Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 232-615-7 | CAS number: 9001-57-4
- 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:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 29 August to 28 or 29 November 2001
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 002
- Report date:
- 2002
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- adopted: 21 September 1998
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3100 (90-Day Oral Toxicity in Rodents)
- Version / remarks:
- August 1998
- Qualifier:
- according to guideline
- Guideline:
- other: Commission Directive 87/302/EEC Part B:Methods for Determination of Toxicity: Subchronic Oral Toxicity Test: 90 day Repeated Oral Dose using Rodent species
- Version / remarks:
- 18 November 1987
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- Ministry of Health Welfare and Sports, Inspectorate for Health Protection, Commodities and Veterinary Public Health, GLP Compliance Monitoring unit, The Netherlands
- Limit test:
- no
Test material
- Reference substance name:
- Xylanase, endo-1,4-
- EC Number:
- 232-800-2
- EC Name:
- Xylanase, endo-1,4-
- Cas Number:
- 9025-57-4
- Molecular formula:
- Not applicable, see remarks.
- IUPAC Name:
- endo-1,4-beta-xylanase
1
Test animals
- Species:
- rat
- Strain:
- other: Hsd Cpb WU rats
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Toxicology Department, Rallis Research Center, Rallis India Limited, Bangalore, India
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 7 weeks
- Weight at study initiation: 208 ± 9.9 - 210 ± 9.7 (males), 153 ± 6.9 - 154 ± 7.3 (females)
- Housing: two rats per cage in in a sterilized suspended standard polypropylene rat cage (size: L 410 x W 282 x H 150 mm) with stainless steel mesh bottom and stainless steel top grill.
- Diet: rats/mice pellet food (Ssniff Spezialdiaten GmbH, Söest, Germany), ad libitum
- Water: deep borewell water passed through activated charcoal filter and exposed to UV rays in aquaguard on-line water filter-cum-purifier, ad libitum
- Acclimation period: 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 -24
- Humidity (%): 30 -70
- Air changes (per hr): 12-15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 24.08. 2001 To: 28./29.11.2001
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: double distilled water
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test substance was dissolved in double distilled water and was prepared daily. The quantities of test substance was not weighed instead volume was measured based on specific gravity (specific gravity 1 06). Approximate quantities of 2000 mg (1.89 mL), 8000 mg (7.55 mL) and 32000 mg (30.19 mL) of test substance were separately mixed and volume of each was made up to 50 mL with double distilled water to get the test substance concentrations of 40, 160 and 640 mg.
- Dose volume: 10 mL/kg bw/day
VEHICLE
- Amount of vehicle: varied, depending on the body weights of the rats recorded during different intervals of treatment period
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Test substance preparations were analysed for protein content by digesting the sample of the test item with concentrated sulphuric acid and total nitrogen content was estimated by Micro-Kjeldahl method on day 1, months 2 and 3 of the treatment period. The total protein content in the test item was calculated by multiplying total nitrogen content by a factor 6.25. The results showed mean concentrations of 34.40 ± 1.01, 135.50 ± 4.48 and 543.18 ± 17.33 mg of the test substance/mL as against the nominal concentrations of 40, 160 and 640 mg/mL.
- Duration of treatment / exposure:
- 90 days
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 400 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 600 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 6 400 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Rationale for animal assignment: Grouping was done based on body weight stratification and distribution. The rats procured for the study were weighed and grouped in to body weight ranges (selected ranges: 191 - 200 g, 201 - 210 g, 211 - 220 g for males and 141 - 150 g, 151 - 160 g for females). These body weight stratified rats were distributed to all the study groups in equal numbers. The rats with extreme body weights were not used for the study. Grouping was done on last day of acclimatization.
- Fasting period before blood sampling for clinical biochemistry: overnight
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once daily
- Cage side observations: clinical signs of toxicity (once a day), pre-terminal deaths (twice a day)
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to initiation of treatment and weekly thereafter
BODY WEIGHT: Yes
- Time schedule for examinations: shortly before test substance administration and weekly thereafter
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
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
WATER CONSUMPTION AND COMPOUND INTAKE: No
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: one day before start of the treatment and at the end of the treatment period prior to sacrifice
- Dose groups that were examined: all dose groups
HAEMATOLOGY: Yes
- Time schedule for collection of blood: two days prior to sacrifice (blood smear: differential leucocyte count), at the end of the treatment period (blood collection)
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked in table 1 were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the treatment period
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked in table 1 were examined.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: at the end of the treatment period (12/13th week of the treatment period)
- Dose groups that were examined: all dose groups
- Battery of functions tested: grip strength / motor activity / sensory activity / other: visual response, auditory response, proprioceptive response, righting reflex
IMMUNOLOGY: No
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (liver, adrenals, kidneys, testes, ovaries, epididymides, uterus, thymus, spleen, brain, heart were collected and weighed)
HISTOPATHOLOGY: Yes (please refer to table 2 in the "Any other information on materials and methods incl. tables" section). All the tissues from control and high dose group rats and gross lesions from low and mid dose group rats were subjected to detailed histopathological examination. The lungs of animals in the low and mid dose groups were subjected to histopathological examination for evidence of infection to provide an assessment of the health status of the animals. - Statistics:
- Body weights, cumulative net body weight gains, food consumption, laboratory investigations (haematology and clinical chemistry), organ weights and organ weight ratio data were compared by Bartlett's test for homogeneity of intra group variances. When the variances proved to be heterogeneous, the data were transformed using appropriate transformation. The data with homogeneous intra group variances were subjected to one-way analysis of variance (ANOVA - Snedecor and Cochran, 1987). Following ANOVA, When 'F' was found to be significant, Dunnett's pairwise comparison (Scheffe 1953) of means of treated groups with the mean of.the control group was done individually. Following a significant difference of a test group with the control group, the dose-response correlation was estimated by including the control and all the treated groups and tested by , t' test.
All analyses and comparisons are evaluated at 5% (P ≤ 0.05) level. Statistically significant differences (P ≤ 0.05) indicated by the a forementioned tests are designated by the superscripts as stated below:
+/- : Significantly higher(+)/lower(-) than the control group
d : Significant dose correlation
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- control and 400, 1600, 6400 mg/kg bw/day: An incidence of alopecia in a female at control group and incidence of hair thinning with hair regrowth in a female each at low and mid doses and in two females at high dose group were observed (incidental finding). For details please refer to table 6 in the " Any other information on results incl. tables" section.
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- 1600 mg/kg bw: in males and females higher food intake was observed in week 8, but was considered an incidental finding. In week 9, a lower food intake was observed in females, but considered an incidental finding.
6400 mg/kg bw/day: lower food intake was observed in week 9 in both sexes and in week 10 in males only. Since the food intake was not consistently affected the effect on food consumption was considered an incidental finding.
For details please refer to table 3 in the " Any other information on results incl. tables" section. - Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- 400 mg/kg bw/day: a higher level of mean corpuscular volume (MCV) was observed in females, but considered incidental as the changes were isolated incidences.
1600 mg/kg bw/day: in males isolated incidences of higher level of MCH, platelets, prothrombin time, neutrophils, and lower level of lymphocytes were observed. Since there were no effects observed at high dose level, the observed effects were considered incidental. In males significantly higher level of MCHC was observed, but considered incidental as the corresponding changes were not observed in RBC and Hb. In females, an incidence of higher level of mean corpuscular volume and a higher level of haematocrit were observed, but considered incidental as the changes were isolated incidences.
6400 mg/kg bw/day: in males a significantly higher level of MCHC was observed, but considered incidental as the corresponding changes were not observed in RBC and Hb. In females, higher neutrophil percentage with lower lymphocyte percentage were observed compared to control, but considered incidental since they were within the range of biological variation.
For details please refer to table 4 in the " Any other information on results incl. tables" section. - Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- 1600 mg/kg bw/day: the creatinine level was significantly higher in males. Although the increase was dose-correlated it was considered incidental as there were no corresponding histopathological changes in the kidneys.
6400 mg/kg bw/day: sodium, chloride and creatinine levels were significantly higher in males. Since the higher levels of chloride and sodium were within the normal range of variation, they were not considered to be treatment-related. Although the creatinine increase was dose-correlated it was considered incidental as there were no corresponding histopathological changes in the kidneys.
For details please refer to table 5 in the " Any other information on results incl. tables" section. - Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- 1600 mg/kg bw/day: a significant decrease in the absolute and relative weight of ovaries was observed in females, but was not considered treatment-related as it was not observed at high dose and there were no corresponding gross and histopathological changes.
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- control/1600 mg/kg bw/day:dilatation of pelvis in kidneys were considered incidental.
400 mg/kg bw/day: enlarged testes and heart were condisered incidental.
control, 400, 1600 and 6400 mg/kg bw/day: a few incidences of skin-alopecia were considered incidental.
6400 mg/kg bw/day: one male showed a white liver focus, this isolated finding was considered incidental.
For details please refer to table 6 in the " Any other information on results incl. tables" section. - Neuropathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- 400 mg/kg bw/day: in males lower grip strength values were observed in forelimbs, but considered incidental as these changes were isolated incidences.
1600 and 6400 mg/kg bw/day: significantly higher incidence of landing foot splay was observed in males and females, but considered incidental as there was no dose-dependency and no change in gait observed in these animals. In mid dose males higher grip strength values were observed in hindlimbs, but considered incidental as these changes were isolated incidences. In females, significantly higher grip strength values were observed in forelimbs at mid and high dose and hindlimbs at high dose, but were also considered incidental findings since dose correlation was not evident.
For details please refer to table 7 in the " Any other information on results incl. tables" section. - Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- control, 400, 1600 and 6400 mgkg bw/day: perivascular lymphocytic infiltration in the lung (minimal to mild) was observed at all doses in females and in males at all doses with exception of the low dose. The incidence of perivascular lymphocytic infiltration in the lungs was not considered treatment-related as there was no intergroup statistical significance. Blood vessel mineralisation (minimal) was observed in males and females at all doses, except in males of the control group. Since the highest indidence was observed in females of the control group this finding was considered incidental.
400 and 6400 mg/kg bw/day: mineralisation in kidneys was observed in one male of the low dose group and one female of the high dose group.
control, 1600 and 6400 mg/kg bw: basophilic tubules (minimal) were observed in kidneys of males.
control and 6400 mg/kg bw/day: hyaline droplets and proteinaceous material were observed in tubular epithelium (minimal to moderate) of the kidneys in males.
The changes in kidneys and other tissues were considered incidental as the incidences were similar or higher in control.
For a detailed overview of all findings and details please refer to table 8 in the " Any other information on results incl. tables" section. - Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- not examined
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 6 400 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no adverse effect observed at this dose level
Target system / organ toxicity
- Critical effects observed:
- no
Any other information on results incl. tables
Table 3: Cagewise average food intake (g/rat/day)
Group |
weeks |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
1 |
2 |
3 |
4 |
5 |
6 |
7 |
8 |
9 |
10 |
11 |
12 |
13 |
males |
||||||||||||||
control |
mean |
25.9 |
27.0 |
27.4 |
27.6 |
27.2 |
26.0 |
26.2 |
25.9 |
29.1 |
28.6 |
25.8 |
25.2 |
25.7 |
SD |
1.22 |
1.03 |
0.98 |
0.84 |
1.58 |
1.91 |
1.39 |
0.59 |
1.59 |
1.53 |
0.67 |
0.96 |
1.35 |
|
400 |
mean |
26.4 |
27. 1 |
27.4 |
27.9 |
26.7 |
26.4 |
26.0 |
26.2 |
27.5 |
27.5 |
25.8 |
25.8 |
26.6 |
SD |
0.50 |
0.69 |
0.98 |
1.49 |
0.94 |
1.07 |
0.76 |
0.31 |
0.99 |
1.52 |
0.57 |
0.91 |
0.64 |
|
1600 |
mean |
27.2 |
27.6 |
28.1 |
28.2 |
28.0 |
25.9 |
26. 9 |
27.6+ |
29.1 |
2 7.8 |
2 7.1 |
26.6 |
27.1 |
SD |
1.46 |
1.41 |
0.96 |
1.22 |
1.21 |
2.54 |
1.57 |
1.09 |
1.81 |
1.45 |
1.59 |
1.58 |
1.45 |
|
6400 |
mean |
26.9 |
27.5 |
27.7 |
28.0 |
27.8 |
26.0 |
24.7 |
25.1 |
24.2- |
25.9- |
25.9 |
25.4 |
25.7 |
SD |
0.83 |
1.12 |
0.75 |
1.30 |
1.01 |
1.19 |
1.26 |
1.19 |
0.78 |
0.95 |
1.34 |
1.64 |
1.05 |
|
females |
||||||||||||||
control |
mean |
17.9 |
18.0 |
18.3 |
19.2 |
19.7 |
19.9 |
18.8 |
17.8 |
22.3 |
20.6 |
17.4 |
17.6 |
17.6 |
SD |
0.71 |
0.63 |
1.00 |
0.87 |
0.90 |
1.57 |
1.21 |
1.25 |
1.34 |
1.38 |
0.98 |
1.69 |
0.79 |
|
400 |
mean |
17.3 |
17.8 |
18.1 |
18.6 |
19.3 |
19.0 |
18.2 |
18.0 |
21.3 |
20.0 |
16.7 |
18.0 |
18.1 |
SD |
0.58 |
0.74 |
0.73 |
0.98 |
1.22 |
1.08 |
0.78 |
0.73 |
1.48 |
1.28 |
0.78 |
0.90 |
0.85 |
|
1600 |
mean |
17.7 |
18.3 |
18.5 |
18.7 |
19.2 |
19.7 |
18.2 |
20.0+ |
18.1- |
19.1 |
17.8 |
18.5 |
18.7 |
SD |
1.07 |
1.08 |
0.79 |
0.89 |
1.21 |
1.51 |
1.15 |
1.63 |
0.62 |
0.86 |
1.36 |
1.33 |
1.47 |
|
6400 |
mean |
18.0 |
18.4 |
19.3 |
19.0 |
19.6 |
18.1 |
17.4 |
20.5 |
18.6- |
19.4 |
16.6 |
17.4 |
17.9 |
SD |
0.60 |
0.56 |
0.78 |
0.68 |
0.57 |
0.78 |
0.41 |
0,45 |
1.02 |
0.82 |
0.75 |
0.36 |
0.93 |
SD Standard deviation
+ significantly higher than the control group
- significantly lower than the control group
Table 4: Summary of haematological results
males |
|
||||||||||||||
|
|
WBC g/L |
RBC L/L |
Hb g/L |
Hct L/L |
MCV fl |
MCH pg |
MCHC g/L |
Plat g/L |
P.T. S |
Neut % |
Lymp% |
Eosi% |
Mono% |
Baso% |
control |
mean |
5.7 |
8.76 |
162 |
0.432 |
49.4 |
18.5 |
375 |
957 |
18.4 |
14.6 |
82.2 |
2.4 |
0.8 |
0.0 |
SD |
1.76 |
0.31 |
3.88 |
0.016 |
1.46 |
0.44 |
9.25 |
139.14 |
1.34 |
5.50 |
5.71 |
2.27 |
1.03 |
0.0 |
|
400 |
mean |
7.4 |
8.55 |
161 |
0.426 |
49.8 |
18.8 |
378 |
1002 |
19.5 |
1 6.0 |
78.3 |
4. 4 |
1.3 |
0.0 |
SD |
2.56 |
0. 39 |
6.53 |
0.021 |
1.61 |
0.34 |
11.89 |
99.08 |
2.08 |
5.01 |
6. l7 |
2.41 |
1.57 |
0.0 |
|
1600 |
mean |
8.6 |
8.40 |
163 |
0.417 |
49.7 |
19.4+ |
391+ |
1081+ |
20.5+ |
26.3+ |
71.1- |
2.1 |
0.5 |
0.0 |
SD |
2.64 |
0.39 |
8.09 |
0.022 |
1.02 |
0.49 |
11.73 |
71.41 |
1.85 |
9.93 |
10.54 |
1.91 |
0.53 |
0.0 |
|
6400 |
mean |
7.2 |
8.76 |
167 |
0.428 |
48.9 |
19.0 |
390+ |
943 |
18.2 |
19.7 |
75.8 |
4.0 |
0.5 |
0.0 |
SD |
2.21 |
0.46 |
5.74 |
0.025 |
1.17 |
0.74 |
13.42 |
82.13 |
1.71 |
7.30 |
7.76 |
2.75 |
0.53 |
0.0 |
|
females |
|
||||||||||||||
|
|
WBC g/L |
RBC L/L |
Hb g/L |
Hct L/L |
MCV fl |
MCH pg |
MCHC g/L |
Plat g/L |
P.T. S |
Neut % |
Lymp% |
Eosi% |
Mono% |
Baso% |
control |
mean |
4.9 |
7.91 |
159 |
0.397 |
50.2 |
20.1 |
400 |
1034 |
15.9 |
11.3 |
85.8 |
1.8 |
1.1 |
0.0 |
SD |
1.03 |
0.29 |
4.57 |
0.014 |
1.11 |
0.65 |
9.60 |
82.49 |
1.60 |
6.04 |
7.13 |
1.62 |
1.45 |
0.0 |
|
400 |
mean |
5.9 |
7.88 |
163 |
0.411 |
52.2+ |
20.7 |
397 |
974 |
15.0 |
18.2 |
78.8 |
1.7 |
1.3 |
0.0 |
SD |
1.45 |
0.31 |
5.10 |
0.018 |
1.64 |
0.80 |
12.83 |
116.11 |
1.03 |
8.72 |
8.72 |
1.34 |
0.67 |
0.0 |
|
1600 |
mean |
5.9 |
7.95 |
164 |
0.415+ |
52.2+ |
20.6 |
395 |
1018 |
15.3 |
15.5 |
80.2 |
2.5 |
1.8 |
0.0 |
SD |
1.88 |
0.26 |
5.25 |
0.013 |
1.37 |
0.59 |
11.74 |
88.66 |
1.29 |
8.54 |
9.75 |
1.84 |
1.62 |
0.0 |
|
6400 |
mean |
5.9 |
7.70 |
159 |
0.395 |
51.3 |
20.6 |
402 |
1006 |
16.1 |
22.3+ |
73.8- |
2.7 |
1.2 |
0.0 |
SD |
1.58 |
0.24 |
4.26 |
0.014 |
1.39 |
0.55 |
8.14 |
89.83 |
1.09 |
8.03 |
8.95 |
1.83 |
1.48 |
0.0 |
SD Standard deviation
+ Significantly higher than the control group
- Significantly lower than the control group
Table 5: Summary of clinical chemistry results
|
males |
|
|
||||||||||||||
|
|
Glu mmol/L |
BUN mmol/L
|
Urea mmol/L |
Tot. Pro g/L |
AST U/L |
ALT U/L |
GGT U/L |
Tot.Bil µmol/L |
Creat µmol/L |
Alb g/L |
Pi mmol/l |
Ca mmol/l |
Chol mmol/l |
Cl mmol/l |
Na mEq/L |
K mEq/L |
control |
mean |
8.28 |
2.45 |
5.25 |
58.4 |
81 |
38 |
3 |
3.60 |
77 |
32.43 |
1.97 |
2.67 |
2.23 |
108 |
143.2 |
4.12 |
SD |
0.72 |
0.20 |
0.42 |
1.62 |
11.83 |
4.88 |
2.07 |
0.62 |
3.74 |
1.05 |
0.17 |
0.05 |
0.42 |
0.92 |
1.64 |
0.24 |
|
400 |
mean |
8.79 |
2.73 |
5.85 |
59.7 |
88 |
36 |
4 |
5.19 |
82 |
33.22 |
2.13 |
2.72 |
2.29 |
109 |
143.9 |
4.10 |
SD |
0.90 |
0.33 |
0.70 |
3.00 |
35.36 |
4.58 |
5.09 |
2.46 |
7.07 |
1.97 |
0.18 |
0.06 |
0.46 |
1.51 |
1.84 |
0.36 |
|
1600 |
mean |
8.52 |
2.49 |
5.32 |
58.3 |
81 |
34 |
3 |
4.70 |
85+ |
31.49 |
2.04 |
2.69 |
2.22 |
108 |
143.5 |
4.24 |
SD |
0.71 |
0.38 |
0.82 |
2.37 |
11.29 |
8.91 |
4.80 |
2.05 |
7.02 |
1.06 |
0.23 |
0.04 |
0.36 |
1.75 |
1.45 |
0.24 |
|
6400 |
mean |
8.74 |
2.55 |
5.45 |
58.7 |
86 |
40 |
3 |
5.25 |
88d+ |
32.67 |
2.10 |
2.68 |
2.13 |
111+ |
145.5+ |
4.22 |
SD |
0.69 |
0.30 |
0.64 |
2.66 |
10.91 |
6.00 |
1.71 |
2.11 |
4.65 |
1.89 |
0.15 |
0.06 |
0.35 |
2.22 |
1.68 |
0.35 |
|
|
females |
|
|
||||||||||||||
|
|
Glu mmol/L |
BUN mmol/L
|
Urea mmol/L |
Tot. Pro g/L |
AST U/L |
|
GGT U/L |
Tot.Bil µmol/L |
Creat µmol/L |
Alb g/L |
Pi mmol/l |
Ca mmol/l |
Chol mmol/l |
Cl mmol/l |
Na mEq/L |
K mEq/L |
control |
mean |
6.99 |
2.64 |
5.64 |
61.7 |
93 |
35 |
3 |
4.08 |
75 |
34.23 |
1.79 |
2.68 |
1.92 |
108 |
144.1 |
4.04 |
SD |
0.42 |
0.26 |
0.56 |
2.87 |
15.77 |
8.71 |
2.13 |
0.82 |
6.00 |
2.15 |
0.32 |
0.06 |
0.22 |
2.01 |
2.73 |
0.37 |
|
400 |
mean |
7.12 |
3.01 |
6.45 |
63.0 |
100 |
34 |
4 |
4.59 |
80 |
34.36 |
1.81 |
2.68 |
1.91 |
108 |
146.1 |
3.95 |
SD |
0.79 |
0.80 |
1.72 |
3.08 |
18.06 |
6.84 |
4.03 |
1.99 |
8.14 |
1.90 |
0.34 |
0.08 |
0.20 |
2.42 |
2.43 |
0.39 |
|
1600 |
mean |
7.08 |
2.77 |
5.92 |
64.3 |
112 |
36 |
5 |
4.54 |
79 |
35.65 |
1.67 |
2.76 |
2.19 |
109 |
145.6 |
4.10 |
SD |
1.06 |
0.32 |
0.68 |
3.06 |
32.9 |
5.14 |
2.67 |
1.65 |
10.55 |
2.09 |
0.29 |
0.08 |
0.33 |
1.89 |
2.96 |
0,30 |
|
6400 |
mean |
7.15 |
2.95 |
6.31 |
63.8 |
101 |
39 |
3 |
3.66 |
83 |
34.69 |
1.82 |
2.71 |
2.05 |
109 |
145.5 |
3.98 |
SD |
0.56 |
0.56 |
1.20 |
2.21 |
14.70 |
7.95 |
0.74 |
0.44 |
4.20 |
2.35 |
0.22 |
0.06 |
0.38 |
2.04 |
3.40 |
0.46 |
SD Standard deviation
+ Significantly higher than the control group
- Significantly lower than the control group
d Dose-response
Table 6: Summary of necropsy findings
|
males |
|
|
|
females |
|
|
|
Dose (mg/kg bw/day) |
control |
400 |
1600 |
64000 |
control |
400 |
1600 |
64000 |
Number of animals examined |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
Number of animals showing gross pathology |
1 |
2 |
1 |
1 |
1 |
3 |
2 |
2 |
Number of animals showing external pathology |
0 |
0 |
0 |
0 |
1 |
1 |
1 |
2 |
Skin alopecia focal |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
Skin-hair thinning and regrowth focal |
0 |
0 |
0 |
0 |
0 |
1 |
1 |
2 |
Number of animals showing visceral organ pathology |
1 |
2 |
1 |
1 |
0 |
2 |
1 |
0 |
Liver-focus white |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
Kidney unilateral/bilateral pelvis dilated |
1 |
0 |
1 |
0 |
0 |
2 |
1 |
0 |
Testes unilateral enlarged, abcess |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
Heart enlarged |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
Table 7: Neurological examination results
Incidences - males |
||||||||||||||
Dose(mg/kg bw/day) |
control |
400 |
1600 |
6400 |
||||||||||
Number of rats |
10 |
10 |
10 |
10 |
||||||||||
1. Visual response |
||||||||||||||
Normal (present) |
10 |
10 |
10 |
10 |
||||||||||
Absent |
0 |
0 |
0 |
0 |
||||||||||
2. Auditory response |
||||||||||||||
Normal |
10 |
10 |
10 |
10 |
||||||||||
No (absent) |
0 |
0 |
0 |
0 |
||||||||||
Exaggerated |
0 |
0 |
0 |
0 |
||||||||||
3. Gait |
||||||||||||||
Normal |
10 |
10 |
10 |
10 |
||||||||||
Abnormal |
0 |
0 |
0 |
0 |
||||||||||
Ataxic |
0 |
0 |
0 |
0 |
||||||||||
4. Landing foot splay(cm) |
|
|
|
|
||||||||||
Mean± |
6.5 |
7.0 |
7.8+ |
8.8+ |
||||||||||
SD |
0.74 |
1.15 |
1.26 |
0.94 |
||||||||||
5. Righting reflex |
||||||||||||||
on back |
|
|
|
|
||||||||||
- Present |
10 |
10 |
10 |
10 |
||||||||||
- Slow |
0 |
0 |
0 |
0 |
||||||||||
- Absent |
0 |
0 |
0 |
0 |
||||||||||
dropped |
|
|
|
|
||||||||||
- Present |
10 |
10 |
10 |
10 |
||||||||||
- Slow |
0 |
0 |
0 |
0 |
||||||||||
- Absent |
0 |
0 |
0 |
0 |
||||||||||
6. Motor activity (Score) |
||||||||||||||
Mean ± |
719 |
666 |
658 |
744 |
||||||||||
SD |
122.26 |
92.56 |
191.67 |
201.92 |
||||||||||
7. Grip strength (g) |
||||||||||||||
Forelimb |
|
|
|
|
|
|||||||||
Mean±. |
1054 |
984 - |
1031 |
1089 |
|
|||||||||
SD |
90.94 |
115.48 |
97.17 |
68.78 |
|
|||||||||
Hindlimb |
|
|
|
|
|
|||||||||
Mean± |
636 |
638 |
712+ |
670 |
||||||||||
SD |
128.38 |
91 .43 |
79.40 |
140.45 |
||||||||||
Incidences - females |
|
|
|
|
|
|||||||||
Dose(mg/kg bw/day) |
control |
400 |
1600 |
6400 |
|
|||||||||
Number of rats |
10 |
10 |
10 |
10 |
|
|||||||||
1. Visual response |
|
|
|
|
|
|||||||||
Normal (present) |
10 |
10 |
10 |
10 |
|
|||||||||
Absent |
0 |
0 |
0 |
0 |
|
|||||||||
2. Auditory response |
|
|
|
|
|
|||||||||
Normal |
10 |
10 |
10 |
10 |
|
|||||||||
No (absent) |
0 |
0 |
0 |
0 |
|
|||||||||
Exaggerated |
0 |
0 |
0 |
0 |
|
|||||||||
3. Gait |
|
|
|
|
|
|||||||||
Normal |
10 |
10 |
10 |
10 |
|
|||||||||
Abnormal |
0 |
0 |
0 |
0 |
|
|||||||||
Ataxic |
0 |
0 |
0 |
0 |
|
|||||||||
4. Landing foot splay (cm) |
|
|
|
|
|
|||||||||
Mean± |
6.1 |
6.1 |
7.8+ |
1.9+ |
|
|||||||||
SD |
0.85 |
1.10 |
0.95 |
1.53 |
|
|||||||||
5. Righting reflex |
|
|
|
|
|
|||||||||
on back |
|
|
|
|
|
|||||||||
- Present |
10 |
10 |
10 |
10 |
|
|||||||||
- Slow |
0 |
0 |
0 |
0 |
|
|||||||||
- Absent |
0 |
0 |
0 |
0 |
|
|||||||||
dropped |
|
|
|
|
|
|||||||||
- Present |
10 |
10 |
10 |
10 |
|
|||||||||
- Slow |
0 |
0 |
0 |
0 |
|
|||||||||
- Absent |
0 |
0 |
0 |
0 |
|
|||||||||
6. Motor activity (Score) |
|
|
|
|
|
|||||||||
Mean ± |
703 |
847 |
757 |
825 |
|
|||||||||
SD |
200.42 |
107.87 |
149.62 |
139.75 |
|
|||||||||
7. Grip strength (g) |
|
|
|
|
|
|||||||||
Forelimb |
|
|
|
|
|
|||||||||
Mean ± |
936 |
978 |
1067+ |
1034+ |
|
|||||||||
SD |
127.15 |
135.58 |
89.40 |
96.54 |
|
|||||||||
Hindlimb |
|
|
|
|
|
|||||||||
Mean± |
575 |
611 |
619 |
664+ |
||||||||||
SD |
85.55 |
98.63 |
97.57 |
102. 05 |
||||||||||
SD Standard deviation
+ Significantly higher than the control group
- Significantly lower than the control group
Table 8: Summary of selected Histopathological findings
|
males |
|
|
|
females |
|
|
|
Dose (mg/kg bw/day) |
control |
400 |
1600 |
64000 |
control |
400 |
1600 |
64000 |
Number of animals examined |
10 |
10/- |
10/- |
10 |
10 |
10/- |
10/- |
10 |
Stomach- cystic glands |
0 |
- |
- |
1 |
0 |
- |
- |
0 |
Colon- parasites |
0 |
- |
- |
1 |
0 |
- |
- |
0 |
Pancreas |
|
|
|
|
|
- |
- |
|
- Atrophy |
1 |
- |
- |
0 |
0 |
- |
- |
0 |
- Adipocytes |
1 |
- |
- |
0 |
0 |
- |
- |
0 |
- Increased cytoplasmic eosinopholia |
0 |
- |
- |
0 |
1 |
- |
- |
0 |
Liver |
|
|
|
|
|
|
|
|
- Haemorrhage |
0 |
- |
- |
1 |
0 |
- |
- |
0 |
- Lymphocytic infiltration |
1 |
- |
- |
0 |
0 |
- |
- |
0 |
- Necrosis |
0 |
- |
- |
2 |
0 |
- |
- |
0 |
- Necrotic foci |
0 |
- |
- |
1 |
0 |
- |
- |
0 |
Lungs |
|
|
|
|
|
|
|
|
- Perivascular lymphocytic infiltration |
1 |
0 |
1 |
3 |
1 |
1 |
4 |
3 |
- Granulocytic infiltration |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- Mineralisation blood vessels |
0 |
1 |
1 |
2 |
3 |
2 |
1 |
2 |
- Chronic pneumonia |
1 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
- Chronic pneumonic foci |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
- Pneumonic foci |
0 |
0 |
1 |
1 |
0 |
0 |
1 |
2 |
- Osseous metaplasia |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
Heart- dilatation |
0 |
1 |
- |
0 |
0 |
- |
- |
0 |
Kidneys |
|
|
|
|
|
|
|
|
- Mineralisation |
0 |
- |
1 |
0 |
0 |
0 |
0 |
1 |
- Dilatation of pelvis |
2 |
- |
1 |
0 |
0 |
2 |
1 |
0 |
- Basophilic tubules |
4 |
- |
1 |
2 |
0 |
0 |
0 |
0 |
- Proteinaceous material in tubules |
2 |
- |
0 |
2 |
0 |
0 |
0 |
0 |
- Hyaline droplets-tubular epithelium |
7 |
- |
0 |
7 |
0 |
0 |
0 |
0 |
Testes |
|
|
|
|
|
|
|
|
- Atrophy-seminiferous |
0 |
1 |
- |
0 |
/ |
/ |
/ |
/ |
- Spermatic granuloma |
0 |
1 |
- |
0 |
/ |
/ |
/ |
/ |
Epididymis- Lymphocytic infiltration |
1 |
- |
- |
0 |
/ |
/ |
/ |
/ |
Ovaries- Follicular cyst(s) |
/ |
/ |
/ |
/ |
0 |
- |
- |
1 |
Uterus- Dilatation |
/ |
/ |
/ |
/ |
3 |
- |
- |
2 |
Thyroids |
|
|
|
|
|
|
|
|
- Ultimobronchial cyst |
1 |
- |
- |
1 |
0 |
- |
- |
0 |
- Ectopic thymus |
1 |
- |
- |
1 |
0 |
- |
- |
1 |
- Accessory parathyroid |
0 |
- |
- |
1 |
0 |
- |
- |
0 |
Parathyroids– Connective tissue proliferation |
1 |
- |
- |
0 |
0 |
- |
- |
0 |
Pituitary |
|
|
|
|
|
|
|
|
- Cysts(s) |
1 |
- |
- |
1 |
0 |
- |
- |
0 |
- Dilated Rathke’s cleft |
4 |
- |
- |
5 |
2 |
- |
- |
2 |
- Eosinopohilic vacuoles |
0 |
- |
- |
1 |
0 |
- |
- |
0 |
Adrenals– Accessory adrenal |
0 |
- |
- |
0 |
1 |
- |
- |
1 |
Skin |
|
|
|
|
|
|
|
|
- Epidermal hyperplasia |
0 |
- |
- |
1 |
1 |
0 |
0 |
0 |
- Necrotising dermatitis |
0 |
- |
- |
0 |
0 |
0 |
0 |
1 |
- Parakeratosis |
0 |
- |
- |
0 |
1 |
0 |
0 |
1 |
- Epithelial hyperplasia |
1 |
- |
- |
0 |
0 |
0 |
0 |
0 |
Thymus |
|
|
|
|
|
|
|
|
- Hemorrhage |
2 |
- |
- |
0 |
2 |
- |
- |
1 |
- Epithelial hyperplasia |
0 |
- |
- |
0 |
0 |
- |
- |
1 |
Mammary gland |
|
|
|
|
|
|
|
|
- Hyperplasia |
/ |
/ |
/ |
/ |
0 |
- |
- |
1 |
- Lymphocytic infiltration/ |
/ |
/ |
/ |
/ |
0 |
- |
- |
1 |
Rectum- Parasites |
1 |
- |
- |
1 |
1 |
- |
- |
0 |
Applicant's summary and conclusion
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.