Reaction mass of disodium hexatitanium tridecaoxide and disodium trititanium heptaoxide

Endpoint summary

Key value for chemical safety assessment

Effects on developmental toxicity

Description of key information

All female rats survived through the end of the study, and no abnormal general clinical signs were observed in any group throughout the study.

There was no test item-related change in cesarean section parameters, including corpora lutea, implantation, resorptions (early and late), dead and live fetuses, sex ratio, pre-implantation loss, post-implantation loss, fetal weight, placental weight and placental macroscopic observation. In addition, there was no test item-related change in the fetal external and visceral examinations.

Oral exposure to TiO2 during pregnancy increased the titanium concentrations in the maternal liver, maternal brain and placenta, but these levels did not induce marked toxicities in maternal animals or affect embryo-fetal development. These results could be used to evaluate the human risk assessment of TiO2 nanoparticle oral exposure during pregnancy

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

was carried out in a good laboratory practice (GLP) facility but was not conducted within the scope of GLP regulations.

Justification for type of information:

Sodium titanates are effectively the sodium salts of the unstable titanic acid (titanium hydroxide). Titanium hydroxide is hard to isolate without rapid hydrolysis to titanium dioxide and sodium chloride. It is therefore proposed to base environmental and health assessment on these two hydrolysis products. There has been extensive research on similar substances in the ‘titanate’ grouping and these all exhibit similar behaviour in that under acid biological conditions (eg if ingested) or if dispersed in water, there is dissociation of the ions and subsequent hydrolysis / oxidation. Read-across justification for the use of TiO2 data is available in section 13.

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Version / remarks:

OECD 414, adopted 22nd January 2001

Principles of method if other than guideline:

TiO2 nanoparticles were orally administered to pregnant Sprague-Dawley rats (12 females per group) from gestation days (GDs) 6 to 19 at dosage levels of 0, 100, 300 and 1000 mg/kg/day, and then cesarean sections were conducted on GD 20.

GLP compliance:

no

Remarks:

was carried out in a good laboratory practice (GLP) facility but was not conducted within the scope of GLP regulations.

Limit test:

no

Specific details on test material used for the study:

TiO2 nanoparticles were obtained from Evonik Industries (Germany) as a fine white powder with a hydrophilic characteristic caused by hydroxyl groups on the surface. The nanoparticles consisted of aggregated primary particles; the mean diameter of the primary particle was approximately 21 nm, and the weight ratio of anatase/rutile was approximately 80/20 according to the manufacturer’s information.

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

Nine-week-old specific pathogen free (SPF) female Sprague-Dawley rats were obtained (Orient Bio Inc., Republic of Korea) and permitted a 5-days period of acclimation to the animal room environment. Females were selected for mating on the basis of adequate body weight and freedom from clinical signs of disease or injuries during the acclimation period.
The animal room environment was automatically controlled according to institutional criteria (target range: temperature of 23 ± 3 °C, relative humidity of 30–70%, approximately 12-h light cycle with 150–300 Lux, and ventilation at 10–20 times/hour). A standard rodent pellet diet irradiated by gamma-ray (PMI Nutrition International, USA) was provided to the animals ad libitum. Titanium was not detected in the rodent pellet diet according to the chemical composition results from the supplier. The animals had ad libitum access to filtered, ultraviolet light-irradiated municipal tap water at all times. Aspen animal bedding material (Bio Lab, Republic of Korea) was sterilized and then provided to the animals in each cage. There were no known contaminants in the food, water and bedding at levels that would be expected to interfere with the results of the study.

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

TiO2 nanoparticles were suspended in deionized water for administration via the gastrointestinal route.
TiO2 nanoparticles were administered by oral gavage to mated females to evaluate the potential maternal and embryo-fetal development toxicity of TiO2 nanoparticles.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

ICP analysis.
In addition, the team also analyzed the internal distribution of titanium in maternal and fetal tissues after repeated oral exposure during pregnancy.

Details on mating procedure:

Females were selected for mating on the basis of adequate body weight and freedom from clinical signs of disease or injuries during the acclimation period. Females were mated by placement in the cage of a male that was maintained only for mating without any treatment. Sixty-four mating-proven female rats were selected for this study. The day of sperm and/or vaginal plugs detection was designated as day 0 of gestation. Pregnancy was determined by confirmation of implantation sites on the uterus at the time of final sacrifice.
Twelve females per group in the toxicology group (total 48 females) and 4 females per group in the tissue distribution group (total 16 females) were used in this study.

Duration of treatment / exposure:

TiO2 nanoparticles were administered daily by oral gavage from GDs 6 to 19 at dose levels of 0, 100, 300 and 1000 mg/kg with a dose volume of 10 mL/kg.

Frequency of treatment:

Daily

Duration of test:

Total of 20 days

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

100 mg/kg bw/day (nominal)

Dose / conc.:

300 mg/kg bw/day (nominal)

Dose / conc.:

1 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

Twelve females per group in the toxicology group (total 48 females) and 4 females per group in the tissue distribution group (total 16 females) were used in this study.

Control animals:

yes, concurrent vehicle

Details on study design:

TiO2 nanoparticles were orally administered to pregnant Sprague-Dawley rats (12 females per group) from gestation days (GDs) 6 to 19 at dosage levels of 0, 100, 300 and 1000 mg/kg/day, and then cesarean sections were conducted on GD 20.

Clinical signs:

no effects observed

Description (incidence and severity):

In the maternal examinations, there were no marked toxicities in terms of general clinical signs, body weight, food consumption, organ weights, macroscopic findings, cesarean section parameters and fetal morphological examinations. In the distribution analysis, titanium contents were increased in the maternal liver, maternal brain and placenta after exposure to high doses of TiO2 nanoparticles.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No test item-related changes in body weight and body weight gain were observed during the study period.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

For food consumption, a statistically significant decrease during the study period (92% of control) at 1000 mg/kg was considered test item-related. However, this decrease did not have toxicological relevance since it was minimal and there was no correlated decreased body weight or body weight gain during the study period.

Details on results:

The distribution analysis of maternal and fetal tissues in this study showed that TiO2 nanoparticles were retained in the maternal liver, maternal brain and placenta at 1000 mg/kg after repeated oral exposure during pregnancy. At 300 mg/kg, the TiO2 nanoparticle level was also slightly elevated in the maternal brain and placenta.

Key result

Dose descriptor:

LOEC

Effect level:

>= 300 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

necropsy findings

Description (incidence and severity):

In the embryo-fetal examinations, there were no marked toxicities in terms of general clinical signs, body weight, food consumption, organ weights, macroscopic findings, cesarean section parameters and fetal morphological examinations.

Key result

Dose descriptor:

LOEC

Effect level:

>= 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

reduction in number of live offspring

changes in sex ratio

skeletal malformations

visceral malformations

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

Conclusions:

All female rats survived through the end of the study, and no abnormal general clinical signs were observed in any group throughout the study.
There was no test item-related change in cesarean section parameters, including corpora lutea, implantation, resorptions (early and late), dead and live fetuses, sex ratio, pre-implantation loss, post-implantation loss, fetal weight, placental weight and placental macroscopic observation. In addition, there was no test item-related change in the fetal external and visceral examinations.
Oral exposure to TiO2 during pregnancy increased the titanium concentrations in the maternal liver, maternal brain and placenta, but these levels did not induce marked toxicities in maternal animals or affect embryo-fetal development. These results could be used to evaluate the human risk assessment of TiO2 nanoparticle oral exposure during pregnancy

Additional information

Sodium titanates are effectively the sodium salts of the unstable titanic acid (titanium hydroxide).  Titanium hydroxide is hard to isolate without rapid hydrolysis to titanium dioxide and sodium chloride. It is therefore proposed to base environmental and health assessment on these two hydrolysis products. There has been extensive research on similar substances in the ‘titanate’ grouping and these all exhibit similar behaviour in that under acid biological conditions (eg if ingested) or if dispersed in water, there is dissociation of the ions and subsequent hydrolysis / oxidation. Read-across justification for the use of TiO2 data is available in section 13.

The focus has been placed on the titanium element of the hydrolysis expected from this substance. Sodium ions are naturally present in cells in the human body and can be tolerated by ingestion of NaCl through inclusion in normal food and as a food additive up to a daily recommended intake of 6g. It is unlikely that the substance under registration would result in an excess of NaCl being ingested or as a result of absorption through lung fluid following inhalation. The amount to achieve this would be in excess of ~50g. Therefore, there is no reason to evaluate the potential toxicology of the sodium element of the hydrolysis further.