Registration Dossier

Administrative data

Description of key information

Key study: Read-across from experimental data on an analogue. Test method OECD 407. The 28 days NOAEL (oral) was determined to be 800 mg/kg bw/day in rats.

Key study: Read-across from experimental data on an analogue. Test method OECD 408. The 90 days NOAEL (oral) was determined to be 100 mg/kg bw/day in male rats and 30 mg/kg bw/day in female rats.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
other: HanRcc:WIST (SPF)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: RCC Ltd, Laboratory Animal Services, CH-4414 Füllinsdorf / Switzerland
- Age at study initiation: Approximately 7 weeks
- Weight at study initiation: Males: 178-194 g at acclimatization (mean 185 g), Females: 134-147 g at acclimatization (mean 139 g).
- Housing: In groups of five in Makrolon type-4 cages with wirenmesh tops and standardized softwood bedding
- Diet (e.g. ad libitum): Pelleted standard Provimi Kliba 3433 (batch no. 67/06) rat maintenance diet (Provimi Kliba AG, CH-4303 Kaiseraugst/ Switzerland) was available ad libitum.
- Water (e.g. ad libitum): Community tap-water from Itingen was available ad libitum in water bottles.
- Acclimation period: 7 days. Under test conditions after health examination. Only animals without any visible signs of illness were used for the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 ºC
- Humidity (%): 30-70 %
- Air changes (per hr): Air-conditioned with 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12-hour fluorescent light/12-hour dark cycle
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
The dose formulations were prepared daily. The test item was weighed into a glass beaker on a tared Mettler balance and the vehicle added. The mixtures were prepared using a magnetic stirrer. Homogeneity of the test item in the vehicle was maintained during the daily administration period using a magnetic stirrer.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentration, homogeneity and stability (after 2 hours) of the dose formulations were determined in samples taken after experimental start. Concentration and homogeneity of the dose formulations were determined in samples taken during week 3 of the treatment. The analyses were performed according to a HPLC method.
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
200 mg/kg bw/day (actual dose received)
Dose / conc.:
800 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
5 animals per sex per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
Based upon the results of a 5-day doserange-finding study in which the test item was administered by gavage to 2 rats per group and sex.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: The animals were observed for clinical signs once before commencement of administration; twice daily on days 1-3; as well as once daily on days 4-28.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: The animals were observed in their home cages, outside their home cages in a standard arena and in the hand. These observations were performed once before commencement of administration and once weekly (weeks 1-3) thereafter.

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were recorded weekly during the pretest and treatment periods and before necropsy.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
The food consumption was recorded once during the pretest period and weekly thereafter.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: After 4 weeks
- Anaesthetic used for blood collection: Yes (light isoflurane anesthesia)
- Animals fasted: Yes (The animals were fasted for approximately 18 hours before blood sampling but allowed access to water ad libitum)
- How many animals: All animals
- Parameters: Erythrocyte count, Hemoglobin, Hematocrit, Mean corpuscular volume, Red cell volume distribution width, Mean corpuscular hemoglobin, Mean corpuscular hemoglobin concentration, Hemoglobin concentration distribution width, Platelet (thrombocyte) count, Reticulocyte count, Reticulocyte maturity index, Methemoglobin, Heinz bodies (to be completely assessed only if changes in methemoglobin are noted), Total leukocyte count, Differential leukocyte count, Coagulation: Thromboplastin time, Activated partial thromboplastin time

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: After 4 weeks
- Anaesthetic used for blood collection: Yes (light isoflurane anesthesia)
- Animals fasted: Yes (The animals were fasted for approximately 18 hours before blood sampling but allowed access to water ad libitum)
- How many animals: All animals
- Parameters: Glucose, Urea, Creatinine, Bilirubin total, Cholesterol total, Triglycerides, Phospholipids, Aspartate aminotransferase, Alanine aminotransferase, Lactate dehydrogenase, Glutamate dehydrogenase, Creatine kinase, Alkaline phosphatase, Gamma-glutamyl-transferase, Sodium, Potassium, Chloride, Calcium, Phosphorus inorganic, Protein total, Albumin, Globulin, Albumin/Globulin ratio

NEUROBEHAVIOURAL EXAMINATION: Yes / No / No data
- Time schedule for examinations: Week 4
- Dose groups that were examined: All animals
- Battery of functions tested:
Grip Strength
Forelimb and hind limb grip strength measurements were performed using a push-pull strain gauge (Mecmesin, AFG 25N). The animals were placed with the forepaws inside a triangular grasping ring and with the hind paws outside a triangular grasping ring. Using one hand, the animals were held towards the base of the tail and steadily pulled away or towards the ring until the grip was broken. Each measurement was repeated three times, the means were calculated and recorded.
Locomotor Activity
Locomotor (decreased or increased) activity was measured quantitatively with AMS Föhr Medical Instruments GmbH (FMI) and DeMeTec GmbH Activity Monitor System. Animals were monitored during the fourth treatment week for a 60-minute period and the total activity of this time period was recorded. Low beams count was reported in 10-minute intervals as well as the total activity of the measuring period.

Sacrifice and pathology:
GROSS PATHOLOGY: Yes. All animals were weighed and necropsied. Descriptions of all macroscopic abnormalities were recorded.
Samples of the following tissues and organs were collected from all animals at necropsy and fixed in neutral phosphate buffered 4 % formaldehyde solution (unless otherwise indicated):
Adrenal glands, Aorta, Bone (sternum, femur including joint), Bone marrow (femur), Brain (4 levels), Cecum, Colon, Duodenum, Epididymides (fixed in Bouin's solution), Esophagus, Eyes with optic nerve (fixed in Davidson's solution), Harderian gland (fixed in Davidson's solution), Heart, Ileum with Peyer's patches, Jejunum with Peyer's patches, Kidneys, Larynx, Lacrimal gland (exorbital), Liver, Lungs (infused with formalin at necropsy), Lymph nodes (mesenteric, mandibular), Mammary gland area, Nasal cavity, Ovaries, Pancreas, Pituitary gland, Prostate gland (incl coagulating gland), Rectum, Salivary glands (mandibular, sublingual), Sciatic nerve, Seminal vesicles, Skeletal muscle, Skin, Spinal cord (cervical, midthoracic, lumbar), Spleen, Stomach, Testes (fixed in Bouin's solution), Thymus, Thyroid (incl. parathyroid gland), Tongue, Trachea, Urinary bladder (infused with formalin at necropsy), Uterus, Vagina, Gross lesions.

ORGAN WEIGHTS: Yes. Brain, Thymus, Spleen, Ovaries, Heart, Kidneys, Testes, Liver, Adrenals, Epididymides

HISTOPATHOLOGY: Yes. Slides of all organs and tissues listed that were collected at scheduled sacrifice from the animals of control and high-dose groups were examined by a pathologist. As test item-related morphologic changes were detected in the organs of high-dose animals, the same organs (kidneys and lungs) from animals of the mid- and low-dose groups were examined.
Statistics:
The following statistical methods were used to analyze the grip strength, locomotor activity, body weight, clinical laboratory investigations, organ weights and ratios:
• The Dunnett-test (many to one t-test) based on a pooled variance estimate were applied if the variables could be assumed to follow a normal distribution for the comparison of the treated groups and the control groups for each sex.
• The Steel-test (many-one rank test) were applied instead of the Dunnett-test when the data can not be assumed to follow a normal distribution.
• Fisher's exact-test were applied to the macroscopic findings.
Clinical signs:
no effects observed
Description (incidence and severity):
No test item-related findings were noted during daily observations at any dose level tested.
Mortality:
no mortality observed
Description (incidence):
All animals survived until scheduled necropsy.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Test item-related changes were noted in the mean body weights and body weight gains of animals treated with 800 mg/kg body weight/day. Animals treated with 800 mg/kg body weight/day showed reduced mean body weights and body weight gains compared to controls with statistical significance in females (p<0.01). These dose-related changes were accompanied by changes in food consumption and were considered to be test item-related.
The mean body weights of the males and females treated with 200 mg/kg/day and 50 mg/kg/day were considered to be unaffected.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
At 800 mg/kg body weight/day, reduced absolute food consumption was noted in males and females and reduced relative food consumption were seen in females only, when compared to controls. Males treated with 200 mg/kg body weight/day showed reduced absolute food consumption towards the end of the treatment phase compared to controls. The mean food consumption of the animals treated with 50 mg/kg/day was unaffected.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
No test item-related findings were noted in the hematology parameters of either sex at any dose level tested.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Test item-related findings indicative of changes in liver metabolism and kidney parameters were noted in animals treated with 800 and 200 mg/kg body weight/day. At 800 mg/kg/day, these changes included increased creatinine levels were noted in males and some females; increased aspartate aminotransferase activity in males and females; increased cholesterol in males; decreased triglycerides in males; decreased potassium in males and females, and decreased albumin levels in females. At 200 mg/kg/day, these changes included elevated creatinine in males and females, elevated cholesterol in males and elevated phospholipids in males. No changes of toxicological relevance were noted at 50 mg/kg/day.
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
FUNCTIONAL OBSERVATIONAL BATTERY
No test item-related findings were noted during the functional observational battery (week 4) at any dose level tested.
Grip Strength
No test item-related changes in the mean grip strength were noted at any dose level tested.
Locomotor Activity
No test item-related changes in the mean locomotor activity were noted at any dose level tested.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Absolute and relative kidney weights were elevated in animals treated with 800 and 200 mg/kg body weight/day compared to controls and considered to be test item-related. Absolute and relative thymus weights were decreased in animals treated with 800 and 200 mg/kg body weight/day and to a lesser degree in animals treated with 50 mg/kg body weight/day. These findings were considered to be test item-related but were not accompanied by relevant microscopical changes.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Tan discoloration was recorded in the kidneys of one male treated with 200 mg/kg/day and in all animals treated with 800 mg/kg/day. This finding was deemed to be test item related and correlated with histological kidney changes.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Microscopically, changes could be found in the kidneys of animals treated with 200 mg/kg/day and 800 mg/kg/day. These changes consisted of a combination of vacuoles in tubular epithelial cells (containing fine granular material), tubular cell necroses, tubular basophilia including tubular regeneration, interstitial nephritis and tubular casts.

Histopathological findings: neoplastic:
not specified
Other effects:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
800 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Key result
Critical effects observed:
no
Conclusions:
The no-observed-adverse-effect-level (NOAEL) was considered to be 800 mg/kg/day.
Executive summary:

Oral administration of the test item to Wistar rats at doses of 50, 200 and 800 mg/kg/day, for 28 days resulted in no deaths, no clinical signs during daily observations, no clinical signs during weekly observations (weeks 1-3), no clinical signs during the functional observational battery (including no changes in mean grip strength or locomotor activity). Test item-related findings were generally restricted to reduced mean daily food consumption in both sexes at 800 mg/kg/day and in males at 200 mg/kg/day, reduced mean body weights and mean body weight gain in males and females treated with 800 mg/kg/day, changes in clinical biochemistry parameters that were generally indicative of alterations in liver metabolism and kidney function at 800 mg/kg/day and 200 mg/kg/day, changes in absolute and relative kidney weights at 800 mg/kg/day and 200 mg/kg/day, as well as macroscopical and microscopical findings in the kidneys of rats treated with 800 mg/kg/day and 200 mg/kg/day. Reduced mean absolute and relative thymus weights noted in rats treated with 800 mg/kg/day 200 mg/kg/day and to a lesser extent in animals treated with 50 mg/kg/day.

Chronic progressive nephropathy (CPN) is a rodent-specific, age-related renal disease, particularly of male rats, characterized by a spectrum of distinct histological changes which may begin early in the animal's life and progress to end-stage renal disease in certain rat strains. CPN is generally regarded as a degenerative to atrophic disease with compensatory regenerative hyperplasia. The proliferative nature of CPN often becomes problematic in advanced to end-stage renal disease. CPN is a rodent specific disease with no apparent similar human kidney disease condition.

Therefore, the no-observed-adverse-effect-level (NOAEL) was considered to be 800 mg/kg/day.

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Read-across from an analogue substance for which a guideline study (Klimish 1) is available.
Reason / purpose:
read-across source
Principles of method if other than guideline:
Read-across approach from data on an analogue substance.
Key result
Dose descriptor:
NOAEL
Effect level:
800 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects at the highest dose tested.
Remarks on result:
other: Based on a read-across from an analogue substance.
Key result
Critical effects observed:
no
Conclusions:
Based on read-across approach from analogue substance P0310, the NOAEL of the substance P-1401 is determined to be 800 mg/kg bw/day.
Executive summary:

Based on experimental results obtained in a study according to OECD 407 on analogue substance P0310 where the NOAEL was determined to be 800 mg/kg bw/day, the read-across approach is applied and the NOAEL for the substance P-1401 is determined to be 800 mg/kg bw/day.

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:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
Less animals per dose than required. Some parameters were not evaluated.
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Females (if applicable) nulliparous and non-pregnant: yes
- Weight at study initiation: Males = 123 g, females = 120g.
- Housing: 5 per cage.
- Diet : ad libitum.
- Water : ad libitum.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2ºC
Route of administration:
oral: gavage
Vehicle:
other: Water and cremophor
Details on oral exposure:
- Amount of vehicle (if gavage): 5mL/kg
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Daily
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
30 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
No. of animals per sex per dose:
5 per sex per dose
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily.

BODY WEIGHT: Yes
- Time schedule for examinations: daily.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the exposure (13 weeks).
- Anaesthetic used for blood collection: Yes.
- Animals fasted: Not specified
- How many animals: 5 rats per dose
- Parameters checked: Hemoglobin, erythrocyte and leukocyte count, MCV, smears.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: After 13 weeks.
- Animals fasted: Not specified
- How many animals: 5 rats per dose.
- Parameters checked: GPT, GOT, SDH, GLDH, bilirubin, urea, creatinine.

URINALYSIS: Yes
- Time schedule for collection of urine: 13 weeks.
- Metabolism cages used for collection of urine: Not specified
- Animals fasted: Not specified
- Parameters checked: albumin, sugar, blood, microscopic sediment investigations,
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: No
Statistics:
The mean values of the animal weights and the absolute and related original weights were calculated and a significance calculation of the results was carried out with the distribution-free rank sums test according to Wilcoxon (1947).
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The increase in the body weight was significantly reduced by a daily dose of 300 mg / kg in the male rats and by 100 - 300 mg / kg in the female rats.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
All values found were in the physiological range.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
All values were in the physiological range.
Urinalysis findings:
no effects observed
Description (incidence and severity):
The values found were within standard ranges. In the urine, no pathological findings were found.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Changes in the organs of the heart, liver, lungs, spleen, kidneys, germs, testes, ovaries) were found in the male and female rats only at the dose levels, which showed a significant reduction of the body weights: in male rats with 300 mg/kg/day and in female rats with 100 and 300 mg/kg/day.
Gross pathological findings:
no effects observed
Description (incidence and severity):
Macroscopic findings of the internal organs: The internal organs showed no macroscopic changes.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
organ weights and organ / body weight ratios
Key result
Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
body weight and weight gain
organ weights and organ / body weight ratios
Key result
Critical effects observed:
no

Table 1. Bodyweights

Dose mg/kg

Average body weight in g

Differences start/end

P

Start

End

Male rats

Control

123

315

192

30

123

322

199

>0,05

100

123

315

192

>0,05

300

123

270

147

< 0.01

Female rats

Control

120

203

83

30

120

205

85

 >0,05

100

120

180

60

<0,01

300

120

171

51

<0,01

Table 2. Haematology

Dose
mg/kg

Hb
g %

Ery
 106

 HbE

Leuko

103

MCV 
µm3

Thromboz
 103

Hematocrit

Male rats

Control

15,2

7,46

20,5

2,9

64

918

48

30

14,5

7,15

20,5

1,5

63

982

45

100

15,2

7,22

21,4

4,0

64

992

46

300

14,7

7,45

19,3

2,5

60

895

45

Female rats

Control

15,4

6,4-6

20,8

5,8

64

966

41

30

15,2

6,82

19,5

4,3

61

1088

41

100

12,2

5,55

22,0

4,6

68

1030

39

300

12,9

5,99

21,5

3,3

66

1014

40

Table 3. Clinical chemistry

Dose

mg/kg

GOT

GPT

SDH

GLDH

Total Bilirubin

mg/100 ml

mU/ml

Male rats

Control

37,1

16,0

1,4

1,1

0,17

30

34,8

16,6

2,0

0,7

0,18

100

32,1

15,6

1,8

0,4

0,16

300

37,1

10,2

1,0

0,4

0,18

Female rats

Control

50,9

18,8

1,5

1,3

0,14

30

33,6

.18,2

0,8

1,6

0,18

100

54,4

19,0

1,2

0,9

0,16

300

55,0

12,9

1,1

1,4

0,15

Dose
mg/kg

Urea (mg/100 ml)

KREATININ (mg/100 ml)

Male rats

Female rat

Male rats

Female rats

Concentration

54,2

55,3

1,18

1,19

30

55,7

54,4

1,15

1,19

100

56,5

55,4

1,25

1,14

300

51,5

55,5

1,21

1,12

Table. Absolute and relative organ weights

Doses

mg/kg

Bodyweight

g

Thyroid

Heart

Lungs

Liver

Spleen

Kidneys

Adrenals

Testes/ovaries

AVERAGE ABSOLUTE ORGAN WEIGHT in mg

 Male rats

Control

315

14,0

791

1480

10119

600

1683

45,5

3096

30

322

13,5

768

1252

10287

584

1650

41,5

3120

100

315

12.9 

758

1315

10077

609

1659

44,5

3158

300

270**

13.9

710**

1414

9168*

604

1932**

44,1

2992

Female rats

Control

203

12,1

551

1105

7606

481

1116

60,5

77,6

30

205

11,5

553

1027

7362

490

1133

65,5

79,1

100

180**

.12,2

515

1108

6963*

458

1115

57,8

76,6

300

171**

11,7

538

899**

6681**

453

1382**

51,6**

63,2*

AVERAGE RELATIVE ORGAN WEIGHTS in mg (per 100 g body weight)

Male rats

Control

 

4.5

252

493

3204

192

536

14.7

990

30

 

4.2

248

389

3190

182

511

12.8

972

100

 

4.1

241

420

3194

194

527

14.2

1004

300

 

5.2

263**

545

3388**

225**

715**

16.6*

1113*

Female rats

Control

 

6.0

272

555

3747

237

551

30.2

38.5

30

 

5.5

270

506

3599

240

553

31.8

38.5

100

 

6.8

292

667

3885

255

622**

33.1

42.3

300

 

6.8

315**

529

3900

265**

810**

30.2

37.0

** = significantly different from controls (p <0.01)

* = significantly different from controls (p <0.05)

Conclusions:
The NOAEL for the test substance after 13 weeks of repeated exposure was 100 mg/kg-bw/day in male rats and 30 mg/kg-bw/day in female rats based on decreaes in bodyweight and organ weights.
Executive summary:

A repeated dose toxicity study was conducted with a method similar to the OECD 408. The test substance was administered on a daily basis for 13 weeks by gavage to 5 rats per sex per dose. Three doses and a concurrent vehicle control were included in the study design, the doses were 30, 100 and 300 mg/kg-bw/day. Cage-side observations were performed daily, body weights were measured weekly, after 13 weeks of exposure blood was collected and hematologic and biochemistry measurements were performed, urynalisis was also performed. After 13 weeks all rats were necropsied and gross pathology on the following organs was performed: thyroid, heart, lungs, liver, spleen, kidney, testes and ovaries, moreover, these organs were weighed and compared to control. The increase in the body weight was significantly reduced by a daily dose of 300 mg / kg in the male rats and by 100 - 300 mg / kg in the female rats. Changes in organ weights (heart, liver, lungs, spleen, kidneys, germs, testes, ovaries) were found in the male and female rats only at the dose levels, which showed a significant reduction of the body weight: in male rats with 300 mg/kg/day and in female rats with 100 and 300 mg/kg/day. The NOAEL for the test substance after 13 weeks of repeated exposure was 100 mg/kg-bw/day in male rats and 30 mg/kg-bw/day in female rats based on decrease in bodyweight and changes in organ weights.

Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Read-across from an analogue substance for which there is available information (Klimish = 2).
Reason / purpose:
read-across source
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
organ weights and organ / body weight ratios
Remarks on result:
other: Based on the read-across from an analogue substance.
Key result
Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
body weight and weight gain
organ weights and organ / body weight ratios
Remarks on result:
other: Based on the read-across from an analogue substance.
Key result
Critical effects observed:
no
Conclusions:
Based on the read-across from an analogue substance, the 13 weeks-NOAEL for P1401 was estimated to be 100 mg/kg-bw/day in male rats and 30 mg/kg-bw/day in female rats.
Executive summary:

Based on the read-across from an analogue substance, the 13 weeks-NOAEL for P1401 was estimated to be 100 mg/kg-bw/day in male rats and 30 mg/kg-bw/day in female rats.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
30 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Two studies are available, one is GLP compliant and of high quality (Klimisch score = 1, since read-across the Klimisch score is 2) and the other of Klimisch score = 2. The database is deemed to be suitable for assessment.
System:
other: body weight and organ weights

Additional information

Key study: Read-across from experimental data on the analogue P0310:

A sub-acute toxicity test was performed with the analogue substance P0310 according to OECD Guideline 407 (GLP study). The test item was administered orally by gavage to young adult Wistar rats at doses of 50, 200 and 800 mg/kg/day, daily for 28 days. Chronic progressive nephropathy (CPN) is a rodent-specific, age-related renal disease, particularly of male rats, characterized by a spectrum of distinct histological changes which may begin early in the animal's life and progress to end-stage renal disease in certain rat strains. CPN is generally regarded as a degenerative to atrophic disease with compensatory regenerative hyperplasia. The proliferative nature of CPN often becomes problematic in advanced to end-stage renal disease. CPN is a rodent specific disease with no apparent similar human kidney disease condition. Therefore, the no-observed-adverse-effect-level (NOAEL) was considered to be 800 mg/kg/day.

Key study: Read-across from experimental data on the analogue CAS 68971-49 -3:

A repeated dose toxicity study was conducted with the analogue CAS 68971 -49 -3 according to OECD Guideline 408. The test substance was administered on a daily basis for 13 weeks by gavage to 5 rats per sex per dose, being the doses 30, 100 and 300 mg/kg bw/day. The increase in the body weight was significantly reduced by a daily dose of 300 mg/kg in the male rats and by 100 - 300 mg / kg in the female rats. Changes in organ weights (heart, liver, lungs, spleen, kidneys, germs, testes, ovaries) were found in the male and female rats only at the dose levels, which showed a significant reduction of the body weight: in male rats with 300 mg/kg/day and in female rats with 100 and 300 mg/kg/day. The NOAEL for the test substance after 13 weeks of repeated exposure was 100 mg/kg-bw/day in male rats and 30 mg/kg-bw/day in female rats based on decrease in bodyweight and changes in organ weights.

Justification for classification or non-classification

Based on available data, the substance is not classified for repeated dose toxicity according to CLP Regulation (EC) no. 1272/2008 since the no evidence of organ disfunction was observed associated with the decrease in organ weights in the 90 days study in rats by oral route (NOAEL = 100 mg/kg bw in males, NOAEL = 30 mg/kg bw/day in females, based on bodyweight and changes in organ weights).