Hydroxycyclohexyl phenyl ketone

Endpoint summary

Description of key information

 Study carried out according to guideline and with GLP compliance. 

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

Study period:

2013

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sulzfeld, Germany
- Age at study initiation: 29-31 days
- Fasting period before study: no, fasting 16-20h before blood sampling and/or necropsy
- Housing: 5/cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 12days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%):30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:

VEHICLE
- Justification for use and choice of vehicle (if other than water): low solubility of the test material
- suspension of the test substance in drinking water and 1% CMC
- produced once a week, stored at RT
- administration volume 10ml

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The analyses of the test-substance preparations were carried out at the Analytical Chemistry Laboratory of Experimental Toxicology and Ecology of BASF SE, Ludwigshafen, Germany.

The stability of the test substance in drinking water containing 1% carboxymethylcellulose for 7 days at room temperature was demonstrated before the start of the administration period.

Homogeneity analyses of the test substance preparations were performed in samples of the highest and lowest concentrations at the start of the administration period.

Duration of treatment / exposure:

91 - 92 d

Frequency of treatment:

daily

Dose / conc.:

100 mg/kg bw/day (actual dose received)

Dose / conc.:

300 mg/kg bw/day (actual dose received)

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale:
range finding study / 28d study

Positive control:

no

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily clinical observation, once a week detailed observation

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD EFFICIENCY:
- calculated as mean food consumption in grams per animal and day

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to start of the study (all) and towards the end (control and high dose group)

HAEMATOLOGY: Yes
- Time schedule for collection of blood: days 29 and 92/93
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: 10/group/sex

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: days 29 and 92/93
- Animals fasted: Yes
- How many animals: 10/group/sex

URINALYSIS: Yes
- Time schedule for collection of urine: day 84

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: days 85 - 88
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / open field

Sacrifice and pathology:

GROSS PATHOLOGY:
Organ weights
1. Anesthetized animals
2. Adrenal glands
3. Brain
4. Epididymides
5. Heart
6. Kidneys
7. Liver
8. Ovaries
9. Spleen
10. Testes
11. Thymus
12. Thyroid glands
13. Uterus with cervix

Organ / Tissue fixation
1. All gross lesions
2. Adrenal glands
3. Aorta
4. Bone marrow (femur)
5. Brain
6. Cecum
7. Cervix
8. Coagulating glands
9. Colon
10. Duodenum
11. Epididymides
12. Esophagus
13. Extraorbital lacrimal glands
14. Eyes with optic nerve (modified Davidson’s solution)
15. Femur with knee joint
16. Harderian glands
17. Heart
18. Ileum
19. Jejunum (with Peyer’s patches)
20. Kidneys
21. Larynx
22. Liver
23. Lungs
24. Lymph nodes (mesenteric and axillary lymph nodes)
25. Mammary gland (male and female)
26. Nose (nasal cavity)
27. Ovaries
28. Oviducts
29. Pancreas
30. Parathyroid glands
31. Pharynx
32. Pituitary gland
33. Prostate
34. Rectum
35. Salivary glands (mandibular and sublingual glands)
36. Sciatic nerve
37. Seminal vesicles
38. Skeletal muscle
39. Skin
40. Spinal cord (cervical, thoracic and lumbar cord)
41. Spleen
42. Sternum with marrow
43. Stomach (forestomach and glandular stomach)
44. Testes
45. Thymus
46. Thyroid glands
47. Trachea
48. Urinary bladder
49. Uterus
50. Vagina

HISTOPATHOLOGY: Yes

Statistics:

STATISTICS OF PATHOLOGY - Weight parameters
Non-parametric one-way analysis using KRUSKAL-WALLIS test (two-sided). If the resulting p-value was equal or less than 0.05, a pairwise comparison of each dose group with the control group was performed using WILCOXON-test (two-sided) for the equal medians, * for p ≤ 0.05 ** for p ≤ 0.01

Statistics of clinical pathology
Blood parameters - For parameters with bidirectional changes: Non-parametric one-way analysis using KRUSKAL-WALLIS test. If the resulting p-value was equal or less than 0.05, a pairwise comparison of each dose group with the control group was performed using WILCOXON-test (two-sided) for the hypothesis of equal medians. For parameters with unidirectional changes: Pairwise comparison of each dose group with the control group using the WILCOXON-test (one-sided) with Bonferroni-Holm adjustment for the hypothesis of equal medians, * for p ≤ 0.05 ** for p ≤ 0.01
Urinalysis parameters - Pairwise comparison of each dose group with the control group using the WILCOXON-test (one-sided) for the hypothesis of equal medians, * for p ≤ 0.05 ** for p ≤ 0.01

Urine pH, volume, specific gravity, color and turbidity - Non-parametric one-way analysis using KRUSKAL-WALLIS test. If the resulting p-value was equal or less than 0.05, a pairwise comparison of each dose group with the control group was performed using WILCOXON-test (two-sided) for the hypothesis of equal medians, * for p ≤ 0.05 ** for p ≤ 0.01

Statistics of clinical examinations
Body weight, body weight change- A comparison of each group with the control group was performed using DUNNETT's test (two-sided) for the hypothesis of equal means, * for p ≤ 0.05 ** for p ≤ 0.01
feces, rearing, grip strength forelimbs, grip strength hindlimbs, foot-splay test, motor activity - Non-parametric one-way analysis using KRUSKAL-WALLIS test (two-sided) or WILCOXON (2-sided)

Clinical signs:

no effects observed

Description (incidence and severity):

Salivation was observed in one of 10 males of test group 1 (100 mg/kg bw/d), in 10 males and 9 females of test group 2 (300 mg/kg bw/d) and in each 10 males and females of test group 3 (1000 mg/kg bw/d).

Injury in the mouth region was observed on one male animal of test group 2 (300 mg/kg bw/d) from day 17 to day 19.

In male animals the first occurrence of slight salivation was noted on administration day 7 in test group 3 (1000 mg/kg bw/d) and on administration day 5 in test group 2 (300 mg/kg bw/d). In test group 1 (100 mg/kg bw/d) salivation slight was noted only on administration day 63. In females the first occurrence of salivation was noted on administration day 5 in test group 3 (1000 mg/kg bw/d) and on administration day 6 in test group 2 (300 mg/kg bw/d).

Females of test group 3 (1000 mg/kg bw/d) showed salivation in different grades and in females of test group 2 (300 mg/kg bw/d) slight salivation was noted.

The observed salivation onset was post application and was not present three hours later.


In common with the observed pathological findings in the stomach the salivation was assessed as a local effect, but was not considered to be an adverse and toxicologically relevant effect.

Note: Inadvertently, clinical examination within 5 hours after treatment was not performed for all animals on study day 65 (17 Apr 2013, see tables IIA 30, IIA 61, IIA 92, IIA 123, IIA 154, IIA 185, IIA 216, IIA 268 and IIA 269). This single deviation did not influence the quality as well as the outcome of the study.

Mortality:

no mortality observed

Description (incidence):

No animal died prematurely in the present study.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weights of males of test group 3 (1000 mg/kg bw/d) was significantly lower from study day 70 to day 91 (up to -10.3% on study day 84).

Mean body weight change of males of test group 3 was significantly lower on study days 70, 77, 84 and 91 (up to -17.4%) and resulting in -16.8% lower value on study day 91.

These findings were assessed as being substance-related and adverse.

Only one single body weight gain value of females of test group 3 was slightly increased on study day 21 (18.1%). This finding was regarded incidental and spontaneous in nature.

The impaired body weights in all groups on study day 84 were because of the withdrawal of food and water for the urinanalysis (the individual animals were transferred to metabolism cages and urine was collected overnight).

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No test substance-related, adverse findings were observed.

Food efficiency:

no effects observed

Description (incidence and severity):

No test substance-related, adverse findings were observed.

Ophthalmological findings:

no effects observed

Description (incidence and severity):

No treatment-related findings were observed.

All findings were assessed incidental in nature, since they occurred in individual animals only and did not show a dose-dependent relationship.

Haematological findings:

no effects observed

Description (incidence and severity):

No treatment-related changes among hematological parameters were observed.

At the end of the study in male rats of test group 3 (1000 mg/kg bw/d) absolute and relative eosinophil counts were decreased and additionally in males of test group 2 (300 mg/kg bw/d) relative eosinophil counts were lower compared to controls. In females of test groups 2 and 3 (300 and 1000 mg/kg bw/d) absolute lymphocyte counts were increased. All mentioned parameter values were within historical control ranges (males: absolute eosinophil counts 0.07-0.18 Giga/L, relative eosinophil counts 1.3-3.5 %; females: absolute lymphocyte counts 2.14-3.54 Giga/L, PART III, Supplement) and therefore, the alterations were regarded as incidental and not treatment-related, (100 mg/kg bw/d) as well as potassium in males of test groups 1, 2 and 3 (100, 300 and 1000 mg/kg bw/d). The means of alanine aminotransferase (ALT) activities in females of test group 3 (1000 mg/kg bw/d) and potassium levels in females of test groups 2 and 3 (300 and 1000 mg/kg bw/d) were within historical control ranges (ALT 0.42-0.81 µkat/L, potassium 3.76-4.47 mmol/L, PART III, Supplement). Therefore, all above mentioned parameter changes were regarded as incidental and not treatment-related.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

At the end of the study, in females of test group 3 (1000 mg/kg bw/d) triglyceride, cholesterol, calcium and inorganic phosphate levels were increased. Calcium and cholesterol values were already higher in females of test group 2 (300 mg/kg bw/d), but the cholesterol mean was within the historical control range (cholesterol 1.06-2.03 mmol/L, PART III, Supplement) and the calcium level was the only one parameter which was altered in individuals of this test group. Therefore, the changes of both mentioned parameters in females of test group 2 (300 mg/kg bw/d) were regarded as treatment-related, but not adverse (ECETOC, Technical
Report No. 85, 2002).

In males of test groups 2 and 3 (300 and 1000 mg/kg bw/d) glucose levels were decreased. The glucose mean of males in test group 2 (300 mg/kg bw/d) was only marginally beyond the historical control range (glucose 5.11-7.16 mmol/L, PART III, Supplement). Therefore, this value in males of test group 2 was regarded as treatment-related, but not adverse.

Some other parameters were changed, but the alterations were not dose-dependent for total protein, albumin and calcium in males test groups 2 and 3 (300 and 1000 mg/kg bw/d), globulins in rats of both sexes of test group 2 (300 mg/kg bw/d) and males of test group 1

Urinalysis findings:

no effects observed

Description (incidence and severity):

No treatment-related, adverse changes among urinalysis parameters were observed.

In males of test group 3 (1000 mg/kg bw/d) transitional epithelial cells and granulated and epithelial cell cast were found in the urine sediment. The transitional epithelial cells were already observed in males of test group 2 (300 mg/kg bw/d). These effects were typical for male rats of this age. They were not found in the corresponding females. These findings were often observed in α2u-globulinuria which was confirmed by histopathology investigations and which was regarded as a rat specific finding without human relevance (Hard et al., 1993).

In males of test groups 2 and 3 (300 and 1000 mg/kg bw/d) pH values in the urine were lower and specific gravity of the urine was higher compared to controls. In females of test group 3 (1000 mg/kg bw/d) urine volume was increased. These findings may be treatment-related, but they were per se not adverse.

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

Deviations from "zero values" were obtained in several rats. However, as most findings were equally distributed between test-substance treated groups and controls, were without a dose-response relationship or occurred in single rats only, these observations were considered to have been incidental. The following examinations were performed during FOB and have to be assessed individually.

Home cage observations:
No test substance-related effects were observed.

Open field observations:
No test substance-related effects were observed.

Sensorimotor tests/reflexes:
No test substance-related findings were observed.

Quantitative parameters:
No test substance-related findings were observed.

MOTOR ACTIVITY
Comparing the single intervals with the control group, interval 8 in males of test group 3 (1000 mg/kg bw/d) was significantly decreased. However, since this finding was a single event and no further significant changes were observed in the respective sum of all intervals, this finding was regarded incidental and spontaneous in nature.

Female animals of test group 3 showed a significantly decreased motor activity in the sum of all intervals but no further significant changes were observed in the respective single intervals. This finding was regarded incidental and spontaneous in nature.

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

See tables below.
The significantly decreased terminal body weight in male animals of test group 3 (1000 mg/kg bw/d) was interpreted as a treatment related effect. Significantly increased absolute liver weights in male and female animals of test groups 2 and 3 (300, 1000 mg/kg bw/d), and the significantly increased relative liver weights in male and female animals of test groups 2 and 3 (300, 1000 mg/kg bw/d) were regarded as treatment related. They correlated to a centrilobular hepatocellular hypertrophy histologically. Significantly increased absolute and relative weights of kidneys in test group 2 and 3 (300, 1000 mg/kg bw/d) males and test group 3 (1000 mg/kg bw/d) females were regarded as treatment related. The significantly increased relative liver weight of males of test group 1 (100 mg/kg bw/d) was regarded to be incidental, since the weight increase was only minimal and there was no histopathologic correlate. The significantly increased relative weights of adrenal glands, brain, epididymides, heart and testes in test group 3 (1000 mg/kg bw/d) males were related to the decreased terminal body weight in these animals.

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Treatment-related findings were observed in the liver, thyroid gland and forestomach of male and female animals and in the kidneys of male animals, with incidences and grading according to the tables below.

In the liver of male and female animals of test groups 2 and 3 (300, 1000 mg/kg bw/d) a minimal up to moderate centrilobular hepatocellular hypertrophy was diagnosed. The centrilobular hepatocellular hypertrophy was regarded as treatment related.

In the kidneys of male animals of test group 3 (1000 mg/kg bw/d) a slightly increased severity of eosinophilic droplets in the cytoplasm of proximal tubular epithelial cells was diagnosed. The eosinophilic droplets stained red with Mallory-Heidenhain. With an immunohistochemical staining, the droplets were confirmed to be alpha2u-globulin. Furthermore, kidneys of male animals of test group 3 showed a slightly increased incidence and severity of basophilic tubules. In males of group 3, basophilic tubules occurred mostly bilaterally, whereas in males of group 1 and 2, basophilic tubules occurred either unilaterally or bilaterally.

The increased severity of eosinophilic droplets in proximal tubular epithelial cells and the increased incidence and severity of basophilic tubules in males of test group 3 are interpreted to be treatment related.

In thyroid glands, the number of animals with minimal (grade 1) or slight (grade 2) follicular hypertrophy/ hyperplasia was increased in males and females of test groups 2 and 3 (300, 1000 mg/kg). In affected animals the number of small follicles was increased or the follicular epithelium was higher, varying in size from cuboidal cells to columnar cells.

Follicular hypertrophy/hyperplasia in male and female animals of test groups 2 and 3 (300, 1000 mg/kg bw/d) was regarded as treatment related. Follicular hypertrophy/hyperplasia in males and females of test group 1 (100 mg/kg bw/d) was interpreted to be incidental, since there was no difference in incidence between males of group 1 and control animals and since to very low incidence in females.

In the forestomach of male and female animals of test groups 1 to 3 (100, 300, 1000 mg/kg bw/d) a minimal (grade 1) squamous cell hyperplasia at the margo plicatus was diagnosed. Furthermore, males and females of test groups 1 to 3 showed an increased incidence and severity of hyperkeratosis with serum lakes at the margo plicatus. The lesion was characterized by compact keratin layers intermingled with an eosinophilic, proteinacous exudate.

The occurrence of hyperplasia and hyperkeratosis at the margo plicatus was regarded to be the primary response to a slight irritant effect of the test substance.

All other findings occurred either individually or were biologically equally distributed over control and treatment groups. They were considered to be incidental or spontaneous in origin and without any relation to treatment.

Details on results:

Mean body weights of males of test group 3 (1000 mg/kg bw/d) was significantly lower from study day 70 to day 91 (up to -10.3% on study day 84).Mean body weight change of males of test group 3 was significantly lower on study days 70, 77, 84 and 91 (up to -17.4%) and resulting in -16.8% lower value on study day 91. These findings were assessed as substance-related and adverse effect.

At the end of the study, in females of test group 3 (1000 mg/kg bw/d) triglyceride, cholesterol, calcium and inorganic phosphate levels were increased. Calcium and cholesterol values were already higher in females of test group 2 (300 mg/kg bw/d), but the cholesterol mean was within the historical control range and the calcium level was the only one parameter which was altered in individuals of this test group. Therefore, the changes of both mentioned parameters in females of test group 2 (300 mg/kg bw/d) were regarded as treatment-related, but not adverse. In males of test groups 2 and 3 (300 and 1000 mg/kg bw/d) glucose levels were decreased. The glucose mean of males in test group 2 (300 mg/kg bw/d) was only marginally beyond the historical control range. Therefore, this value in males of test group 2 was regarded as treatment-related, but not adverse.

Increased absolute and relative liver and kidney weights in males and females of the mid- and high dose group. Significantly increased absolute liver weights in male and female animals of test groups 2 and 3 (300, 1000 mg/kg bw/d), and the significantly increased relative liver weights in male and female animals of test groups 2 and 3 (300, 1000 mg/kg bw/d) were regarded as treatment related. They correlated to a centrilobular hepatocellular hypertrophy histologically. Significantly increased absolute and relative weights of kidneys in test group 2 and 3 (300, 1000 mg/kg bw/d) males and test group 3 (1000 mg/kg bw/d) females were regarded as treatment related.

Treatment-related findings were observed in the liver, thyroid gland and forestomach of male and female animals and in the kidneys of male animals. In the liver of male and female animals of test groups 2 and 3 (300 1000 mg/kg bw/d) a minimal up to moderate centrilobular hepatocellular hypertrophy was diagnosed. The centrilobular hepatocellular hypertrophy was regarded as treatment related. In the kidneys of male animals of test group 3 (1000 mg/kg bw/d) a slightly increased severity of eosinophilic droplets in the cytoplasm of proximal tubular epithelial cells was diagnosed. The eosinophilic droplets stained red with Mallory-Heidenhain. With an immunohistochemical staining, the droplets were confirmed to be alpha2u-globulin. Furthermore, kidneys of male animals of test group 3 showed a slightly increased incidence and severity of basophilic tubules. In males of group 3, basophilic tubules occurred mostly bilaterally, whereas in males of group 1 and 2, basophilic tubules occurred either unilaterally or bilaterally. The increased severity of eosinophilic droplets in proximal tubular epithelial cells and the increased incidence and severity of basophilic tubules in males of test group 3 are interpreted to be treatment related. Follicular hypertrophy/hyperplasia in male and female animals of test groups 2 and 3 (300, 1000 mg/kg bw/d) was regarded as treatment related. The occurrence of hyperplasia and hyperkeratosis at the margo plicatus (males and females, all treatment groups) was regarded to be the primary response to a slight irritant effect of the test substance.

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

histopathology: non-neoplastic

organ weights and organ / body weight ratios

Critical effects observed:

not specified

ABSOLUTE ORGAN WEIGHTS

	Male animals			Female animals
Test group (mg/kg bw/d)	1 (100)	2 (300)	3 (1000)	1 (100)	2 (300)	3 (1000)
Terminal body weight	99%	99%	89%**
Kidneys	104%	112%*	115%**	100%	105%	115%
Liver	104%	113%**	120%**	101%	112%	131%

* p ≤ 0.05

**p ≤0.01

RELATIVE ORGAN WEIGHTS

	Male animals			Female animals
Test group (mg/kg bw/d)	1 (100)	2 (300)	3 (1000)	1 (100)	2 (300)	3 (1000)
Adrenal glands	104%	104%	118%*
Brain	100%	99%	109%*
epididymides	102%	102%	115%**
Heart	102%	105%	111%**
Kidneys	105%	113%**	129%**	103%	108%	122%**
Liver	105%*	114%**	135%**	104%	114%**	138%**
Testes	104%	105%	117%**

* p ≤ 0.05

**p ≤0.01

HISTOPATHOLOGY

Liver	Male animals				Female animals
Test group (mg/kg bw/d)	0 (0)	1 (100)	2 (300)	3 (1000)	0 (0)	1 (100)	2 (300)	3 (1000)
No. of animals	10	10	10	10	10	10	10	10
Hypertrophy, centribular	0	0	8	10	0	0	10	10
Grade 1			6	3			8
Grade 2			2	7			2	5
Grade 3								5

Kidneys	Male animals
Test group (mg/kg bw/d)	0 (0)	1 (100)	2 (300)	3 (1000)
No. of animals	10	10	10	10
Eosinophilic droplets	10	10	9	10
Grade 1	4	7	3
Grade 2	3	2	4	2
Grade 3	3	1	2	8
Basophilic tubules	5	6	5	10
Grade 1	5	6	5	7
Grade 2				3

Thyroid glands	Male animals				Female animals
Test group (mg/kg bw/d)	0 (0)	1 (100)	2 (300)	3 (1000)	0 (0)	1 (100)	2 (300)	3 (1000)
No. of animals	10	10	10	10	10	10	10	10
Hypertrophy/hyperplasia, follicular	2	2	4	8	0	1	3	7
Grade 1	2	2	4	6		1	3	7
Grade 2				2

Forestomach	Male animals				Female animals
Test group (mg/kg bw/d)	0 (0)	1 (100)	2 (300)	3 (1000)	0 (0)	1 (100)	2 (300)	3 (1000)
No. of animals	10	10	10	10	10	10	10	10
Hyperkeratosis with serum lakes	2	7	10	9	0	4	9	8
Grade 1	2	7	3	2		3	3	6
Grade 2			7	7		1	6	2
Hyperplasia, squamous cell	0	2	7	8	0	1	4	6
Grade 1		2	7	8		1	4	6

Conclusions:

In conclusion, the oral administration of of the test item by gavage over a period of 3 months revealed no signs of systemic toxicity in male and female animals at dose levels up to 300 mg/kg bw/d. Thus, the no observed adverse effect level (NOAEL) for general systemic toxicity was 300 mg/kg bw/d in males and females.

Executive summary:

In this guideline (OECD 408) study conducted with GLP certification, the 90 day repeat dose NOAEL of the test material in the rat was determined to be 300 mg/kg bw/day. Test doses were set at 100, 300, & 1000 mg/kg bw/day. 20 rats (10 male, 10 female) were used in each test group. The test material was administered daily by gavage. Adverse, treatment related effects were reported at the 1000 mg/kg bw/day group (bodyweight, organ weight, and histopathology), with treatment related effects (which were not interpreted as adverse) at the 300 mg/kg bw/day group (histopathology). Target organs were identified as the liver, kidneys, thyoid gland, and forestomach in both male and female animals. The test result does not trigger classification for target organ toxicity after repeated exposure under the criteria of the EU Classification, Labelling, and Packaging (CLP) regulation (1272/2008).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

1

System:

gastrointestinal tract

Organ:

kidney

liver

thyroid gland

other: forestomach

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

Justification for classification or non-classification

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

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is not considered to be classified for repeated dose toxicity under Regulation (EC) No. 1272/2008.