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Administrative data

Description of key information

For the oral route, a 90-day (gavage) study with rats (GLP and OECD TG 408) was performed with dose levels of 2.5, 12 and 60 mg/kg bw/day that gave a NOAEL of 2.5 mg/kg bw/day. Furthermore, a 28-day reproduction/developmental toxicity screening study (GLP and OECD TG 422) was performed with structural analogue PACM with dose levels of 15, 50 and 100 mg/kg bw/day that gave a NOAEL of 15 mg/kg bw/day.
For the inhalation route, a 90-day study with rats (GLP and OECD TG 413) was performed with concentrations of 2, 12 and 48 mg/m3. The NOAEC was 12 mg/m3 for local and systemic effects.

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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study (OECD 408)
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dr. Karl Thomae GmbH, Biberach, Germany
- Age at study initiation: 42 days
- Weight at study initiation: males: 178 (168 - 193) g; females: 147 ( 139 - 157) g
- Housing: single
- Diet: Kliba-Labordiaet Ratte/Maus/Hamster Haltung GLP 343 Mehl, ad libitum
- Water: ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24 °C
- Humidity (%): 30-70 %
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
other: 0.5 % CMC (carboxymethyl cellulose)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
gas chromatography
Duration of treatment / exposure:
3 month
Frequency of treatment:
each working day (5 days/week)
Remarks:
Doses / Concentrations:
2.5, 12, 60 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
test group: 30;
control group: 10
Control animals:
yes
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: before and after the application period
- Dose groups that were examined: control and high dose

HAEMATOLOGY: Yes
- Time schedule for collection of blood: day 29 and 85
- Anaesthetic used for blood collection: No data
- Animals fasted: yes, overnight
- How many animals: all
- Parameters examined: Erythrocyte count, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), thrombocyte count.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: day 29 and 85
- Animals fasted: Yes
- How many animals: all
- Parameters examined: aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyltranspeptidase, sodium, potassium, chloride, inorganic phosphorus, calcium, bilirubin total, creatinine, glucose, urea, total protein, albumin, cholesterol, triglycerides.

URINALYSIS: Yes
- Time schedule for collection of urine: day 23 and 79
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No data
- Parameters examined: Nitrite, pH-Value, hemoglobin, protein, glucose, ketone bodies, bilirubin, urobilinogen, sediment, volume.

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER:
blood was sampled from all surviving animals of both sexes for immunological determinations after about 8 and 13 test weeks.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Details on results:
CLINICAL SIGNS AND MORTALITY
60 mg/kg bw : On day 71 one male was sacrificed moribund. Deteriorated general state of health with differently discolored regions of various localizations in the animals of both sexes was observed.

BODY WEIGHT AND WEIGHT GAIN
60 mg/kg bw: Significantly retarded body weight gain in both sexes.
12 mg/kg bw: Significantly retarded body weight gain in the female animals, which was present in the males only as a trend.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
60 mg/kg bw: Reduced feed consumption in the males and females.
12 mg/kg bw: Slight reduction of the feed consumption in the females.

OPHTHALMOSCOPIC EXAMINATION
No abnormalities

HAEMATOLOGY
60 mg/kg bw: Increase of the lymphocyte values with changed nuclear structure in both sexes. Increase of the monocyte and neutrophilic polymorphonuclear granulocytes in the females. Decrease of the mean cell volume, mean hemoglobulin content of the individual erythrocyte, of the chloride and creatinine values in both sexes. Decrease of the total protein, albumin, globulins and triglyceride levels in the males. Increased inorganic phosphate in the females.

CLINICAL CHEMISTRY
60 mg/kg bw: Increase of the alanine aminotransferase, aspartate aminotransferase, leukocyte and lymphocyte values in both sexes.
12 mg/kg bw: Increase of the aspartate aminotransferase values in the males.

URINALYSIS
60 mg/kg bw: Increase of the erythrocyte and leukocyte values, of renal and round-cell epithelias, bacterias and roundcell epithelias without nucleus in the urine of both sexes.
12 mg/kg bw: Increase of bacterias and round-cell epithelias without nucleus in the urine of both sexes. Increase of erythrocytes in the urine of the males and single renal and round-cell epithelias in both sexes

ORGAN WEIGHTS
60 mg/kg bw: Increase of the absolute liver weights in the females. Increase of the relative liver weights in the males and females. Increase of the relative kidney weights of the males and females. Increase of the absolute adrenal weights of the males and females. Increase of the relative adrenal weights of the males and females.
12 mg/kg bw: Increase of the relative liver weights in the males. Increase of the absolute kidney weights in the males. Increase of the relative kidney weights in the males and females.

HISTOPATHOLOGY: NON-NEOPLASTIC
60 mg/kg bw: Histopathology revealed microvacuolar degeneration of the liver of most animals. The lesion was qualitatively more distinct in the female than in the male animals. Vacuolar tubulopathy was seen in the kidneys of all animals that were sacrificed at the end of the study. Vacuolar myocardial degeneration was observed in the heart of all male and female animals. The adrenal glands of all male and female animals showed the picture of a progressive transformation.
12 mg/kg bw: Histopathology revealed vacuolar tubulopathy in the kidneys of some male and female animals. The heart of most animals was found to show vacuolar myocardial degeneration

OTHER: The immunological examinations elicited no adverse effects on the humoral parameters examined.
Dose descriptor:
NOAEL
Effect level:
2.5 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Critical effects observed:
not specified

In conclusion, it may be stated that the 3-month administration of Laromin C 260 to male and female rats at a dose of 60 mg/kg b.w. each working day by gavage led to clear toxic findings, such as reduced feed consumption, retarded body weight gain, impaired general state of health, changes of the hematologic (white and red blood counts), enzymatic, clinicochemical and urinanalytical parameters as well as hepato and nephrotoxic, myocardially toxic and adrenotoxic (progressive transformation) effects.

12 mg/kg b.w. led in the female animals to a reduced feed consumption, in the animals of both sexes to a retarded body weight gain, and to an increase of the aspartate aminotransferase values in the male animals. Urinalysis detected in both sexes an increased number of bacterias, of round-cell epithelias with and without nucleus, and of renal epithelias and in the male animals an increase of erythrocytes. The pathological examinations exhibited hepato and nephrotoxic and myocardially toxic findings.

  

2.5 mg/kg b.w. caused no differences when compared with the control .

 

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
2.5 mg/kg bw/day
Study duration:
subchronic
Species:
rat

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study (OECD 413)
Qualifier:
according to
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dr. KarL Thomae GmbH, Germany
- Age at study initiation: 8 weeks
- Weight at study initiation: males: 247 (226 - 266) g, females: 171 (159 - 181) g
- Housing: single
- Diet: SSNIFF R 10 mm Pellets, ad libitum
- Water: water ad libitum
- Acclimation period: 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24 °C
- Humidity (%): 30-70 %
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
inhalation
Type of inhalation exposure:
nose/head only
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: 3.5, 1.5, and 2.8 µm, respectively.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
gas chromatography
Duration of treatment / exposure:
3 months
Frequency of treatment:
6 hours each working day (5 days/week)
Remarks:
Doses / Concentrations:
0.002, 0.012, 0.048 mg/l (2, 12, 48 mg/m3)
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
2.1±0.58 µg/l, 12.4±12.63 µg/l, 48.2±10.48 µg/l
Basis:
analytical conc.
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
- Dose selection rationale: pre study
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data

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 data

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: before and at the end of the study
- Dose groups that were examined: control and high dose group

HAEMATOLOGY: Yes
- Time schedule for collection of blood: before first exposure and at day 87.
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all
- Parameters examined: Erythrocyte count, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), leucocyte count, thrombocyte count.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: before first exposure and at day 87.
- Animals fasted: No data
- How many animals: all
- Parameters examined: aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, sodium, potassium, chloride, inorganic phosphorus, calcium, bilirubin total, creatinine, glucose, urea, total protein, albumin, cholesterol, triglycerides.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes, adrenal gland, bone with marrow, brain, esophagus, eyes, heart, large intestine (cecum, colon, rectum), small intestine (duodenum, jejunum, ileum), kidney, larynx, liver, lungs, ovary, pancreas, pituitary gland, salivary gland, skin, spleen, stomach testis, thymus, thyroid gland, urinary bladder, and uterus, aorta, sternum, skeletal muscles, lacrimal gland, accessorius sex glands, mesenteric lymph nodes, all macroscopic alterations.
Details on results:
CLINICAL SIGNS AND MORTALITY
There were no mortalities in the control and high dose groups. One female at 2 µg/l and one male at 12 µg/l died intercurrently after 37 and 48 exposures, respectively. Deaths were judged to be of spontaneous nature.

Scattered occurrence of observations throughout all test groups without relation to dose were noted. No specific substance-related effect noted.

BODY WEIGHT AND WEIGHT GAIN
Compared to control animals statistically reduced mean body weight gain (p<0.01) and reduced body weight from day 50 onwards (p<0.01) was seen in high dose male rats. Body weight was reduced by approx 14% compared to controls on day 85. In high dose females body weight change was significantly reduced (p<0.05) from day 71 onwards. Terminal body weight in females was reduced by 8% and statistically different from controls animals. No other statistically significant effect on body weight parameters were noted.

OPHTHALMOSCOPIC EXAMINATION
no changes in any of the dose groups noted.

HAEMATOLOGY
Significant (p<0.05) reductions in hemoglobin, hemoglobin per erythrocyte, and in mean corpuscular hemoglobin concentration (MCHC) were noted in the male high dose rats only. Polychromatosis was noted.
Clotting test: statistically significant clotting time increase was only seen in females but not in males. This effect was not considered to be treatment related.

CLINICAL CHEMISTRY
Animals at 12 µg/l: statistically significant, but marginal increase of alkaline phosphatase (5.658 µkat/l vs. 4.949 µkat/l in controls) and GPT (glutamate pyruvate transaminase; 1.043 µkat/l vs. 0.845 µkat/l in controls) in male rats. GOT (glutamate oxalo-acetate transaminase) was not changed in male rats. Increase of alkaline phosphatase was only seen in this test group. No other change was noted in male or female animals.

Animals at 48 µg/l: statistically significant increase of GOT and GPT (but not alkaline phosphatase) compared with controls in male rats, but not in females rats. Activity of GPT in serum was 1.081 µkat/l vs. 0.845 µkat/l in control animals (p<0.01). A significant (p<0.01) decrease of serum triglycerides in high dose males was considered to result from a decreased food consumption which was assumed because of the reduced body weight development in this group. This finding was therefore regarded to be a secondary effect.

ORGAN WEIGHTS
Relative organ weight of liver, lung, and kidney was significantly increased in high dose male and female animals on the 1% or 5% level of significance. Relative weight of adrenals (p<0.05) and testes (p<0.01), and absolute lung weight (1.41 g vs. 1.18 g in controls) were significantly increased only in high dose male rats.

HISTOPATHOLOGY: NON-NEOPLASTIC
No effects in low and medium dose animal groups.
Effects in high dose animals included: Local irritative effects on the skin and slight hyperkeratosis in 7/10 male rats. Minimal to slight vacuolization of the craniodorsal olfactory epithelium in both male (2/10) and female (1/10 animals) rats. Significantly increased incidence of slight tubulonephrosis was noted in male rats only (6/10 vs. 1/10 in male controls; 9/10 females vs. 7/10 controls), and extramedulary haematopoesis in spleen was noted only in female rats (9/10). Hemosiderin was noted in spleen of all high dose animals.
Dose descriptor:
NOAEC
Remarks:
systemic toxicity
Effect level:
12 mg/m³ air
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
12 mg/m³
Study duration:
subchronic
Species:
rat

Additional information

Oral

In a subchronic oral toxicity study (OECD TG 408 and GLP), rats were exposed to 0, 2.5, 12 and 60 mg/kg bw/day by gavage over 3 months (BASF AG, 1990b). Deaths occurred in the low dose (one female after 37 exposures) and mid dose group (one male, 47 exposures). No substance-related effect was however noted. At the high dose level (60 mg/kg bw/day) body weight development/food consumption were clearly impaired (body weight -42 % in males, -20 % in females) and the general state of health was poor. The relative weights of liver, kidney, adrenals, and testes were significantly increased in males (p < 0.01) whereas absolute weights of adrenals were increased (p < 0.01) and absolute weight of testes (-18 %, p < 0.05) and liver (p < 0.01) were significantly decreased, and absolute kidney weight was unchanged. An atrophy of the seminiferous tubuli (4/10 focal, 2/10 diffuse) and reduced contents of the seminal vesicles in all high dose males was noted. These changes as well as the decreased absolute weight of testes were interpreted as consequence of the marked impairment on body weight. As the body weight was reduced more than the testes weight, the relative testes weight was increased. Liver, white and red blood cells, kidneys, adrenal gland and heart were the target organs showing also histopathological alterations. At 12 mg/kg bw/day the latter effects were generally less pronounced and no effects on testes were observed. Female but not male body weight was reduced by 7 % at day 85. Relative kidney weight was increased in both sexes, relative liver weight was only increased in male rats. Absolute organ weight change was only noted in kidney of males, no other statistical significant change was noted in any other organ nor in females. A NOAEL was achieved at 2.5 mg/kg bw/day.

Furthermore there is an oral combined 28 -day repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422) with structural analogue 4,4'-methylenedicyclohexanamine (PACM) available:

Four groups of ten male and ten female Wistar Han rats were exposed by oral gavage to the test substance dosed in propylene glycol at 0, 15, 50 and 100 mg/kg bw/day (NOTOX, 2010). Due to toxicity observed in females in the main study at 150 mg/kg including clinical signs (hunched posture, rales and piloerection) and marked body weight loss, the dose level was lowered to 100 mg/kg bw on Day 12 of treatment, and the pre-mating period was consequently extended to 3 weeks instead of 2 to allow for partial recovery before mating. Males were exposed for 36 days, i.e. 3 weeks prior to mating, during mating, and up to termination. High dose animals were exposed for 11 days to 150 mg/kg and 25 days (males) or 37-41 days (females) to 100 mg/kg. Females were exposed for 48-52 days, i.e. during 3 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation. The following parameters were evaluated: mortality / viability, clinical signs, functional observations, body weights, food consumption, reproduction/developmental parameters, observations pups, clinical pathology, macroscopy, organ weights, and histopathology. Chemical analyses of formulations were conducted once during the study to assess accuracy, homogeneity and stability. There were treatment-related and toxicologically relevant effects at 50 and 100 mg/kg bw. At the high dose, two females were euthanized in extremis. Clinical signs including hunched posture, yellow feces, piloerection, lean appearance, ptosis, lethargy, chromodacryorrhoea, and rales. Body weights, body weight gains and food consumption were reduced. Clinical biochemistry parameters were affected including increased aspartate aminotransferase (ASAT) and reduced creatinine levels (both sexes). Treatment related microscopic findings of various organs at 100 mg/kg bw were noted, including: the stomach (vaculolation of the stomach musculature; both sexes), liver (centrilobular vacuolation; both sexes), brain (vacuolation of the choroid plexus; both sexes), skeletal muscle (vacuolar myofiber degeneration and myofiber degeneration; both sexes), and the eyes (vacuolation of the cuboidal epithelium of the iris; both sexes). At 50 mg/kg bw exposure, slight reductions in body weights and food consumption were noted on a few occasions, but at the degree observed were not considered to be biologically significant. Microscopic findings were noted for various organs, including the stomach (vaculolation of the stomach musculature; both sexes), liver (centrilobular vacuolation; both sexes), skeletal muscle (vacuolar myofiber degeneration and myofiber degeneration; both sexes), and the eyes (vacuolation of the cuboidal epithelium of the iris; both sexes). No toxicologically relevant changes were seen at 15 mg/kg bw. Treatment with the test substance by oral gavage in male and female Wistar Han rats at dose levels of 15, 50 and 100 mg/kg body weight/day revealed parental toxicity at 50 mg/kg bw characterized by microscopic findings in various organs and at 100 mg/kg body weight/day characterized by changes in body weights, food consumption, clinical biochemistry parameters, organ to body weight ratio changes and histopathological findings in various organs. Based on these results, the systemic NOAEL was 15 mg/kg bw/day.

Inhalation

In a subchronic inhalation study (OECD TG 413 and GLP), rats were exposed to aerosol concentrations of 0, 2, 12 and 48 mg/m³ for 3 months (6 hours/day and 5 days/week) (BASF AG, 1992a). No mortalities occurred. In the high exposure group local irritative effects, typical for alkaline compounds such as amines were observed for the skin (slight hyperkeratosis in 7/10 animals) and upper airways (nasal mucosa, slight vacuolization of olfactory epithelium in 2/10 high dose males, and in 1/10 high dose females). A clear and statistically significant depression of body weight development was noted in animals of both sexes. Compared to control animals terminal body weight was significantly reduced by 14 % in males (p < 0.01) and 8 % in females (p < 0.05). Systemic toxicity was mild. Relative organ weight of liver, lung, and kidney was significantly increased in high dose male and female animals on the 1 % or 5 % level of significance. Relative weight of adrenals (p < 0.05) and testes (p < 0.01) and absolute lung weight (1.41 g vs. 1.18 g in controls, p < 0.05) were significantly increased only in high dose male rats. The relative organ weight changes were largely influenced by reduced body weights and were judged to be of minor relevance. Pathological correlates were not found for any of these organs, and histological alterations in the testes were not seen.

The liver was also a target organ in high dose male rats, but not in high dose females, as substantiated by significant increases of serum transaminases GOT and GPT (glutamate oxalo-acetate transaminase and glutamate pyruvate transaminase, both on the p < 0.01 level). Activity of GPT in serum was 1.081 μkat/l in high dose male rats compared to 0.845 μkat in control animals. However, no histopathological correlate was seen. Red blood cells were affected in high dose male rats as substantiated by significant reductions (p < 0.05) of hemoglobin, hemoglobin per erythrocyte, mean corpuscular hemoglobin concentration, and polychromatosis. In spleen hemosiderin was noted in all high dose animals and extramedulary haematopoesis (9/10 high dose females) was indicative of a mild anemic effect. A test substance related effect on kidneys was of borderline significance (slight tubular nephrosis in 6/10 high dose males vs. 1/10 male controls; in females 7/10 mid dose and 9/10 high dose rats vs. 7/10 control animals) with increased relative kidney weights (p < 0.01) and increased urea concentration in females (p < 0.01; unchanged in males). In the mid dose animals only a marginal yet significant increase of GPT and alkaline phosphatase levels (both at p < 0.05) in the male rats were seen. Alkaline phosphatase (AP) was not significantly increased in animals at the higher dose level. Therefore no dose-relation was given for AP, and this finding was not regarded as a treatment-related effect. The increase of GPT in mid dose males was marginal (1.043 μkat/l vs. 0.845 μkat/l in controls). GOT (glutamateoxaloacetate transaminase) was not affected in this animal group. No substance-related effect was noted in the low dose groups.

The marginal increase in GPT level at 12 mg/m3 was not considered toxicologically relevant in the absence of an increase in GOT levels and any other effects in the liver. Therefore, the NOAEC was set at 12 mg/m3.

Conclusion

The results of the sub-chronic studies with DMDC and the results of the sub-acute study with PACM revealed distinctive and comparable toxic effects on the liver, kidney, and muscle tissues as main target organs. Additionally, the NOAELs determined are entirely in the same range: NOAELDMDC = 2.5 mg/kg bw and NOAELPACM = 5 mg/kg bw (by applying a 28-days to 90-days exposure duration extrapolation factor of three).


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

Repeated dose toxicity: inhalation - systemic effects (target organ) digestive: liver

Justification for classification or non-classification

In the 90-day oral toxicity study in rats, liver, white and red blood cells, kidneys, adrenal glands and heart were the target organs for toxic effect showing also histopathological alterations: histopathology revealed microvacuolar degeneration of the liver of most animals. The lesion was qualitatively more distinct in the female than in the male animals. Vacuolar tubulopathy was seen in the kidneys of all animals that were sacrificed at the end of the study. Vacuolar myocardial degeneration was observed in the heart of all male and female animals. The adrenal glands of all male and female animals showed the picture of a progressive transformation. At the high dose level (60 mg/kg bw/day) body weight development/food consumption were clearly impaired and the general state of health was poor. While the toxic effects at the mid dose of 12 mg/kg bw/day were generally less pronounced, histopathological examinations revealed vacuolar tubulopathy in the kidneys of some male and female animals, and the heart of most animals was found to show vacuolar myocardial degeneration. The NOAEL was achieved at 2.5 mg/kg bw/day.

According to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008, the classification is STOT RE Cat.2 (H373) for repeated dose toxicity.