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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
repeated dose toxicity: oral, other
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Experimental data fro various test chemicals
Justification for type of information:
WoE for the target CAS is summarized based on data from various test chemicals
Cross-reference
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
repeated dose toxicity: oral, other
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data is from J-check
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Principles of method if other than guideline:
Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD TG422) was performed to evaluate the toxic nature of the test chemical upon repeated dosing by oral route.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: No data
- Age at study initiation: 10 weeks old / Recovery: 0, 500 mg/kg/day
- Weight at study initiation: No data
- Fasting period before study: No data
- Housing: No data
- Diet (e.g. ad libitum): No data
- Water (e.g. ad libitum): No data
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%):No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data

IN-LIFE DATES: From: To: No data
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
No data available
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
Male:42 days
Female: 42- 58 days (from 14 days before mating to day 5 of lactation)
Frequency of treatment:
No data available
Remarks:
Doses / Concentrations:
0, 80, 200, 500 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
No data available
Control animals:
yes, concurrent vehicle
Details on study design:
No data available
Positive control:
No data available
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data
- Time schedule: No data
- Cage side observations checked in table [No.?] were included. No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: No data

BODY WEIGHT: Yes
- Time schedule for examinations: No data

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: 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

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations: No data

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: No data
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data

URINALYSIS: Yes
- Time schedule for collection of urine: No data
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined. No data

NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data

OTHER: No data
Sacrifice and pathology:
Sacrifice and pathology
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
No data
Statistics:
No data
Clinical signs:
no effects observed
Description (incidence and severity):
No effect
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Male: Decrease in the body weight gain (500 mg/kg/day, tendency), Decrease in the rate of body weight gain (500 mg/kg/day)
Female: Decrease in the body weight (500 mg/kg/day), Decrease in the body weight gain (200, 500 mg/kg/day and Recovery 500 mg/kg/day), Decrease in the rate of body weight gain (Recovery 500 mg/kg/day)
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Male: No effect
Female: Decrease in the food consumption (200 and 500 mg/kg/day)
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Male: Decrease in the WBC (200 and 500 mg/kg/day, tendency), Decrease in the RET (500 mg/kg/day), Decrease in the percentage of Eosinophil (500 mg/kg/day)
Female: Decrease in the Hct (500 mg/kg/day and Recovery 500 mg/kg/day), Decrease in the WBC (500 mg/kg/day, tendency), Decrease in the percentage of Lymphocyte (500 mg/kg/day, tendency), Decrease in the RBC (Recovery 500 mg/kg/day), Increase in the MCHC (Recovery 500 mg/kg/day)
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Male: Decrease in the AST (200 mg/kg/day), Decrease in the ALT (200 and 500 mg/kg/day), Decrease in the creatinine (500 mg/kg/day), Decrease in the beta-glb (500 mg/kg/day)
Female: No effect
Urinalysis findings:
no effects observed
Description (incidence and severity):
No effect
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Male: Decrease in the spleen weight (Absolute and Relative) (200 mg/kg/day), Increase in the spleen weight (Absolute) (Recovery 500 mg/kg/day, tendency), Increase in the spleen weight (Relative) (Recovery 500 mg/kg/day), Decrease in the testes weight (Absolute) (Recovery 500 mg/kg/day)
Female: Decrease in the spleen weight (Absolute and Relative) (500 mg/kg/day)
Gross pathological findings:
no effects observed
Description (incidence and severity):
No effect
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Male: No effect
Female: Atrophy of white pulp in the spleen (500 mg/kg/day)
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
Clinical signs and mortality: No effect

Body weight and weight gain:
Male: Decrease in the body weight gain (500 mg/kg/day, tendency), Decrease in the rat
e of body weight gain (500 mg/kg/day)

Female: Decrease in the body weight (500 mg/kg/day), Decrease in the body weight gain (200, 500 mg/kg/day and Recovery 500 mg/kg/day), Decrease in the rate of body weight gain (Recovery 500 mg/kg/day)

Food consumption and compound intake:
Male: No effect

Female: Decrease in the food consumption (200 and 500 mg/kg/day)

Food efficiency: No data

Water consumption and compound intake: No data

Opthalmoscopic examination: No data

Haematology
Male: Decrease in the WBC (200 and 500 mg/kg/day, tendency), Decrease in the RET (500 mg/kg/day), Decrease in the percentage of Eosinophil (500 mg/kg/day)

Female: Decrease in the Hct (500 mg/kg/day and Recovery 500 mg/kg/day), Decrease in the WBC (500 mg/kg/day, tendency), Decrease in the percentage of Lymphocyte (500 mg/kg/day, tendency), Decrease in the RBC (Recovery 500 mg/kg/day), Increase in the MCHC (Recovery 500 mg/kg/day)

Clinical chemistry
Male: Decrease in the AST (200 mg/kg/day), Decrease in the ALT (200 and 500 mg/kg/day), Decrease in the creatinine (500 mg/kg/day), Decrease in the betaglb (500 mg/kg/day)

Female: No effect

Urinanalysis: No effect

Neurobehaviour: No data

Organ weights
Male: Decrease in the spleen weight (Absolute and Relative) (200 mg/kg/day), Increase in the spleen weight (Absolute) (Recovery 500 mg/kg/day, tendency), Increase in the spleen weight (Relative) (Recovery 500 mg/kg/day), Decrease in the testes weight (Absolute) (Recovery 500 mg/kg/day)

Female: Decrease in the spleen weight (Absolute and Relative) (500 mg/kg/day)

Gross pathology: No effect

Histopathology
Male: No effect

Female: Atrophy of white pulp in the spleen (500 mg/kg/day)
Dose descriptor:
NOAEL
Effect level:
80 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant changes were noted
Critical effects observed:
not specified
Conclusions:
The No Observed Adverse effect level (NOAEL) for the test chemical is considered to be 80 mg/Kg bw/day in male and female Crl:CD (SD) rats.
Executive summary:

Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD TG422) was performed to evaluate the toxic nature of the test chemical upon repeated dosing by oral route. The test was performed onmale and female Crl:CD (SD) rats at dose levels of 0, 80, 200, 500 mg/kg/day. The animals were observed for clinical signs, body weight, food consumption, urinalysis, hematological and blood biochemistry parameters, gross and histopathological changes. On the basis of observations made, the No Observed Adverse effect level (NOAEL) for the test chemical is considered to be 80 mg/Kg bw/day in male and femaleCrl:CD (SD) rats.

Data source

Reference
Reference Type:
review article or handbook
Title:
WoE of repeated dose oral toxicity study for CAS no 52605-52-4
Author:
Sustainability Support Services (Europe) AB
Year:
2018
Bibliographic source:
WoE report, Sustainability Support Services (Europe) AB, 2018

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Principles of method if other than guideline:
WoE for the target CAS is summarized based on data from various test chemicals
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1-(3-chlorophenyl)-4-(3-chloropropyl)piperazinium chloride
EC Number:
258-038-0
EC Name:
1-(3-chlorophenyl)-4-(3-chloropropyl)piperazinium chloride
Cas Number:
52605-52-4
Molecular formula:
C13H18Cl2N2.ClH
IUPAC Name:
1-(3-chlorophenyl)-4-(3-chloropropyl)piperazin-1-ium chloride
Details on test material:
- Name of the test chemical: 1-(3-chlorophenyl)-4-(3-chloropropyl) piperazine hydrochloride
- Molecular formula: C13H18Cl2N2ClH
- Molecular weight: 309.6661 g/mol
- Substance tpe: Organic

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
2. TEST ANIMALS
- Source: No data
- Age at study initiation: 10 weeks old / Recovery: 0, 500 mg/kg/day
- Weight at study initiation: No data
- Fasting period before study: No data
- Housing: No data
- Diet (e.g. ad libitum): No data
- Water (e.g. ad libitum): No data
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%):No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data

IN-LIFE DATES: From: To: No data

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
No data available
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
2. Male:42 days
Female: 42- 58 days (from 14 days before mating to day 5 of lactation)
Frequency of treatment:
No data available
Doses / concentrations
Remarks:
2. Doses / Concentrations:
0, 80, 200, 500 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
No data available
Control animals:
yes, concurrent vehicle
Details on study design:
No data available
Positive control:
No data available

Examinations

Observations and examinations performed and frequency:
2. CAGE SIDE OBSERVATIONS: No data
- Time schedule: No data
- Cage side observations checked in table [No.?] were included. No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: No data

BODY WEIGHT: Yes
- Time schedule for examinations: No data

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: 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

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations: No data

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: No data
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data

URINALYSIS: Yes
- Time schedule for collection of urine: No data
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined. No data

NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data

OTHER: No data
Sacrifice and pathology:
2. Sacrifice and pathology
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
No data
Statistics:
No data

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No effect
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
2. Male: Decrease in the body weight gain (500 mg/kg/day, tendency), Decrease in the rate of body weight gain (500 mg/kg/day)
Female: Decrease in the body weight (500 mg/kg/day), Decrease in the body weight gain (200, 500 mg/kg/day and Recovery 500 mg/kg/day), Decrease in the rate of body weight gain (Recovery 500 mg/kg/day)
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
2. Male: No effect
Female: Decrease in the food consumption (200 and 500 mg/kg/day)
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
2. Male: Decrease in the WBC (200 and 500 mg/kg/day, tendency), Decrease in the RET (500 mg/kg/day), Decrease in the percentage of Eosinophil (500 mg/kg/day)
Female: Decrease in the Hct (500 mg/kg/day and Recovery 500 mg/kg/day), Decrease in the WBC (500 mg/kg/day, tendency), Decrease in the percentage of Lymphocyte (500 mg/kg/day, tendency), Decrease in the RBC (Recovery 500 mg/kg/day), Increase in the MCHC (Recovery 500 mg/kg/day)
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
2. Male: Decrease in the AST (200 mg/kg/day), Decrease in the ALT (200 and 500 mg/kg/day), Decrease in the creatinine (500 mg/kg/day), Decrease in the beta-glb (500 mg/kg/day)
Female: No effect
Urinalysis findings:
no effects observed
Description (incidence and severity):
No effect
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
2. Male: Decrease in the spleen weight (Absolute and Relative) (200 mg/kg/day), Increase in the spleen weight (Absolute) (Recovery 500 mg/kg/day, tendency), Increase in the spleen weight (Relative) (Recovery 500 mg/kg/day), Decrease in the testes weight (Absolute) (Recovery 500 mg/kg/day)
Female: Decrease in the spleen weight (Absolute and Relative) (500 mg/kg/day)
Gross pathological findings:
no effects observed
Description (incidence and severity):
No effect
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
2. Male: No effect
Female: Atrophy of white pulp in the spleen (500 mg/kg/day)
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
2. Clinical signs and mortality: No effect

Body weight and weight gain:
Male: Decrease in the body weight gain (500 mg/kg/day, tendency), Decrease in the rat
e of body weight gain (500 mg/kg/day)

Female: Decrease in the body weight (500 mg/kg/day), Decrease in the body weight gain (200, 500 mg/kg/day and Recovery 500 mg/kg/day), Decrease in the rate of body weight gain (Recovery 500 mg/kg/day)

Food consumption and compound intake:
Male: No effect

Female: Decrease in the food consumption (200 and 500 mg/kg/day)

Food efficiency: No data

Water consumption and compound intake: No data

Opthalmoscopic examination: No data

Haematology
Male: Decrease in the WBC (200 and 500 mg/kg/day, tendency), Decrease in the RET (500 mg/kg/day), Decrease in the percentage of Eosinophil (500 mg/kg/day)

Female: Decrease in the Hct (500 mg/kg/day and Recovery 500 mg/kg/day), Decrease in the WBC (500 mg/kg/day, tendency), Decrease in the percentage of Lymphocyte (500 mg/kg/day, tendency), Decrease in the RBC (Recovery 500 mg/kg/day), Increase in the MCHC (Recovery 500 mg/kg/day)

Clinical chemistry
Male: Decrease in the AST (200 mg/kg/day), Decrease in the ALT (200 and 500 mg/kg/day), Decrease in the creatinine (500 mg/kg/day), Decrease in the betaglb (500 mg/kg/day)

Female: No effect

Urinanalysis: No effect

Neurobehaviour: No data

Organ weights
Male: Decrease in the spleen weight (Absolute and Relative) (200 mg/kg/day), Increase in the spleen weight (Absolute) (Recovery 500 mg/kg/day, tendency), Increase in the spleen weight (Relative) (Recovery 500 mg/kg/day), Decrease in the testes weight (Absolute) (Recovery 500 mg/kg/day)

Female: Decrease in the spleen weight (Absolute and Relative) (500 mg/kg/day)

Gross pathology: No effect

Histopathology
Male: No effect

Female: Atrophy of white pulp in the spleen (500 mg/kg/day)

Effect levels

Dose descriptor:
NOAEL
Effect level:
80 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant changes were noted

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The No Observed Adverse effect level (NOAEL) for the test chemical is considered to be 80 mg/Kg bw/day in male and female Crl:CD (SD) rats.
Executive summary:

Data available for the test chemical was reviewed to determine the toxic nature of the target chemical. The studies are as mentioned below:

Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD TG422) was performed to evaluate the toxic nature of the test chemical upon repeated dosing by oral route. The test was performed onmale and female Crl:CD (SD) rats at dose levels of 0, 80, 200, 500 mg/kg/day. The animals were observed for clinical signs, body weight, food consumption, urinalysis, hematological and blood biochemistry parameters, gross and histopathological changes. On the basis of observations made, the No Observed Adverse effect level (NOAEL) for the test chemical is considered to be 80 mg/Kg bw/day in male and femaleCrl:CD (SD) rats.