those of the controls.
Practically in all counts the values of the eosinophil granulocytes were at the upper normal limit or slightly higher. A subclinical parasitic infection (Strongyloides spp.) in the population was suspected, but a coprologic survey during week 16 gave only negative results. During week 15 two dogs were given 12.5 mg/dog SYNACTHEN R , a synthetic ACTH preparation. 7 hours later the number of eosinophils was below of 50 % of the pretest level, indicating that the function of the adrenal cortex was intact.

CLINICAL CHEMISTRY:
The values were generally unremarkable and comparable to those of the controls.
An elevation of bilirubin values with a positive trend from the control to the highest dosage group was seen in all treated groups at weeks 4, 9 and 13. The range of individual values was however wide, particularly in the females of the 10000 ppm group. Elevated bilirubin levels as observed in the treatment groups are usually correlated with:
- jaundice
- increase in the activity of alkaline phosphatase
- increase of urinary excretion of bile pigments
- histopathologic changes in the liver
Since none of these conditions was observed, the elevated bilirubin concentration in the treatment groups is considered as artifactions and without toxicological relevance.

URINALYSIS:
The values were generally unremarkable and comparable to those of the controls.

NEUROBEHAVIOUR:
No impairment of the auditory perception was found.

ORGAN WEIGHTS:
Organ weights and ratios for the compound treated dogs were comparable to those of the control animals with the exception of a slightly increased incidence of higher liver weights and ratios in the dogs of the 3000 and 10000 ppm groups. There was +20% and +60% increase in the ratios (liver/body) in males, and +19% and +21% increase in the ratios in females of the 3000 and 10000 ppm groups at the end of treatment period, respectively (p<0.05). After the end of recovery period, there was slight decrease in the 3000 ppm male and 45% increase in the ratios of 10000 ppm male. In females, there was +26% and 19% increase in the ratios of 3000 and 1000 ppm groups, respectively. Only one animal per dose group was used in the recovery group.

GROSS PATHOLOGY:
No compound related gross anatomical changes were noted.

HISTOPATHOLOGY: NON-NEOPLASTIC:
In two treated dogs (32 f from the 1000 ppm group and 13 m from the 3000 ppm group) and in one control animal (28 f) minute green brown pigmented droplets were found in very occasional biliary canaliculi of the liver. However no correlation between elevated or transitionally elevated concentration of serum bilirubin levels noted in a few treated dogs at biochemical examination, and histopathological findings in the liver could be established. All other changes seen in some control and treated dogs described within the microscopical findings in individual dogs were only incidental in nature mostly due to parasitic infestation. They were not related to the treatment.

Dose descriptor:

NOAEL

Effect level:

ca. 34 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

other: non-reversible increase in liver weight at higher dose level

Critical effects observed:

not specified

Conclusions:

The test substance was administered to dogs in a daily diet over a period of 3 month. The strong increase in liver weight and liver / body weight ratio at the dogs of the 3000 and 10000 ppm group after treatment period and non-reversible effects after recovery period can be considered as an adverse effect. Thus, the NOAEL is considered to be 1000 ppm (34 mg/kg bw).

Executive summary:

The test article was administered to dogs in a daily diet over a period of 3 month. None of the animals died, gross pathology and histopathology were without findings at any dose levels. In-life observation revealed no signs of systemic effects but a significant increase in liver weight was observed. The effect was reduced during post-observation. Since the increase in liver weight at the 3000 ppm group (female) was at the end of the recovery period 26 %, the NOAEL for the test compound is considered to be 1000 ppm (34 mg/kg bw).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

34 mg/kg bw/day

Study duration:

subchronic

Species:

dog

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1979

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline without GLP, acceptable with restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

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

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

other: RAI f

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: bred on the premises of CIBA-GIEGY limited
- Age at study initiation: 5-6 weeks
- Weight at study initiation: males 174-178 g; females 172-176 g
- Housing: 5/cage
- Diet (e.g. ad libitum): pelleted standard diet, Nafag No. 890 (NAFAG, Gossau SG, Switzerland)
- Water (e.g. ad libitum): tap water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2
- Humidity (%): 55±10
- Air changes (per hr): 15

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

not specified

Vehicle:

clean air

Remarks on MMAD:

MMAD / GSD: Particle size analysis of the chamber airborne particles showed that > 70 % were smaller than 7 micron in diameter (20 to 30 % above 7 µm; 30 to 40 % 3-7 µm; 25 to 35% 1-3 µm; 15-25 % 0-1 µm)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- According to the method of Sachsse et al. (In: Proceedings of the Europ. Soc. for the Study of Drug Toxicity. Vol. XV, pp. 239-251, Zurich, June 1973)
- Method of holding animals in test chamber: The animals were kept separately in PVC tubes which were positioned radially around the exposure chamber.
- System of generating particulates/aerosols: The test article was generated as a dust in three different amounts with the help of a Grafix Exaktomat Injector (Cerutti AG., Bern, Switzerland) into an airstream discharged into the exposure chamber through a nozzle under a pressure of 2 atm, at a rate of 20 L/min.
- Temperature, humidity in air chamber: ca. 25 °C, 43-61 %
- Method of particle size determination: Gravimetrically with a 4 stage Cascade Impactor on selectron filters, pore size 0.2 um and 25 mm diameter (Schleicher und Schuell, Feldbach, Switzerland)

TEST ATMOSPHERE
- Brief description of analytical method used: Gravimetrically on selectron filters, pore size 0.2 um and 50 mm in diameter (Schleicher und Schuell, Feldbach, Switzerland)
- Samples taken from breathing zone: yes, in the vicinity of the animals throughout the exposure time

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

21 days

Frequency of treatment:

6 h/day, 5 times/week

Remarks:

Doses / Concentrations:
23±3, 128±8, 543±12 mg/m3
Basis:
analytical conc.

No. of animals per sex per dose:

10

Control animals:

yes, sham-exposed

Details on study design:

- Post-exposure recovery period in satellite groups: 21 days (all groups)

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked: mortality, symptoms

BODY WEIGHT: Yes
- Time schedule for examinations: daily, except weekends

FOOD CONSUMPTION:
- Food consumption for each animal determined: Yes, twice weekly

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: Yes

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: weekly
- Dose groups that were examined: all

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at test day 21
- Anaesthetic used for blood collection: No
- Animals fasted: Yes, overnight
- How many animals: 5 males and 5 females
- Parameters checked: Haemoglobin (Hb), Methaemoglobin (MHb), Erythrocytes (RBC), Packed Cell Volume (PCV), Mean Corpuscular Volume (MCV), Mean Corpuscular Haemoglobin (MCH), Reticulocytes, Inclusion Bodies (Heinz Bodies), Thrombocytes, Prothrombin Time, Activated Partial Thromboplastin Time, Leucocytes (total count and differential count)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at test day 21
- Animals fasted: Yes, overnight
- How many animals: 5 males and 5 females
- Parameters checked: Glucose, Urea (Urea-N), Glutamate-Oxalacetate Transaminase (GOT), Glutamate-Pyruvate Transaminase (GPT), Lactate Dehydrogenase (LDH), Alkaline Phosphatase (AP), Y-Glutamyl Transpeptidase (y-GT), Total Protein, Protein Electrophoresis, Electrolytes (Na, K)

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Other examinations:

The following organs were weighed: heart, lungs, liver, kidneys, adrenals, thymus, brain, gonads. Organ to body weight and organ to brain weight ratios were calculated for each of these organs.

Statistics:

- for Laboratory Investigations, Student's "t" test and the analysis of variance were employed to assess the significance of difference between concentration groups and controls whenever indicated.
- for others than Laboratory Investigations, a uni-variate statistical analysis was conducted.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

no effects observed

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

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY:
During the exposure and recovery period no toxic symptoms were observed in the rats of the test and control groups.

BODY WEIGHT AND WEIGHT GAIN:
No differences in the bodyweights were observed in the rats of the test and control groups during the exposure and recovery period.

FOOD CONSUMPTION:
There was only a slight but significant (sign.l = 0.01) reduction of food consumption in male rats of highest dose group at day 13 of the exposure period.

FOOD EFFICIENCY:
The mean food conversion of all treated rats was comparable to that of the controls during the 21-day exposure and the following recovery period.

OPHTHALMOSCOPIC EXAMINATION:
No ocular changes were observed

HAEMATOLOGY:
The observed haematological findings between treated rats and controls were generally unremarkable.

CLINICAL CHEMISTRY:
In the assessment of blood chemistry values the findings were unremarkable and comparable to those of the controls.

ORGAN WEIGHTS:
There were no obvious differences in absolute organ weights, organ to body weight and organ to brain weight ratios between the treated and control rats.

GROSS PATHOLOGY:
No compound related gross anatomical changes were noted in the treated animals.

HISTOPATHOLOGY: NON-NEOPLASTIC:
All microscopical findings were only incidental in nature and not related to treatment.

Dose descriptor:

NOEC

Effect level:

>= 543 mg/m³ air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects at the highest dose tested.

Critical effects observed:

not specified

Conclusions:

There were no reactions to treatment for all the parameters investigated. It can be inferred from the observations made during the above study that the "no observable effect level" is above 543 mg/m3 air for male and female rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

543 mg/m³

Study duration:

subacute

Species:

rat

Additional information

Discussion

The substance was investigated in various oral toxicity studies with different species which identified enlargement of the liver as predominant effect. Further studies indicated that the enlargement of liver is accompanied by enzyme induction. In chronic feeding studies with rats, increases in thyroid weight accompanied by a decrease in body weight at top dose level were observed. In contradiction to other species, rats do not possess a thyroxin binding protein which protects thyroid hormones from elimination by metabolizing enzymes. Therefore, the effects of potential metabolites of the test article on the thyroid are more distinct in the rat than in other species.

Oral route:

Effects on liver and thyroid

The subchronic toxicity study in dogs (CIBA-GEIGY 1981) was performed similar to OECD guideline 409. Six dogs per dose group were fed with test material in a daily diet for 3 months at dose levels of 1000, 3000 and 10000 ppm (equivalent to 31.5, 92.2 and 295.4 mg/kg bw/day in males and 34.5, 97.2 and 335.7 mg/kg bw/day in females). After the treatment period, one animal per sex and dose group was fed with a control diet. Organ weight analysis revealed significant increases in liver weights and liver / body weight ratios in the dogs of the 3000 and 10000 ppm groups which recovered partially during post-observation period. The non-reversible increase in liver weight of 37 % is considered as adverse effect. Thus, the NOAEL is considered to be 500 ppm (34 mg/kg bw/day).

In a 104-weeks study, groups of 100 rats (50 males and 50 females) were fed with the test compound at 500, 1500 or 5000 ppm (equivalent to 22, 64 and 218 mg/kg bw/day in males and 27, 81 and 275 mg/kg bw/day in females) (Huntingdon, 1974). Organ weight analysis revealed significant increases in liver and thyroid weight in rats treated with 1500 ppm and 5000 ppm. The effect in the 5000 ppm group after the treatment period was about 28 % (male) and the increase in thyroid weight in the 5000 ppm group 62 % (male) and 53 % (female). This strong, non-reversible increase in liver and thyroid weight is, although histopathology was without any finding, considered as adverse effect. Thus, the NOAEL is considered to be 1500 ppm (64 mg/kg bw for males and 81 mg/kg bw for females).

In a 28-day study, rats (5/sex/dose) received 0, 5, 30, 100 and 300 mg/kg bw/day of the test article by oral gavage (Hazleton, 1991). Increases of liver weight were observed at 100 and 300 mg/kg bw with hypertrophy at 300 mg/kg bw. Based on the liver effects the NOAEL was set at 30 mg/kg bw/day.

In another subchronic study (Pharmacology Institute, RFW University, Bonn, 1964), groups of 20 rats were treated via oral-gavage with test material for 10 weeks at dose levels of 200, 1000 and 5000 mg/kg bw. No alterations were observed in the tested parameters.

Furthermore, a carcinogenicity study in mice was performed. Animals were fed with test material at dose levels of 0.6, 5.4 and 58 mg/kg bw/day in males and 0.6, 5.4 and 54 mg/kg bw/day in females for 104 weeks. No indication of toxicity was observed. Organ weights were not different those of control animals.

Effects on hepatic enzymes activity and content

In a 4-weeks oral-gavage study (Hazleton, 1991), performed similar to OECD guideline 407 and GLP, groups of 10 rats (5 male and 5 females) were treated with the test article at dose levels of 5, 30, 100 and 300 mg/kg bw/day to estimate the effects of the substance on selected biochemical parameters. A dose-dependend increase in liver enzyme content and activity was observed, including cytochrome P-450, mixed-function oxidase isoenzymes and UDP glucuronosyl transferase.

The hepatotoxicity effects of the test substance were specifically investigated separately in several repeated dose oral studies in rats CIBA-GEIGY Limited, 1977a, CIBA-GEIGY, 1977b, Huntingdon Research Centre, 1973). The substance causes increased liver weight and activity of most of the microsomal monooxygenases together with the cytochrome P-450 content and caused proliferation of the smooth endoplasmic reticulum. These effects were partially reversible.

Inhalation route:

In the only study (CIBA-GEIGY 1979), performed comparable to OECD guideline 412, groups of 20 rats (10 males and 10 females) were exposed to substances aerosols for 21 days (6 h/day, 5 times/week) at concentration of 23, 128 and 543 mg/m3. More than 70% of the particles had a diameter of less than 7 µm and 25 to 35% were in the range of 1-3 µm. There were no reactions to treatment for all the parameters investigated. It can be inferred from the observations made during the above study that the NOEL is at or above 543 mg/m³ air for male and female rats.

Dermal route:

no data available

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Comparable to guideline.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Comparable to guideline

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available studies are considered reliable and suitable for classification purposes under 67/548/EEC. No serious and irreversible effects were observed upon subchronic exposure at less than 50 mg/kg bw. As a result the substance is not considered to be classified for repeated dose toxicity under Directive 67/548/EEC, as amended for the 28th time in Directive 2001/59/EC.

 

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. No serious adverse effects were observed at doses of less than 300 mg/kg bw upon subchronic exposure. Liver enlargement was not accompanied by histopathology findings. As a result the substance is not considered to be classified for repeated dose toxicity under Regulation (EC) No. 1272/2008.