Diiron titanium pentaoxide

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

This oral toxicity study was performed as a limit test. The study was not performed under GLP regulations.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1982

Report date:

1982

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Version / remarks:

1981

Deviations:

yes

Remarks:

ophthalmological examinations have not been performed; Functional : observation battery (FOB) was not performed;

GLP compliance:

no

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Diiron titanium pentaoxide

EC Number:

234-679-1

EC Name:

Diiron titanium pentaoxide

Cas Number:

12023-27-7

Molecular formula:

Fe2O5Ti

IUPAC Name:

titanium(4+) diiron(3+) pentaoxidandiide

Test material form:

solid: particulate/powder

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: mean males: 183 g (157-212); mean females 162 g (145-184)
- Housing: individual housing of animals in Makrolon cages type III
- Diet: ad libitum, Altromin Standard Diet
- Water: ad libitum), tap water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-31
- Humidity (%): 40 - 75
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: feed

Details on oral exposure:

DIET PREPARATION
The test material was incorporated into feed pellets (Altromin standard diet TPF No. 1324) Content of test material in feed: 5% (w/w)

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

90 days

Frequency of treatment:

7 days/week

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

50 000 ppm

Remarks:

nominal in diet

Doses / concentrations 2

Dose / conc.:

6 750 ppm

Remarks:

based on diiron titanium pentaoxide content

No. of animals per sex per dose:

feed control: 40 animals/sex
placebo group (mica): 20 animals/sex
treatment group: 20 animals/sex

Control animals:

yes

yes, concurrent no treatment

Details on study design:

Groups of 40 rats (20 males and 20 females) received the pigments incorporated into feed pellets at the highest internationally recommended concentration of 50,000 ppm, for the males and females, respectively. One placebo group (20 males and 20 females) received feed pellets containing mica only at 50,000 ppm. In addition, a control group consisting of 80 rats (40 males and 40 females) were fed exclusively with standard commercial feed pellets. Treatment was for 3 months followed by a 2-months recovery period. Hematology, clinical chemistry and urinalysis were performed on half of the animals in each group, 4 and 12 weeks after start of the study and once during the follow-up phase (20 weeks after start of the study). Half of the animals were killed at the end of the 2-months recovery phase. All animals were subjected to gross pathological and histopathological examinations.

Positive control:

No

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION AND COMPOUND INTAKE: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: weeks 4 and 12 (during treatment) and at the end of the recovery period (week 20)
- Animals fasted: Yes
- How many animals: half of each group
- Parameters checked: hemoglobin, red blood cells, reticulocyte count, white blood cells, differential count in %

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: weeks 4 and 12 (during treatment) and at the end of the recovery period (week 20)
- Animals fasted: Yes
- How many animals: half of each group
- Parameters checked: sodium, potassium, calcium, inorganic phosphorus, glucose, urea, creatinine, bilirubin, protein, cholesterol, triglceride, glutamic pyruvic transaminase, alkaline phosphatase

URINALYSIS: Yes
- Time schedule for collection of urine: weeks 4 and 12 (during treatment) and at the end of the recovery period (week 20)
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked: pH, protein, glucose, urobilinogen

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No

Sacrifice and pathology:

Animals were sacrificed under CO2 anesthesia by incision of the abdominal vessels and exsanguination.

GROSS PATHOLOGY: Yes
Organ weights: Heart, liver, kidneys, spleen, thymus, testes/ovaries, prostate/uterus, adrenals, thyroids, pituitary, brain, eyes

HISTOPATHOLOGY: Yes
Organ weights: Heart, liver, kidneys, spleen, thymus, testes/ovaries, prostate/uterus, adrenals, thyroids, pituitary, brain, eyes

Statistics:

Dunnett's multiple t-test
Bartlett's test

Results and discussion

Results of examinations

Clinical signs:

effects observed, non-treatment-related

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

higher in all pigments and placebo control (mica) group. Can be explained by the 5% foreign material in food.

Food efficiency:

no effects observed

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

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:

effects observed, non-treatment-related

Histopathological findings: neoplastic:

not examined

Effect levels

1

Key result

Dose descriptor:

NOAEL

Effect level:

50 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: highest dose tested

2

Key result

Dose descriptor:

NOAEL

Effect level:

> 550 mg/kg bw/day (actual dose received)

Based on:

other: content of diiron titanium pentaoxide in test material

Sex:

male/female

Basis for effect level:

other: highest dose tested

Remarks on result:

other: Based on the concentration of diiron titanium pentaoxide (13.5%) and the food consumption the mean daily intake of diiron titanium pentaoxide can be calculated as 534 and 603 mg/kg bw/d for males and females, respectively.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

No adverse effects have been observed in rats treated orally with diiron titanium pentaoxide as a component of pearlescent pigments for a time period of 90 days. Based on (i) a concentration of the pearlescent pigment in the food of 50000 ppm (ii) the concentration of diiron tiitanium pentaoxide in the pearlescent pigments and (iii) the food consumption of the rats, a NOAEL of > 550 mg/kg bw/day could be derived for diiron titanium pentaoxide.

Executive summary:

A subchronic feeding toxicity study equal to OECD TG 408 was performed to investigate the toxicity of different mica-based pearlescent pigments.

Groups of 40 rats (20 males and 20 females) received the pigments incorporated into feed pellets at the highest internationally recommended concentration of 50,000 ppm, for the males and females, respectively. One placebo group (20 males and 20 females) received feed pellets containing mica only at 50,000 ppm. In addition, a control group consisting of 80 rats (40 males and 40 females) were fed exclusively with standard commercial feed pellets. Treatment was for 3 months followed by a 2-months recovery period. Hematology, clinical chemistry and urinalysis were performed on half of the animals in each group, 4 and 12 weeks after start of the study and once during the follow-up phase (20 weeks after start of the study. Half of the animals were killed at the end of the 2-months recovery phase. All animals were subjected to gross pathological and histopathological examinations.

No treatment related mortalities occurred during the study. A slight increase of body weights was observed in females receiving the second pigment compared to the feed control group 1. Food intake was temporarily or permanently increased in males and females of all groups treated with mica or mica-based pigments due to the 5% mineralic content in the diet. No treatment-related effects were observed in haematology or clinical chemistry. Gross pathology revealed a discoloration of the gut content in the animals of the treatment groups which was not observed in the recovery animals and which is not considered to be an adverse effect. All histopathological findings encountered were considered to have arisen spontaneously. In conclusion, no adverse effects were observed in rats treated with mica pigments at 50000 ppm. Thus, based on the results of this study the NOAEL for Fe2TiO5-containing pigments exceeds 50,000 ppm corresponding to 3,952 and 4,466 mg/kg bw/day.

Based on the concentration of Diiron titanium pentaoxide (13.5%) in this pigment and the food consumption during the subchronic toxicity study the mean daily intake of Diiron titanium pentaoxide can be calculated as 534 mg/kg bw/day and 603 mg/kg bw/day for male and female rats, respectively. As these mean daily intakes of diiron titanium pentaoxide by rats over a period of 90 days did not induce any adverse effects, a NOAEL of > 550 mg/kg bw/day can be deduced for Diiron titanium pentaoxide on the basis of this study.