Titanium carbide

Endpoint summary

Description of key information

Bioelution data for TiC support read-across between TiO2 and TiC. Details are given in the read-across report attached to section 13.

Titanium dioxide did not show adverse effects in a chronic oral repeated dose toxicity study in mice and rats, with a NOAEL of 50,000 ppm (equivalent to 6,500 mg/kg bw/day in mice and 3,500 mg/kg bw/day in rats).

The results from the bioelution tests with TiC together with the practical insolubility of the test material in a transformation/dissolution test show that no to verly low bioavailability via the inhalation and dermal route can be expected.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

chronic toxicity: oral

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

For details and justification of read-across please refer to the report attached in section 13 of IUCLID.

Reason / purpose for cross-reference:

read-across source

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

The clinical signs observed in the dosed groups were comparable with those of the control group and included protrusion of the eyes, bloody crust surrounding the eyes, palpable nodules, tissue masses and/or wart-like lesions, localized sores, irritation and swelling of the testes, hunched appearance, and/or thinness. Alopecia (localized or generalized) was noted in all the control and dosed groups; however, more was observed in the control females than in the dosed females. The areas of alopecia were primarily located around the nose and head and progressed to generalized alopecia in some of the animals. The type of feed-hopper used in this study may have caused the alopecia around the nose. Animals in all of the dosed groups had white feces.

Mortality:

mortality observed, treatment-related

Description (incidence):

In male mice, the result of the Tarone test for dose-related trend in mortality is not significant, but in females, the result of the Tarone test shows a significant (P = 0.001) positive dose-related trend. Forty out of fifty (80%) of the high-dose males, 40/50 (80%) of the low-dose males, and 32/50 (64%) of the matched-control males were still alive at week 104. In females, 33/50 (66%) of the high-dose group, 39/50 (78%) of the low-dose group, and 45/50 (90%) of the matched controls were alive at week 104.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Administration of TiO2 had no effect on the mean body weights of either the male or the female mice.

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

A low incidence of neoplasia was observed in both the control mice and dosed mice. These neoplasms were of the usual number and type observed in mice of this age and strain. A slightly increased number of hepatocellular carcinomas was observed in the high-dose males; the incidence of tumors was not increased over that observed in historical-control groups of mice of this age and strain. Degenerative, proliferative, and inflammatory lesions were also of the usual number and kind observed in aged B6C3F1 mice.

Dose descriptor:

NOAEL

Effect level:

50 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: With the exception of white faeces, there was no other clinical sign that was judged to be related to titanium dioxide exposure.

Critical effects observed:

not specified

In the male and female mice, no tumors occurred in dosed groups at incidences that were significantly higher than those for corresponding control groups.

Conclusions:

Based on the histopathological examination, TiO2 was neither toxic nor carcinogenic to mice under the conditions of this bioassay.

Executive summary:

In a chronic toxicity study titanium dioxide (> 98% purity) was administered to 50 B6C3F1 mice per sex and dose in the diet at dose levels of 0, 25000, and 50000 ppm for 103 weeks.

Administration of titanium dioxide had no appreciable effect on the mean body weights of mice of either sex. With the exception of white feces, there was no other clinical sign that was judged to be related to the administration of titanium dioxide. Survival of the male mice at the end of the bioassay was not affected by the test chemical; mortality in female mice was dose related. Sufficient numbers of dosed and control mice of each sex were at risk for development of late-appearing tumors.

A NOAEL of 50000 ppm was established. Based on the histopathological examination, titanium dioxide was neither toxic nor carcinogenic to mice under the conditions reported.

This information is used in a read-across approach in the assessment of the target substance. For justification of read-across please refer to the attached read-across report (see IUCLID section 13).

Reference 2

Endpoint:

chronic toxicity: oral

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

For details and justification of read-across please refer to the report attached in section 13 of IUCLID.

Reason / purpose for cross-reference:

read-across source

Clinical signs:

no effects observed

Description (incidence and severity):

The clinical signs observed in the dosed groups were generally comparable to those of the control group and included alopecia, sores, and lacrimating, protruding, and/or pale eyes. From weeks 88 through 104, hunched appearance and thinness were noted more frequently in the dosed males and females than in their respective controls. Urine stains were noted on the dosed rats of each sex. Animals in all of the dosed groups had white feces.

Mortality:

no mortality observed

Description (incidence):

In the male rats, 36/50 (72%) of the high-dose group, 37/50 (74%) of the low-dose group and 31/50 (62%) of the matched controls were alive at week 104. In the females, 34/50 (68%) of the high-dose group, 36/50 (72%) of the low-dose group and 36/50 (72%) of the matched controls were alive at week 104. Sufficient numbers of rats of each sex were at risk for the development of late-appearing tumors.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Administration of Titanium dioxide had no effect on the mean body weights of either the male or the female rats.

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

The tumor types have been encountered previously as a spontaneous lesion, and with only a few exceptions, occurred with no appreciable difference in frequency between control and dosed groups. In the male rats, pheochromocytomas of the adrenal medulla (matched control: 7/49 (14 %); low dose: 9/49 (18 %); high dose: 14/50 (28 %)) and fibromas of the subcutaneous tissue (matched control: 1/49 (2 %); low dose: 5/50 (10 %); high dose 5/50 (10 %) were observed with slightly greater frequency in dosed groups; the number of neoplasms was compatible with incidences of these tumours in historical-control rats of this age and strain. In the female rats, endometrial stromal polyps were observed more frequently in dosed groups (matched control: 6/50 (12 %); low dose: 15/50 (30 %); high dose 10/49 (20 %)) than in control groups, but the incidence of lesions is comparable with that in historical controls. The incidence of these tumours is not significant when compared with that in the control. Thus, these lesions are not considered to be related to administration of Titanium dioxide.

Dose descriptor:

NOAEL

Effect level:

50 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: With the exception of white faeces, there was no other clinical sign that was judged to be related to titanium dioxide exposure.

Critical effects observed:

not specified

In the female rats, C-cell adenomas or carcinomas of the thyroid occurred at incidences that were dose related (P = 0.013), but were not high enough (P = 0.043 for direct comparison of the high-dose group with the control group) to meet the level of P = 0.025 required by the Bonferroni criterion (controls 1/48, low- dose 0/47, high-dose 6/44). Thus, these tumors of the thyroid were not considered to be related to the administration of the test chemical.

Inflammatory, degenerative, and hyperplastic lesions that occurred were similar in number and kind to those naturally occurring lesions found in aged Fischer 344 rats. Based on the histopathologic examination, Titanium dioxide was neither toxic nor carcinogenic to Fischer 344 rats under the conditions of this bioassay.

Conclusions:

In conclusion, based on the histopathological examination, titanium dioxide was neither toxic nor carcinogenic to F344 rats under the conditions reported.

Executive summary:

In a chronic toxicity study titanium dioxide (>98% purity) was administered to 50 F344 rats per sex and dose in the diet at dose levels of 0, 25000, and 50000 ppm for 103 weeks.

Administration of titanium dioxide had no appreciable effect on the mean body weights of rats of either sex. With the exception of white feces, there was no other clinical sign that was judged to be related to the administration of titanium dioxide. Survival of the rats at the end of the bioassay was not affected by the test chemical. Sufficient numbers of dosed and control rats of each sex were at risk for development of late-appearing tumors.

In the female rats, C-cell adenomas or carcinomas of the thyroid occurred at incidences that were dose related (P= 0.013), but were not high enough (P= 0.043 for direct comparison of the high-dose group with the control group) to meet the level of P= 0.025 required by the Bonferroni criterion (controls 1/48, low-dose 0/47, high-dose 6/44). Thus, these tumors of the thyroid were not considered to be related to the administration of the test chemical.

It is concluded that under the conditions of this bioassay, titanium dioxide was neither toxic nor carcinogenic by the oral route for Fischer 344 rats. A NOAEL of 50000 ppm was established.

This information is used in a read-across approach in the assessment of the target substance. For justification of read-across please refer to the attached read-across report (see IUCLID section 13).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

3 500 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

The key study is compliant and of good quality (Klimisch score II).

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Potential titanium ion release by different routes of human exposure can be compared for different titanium substances by using in vitro bioelution testing. Bioelution has been assessed for TiC in four artificial body fluids. These data support read-across between TiO2 and TiC. Details are given in the attached read across report. A chronic repeated dose study with titanium dioxide for the investigation of possible carcinogenicity was conducted by the National Cancer Institute (1979). Titanium dioxide was administered via feed to Fischer 344 rats and B6C3F1 mice. It was concluded that under the conditions of this assay the test substance was neither toxic nor carcinogenic by the oral route for Fisher 344 rats or B6C3F1 mice up to a level of 50,000 ppm in the diet (equivalent to 6,500 mg/kg bw/day in mice and 3,500 mg/kg bw/day in rats).

Bioelution results for TiC in simulated interstitial fluid and simulated lysosomal fluid, representing mucosal fluids in the deep lung and phagosomal compartments, respectively (Cappellini D., 2012, see IUCLID section 7.1.1), demonstrated that the titanium release was below the detection limit in simulated interstitial fluid after 24 hours. Under the relatively harsh conditions in lysosomal fluid, titanium release was very low (0.08% after 24 hours). In conjunction with the practical insolubility of the substance in a transformation/dissolution test (Rodriguez et al., 2012, see IUCLID section 4.8), these results indicate no to very low bioavailability of titanium carbide via inhalation exposure. Based on these results, no adverse effects are to be expected after repeated dose inhalation exposure to the test substance. The performance of a repeated dose toxicity study via the inhalation route is therefore scientifically not justified.

According to the data requirements outlined in Annex VIII, 8.6 of Regulation (EC) 1907/2006, data for the repeated dose toxicity endpoint shall be provided for the most appropriate route of administration, having regard to the likely route of human exposure. Due to the practical insolubility of the substance as demonstrated in a transformation/dissolution test (Rodriguez et al., 2012, see IUCLID section 4.8), the physicochemical properties do not suggest relevant dermal absorption potential of the test substance. In addition, results from a bioelution assay with TiC in a set of artificial fluids (Cappellini D., 2012, see IUCLID section 7.1.1) showed very low titanium release levels, with the highest release rates in simulated gastric fluid. These results suggest that the oral route is more relevant for exposure to the test substance. Since read-across data for the repeated dose endpoint via the oral route are provided in section 7.5.1, the performance of a repeated dose study via the dermal route is scientifically not justified. 

Justification for classification or non-classification

Based on the results of a bioelution assay in different simulated body fluids and solubility data for the test item titanium carbide, no to very low bioavailability can be expected via the dermal and inhalation routes.

Therefore, the oral route is considered more appropriate for the assessment of toxicity of titanium carbide. The results of a chronic oral repeated dose study with the read-across partner titanium dioxide in mice and rats demonstrated a lack of adverse effects up to a level of 50,000 ppm in the diet. Therefore, the NOAEL was established to be 6,500 mg/kg bw/day in mice and 3,500 mg/kg bw/day in rats.

The classification criteria according to Regulation (EC) 1272/2008 as specific target organ toxicant (STOT) repeated exposure, oral, are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and the no observed adverse effect level (NOAEL) via oral application is above the guidance value for a Category 2 classification (100 mg/kg bw/day). Therefore, no classification for specific target organ toxicant (STOT) repeated exposure is required.