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EC number: - | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1990-01-17 to 1990-10-09
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 990
- Report date:
- 1990
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- EPA OTS 798.2650 (90-Day Oral Toxicity in Rodents)
- Version / remarks:
- EPA TSCA Guildelines, 40 CFR PART 798.2650
- Deviations:
- not specified
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Phenol
- EC Number:
- 203-632-7
- EC Name:
- Phenol
- Cas Number:
- 108-95-2
- Molecular formula:
- C6H6O
- IUPAC Name:
- phenol
- Reference substance name:
- 1-chlorododecane
- Molecular formula:
- C12H25Cl
- IUPAC Name:
- 1-chlorododecane
- Reference substance name:
- 1-Dodecanol
- Cas Number:
- 112-53-8
- Molecular formula:
- C12H26O
- IUPAC Name:
- 1-Dodecanol
- Reference substance name:
- 1-Tetradecanol
- Cas Number:
- 112-72-1
- Molecular formula:
- C14H30O
- IUPAC Name:
- 1-Tetradecanol
- Reference substance name:
- triphenyl phosphate
- Cas Number:
- 115-86-6
- Molecular formula:
- C18H15O4P
- IUPAC Name:
- triphenyl phosphate
- Reference substance name:
- -
- EC Number:
- 431-760-5
- EC Name:
- -
- Cas Number:
- 27460-02-2
- Molecular formula:
- C24H35O4P
- IUPAC Name:
- dodecyl diphenyl phosphate
- Reference substance name:
- diphenyl tetradecyl phosphate
- Cas Number:
- 142474-86-0
- Molecular formula:
- C26H39O4P
- IUPAC Name:
- diphenyl tetradecyl phosphate
- Reference substance name:
- Didodecyl phenyl phosphate
- Cas Number:
- 56827-93-1
- Molecular formula:
- C30H55O4P
- IUPAC Name:
- Didodecyl phenyl phosphate
- Test material form:
- liquid
Constituent 1
Constituent 2
Constituent 3
Constituent 4
Constituent 5
Constituent 6
Constituent 7
Constituent 8
Test animals
- Species:
- rat
- Strain:
- other: Crl:CD®BR
- Details on species / strain selection:
- Rats were chosen as the appropriate test species because they have been used historically in safety evaluation studies and are recommended by appropriate regulatory agencies.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- A total of 64 male and 63 female Sprague-Dawley rats, Crl:CD®BR, was received on March 13, 1990, from Charles River Laboratories, Inc., Raleigh, North Carolina.
The animals were approximately 4 weeks of age at the time of receipt.
At initiation of dosing, the rats were approximately 6 weeks of age with body weights ranging from 184.1 to 223.7 g for males and from 145.3 to 189.4 g for females
All animals were acclimated to the laboratory environment for approximately 2 weeks and examined for general physical condition and any clinical signs of disease by a staff veterinarian prior to release from quarantine.
Rats were housed in stainless-steel, hanging, wire-mesh cages (2 per cage); following randomization, the animals were housed individually.
During the quarantine and study periods, the room temperature and relative humidity were recorded twice daily. Environmental controls were set to maintain the temperature and humidity at 72±6°F and 50±20%, respectively. An artificial light cycle of 12 hours light and 12 hours dark was maintained by an automatic timing device.
Administration / exposure
- Route of administration:
- oral: gavage
- Details on route of administration:
- The oral gavage route was chosen because potential human exposure is by the oral route.
- Vehicle:
- corn oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
The desired amount of the test material was weighed on an appropriate balance into a beaker and then transferred into a precalibrated beaker. The original beaker was then washed with the vehicle and the wash was poured into the precalibrated beaker in order to ensure that all the residual test material was transferred. Additional corn oil was added to the test material in the precalibrated beaker to attain the desired volume, and the test material and corn oil were mixed on a magnetic stirrer for approximately 30 minutes. The mixtures were then transferred into clear jars for dosing. Dosing formulations were mixed weekly.
The vehicle control and test material were adminstered in the same week as they were formulated. Dose mixtures were removed from refrigeration 1 hour prior to dosing and stirred continuously during dosing. The dose administered was calculated and adjusted weekly for each animal based on the most recently recorded body weight.
VEHICLE
- Justification for use and choice of vehicle (if other than water): Corn Oil, justification not specified
- Concentration in vehicle: 0, 25, 70, or 200 mg/mL for Groups 1, 2, 3, and 4, respectively.
- Amount of vehicle (if gavage): 10 mL/Kg
- Lot/batch no. (if required): 9G 25 14:25
- Purity: assumed to be 100% - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Verification of the concentration of dosing mixtures was performed on samples collected during Weeks 1 and 4 of study. The analytical chemistry methods are appended to the Analytical Chemistry Report
- Duration of treatment / exposure:
- at least 28 days
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- Group 1 (Control)
- Dose / conc.:
- 250 mg/kg bw/day (nominal)
- Remarks:
- Group 2 (Low dose)
- Dose / conc.:
- 700 mg/kg bw/day (nominal)
- Remarks:
- Group 3 (Mid dose)
- Dose / conc.:
- 2 000 mg/kg bw/day (nominal)
- Remarks:
- Group 4 (High dose)
- No. of animals per sex per dose:
- 10/rats/sex/dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
- Rationale for animal assignment (if not random): Rats were selected for the study using a computer generated weight-randomization procedure which assigned them to treatment groups by eliminating the animals with extreme body weights (± 2 S.D. of the mean body weight).
- Fasting period before blood sampling for clinical biochemistry: Not specified
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All rats observed twice daily for mortality and moribundity
DETAILED CLINICAL OBSERVATIONS: Yes. Clinical observations for obvious indications of a toxic and/or pharmacologic effect were performed 1 to 2 hours postdose and effects and other pertinent observations recorded.
- Time schedule: 1 to 2 hours post dose
BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were recorded prior to initiation of dosing, at weekly intervals thereafter through week 4, and at termination.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes. Individual food consumption was measured weekly.
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: Not specified
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Ophthalmoscopic examinations were performed on each animal prior to treatment and during Week 4 (prior to scheduled necropsy) using an indirect ophthalmoscope and 1% Mydriacyl® for pupil dilation
- Dose groups that were examined: all animals
HAEMATOLOGY: Yes
- Time schedule for collection of blood: During the week prior to initiation of dosing (week -1) and during the last week of treatment (week 4)
- Anaesthetic used for blood collection: Yes (ketamine)
- Animals fasted: Yes overnight fast
- How many animals: Not specified
- Parameters checked in table [No.2] were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: During the week prior to initiation of dosing (week -1) and during the last week of treatment (week 4)
- Animals fasted: Yes overnight fast
- How many animals: Not specified
- Parameters checked in table [No.3] were examined.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
IMMUNOLOGY: No - Sacrifice and pathology:
- All animals not selected for the study were sacrificed on Day 8 of the study by CO2 inhalation and exsanguination
A necropsy was performed on the one animal which was designated an unscheduled death
After at least 28 days of treatment, all surviving rats were weighted, anesthetised with sodium pentobarbital, and exsanguinated. A necropsy was conducted on each animal
A necropsy included an examination of the following:
External surface of the body
All orifices
Cranial cavity
Carcass
External surface of the brain; the external surface of the spinal cord and cut surfaces of the brain and spinal cord were examined at the time of tissue trimming, should histopathology require
Nasal cavity and paranasal sinuses
Thoracic, abdominal, and pelvis cavities and their viscera
Cervical tissues and organs - Statistics:
- Weekly (weeks 1-4) and total (weeks 1-4) food consumption, clinical pathology data (except cell morphology data), and organ weight data of the control group were compared statistically to the data of the compound treated groups of the same sex. If variances of untransformed data were heterogenous, the data were transformed to achieve variance homogeneity. When the series of transformations was unsuccessful in achieving variance homogeneity, analyses were performed on rank transformed data. Group comparisons were routinely performed at the 5% two-tailed probability level.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Most of the observations noted for the nasal-orbital area in rats of both sexes of all dose groups were the result of trauma induced by blood collection on Week 4.
Urine stains were noted during cageside observations and weekly physical examinations. Although urine stains were noted among all groups, the observation occurred at a higher incidence in Group 4, suggesting a treatment-related effect (Table 2).
Pre- and post-dose incidences of salivation were observed in the Group 4 males and females (Table 3). Due to the inconsistent distribution over time, the noted salivation, although related to treatment, was judged to be a direct effect of the compound on the oral cavity as the result of dosing technique and/or conditioned response of the rats to dosing. - Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- No compound-related deaths were observed through the study period. One Group 3 female (04934) died during Week 4 following scheduled blood collection; the death being attributed to the blood collection procedure and was considered to be accidental.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Mean body weights were comparable between treated and contro groups for both sexes at all intervals.
- Food consumption and compound intake (if feeding study):
- not specified
- Description (incidence and severity):
- Mean food consumption values were significantly increased as compared to control values for Group 4 animals at weeks 2 and 3, Group 4 females at week 4, and Group 3 females at week 3. Significant increases compared to control values were observed in the total food consumption values (weeks 1-4) for Group 4 animals and Group 3 females. Notably, increased food consumption in treated animals was not accompanied by increased body weight gain.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No treatment-related ophthalmoscopic abnormalities were observed.
1 Male (Group 1 04881) - scarring of the left cornea and retinal degeneration of the left fundus
1 female (Group 2 04917) observed scarring of the left cornea - Haematological findings:
- no effects observed
- Description (incidence and severity):
- No significant differences were observed in treated groups when compared with concurrent control animals. There was no evidence of an effect that could be attributed to treatment with the test material.
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- No significant differences were observed in treated groups when compared with concurrent control animals. There was no evidence of an effect that could be attributed to treatment with the test material.
Week 4 cholinesterase values were increased substantially fro Group 1-4 females as compared to week -1. Such increases are not unusual for maturing female rats of this strain, and the lack of a similar response in male rats was also considered typical. - Urinalysis findings:
- not examined
- 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):
- The absolute and relative liver weight values were significantly increased as compared to control values for Group 4 animals. Additionally, the mean liver-to-terminal body weight value of the Group 3 males was significantly increased as compared to control.
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Observations noted in the liver of animals sacrificed at termination included pale or pale area, cyst, and raised area. In addition, a mass was observed in the liver of one Group 2 female rat. Findings in the kidney included pale, dilated pelvis, and cyst. Neither the incidence nor distribution of the liver or kidney findings among the groups indicated a treatment-related effect. All other observations noted for the animals sacrificed at termination are considered to be incidental. The Group 3 female that died (accidental death) during week 4 had no observations at necropsy.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- All lesions noted during the terminal sacrifice were considered to be incidental findings or part of spontaneous disease complexes pf laboratory rats. There was no microscopically discernible increase in the incidence or severity of these lesions in the treated animals. The lesions were typical of those expected in a group of laboratory rats of that age.
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 250 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Systemic Toxicity
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 700 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Systemic Toxicity
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 2 000 mg/kg bw/day (nominal)
- System:
- hepatobiliary
- Organ:
- liver
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
Any other information on results incl. tables
Table 4. Number of Animals Exhibiting Urine Stainsa |
||||||||
Week(s) |
Group 1 (Control) |
Group 2 (250 mg/Kg/day) |
Group 3 (700 mg/Kg/day) |
Group 4 (2000 mg/Kg/day) |
||||
Male |
Female |
Male |
Female |
Male |
Female |
Male |
Female |
|
1 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
2 |
0 |
0 |
0 |
0 |
0 |
1 |
2 |
2 |
3 |
1 |
0 |
0 |
0 |
0 |
0 |
4 |
1 |
4b |
1 |
0 |
1 |
0 |
1 |
0 |
3 |
0 |
1-4 |
1 |
0 |
1 |
0 |
1 |
1 |
6 |
2 |
a Number of animals observed to have urine stains at least once during the designated interval
b Week 4 includes 2 days of Week 5 (until termination)
Table 5. Number of Animals Exhibiting Salivationa |
||||
Week(s) |
Pre-dose |
Post-dose |
||
Male |
Female |
Male |
Female |
|
1 |
10 |
10 |
0 |
0 |
2 |
4 |
4 |
4 |
2 |
3 |
0 |
0 |
0 |
3 |
4 |
0 |
0 |
1 |
0 |
1-4 |
10 |
10 |
4 |
3 |
a Number of animals observed pre- or post-dose salivation at least once during the designated interval
Table 6. Mean body weight change (g) – 28 day tox study in rats with XP2563 – males
Group and dose level (mg/kg) |
|
Mean body weight change (g) |
||||
Week 0-1 |
Week 1-2 |
Week 2-3 |
Week 3-4a |
Weeks 0-4 |
||
1 – 0.000 |
Mean |
62.7 |
49.0 |
44.8 |
24.3 |
181.0 |
sd |
5.77 |
8.00 |
4.79 |
4.88 |
13.82 |
|
N |
10 |
10 |
10 |
10 |
10 |
|
2 – 250.000 |
Mean |
58.4 |
46.5 |
41.9 |
24.0 |
170.8 |
sd |
6.76 |
8.80 |
7.23 |
8.40 |
19.33 |
|
N |
10 |
10 |
10 |
10 |
10 |
|
3- 700.000 |
Mean |
60.7 |
52.4 |
41.5 |
21.1 |
175.8 |
sd |
8.26 |
8.85 |
8.00 |
12.55 |
25.58 |
|
N |
10 |
10 |
10 |
10 |
10 |
|
4 – 2000.000 |
Mean |
54.7 |
51.2 |
47.5 |
18.5 |
181.9 |
sd |
4.37 |
7.27 |
6.93 |
9.70 |
22.55 |
|
N |
10 |
10 |
10 |
10 |
10 |
Table 7. Mean body weight change (g) – 28 day tox study in rats with XP2563 – females
Group and dose level (mg/kg) |
|
Mean body weight change (g) |
||||
Week 0-1 |
Week 1-2 |
Week 2-3 |
Week 3-4a |
Weeks 0-4 |
||
1 – 0.000 |
Mean |
26.3 |
17.8 |
22.9 |
7.3 |
74.4 |
sd |
5.36 |
7.04 |
4.71 |
5.68 |
8.57 |
|
N |
10 |
10 |
10 |
10 |
10 |
|
2 – 250.000 |
Mean |
29.1 |
19.3 |
20.8 |
7.4 |
76.8 |
sd |
5.47 |
4.46 |
2.24 |
9.12 |
9.16 |
|
N |
10 |
10 |
10 |
10 |
10 |
|
3- 700.000 |
Mean |
28.6 |
20.4 |
21.1 |
12.3 |
83.0 |
sd |
6.12 |
3.33 |
6.42 |
4.65 |
9.41 |
|
N |
10 |
10 |
10 |
9 |
9 |
|
4 – 2000.000 |
Mean |
25.3 |
19.3 |
19.7 |
9.6 |
74.0 |
sd |
11.63 |
8.21 |
7.20 |
7.66 |
14.49 |
|
N |
10 |
10 |
10 |
10 |
10 |
a – animals were fasted overnight prior to blood collection during Week 4
Table 8. Mean food consumption and standing deviations (g/wk) – 28 day tox study in rats with XP2563 – males
Group and dose level (mg/kg) |
|
Mean food consumption and standing deviations (g/wk) |
Mean total food consumption and sd (g) |
|||
Week 1 |
Week 2 |
Week 3 |
Week 4a |
Weeks 1-4 |
||
1 – 0.000 |
Mean |
156.6 |
154.4 |
147.1 |
125.5 |
583.6 |
sd |
10.79 |
16.73 |
12.52 |
10.53 |
43.24 |
|
N |
10 |
10 |
10 |
10 |
10 |
|
2 – 250.000 |
Mean |
152.9 |
148.3 |
149.7 |
127.5 |
578.4 |
sd |
9.35 |
11.55 |
13.75 |
12.36 |
37.78 |
|
N |
10 |
10 |
10 |
10 |
10 |
|
3- 700.000 |
Mean |
156.0 |
160.3 |
152.4 |
126.0 |
594.7 |
sd |
9.01 |
9.62 |
16.14 |
11.05 |
33.86 |
|
N |
10 |
10 |
10 |
10 |
10 |
|
4 – 2000.000 |
Mean |
157.1 |
170.6 |
170.3 |
138.6 |
636.6* |
sd |
6.79 |
13.7 |
13.30 |
15.37 |
41.68 |
|
N |
10 |
10 |
10 |
10 |
10 |
Table 9. Mean food consumption and standing deviations (g/wk) – 28 day tox study in rats with XP2563 – females
Group and dose level (mg/kg) |
|
Mean food consumption and standing deviations (g/wk) |
Mean total food consumption and sd (g) |
|||
Week 1 |
Week 2 |
Week 3 |
Week 4a |
Weeks 1-4 |
||
1 – 0.000 |
Mean |
104.5 |
100.5 |
100.2 |
86.4 |
391.8 |
sd |
11.36 |
15.21 |
11.64 |
8.71 |
43.02 |
|
N |
10 |
10 |
10 |
10 |
10 |
|
2 – 250.000 |
Mean |
112.9 |
112.4 |
108.2 |
93.5 |
429.9 |
sd |
11.09 |
10.34 |
9.85 |
8.98 |
25.24 |
|
N |
10 |
10 |
9 |
10 |
9 |
|
3- 700.000 |
Mean |
112.9 |
114.8 |
121.3* |
104.6 |
454.0* |
sd |
10.48 |
12.00 |
19.02 |
28.89 |
64.72 |
|
N |
10 |
10 |
10 |
9 |
9 |
|
4 – 2000.000 |
Mean |
115.8 |
127.4* |
125.6* |
107.1* |
482.2* |
sd |
19.38 |
25.08 |
17.67 |
14.47 |
54.41 |
|
N |
10 |
9 |
10 |
10 |
9 |
a – animals were fasted overnight prior to blood collection during Week 4
* Significantly different from control values, p≤0.05
Table 10. Gross Pathological Incidence Summary |
||||||||
Organ and Key Word(s) or Phrase |
Number of Animals Affected |
|||||||
Males |
Females |
|||||||
Control |
250 mg/Kg/day |
700 mg/Kg/day |
2000 mg/Kg/day |
Control |
250 mg/Kg/day |
700 mg/Kg/day |
2000 mg/Kg/day |
|
Number |
10 |
10 |
10 |
10 |
10 |
10 |
9 |
10 |
Liver |
|
|
|
|
|
|
|
|
Number Examined |
10 |
10 |
10 |
10 |
10 |
10 |
9 |
10 |
Not Remarkable |
9 |
10 |
8 |
8 |
9 |
8 |
9 |
10 |
Pale Area |
1 |
0 |
1 |
1 |
0 |
0 |
0 |
0 |
Cyst |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
Pale |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
Raise Area |
0 |
0 |
1 |
1 |
0 |
0 |
0 |
0 |
Mass |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
|
||||||||
Kidney |
|
|
|
|
|
|
|
|
Number Examined |
10 |
10 |
10 |
10 |
10 |
10 |
9 |
10 |
Not Remarkable |
10 |
9 |
6 |
8 |
9 |
10 |
8 |
10 |
Cyst |
0 |
0 |
2 |
0 |
0 |
0 |
1 |
0 |
Pelvis Dilated |
0 |
0 |
1 |
1 |
0 |
0 |
0 |
0 |
Pale |
0 |
1 |
1 |
1 |
1 |
0 |
0 |
0 |
Table 11. Absolute Liver Weight, Mean Liver to Terminal Body Weight, and Mean Liver to Brain Weight Observations |
||||||||
Organ |
Males |
Females |
||||||
Control |
250 mg/Kg/day |
700 mg/Kg/day |
2000 mg/Kg/day |
Control |
250 mg/Kg/day |
700 mg/Kg/day |
2000 mg/Kg/day |
|
Number |
10 |
10 |
10 |
10 |
10 |
10 |
9 |
10 |
Absolute Liver Weight |
||||||||
Number in Group |
10 |
10 |
10 |
10 |
10 |
10 |
9 |
10 |
Mean |
11.49 |
11.22 |
11.97 |
12.70* |
7.46 |
7.94 |
7.94 |
8.93* |
Standard Deviation |
0.80 |
1.28 |
1.26 |
1.22 |
1.14 |
0.64 |
0.61 |
0.93 |
Liver to Terminal Body Weight |
||||||||
Number in Group |
10 |
10 |
10 |
10 |
10 |
10 |
9 |
10 |
Mean |
3.022 |
3.191 |
3.352* |
3.606* |
3.311 |
3.402 |
3.423 |
3.965* |
Standard Deviation |
0.137 |
0.222 |
0.209 |
0.199 |
0.405 |
0.228 |
0.203 |
0.387 |
Liver to Brain Weight |
||||||||
Number in Group |
10 |
10 |
10 |
10 |
10 |
10 |
9 |
10 |
Mean |
5.137 |
5.301 |
5.708 |
6.081* |
3.809 |
3.917 |
4.042 |
4.435* |
Standard Deviation |
0.496 |
0.592 |
0.706 |
0.485 |
0.561 |
0.301 |
0.401 |
0.502 |
* Significantly different from control p≤0.05
Applicant's summary and conclusion
- Conclusions:
- Oral administration of XP2563 to rats at a dose level of 2000 mg/kg/day for at least 28 days was associated with an increased incidence of urine stains and increases in absolute and relative liver weights. Increased food consumption was observed at the 700 and 2000 mg/kg/day dose levels. Under the conditions of this study, and dose level of 700 mg/kg/day elicited increases in food consumption only, and therefore is considered to be the no-observable-adverse-effect-level (NOAEL); the dose of 250 mg/kg/day did not elicit any consistent or apparent treatment-related changes; therefore, 250 mg/kg/day is considered to be the no-observable-effect-level (NOEL)
- Executive summary:
80 young adult rats were stratified by weight, randomly assigned to 1 of 4 groups (10 rats/sex/group), and dosed daily, by oral gavage, with XP2563 or corn oil at a dose volume of 10.0 ml/kg for at least 28 days. Group assignments were as follows: Group 1 (vehicle control), Group 2 (250 mg/kg/day), Group 3 (700 mg/kg/day), Group 4 (2000 mg/kg/day).
Clinical observations, periodic body weight and food consumption determinations, clinical pathology tests, ophthalmoscopic examinations, selected organ weights, and microscopic examination of selected tissues and organs were utilised to detect treatment-related effects.
There were no treatment-related deaths during the study. One Group 3 female (04934) died during Week 4 following scheduled blood collection; the death is attributable to the blood collection procedure and is considered to be accidental. No compound-related effects were noted in body weights, clinical pathology tests, ophthalmoscopic examinations, gross necropsy findings, or microscopic examination of selected tissues and organs.
Treatment-related clinical signs included an increased incidence of urine stains in Group 4 animals. In addition, pre- and postdose salivation was noted in several Group 4 animals. It is thought that the salivation was a direct result of the test material on the oral cavity due to the dosing technique and/or a conditioned response to the dosing procedure. Treatment-related increases in mean food consumption values were noted for Group 4 animals at Weeks 2 and 3; Group 4 females at Week 4; and Group 3 females at Week 3, total food consumption values (Weeks 1-4) were significantly higher than controls for Group 4 animals and Group 3 females. In addition, significant treatment-related increases were noted in the mean absolute and relative liver weight values for Group 4 animals. However, the changes in liver weight could not be correlated with any microscopic finding in this tissue or with any changes in clinical pathology parameters diagnostic of hepatic dysfunction.
In conclusion, oral administration of XP2563 to rats at a dose level of 2000 mg/kg/day for at least 28 days was associated with an increased incidence of urine stains and increases in absolute and relative liver weights. Increased food consumption was observed at the 700 and 2000 mg/kg/day dose levels. Under the conditions of this study, and dose level of 700 mg/kg/day elicited increases in food consumption only, and therefore is considered to be the no-observable-adverse-effect-level (NOAEL); the dose of 250 mg/kg/day did not elicit any consistent or apparent treatment-related changes; therefore, 250 mg/kg/day is considered to be the no-observable-effect-level (NOEL).
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