Registration Dossier

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study performed in accordance with OECD guidelines and GLP. Data from reliable source (Japanese Ministry of Health, Labour and Welfare). No English test report is available (study in Japanese), but an English summary and all tables and figures in English are available.
Justification for type of information:
Read Across to an analogue based on structural similarity. An analogue justification is attached to section 13 of the dataset.
Cross-reference
Reason / purpose:
read-across source
Reference
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: see 'Remark'
Remarks:
Study performed in accordance with OECD guidelines and GLP. Data from reliable source (Japanese Ministry of Health, Labour and Welfare). No English test report is available (study in Japanese), but an English summary and all tables and figures in English are available.
Justification for type of information:
Read Across to an analogue based on structural similarity. An analogue justification is attached to section 13 of the dataset.
Reason / purpose:
read-across: supporting information
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Fischer 344/DuCrj
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: the average weight of males was 126 g and 99 g of the females
Route of administration:
oral: drinking water
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Stability was confirmed using quantitative HPLC analysis
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Daily, the test substance was administered to the drinking water.
Remarks:
Doses / Concentrations:
0, 96, 185, 369, 687, and 1514 mg/kg/day in males and 163, 313, 652, 1000, and 1702 mg/kg/day in females
Basis:
actual ingested
Remarks:
Doses / Concentrations:
0, 1250, 2500, 5000, 10000, and 20000 mg/L
Basis:
nominal in water
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION, WATER CONSUMPTION AND BODY WEIGHT:
- Time schedule: weekly

HAEMATOLOGY:
- Time schedule for collection of blood: The surviving animals were bled at the end of the study.
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: Haematology was examined in every male rat from all dose groups. Haematology in female rats was examined in all rats from all dose groups with the exception from 1 rat in the control group.
- Parameters: Red blood cell count, haemoglobin, haematocrit, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration, platelet count, reticulocytes, prothrombin time, activated partial thromboplastin, white blood cell count, and differential white blood cell count.

CLINICAL CHEMISTRY:
- Time schedule for collection of blood: The surviving animals were bled at the end of the study.
- Animals fasted: No data
- How many animals: All animals
- Parameters: Plasma chemistry analyses included total protein, albumin, A/G ratio, total bilirubin, glucose, total cholesterol, triglyceride, phospholipid, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), γ-glutamyl transpeptidase, creatine phosphokinase, urea nitrogen, creatinine, sodium, potassium, chloride, calcium, and inorganic phosphorus.

URINALYSIS:
- Time schedule for collection of urine: Urine samples were collected for urinalyses at the end of treatment.
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters: pH, protein, glucose, ketone body, bilirubin, occult blood, and urobilinogen
Sacrifice and pathology:
GROSS PATHOLOGY AND HISTOPATHOLOGY: Yes, gross pathology at necropsy, organ weights (thymus, adrenal, testes, ovary, heart, lung, kidney, spleen, liver, brain, and thyroid) and histopathology were conducted.
Statistics:
Incidences of non-neoplastic lesions and urinalysis were analyzed by Chi-square test. Changes in body weight, water consumption, food consumption, hematological and blood biochemical parameters, and organ weights were analyzed by Dunnett’s test.
Details on results:
CLINICAL SIGNS AND MORTALITY
Soiled fur around genitalia was observed in all animals administered with 20,000 mg/L test substance and in a few animals exposed to 5000 and 10,000 mg/L. One male rat in the 20000 mg/L dose group did not survive the 13th study week, all other animals survived until necropsy.

BODY WEIGHT AND WEIGHT GAIN
After 13 weeks a significant decrease in body weight was observed in both sexes of the 20,000 mg/L dose group (±19% lower compared to the control group). Decrease in body weight was also observed in females administered with 10,000 mg/L test substance (±8% lower compared to the control group)

FOOD CONSUMPTION AND WATER CONSUMPTION
During the entire study a decrease in food consumption was observed in males and females in the 20,000 mg/L dose groups (±20% relative to controls) and in females in the 10,000 mg/L dose group (±10% relative to controls). During the entire study water consumption was decreased in females administered with 20,000 mg/L. The decrease in females was approximately 30-40%. In males dosed with 5000, 10000, and 20000 mg/L decreased water consumption was observed untill the 9th week of the study.

HAEMATOLOGY
Red blood cell count and platelet count were reduced in the 10000 and 20000 mg/L dose groups of both sexes. In males platelet count was also reduced in animals exposed to 5000 mg/L. The reduction of platelets in the 5000 mg/L dose group was less then 10% compared to controls and no changes were observed in coagulation parameters. Therefore no evidence of a functional effect was present. In the 10000 and 20000 mg/L dose groups in females and in the 20000 mg/L dose group in males haemoglobin was reduced. MCV and MCH were increased in males (10000 and 20000 mg/L) and females (20000 mg/L). In females administered with 20000 mg/L an increased reticulocyte count was measured.

CLINICAL CHEMISTRY
In males exposed to 20000 mg/L test substance a reduction in total protein, glucose, sodium, calcium and an increase in A/G ratio, total cholesterol, phospholipids, urea nitrogen, potassium was observed. In the 10000 mg/L dose group only the effects on total protein, cholesterol, phospholipids, sodium and potassium were present. No effects were observed at lower dose levels. In female exposed to 20000 mg/L increases in A/G ratio, ALP, and urea nitrogen was observed. In the 10000 mg/L dose group total protein was decreased and urea nitrogen was increased.

URINALYSIS
Statisticaly significant decrease in pH was observed after administration of 20000 mg/L in both sexes. This could be the result of excretion of 2-phenoxyacetic acid, the major metabolite of the test substance.

ORGAN WEIGHTS
In the 10000 mg/L dose groups, the relative liver weight was increased in males and females. In addition in females absolute adrenal weight was decreased and relative kidney and brain weights were increased. In males of the 20000 mg/L dose group a decrease in absolute thymus, testes, heart, lung, and spleen was observed. In addition an increase in relative testes, lung, kidney, liver, brain, and thyroid was determined. In females of the 20000 mg/L dose group decreases in absolute thymus, adrenals, ovaries, heart, lungs, and spleen weights were determined. Relative kidney, liver, and brain weights were increased.

HISTOPATHOLOGY
In 2 males and 1 female dosed with 10000 mg/L, slight urothelial hyperplasia of the renal pelvis was observed. Slight to moderate urothelial hyperplasia was observed in 6 males of the highest dose group. In 2 and 7 females dosed with 10000 and 20000 mg/L test substance, respectively slight to moderate urinary bladder transitional epithelial hyperplasia was observed. Slight urinary bladder transitional epithelial hyperplasia was also observed in one male of the high dose group.

ANALYTICAL DATA DRINKING WATER:
Analytical data verified that the test material content in drinking water was within acceptable limits of the target concentrations (101-102%).
Dose descriptor:
NOAEL
Effect level:
369 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Decreased red blood cells and haemogobin; increased MCV and MCH; increased incidence of slight to moderate hyperplasia in the kidney and urinary bladder.
Critical effects observed:
not specified

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2003
Report Date:
2003

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 2-Phenoxyethanol
- Analytical purity: 99.9%
- Lot/batch No.: WAL415

Test animals

Species:
rat
Strain:
Fischer 344/DuCrj
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: the average weight of males was 126 g and 99 g of the females

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Stability was confirmed using quantitative HPLC analysis
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Daily, the test substance was administered to the drinking water.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 96, 185, 369, 687, and 1514 mg/kg/day in males and 163, 313, 652, 1000, and 1702 mg/kg/day in females
Basis:
actual ingested
Remarks:
Doses / Concentrations:
0, 1250, 2500, 5000, 10000, and 20000 mg/L
Basis:
nominal in water
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION, WATER CONSUMPTION AND BODY WEIGHT:
- Time schedule: weekly

HAEMATOLOGY:
- Time schedule for collection of blood: The surviving animals were bled at the end of the study.
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: Haematology was examined in every male rat from all dose groups. Haematology in female rats was examined in all rats from all dose groups with the exception from 1 rat in the control group.
- Parameters: Red blood cell count, haemoglobin, haematocrit, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration, platelet count, reticulocytes, prothrombin time, activated partial thromboplastin, white blood cell count, and differential white blood cell count.

CLINICAL CHEMISTRY:
- Time schedule for collection of blood: The surviving animals were bled at the end of the study.
- Animals fasted: No data
- How many animals: All animals
- Parameters: Plasma chemistry analyses included total protein, albumin, A/G ratio, total bilirubin, glucose, total cholesterol, triglyceride, phospholipid, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), γ-glutamyl transpeptidase, creatine phosphokinase, urea nitrogen, creatinine, sodium, potassium, chloride, calcium, and inorganic phosphorus.

URINALYSIS:
- Time schedule for collection of urine: Urine samples were collected for urinalyses at the end of treatment.
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters: pH, protein, glucose, ketone body, bilirubin, occult blood, and urobilinogen
Sacrifice and pathology:
GROSS PATHOLOGY AND HISTOPATHOLOGY: Yes, gross pathology at necropsy, organ weights (thymus, adrenal, testes, ovary, heart, lung, kidney, spleen, liver, brain, and thyroid) and histopathology were conducted.
Statistics:
Incidences of non-neoplastic lesions and urinalysis were analyzed by Chi-square test. Changes in body weight, water consumption, food consumption, hematological and blood biochemical parameters, and organ weights were analyzed by Dunnett’s test.

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY
Soiled fur around genitalia was observed in all animals administered with 20,000 mg/L test substance and in a few animals exposed to 5000 and 10,000 mg/L. One male rat in the 20000 mg/L dose group did not survive the 13th study week, all other animals survived until necropsy.

BODY WEIGHT AND WEIGHT GAIN
After 13 weeks a significant decrease in body weight was observed in both sexes of the 20,000 mg/L dose group (±19% lower compared to the control group). Decrease in body weight was also observed in females administered with 10,000 mg/L test substance (±8% lower compared to the control group)

FOOD CONSUMPTION AND WATER CONSUMPTION
During the entire study a decrease in food consumption was observed in males and females in the 20,000 mg/L dose groups (±20% relative to controls) and in females in the 10,000 mg/L dose group (±10% relative to controls). During the entire study water consumption was decreased in females administered with 20,000 mg/L. The decrease in females was approximately 30-40%. In males dosed with 5000, 10000, and 20000 mg/L decreased water consumption was observed untill the 9th week of the study.

HAEMATOLOGY
Red blood cell count and platelet count were reduced in the 10000 and 20000 mg/L dose groups of both sexes. In males platelet count was also reduced in animals exposed to 5000 mg/L. The reduction of platelets in the 5000 mg/L dose group was less then 10% compared to controls and no changes were observed in coagulation parameters. Therefore no evidence of a functional effect was present. In the 10000 and 20000 mg/L dose groups in females and in the 20000 mg/L dose group in males haemoglobin was reduced. MCV and MCH were increased in males (10000 and 20000 mg/L) and females (20000 mg/L). In females administered with 20000 mg/L an increased reticulocyte count was measured.

CLINICAL CHEMISTRY
In males exposed to 20000 mg/L test substance a reduction in total protein, glucose, sodium, calcium and an increase in A/G ratio, total cholesterol, phospholipids, urea nitrogen, potassium was observed. In the 10000 mg/L dose group only the effects on total protein, cholesterol, phospholipids, sodium and potassium were present. No effects were observed at lower dose levels. In female exposed to 20000 mg/L increases in A/G ratio, ALP, and urea nitrogen was observed. In the 10000 mg/L dose group total protein was decreased and urea nitrogen was increased.

URINALYSIS
Statisticaly significant decrease in pH was observed after administration of 20000 mg/L in both sexes. This could be the result of excretion of 2-phenoxyacetic acid, the major metabolite of the test substance.

ORGAN WEIGHTS
In the 10000 mg/L dose groups, the relative liver weight was increased in males and females. In addition in females absolute adrenal weight was decreased and relative kidney and brain weights were increased. In males of the 20000 mg/L dose group a decrease in absolute thymus, testes, heart, lung, and spleen was observed. In addition an increase in relative testes, lung, kidney, liver, brain, and thyroid was determined. In females of the 20000 mg/L dose group decreases in absolute thymus, adrenals, ovaries, heart, lungs, and spleen weights were determined. Relative kidney, liver, and brain weights were increased.

HISTOPATHOLOGY
In 2 males and 1 female dosed with 10000 mg/L, slight urothelial hyperplasia of the renal pelvis was observed. Slight to moderate urothelial hyperplasia was observed in 6 males of the highest dose group. In 2 and 7 females dosed with 10000 and 20000 mg/L test substance, respectively slight to moderate urinary bladder transitional epithelial hyperplasia was observed. Slight urinary bladder transitional epithelial hyperplasia was also observed in one male of the high dose group.

ANALYTICAL DATA DRINKING WATER:
Analytical data verified that the test material content in drinking water was within acceptable limits of the target concentrations (101-102%).

Effect levels

Dose descriptor:
NOAEL
Effect level:
369 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Decreased red blood cells and haemogobin; increased MCV and MCH; increased incidence of slight to moderate hyperplasia in the kidney and urinary bladder.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion