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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
repeated dose toxicity: oral, other
Remarks:
OECD Guideline 407
Type of information:
experimental study
Adequacy of study:
key study
Study period:
25th August 2008 - 19th March, 2009
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2009
Report date:
2009

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Testing Methods Concerning New Chemical Substances (Notification No. 1121002, PFSB, MHLW; No. 2 of November 13, 2003, MIB, METI; No. 031121002, EPB, MOE; dated November 21, 2003)
Deviations:
no
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Dialuminium titanium pentaoxide
EC Number:
234-456-9
EC Name:
Dialuminium titanium pentaoxide
Cas Number:
12004-39-6
Molecular formula:
Al2O5Ti
IUPAC Name:
Dialuminum titanium pentaoxide
Test material form:
solid: particulate/powder
Details on test material:
- Name of test material (as cited in study report): Aluminium titanium oxide
- Physical state: White powdery solid

Test animals

Species:
rat
Strain:
other: Crl:CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Japan, Inc., 3-17-6, Shinyokohama, Kouhoku-ku, Yokohama-shi, Kanagawa 222-0033, Japan
- Age at study initiation: 6-week-old
- Weight at study initiation: 237.2-247.9 g (males); 179.4-183.8 g (females)
- Fasting period before study: not reported
- Housing: Individually housed in stainless steel cages (W226 × D346 × H198 mm).
- Diet (e.g. ad libitum): Pellet diet (CRF-1, Oriental Yeast Co., Ltd.) ad libitum.
- Water (e.g. ad libitum): Well water with 2ppm sodium hypochlorite added, ad libitum.
- Acclimation period: 13 days for males and 14 days for females

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22° to 25°C)
- Humidity (%): 55%
- Air changes (per hr): 10 to 20 times per hour
- Photoperiod (hrs dark / hrs light): 12-hour (7:00 to 19:00) illumination

IN-LIFE DATES: From: 4th September 2008 To: 31st October 2008.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.5 w/v% Methyl cellulose solution
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
The dosing formulations were administered with a stomach tube and a disposable syringe. The dosing formulations were stirred with a magnetic stirrer before and during administration under confirmation of homogeneous suspension.

The required amount of the test substance was weighed precisely and transferred to a mortar. A small amount of the vehicle was added to the test substance and suspended with a pestle. After confirmation of homogeneous suspension, the mixture was transferred to a measuring cylinder. The mortar was washed out with a small amount of the vehicle several times and agitated with a pestle, and then washings were transferred to the measuring cylinder. This operation was repeated several times to wash out the mortar completely. The vehicle was added to the measuring cylinder and the suspension was precisely made up to the required volume. The dosing formulation was mixed by turning the measuring cylinder upside down, and then transferred to a beaker. The dosing formulation was taken into brown vessels while being stirred with a magnetic stirrer.

The preparation was conducted once a week.

VEHICLE
- Concentration in vehicle: 10, 30, 100 mg/mL
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dose levels were confirmed gravimetrically; dosing suspension stability and homogeneity were also confirmed.
Duration of treatment / exposure:
28 days. After the administration period, the animals in the control and high-dose groups were subjected to a 2-week (14-day) recovery period.
Frequency of treatment:
Test animals were treated once daily.
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
30 rats per sex were used in total:
Control: 10 male and 10 female (5 of each sex used for recovery study)
Low dose: 5 male and 5 female
Middle dose: 5 male and 5 female
High dose: 10 male and 10 female (5 of each sex used for recovery study).
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: A preliminary 7-day oral dose toxicity study of aluminium titanium oxide was conducted in which no significant toxicity relating to the test substance administration was noted even in the 1000 mg/kg bw/d group. Therefore, 1000 mg/kg bw/d, the maximum dose level able to be tested in a repeated dose toxicity study according to the guideline of this study, was selected for the high dose level in this study, and 300 and 100 mg/kg bw/d were selected as the middle and low dose levels, respectively, with a common ratio about 3 from the high dose level.

This method of administration is commonly used for oral administration in rats. The dose levels were set at 100, 300, and 1000 mg/kg bw/d, with a dose volume of 10 mL/kg bw. The control animals received the same volume of the vehicle. The individual dose volume was calculated based on the most recent body weight.
Positive control:
Not required for this study type

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Before the start of administration and once a week during the administration period in the afternoon.
- Cage side observations included: posture, convulsions, stereotypies and/or bizarre behaviours, and tremors.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Clinical signs and mortality were observed twice daily (before and after administration [2 to 4 hours after administration]) during the administration period and once a day during the recovery period.

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were measured once a week throughout administration and recovery periods. Moreover, body weights were also measured at the end of the administration and recovery periods. The final body weight was measured for the scheduled necropsy animals.

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, Food consumption was measured once a week throughout the administration and recovery periods. Moreover, food consumption was also measured at the end of the administration and recovery periods.
- 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

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood sampling was conducted at necropsy after the end of the administration and recovery periods.
- Anaesthetic used for blood collection: Yes (identity), intraperitoneal injection of sodium pentobarbital at 30 mg/kg
- Animals fasted: No data
- How many animals: All animals
- Parameters checked included: Leukocyte, erythrocyte, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, reticulocyte ratio, platelets, differential luekocyte, prothrombin time and activated partial thromboplastin time.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Blood sampling was conducted at necropsy after the end of the administration and recovery periods.
- Animals fasted: No data
- How many animals: All animals
- Parameters checked included: Total protein, albumin, albumin/globulin ratio, total bilirubin, GOT, GPT, glutamyl transpeptidase, alkaline phosphatase, total cholesterol, triglycerides, phospholipids, glucose, blood urea nitrogen, creatinine, inorganic phosphorus, calcium, sodium, potassium, chloride.

URINALYSIS: Yes
- Time schedule for collection of urine: Conducted in week 4 and collected successively for about 24 hours.
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Food was given after the fresh urine collection, and water was given during the urine collection.
- Parameters checked included: Volume, colour, osmotic pressure, sodium, potasium, chloride, pH, protein, glucose, ketone body, bilrubin, occult blood, urobilinogen and urine sediments, including epithelial cells, erythrocytes, leukocytes, casts and noncellular sediment.

NEUROBEHAVIOURAL EXAMINATION: No

OTHER:
Organ weights: After necropsy at the end of the administration and recovery periods, the following organs were weighed (absolute weight) and the ratio of organ weight to the body weight (relative weight) was calculated on the basis of the body weight measured on the day of necropsy. Examined organs included: brain, heart, thymus, liver, spleen, kidneys, adrenals, testes, epididymides and ovaries.

Histopathology: Organs and tissues examined included: Cerebrum, Thymus, Prostate, Cerebellum, Liver, Epididymis, Medulla oblongata/Pons, Pancreas, Testis,Pituitary, Spleen, Ovary, Spinal cord (thoracic), Trachea Urinary bladder, Eye, Kidney, Uterus, Optic nerves, Adrenal, Vagina, Harderian gland, Esophagus, Femur, Submaxillary lymph node, Stomach, Bone marrow (femur), Submaxillary gland, Duodenum, Sternum, Sublingual gland, Jejunum, Bone marrow (sternum), Parotid gland, Ileum (with Peyer's patch), Mammary gland, Thyroid, Cecum, Skin (lower abdominal region), Parathyroid, Colon, Aorta (thoracic region), Tongue, Rectum, Sciatic nerve, Lung (with bronchi), Mesenteric lymph node, M. biceps femoris, Heart, Seminal vesicle.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
At the end of the administration and recovery periods, animals were euthanized by exsanguination after blood sampling. All organs and tissues were immediately examined macroscopically.
Other examinations:
Grip strength
The grip strength was measured in Week 4 in the afternoon. As a result of the measurement in Week 4, since a significant high value for forelimb grip strength was seen in males of the high dose group, the measurement for all recovery males was conducted in the afternoon in Recovery Week 2. Grip strength was determined twice for both the forelimbs and hindlimbs using a grip dynamometer and the mean was calculated.

Motor activity
The motor activity was examined in Week 4 in the afternoon. As a result of the measurement in Week 4, since no change related to test substance administration was observed in Week 4, measurement in Recovery Week 2 was not conducted. Motor activity was recorded individually using a motor activity-measuring device to measure motor activity individually in cages. Data were measured every 10 minutes from the start of the measurement, while a total of 1 hour was measured.

Sensory reactivity to stimuli
For all animals, examination of sensory reactivity to stimuli was conducted in week 4 in the afternoon. Since no change related to test substance administration was observed in Week 4, examination in Recovery Week 2 was not conducted. Auditory, visual, touch, pain, and righting reflex and pupil responses were observed in the field or on the working table.
Statistics:
Bartlett's test was performed to compare the variances among groups (significant level: p<0.05). If the groups of data were homogeneous, Dunnett's multiple
comparison test was performed relative to the control group. If the groups of data were heterogeneous, Steel's multiple comparison test was performed relative to the control group.

For detailed clinical observation (except for defecation and urination in observation on the open field) and examination of sensory reactivity to stimuli, Wilcoxon rank-sum test was conducted.

For urinalysis (the result of urinary test strip, urine color and urine sediment), grades were converted to numerical values. The numerical values of each group were compared with those of the control group by Steel's multiple comparison test.

For necropsy, Fisher’s exact test was used. For the histopathological examination, grades were converted to numerical values. The numerical values of each group were compared with those of the control group by Mann-Whitney's U test.
In either case, the two-tailed test was used and levels of 1% and 5% were considered significant.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Any changes observed were not considered to be treatment related as they were not dose-dependent.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
Any changes observed were not considered to be treatment related as they were not dose-dependent.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Any changes observed were not considered to be treatment related as they were not dose-dependent.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
low value of the urine volume and a high value of the osmotic pressure were seen in females of the 300 mg/kg group, and a high value of the osmotic pressure was seen in females of the 1000 mg/kg group
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
No clinical signs or mortalities were observed in any of the test animals during the administration or recovery periods.

BODY WEIGHT AND WEIGHT GAIN
Throughout the administration and recovery periods, each test substance group indicated comparable body weight changes to the control group.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Throughout the administration and recovery periods, no change related to the test substance administration was seen in either sex of any test substance group. Although a significantly low value was seen in females of the 1000 mg/kg group on Recovery Day 14, this change was judged to be unrelated to the test substance administration, since it was not seen during the administration period.

HAEMATOLOGY
In the examination in Week 4, no change related to the test substance administration was seen in either sex of any test substance group. Although prolongation of PT was seen in females of the 300 mg/kg group, this change was judged to be unrelated to the test substance administration, since it was not dose-dependent.
In the examination in Recovery Week 2, no change related to the test substance administration was seen in either sex of any test substance group. Although shortening of APTT was seen in females of the 1000 mg/kg group, this change was judged to be unrelated to the test substance administration, since it was not seen at the end of the administration period.

CLINICAL CHEMISTRY
In the examination in Week 4, no change related to the test substance administration was seen in either sex of any test substance group. Although a low value of the glucose was seen in females of the 100 mg/kg group, this change was judged to be unrelated to the test substance administration, since it was not dose-dependent.
In the examination in Recovery Week 2, no change related to the test substance administration was seen in either sex of the 1000 mg/kg.

URINALYSIS
In the examination in Week 4, a low value of the urine volume and a high value of the osmotic pressure were seen in females of the 300 mg/kg group, and a high value of the osmotic pressure was seen in females of the 1000 mg/kg group. In the examination in Recovery Week 2, no significant difference was seen in any item in females of the 1000 mg/kg group.

ORGAN WEIGHTS
In the examination in Week 4, no change related to the test substance administration was seen in either sex of any test substance group.
In the examination in Recovery Week 2, no change related to the test substance administration was seen in either sex of any test substance group. Although high absolute heart and kidney (right) weights were seen in males of the 1000 mg/kg group, these changes were judged to be unrelated to the test substance administration, since these were not dose-dependent.

GROSS PATHOLOGY
In the examination in Week 4, no abnormality was seen in any animals.
In the examination in Recovery Week 2, unilateral hypertrophy of the testis was noted in 1 male each of the control and 1000 mg/kg groups. However, as this change was not noted at the end of the administration period, it was judged to be unrelated to the test substance administration.

HISTOPATHOLOGY: NON-NEOPLASTIC
In the examination in Week 4, no change related to the test substance administration was seen in either sex of any test substance group.
Although mineralization in the pulmonary artery in 1 male and female each and ectopic thymic tissue in the thyroid gland in 1 male were noted in the 1000 mg/kg group, these are generally observed changed in normal animals, and the incidence was low as only in 1 animal each, these changes were judged to be not related to the test substance administration. Moreover, although focal hemorrhage in the pulmonary alveoli and lymphocytic infiltration in the prostate gland were noted in 1 male each of the control and 1000 mg/kg groups, there was no difference in the degree of the findings and the incidence was low, these were judged to be not related to the test substance administration.
As the changes noted only in the control group, mononuclear cell infiltration in the liver was noted in 2 males, and lymphocyte infiltration in the parotid gland, pancreas, and kidneys, osseous metaplasia in the lung, basophilic renal tubules and protein cast in the kidney, ultimobranchial remnant in the thyroid gland were noted in 1 male each.
Although the specimen of the parathyroid gland could not be prepared in 1 male of the control group, it could be examined in the other animals; and therefore, it was considered to have no effect on the evaluation of the toxicity.

FUNCTIONAL OBSERVATION BATTERY
Detailed clinical observation did not reveal any effects of treatment throughout the administration period. Assessment of sensory reactivity to stimuli at Week 4 did not show any effects of treatment. A significantly higher forelimb grip-strength was seen in males at 1000 mg/kg bw/d at Week 4 but the effect is not considered to be treatment-related in isolation; other parameters were unaffected by treatment and the measured value was within thenormal background range. A similar effect was not seen in Recovery Week 2. Motor activity measurement at Week 4 showed a significantly low value for females at 300 mg/kg bw/d for the 30-40 minute period only. This finding is not considered to be related to treatment in the absence of a dose-response relationship.

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects of treatment were observed at the highest dose level of 1000 mg/kg bw/d

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
No effects of treatment were observed in this study at the limit dose level of 1000 mg/kg bw/d.
Executive summary:

In a study conducted to determine the oral toxicity of aluminium titanium oxide, the test material was administered repeatedly to male and female Crl:CD(SD) rats at doses of 0 (control), 100, 300 and 1000 mg/kg bw/d for 28 days. The test substance was administered by oral gavage, in a dosing volume of 10mL/kg, with a vehicle (0.5% methylcellulose solution) given to the control group. To determine the reversibility of the toxic effects in the control and 1000 mg/kg bw/d groups, a 14 -day recovery period was included.

The toxicity was evaluated based on the clinical signs, functional observation battery, body weights, food consumption, urinalysis, hematology, blood biochemistry, necropsy, organ weights, and histopathology.

As no test substance-related changes were observed in any of the test parameters, the NOAEL is considered to be 1000 mg/kg bw/d in both males and females under the conditions of this study.