Titanium tetraisopropanolate

Carcinogenicity

Description of key information

Due the lack of carcinogenic potential of the degradation products of titanium tetraisopropanolate, there is no indication of carcinogenicity of this substance.

Key value for chemical safety assessment

Carcinogenicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: inhalation

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

not reported

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Data obtained from peer-reviewed publication. Read-across justification: The substance is hydrolytically unstable. When it comes in contact with water or moisture complete hydrolysis will take place with no significant reaction products other than alcohol and hydrated titanium dioxide. This rapid hydrolysis (hydrolysis half-life < 3 minutes to < 2 hours) is the driving force for the toxicokinetics of target substance. Because of the rapid hydrolysis, the influence of the mode of administration through inhalation, dermal and oral is related to the hazardous degradation product (alcohol) released from the target substance. The identification of degradation products from the hydrolysis study conducted for the target substance verifies that there are no impurities in the alcohol released from the target substance, which might change the hazardous properties of the target substance compared to the properties of the pure alcohol. As there is a mechanistic reasoning to the read-across, the unnecessary animal testing is avoided by using the read-across data from the degradation product (relevant alcohol) to evaluate irritation, sensitization and the short term and long-term toxicological effects and mutagenicity of the target substance.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Deviations:

yes

Remarks:

opthalmology examinations, food and water consumption, and clinical chemistry not reported

GLP compliance:

yes

Species:

other: mouse and rat

Strain:

other: CD1 mouse and Fischer 344 rat

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Portage, MI (mice), Harlan Sprague Dawley, Inc. Indianapolis, IN (rats)
- Age at study initiation: 7-weeks (rats and mice )
- Housing: 2 per cage in stainless steel wire mesh cages (acclimatization period), individually during the study
- Diet (e.g. ad libitum): Pelleted, certified AGWAY PROLAB Animal Diet Mouse 3000, AGWAY PROLAB Animal Diet Rat 3000, ad libitum except during exposures
- Water (e.g. ad libitum): tap water, ad libitumexcept during exposures
- Acclimation period: 3 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): not reported
- Humidity (%): not reported
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 4320-liter stainless steel and glass Inhalation chamber
- Method of holding animals in test chamber: cage in chamber
- Temperature, humidity, pressure in air chamber: 20-29°C, 39-59
- Air flow rate: 900 L/min
- Air change rate: 14 air changes/hour

TEST ATMOSPHERE
- Brief description of analytical method used: analyzed approximately twice each hour during the 6-hour exposure period by flame ionization gas chromotography

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analyzed approximately twice each hour during the 6-hour exposure period by flame ionization gas chromotography.

Duration of treatment / exposure:

Rats
Interim sacrifice (72 weeeks) Core group (104 weeks)
0ppm 10 (m) / 10 (f) 65 (m) / 65 (f)
500ppm 10 (m) / 10 (f) 65 (m) / 65 (f)
2500ppm 10 (m) / 10 (f) 65 (m) / 65 (f)
5000ppm 10 (m) / 10 (f) 65 (m) / 65 (f)

Mice
Interim sacrifice (54 weeeks) Core group (78 weeks) Recovery group
0ppm 10 (m) / 10 (f) 55 (m) / 55 (f) 10 (m) / 10 (f)
500ppm 10 (m) / 10 (f) 55 (m) / 55 (f) 10 (m) / 10 (f)
2500ppm 10 (m) / 10 (f) 55 (m) / 55 (f) 10 (m) / 10 (f)
5000ppm 10 (m) / 10 (f) 55 (m) / 55 (f) 10 (m) / 10 (f)

Frequency of treatment:

Animals assigned to the core group were exposed for 6 hours/day for 5 consecutive days/week for at least 78 weeks (mice) and 104 weeks (rats). The mice assigned to the interim sacrifice group and to the recovery group were exposed for 6 hours/day for 5 consecutive days/week for 54 weeks. Mice in the recovery group were held until week 78 before being euthanized. The rats assigned in the interim sacrifice group were exposed for 6 hours/day for 5 consecutive days/week for 72 weeks.

Post exposure period:

Mice in the recovery group were exposed for 54 weeks but were euthanized at week 78

Remarks:

Doses / Concentrations:
0, 500, 2500, 5000 ppm
Basis:
nominal conc.

No. of animals per sex per dose:

Mice
Core group: 55/sex/dose
Interim Sacrifice group: 10/sex/dose
Recovery group: 10/sex/dose

Rats
Core group: 65/sex/dose
Interim Sacrifice group: 10/sex/dose

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale: based on 9-day preliminary study, where mortality was observed at 10 000ppm and as a result of of toxic effects observed at 5000ppm in a previous subchronic study
- Rationale for animal assignment (if not random): random

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day before and after each exposure

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly for the first 14 weeks and every other week thereafter

OPHTHALMOSCOPIC EXAMINATION: No (mice) , Yes (rats)
- Prior to the first exposure and at 17 months, 19 months, and the terminal euthanasia

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at 12 months and 18 months (mice), 13 months and 19 months and 24-25 months (rats)
- Anaesthetic used for blood collection: Yes : slightly anesthetized wtih methoxyflurane
- Animals fasted: No
- How many animals: all surviving animals

URINALYSIS: No (mice), Yes (rats)
- Time schedule for collection of urine: week 57, 59, 74, and 104
- Metabolism cages used for collection of urine: No
- Animals fasted: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

effects observed, treatment-related

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
Mice:
No differences in mean survival time were noted for any of the isopropanol exposure groups. Clinical signs noted in some male and female mice during exposures to 500 ppm included hypoactivity, lack of a startle reflex, ataxia, prostration, and narcosis. Hypoactivity, lack of startle reflex, and narcosis were also noted for some male ane female animals during exposure to 2500ppm. No clinical signs were noted for male or female animals during exposure to 500 ppm.
Rats:
No significant differences were noted for male rats from 500 or 2500 groups or any female rats. In males and females exposed to 5000 ppm; hypoactivity, lack of a startle reflex, and narcosis were identified. In males and females exposed to 2500 ppm; hypoactivity, and a lack of a startle reflex were observed. No effects in 500 ppm group. During non-exposure periods in males 5000 ppm group emaciation and dehydration was observed. In males and females in 5000 ppm there was greater numbers of rats with urine stains and swollen periocular tissue (females only). Females in the 2500 ppm group also had increased incidence of urine stains.

BODY WEIGHT AND WEIGHT GAIN
Mice:
Concentration-related increases in body weight and weight gain were observed for male mice at most time ponts throughout the study, however, statistical significance was typically achieved only for the 2500 and 5000 ppm groups beginning at study week 6 and 3, respectively.
Rats:
-Decreased body weights were observed for male rats from the 5000 ppm group in the first and second weeks of exposure, and then increased and at the end of week 6 body weights were increased significantly over the control group. Increased body weights were also noted for male rats from the 2500 ppm group.
-Decreased body weights were observed for female rats from the 5000 ppm group in the first and second weeks of exposure, and then increased and at the end of week 5 body weights were increased significantly over the control group. Increased body weights were also noted for female rats from the 500 ppm group. At week 72, all female body weights were significantly increased when compared to the control group.

OPHTHALMOSCOPIC EXAMINATION
Rats:
There were no notable increased frequencies of eye lesions for male and female rats

HAEMATOLOGY
Mice:
No exposure-related changes in hematologic parameters were observed for male or female mice from any of the isopropanol exposed groups that were examined at 12 moths or at terminal sacrifice.
Rats:
No exposure-related changes in hematologic parameters were observed for male or female rats from any of the isopropanol exposed groups that were examined at 13 months, 19 months or at the terminal sacrifice.

URINALYSIS
Rats:
-In males in the 5000 ppm group, at 13 months decrease in osmolality and increase in total protein and total volume were reported. Total glucose excreted in the urine was increased in the 2500 and 5000 ppm group.
-In females rats in the 5000 ppm group, a decrease in osmolality and an increase in total volume was reported. At 17 months, total glucose excreted in the urine was increased for females in the 5000 ppm group.

ORGAN WEIGHTS
Mice:
A concentration -related increase in absolute and relative liver weight was noted for female mice at the terminal sacrifice, however, statistical significance was only achieved for animals from the 5000 ppm group.
Rats:
- At the interim sacrifice, absolute and relative kidney weights were increased for male rats in the 5000 ppm group. Relative liver weights were increased for male rats in the 2500 ppm group. Concentration-related increases in absolute and relative testes weight was reported for male rats in 5000 ppm group. In females, increases in absolute and relative lung weight for rats in the 5000 ppm was reported.
-At the terminal sacrifice, increase in relative liver weight was noted for male rats in 2500 ppm group. In females, an increase in absolute and relative liver and kidney weights were noted for the 5000 ppm group.

GROSS PATHOLOGY
Mice:
At terminal sacrifice, an increased frequency of seminal vesicle enlargement was noted at necropsy for male mice from the 5000 ppm group. In addition, the frequencey of this finding was increased for male mice from the 2500 and 5000 ppm groups which were found dead or sacrificed morbund. There were not exposure-related gross lesions noted for female animals at necropsy.
Rats:
- At the interim sacrifice, an increase in granular kidneys in male rats from the 2500 and 5000 ppm groups were noted
- At the terminal sacrifice, an increase in granular kidneys in male rats from the 2500 ppm group was noted. Increased frequencies of gross lesions for male rats that died included increase incidence of thickened stomachs, granular kidneys, and color change of the kidneys for animals in 2500 and 5000 ppm groups.
- For females that died before the end of the study, an increased incidence of thickened stomachs was noted for animals from the 5000 ppm group and granular kidneys were noted for animals from the 2500 and 5000 ppm groups.

HISTOPATHOLOGY: NON-NEOPLASTIC
Mice:
Upon microscopic evaluation, there were no nonneoplastice or neoplastic lesions observed that were believed to be related to the isopropanol exposures for male and female mice which were sacrificed at week 55.
Rats:
- At the interim sacrifice, male rats from the 5000 ppm group had an increased frequency of testicular seminiferous tubule atrophy.
-Increased frequencies of kidney lesions were observed in male rats in the 2500 and 5000 dose groups that died during the study. Increased in the frequency of mineralization in the heart, aorta, vasculature, stomach, larynx, trachea, lungs, kidney, cornea, and testes was noted for male rats in the 2500 and 5000 ppm dose groups that died during the study. Additionally, basophilic cell foci in the liver, splenic hemosiderosis, rhinitis, and squamous metaplasisa of the respiratory epithelium in the nasal cavity were reported for male rats in the 5000 ppm group that died during the study.
-Increased severity of glomerulosclerosis was observered in female rats in the 5000 ppm group. Renal disease was also increased in female rats in the 5000 ppm group.
- For female rats that died during the study, increased frequencies of mineralization in the heart, aorta, vasculature, stomach, larynx, trachea, lungs and kidney. Increase in myocardial degeneration, atrial thrombosis, splenic hemosiderosis, ocular keratitis, inflammatory and metaplastic changes in the nasal cavity, squamous metaplasia of the respiratory epithelium and glandular ectasia in the gastric mucosa was also evident in females in the 5000 ppm group that died during the study.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
Mice:
-Upon microscopic evaluation, there were no neoplastic lesions observed that were believed to be related to the isopropanol exposures for male and female mice which were sacrificed at week 55.
Rats:
-Dose-related increase in interstitial cell adenomas of the testis in male rats at interim sacrifice, at the terminal sacrifice, and in male rats that died during the study. The increased incidence of testicular tumors appeared to be reflective of abnormally low incidence (64,9%) in the control group. According to the historical data, incidence rate has has been reported to be high as 88% in NTP inhalation studies.

Relevance of carcinogenic effects / potential:

A few neoplastic lesions were noted microscopically for isopropanol (IPA)-exposed mice; however, these findings were minimal in degree and not biologically significant. For rats, a number of non-neoplastic lesion were observed, with the most significant lesion being observed in kidney. There were no increased frequencies of neoplastic lesions noted for female rats from any IPA exposure group. The only tumor type observed for male rats was an increase in interstitial cell adenomas of the testis, but this increase was believed to be an artifact of an unusually low incidence in the control group.

Dose descriptor:

NOEL

Remarks:

mouse

Effect level:

> 5 000 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Dose descriptor:

NOEL

Remarks:

mouse

Effect level:

500 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: overall effects

Remarks on result:

other: Effect type: toxicity (migrated information)

Dose descriptor:

NOEL

Remarks:

rat

Effect level:

> 5 000 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Dose descriptor:

NOEL

Remarks:

rat

Effect level:

500 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: overall effects

Remarks on result:

other: Effect type: toxicity (migrated information)

Read-across justifications and data matrices are presented in IUCLID section 13.

Conclusions:

Exposure of mice for 18 months and rats for 24 months to propan-2-ol vapor produced clinical signs of toxicity (e.g., hypoactivity, lack of startle reflect, narcosis, ataxia, or prostation) during the exposures at 2500 and 5000ppm as well as increases in body weight and body weight gain. Urinalysis and urine chemistry changes indicative of kidney damage were noted for male rats from the 2500 and 5000 ppm groups and female rats from the 5000ppm group. Thus, the NOEL for toxic effect was 500ppm for both species and the NOEL for oncogenicity effects was determined to be greater than 5000ppm.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Justification for classification or non-classification

The weight of evidence based on the decomposition of titanium tetraisopropanolate (rapid hydrolysis, half-life < 3 minutes) and the non carcinogenic properties of the degradation products indicate non carcinogenicity of this substance. Classification regarding carcinogenicity is not required according to the CLP Regulation No. 1272/2008 and EU Directive 67/548/EEC.

Additional information

Carcinogenicity study is not required for substances registered under REACH Annex IX. In addition, there is enough evidence available from in vivo carcinogenicity studies of the main hydrolysis products to conclude that this substance is not carcinogenic.

The testing is considered scientifically unjustified as this substance is hydrolytically unstable (half-life < 3min) when it comes in contact with water or moisture. Because of rapid hydrolysis the intrinsic carcinogenic properties are related to the oncogenic potential of the decomposition products. After hydrolysis no significant reaction products other than isopropyl alcohol (IPA) and non-hazardous hydrated titanium dioxide exist (Scholz, T. 2010).There is no evidence of carcinogenic risk of titanium dioxide (IARC, 2010) and isopropanol (IARC, 1999) to humans and to experimental animals.

In the publication by Burleigh-Flayer, H. et al. (1997) oncogenic potential of IPA was investigated in a chronic inhalation study. Mice and rats were exposed to IPA vapor at the concentrations of 0, 500, 2500, 5000 ppm for 78 and 104 weeks, respectively. A few neoplastic lesions were noted microscopically for IPA-exposed mice; however, these findings were minimal in degree and not biologically significant. For rats, a number of non-neoplastic lesions were observed, with the most significant lesion being observed in kidney. There were no increased frequencies of neoplastic lesions noted for female rats from any IPA exposure group. The only tumor type observed for male rats was an increase in interstitial cell adenomas of the testis, but this increase was believed to be an artifact of an unusually low incidence in the control group. Based on the experimental results of this study, the NOEL for oncogenicity effects was determined to be greater than 5000ppm.

The other decomposition product of this substance is titanium dioxide which is insoluble solid hydrated precipitate. Thus, titanium dioxide is expected to lack bioavailability. As it is also non-classified substance it is relevant not to consider titanium dioxide in the chemical safety assessment. Evidence of non-carcinogenicity of titanium and several of its compounds comes from their vast use as an implant material in orthopedics and oral surgery (Friberg, L. et al. 1986).

Due to lack of mutagenicity, a carcinogenic potential of titanium tetraisopropanolate based on mutagenic effects can be ruled out.As a conclusion, the weight of evidence based on the non-carcinogenic properties of the degradation products and non-mutagenicity of substance itself indicates non carcinogenicity of titanium tetraisopropanolate.

Justification for selection of carcinogenicity via inhalation route endpoint:
Unstable substance and therefore intrinsic properties are related to the main degradation product IPA. Study is reliable with restrictions