2

Table of Contents

1. EXECUTIVE SUMMARY .......................................................................................................................... 2

Regulatory Recommendation ...................................................................................................................5

2. BACKGROUND....................................................................................................................................... 5

3. SUMMARY OF USES .............................................................................................................................. 6

4. PHYSICAL AND CHEMICAL PROPERTIES ................................................................................................ 6

5. HUMAN HEALTH ASSESSMENT............................................................................................................. 7

5.1 Summary of Toxicity Data .............................................................................................................7

5.2 Toxicity Endpoint Selection.........................................................................................................21

6. EXPOSURE ASSESSMENT..................................................................................................................... 22

6.1 Cancer. ........................................................................................................................................22

7. RESIDENTIAL EXPOSURE/RISK PATHWAY ........................................................................................... 23

8. AGGREGATE RISK AND DETERMINATION OF SAFETY ......................................................................... 23

8.1 Acute Aggregate Risk ..................................................................................................................23

8.2 Short-Term/Intermediate-Term Aggregate Risk.........................................................................24

8.3 Long-Term Aggregate Risk ..........................................................................................................24

9. OCCUPATIONAL EXPOSURE/RISK PATHWAY ...................................................................................... 24

9.1 Handler Risk ................................................................................................................................24

9.2 Occupational Post Application Risk.............................................................................................25

10. CUMULATIVE EXPOSURE ................................................................................................................ 25

11. ENVIRONMENTAL FATE CONSIDERATIONS..................................................................................... 25

12. ECOTOXICITY................................................................................................................................... 25

13. ENVIRONMENTAL JUSTICE STATEMENT ......................................................................................... 26

14. RISK CHARACTERIZATION................................................................................................................ 27

REFERENCES................................................................................................................................................ 28

1. EXECUTIVE SUMMARY
3

United Phosphorus, Inc. submitted a petition (PP 1E7918) requesting an amendment of an 

existing tolerance exemption for the food use inert ingredient, titanium dioxide (CAS Reg. No. 13463-67-

7) when used as a pesticide in or on growing crops as an inert ingredient (UV protectant) in 

microencapsulated formulations of the insecticide lambda-cyhalothrin at no more than 3.0% by weight 

of the formulation (40 CFR § 180.1195). The petitioner wishes to amend 40 CFR § 180.1195 to include

the use of titanium dioxide as an inert ingredient (UV-stabilizer) at no more than 5% in napropamide 

pesticide formulations.

The titanium dioxide that will be used is pigmentary grade which is between 0.25 μm (250 nm)

and 80 μm (80,000 nm) and not considered a nano-material. The open literature acute toxicity studies 

show that titanium dioxide has very low acute toxicity. Acute oral and dermal toxicity studies have 

titanium dioxide categorized as EPA Toxicity Category IV. Eye irritation was also given an EPA Toxicity 

Category IV rating. Titanium dioxide is also not considered a sensitizing agent. No acute inhalation study 

was submitted but a lung instillation study provided by the petitioner showed statistically significant 

amount of inflammation immediately after the exposure but was not present after one month with 

concentrations up to 10 mg/kg.

In a 28 day lung instillation open literature subchronic toxicity study, one formulation of 

titanium dioxide with silicon had a slight fibrogenic effect however the toxicity of other formulations of 

titanium dioxide were comparable to that of a nuisance dust. In a 90 day lung instillation study, there 

were statistically significant signs of inflammation immediately after exposure but were absent after one 

month. 

In mice and rats, a 90 day oral toxicity study and chronic carcinogenicity studies were performed 

by the National Cancer Institute (NCI) via dietary route of exposure to titanium dioxide, There was no 

oral toxicity present at doses up to 50,000 ppm based on mortality, mean body weight gain, 

pathological findings or clinical observations in mice and rats. In a separate study, two groups of 10 male 

and 10 female rats were given 0 or 10 percent (approximately 100,000 ppm) N.F. grade TiO2 in their diet 

for 30-34 days. No treatment related effects were observed in this study (West, B.Wyzan, H., 1963). 

Three groups of two dogs were given orally 0.05, 0.1 and 0.15 g of TiO2. Every five days the dose was 

increased by the same amounts. One dog of each group was kept for one month, the other for two 

months. No toxic effects were seen in dogs (Vernetti-Blina, 1928). In a study with two guinea-pigs, two 

rabbits, two cats and one dog were fed technical grade TiO2 for 390 days. The dog received 9 g/day, 

rabbits and cats, 3 g/day, guinea pigs 0.6 g/day. No signs of systemic toxicity were observed in these 

animals (Lehmann & Herget, 1927).

A three months subchronic toxicity study was conducted on albino rats fed diets containing 0, 

1.0, 3.16 and 10 % with titanium dioxide coated-mica (TCM). No compound related effects on behavior, 

growth, food consumption or mortality were observed. Organs and tissues showed neither consistent 

gross changes nor histopathological changes that could be attributed to dietary administration of TCM.

In a male reproductive parameter study, a LOAEL was determined to be 1% titanium dioxide in 

the diet which is estimated to be about 500 mg/kg/day, however the particle size used for testing was 
4

not reported and thought to be nanosized based on its comparative toxicity to other nanosized studies 

in the open literature. No other reproductive or developmental studies were provided.

The results of genotoxicity test on titanium dioxide are mixed. Based on four open literature 

genetic toxicity studies with titanium dioxide, human lymphocytes and SCE were increased in a doserelated manner at titanium dioxide concentrations of 2 μM and above and micronuclei were increased 

at concentrations of 5 μM and above. Titanium dioxide did not induce micronuclei in BEAS 2B cells. 

Treatment of both BEAS 2B and A594 cells with titanium dioxide resulted in DNA damage as measured in 

the Comet assay, however there were no increases in the formation of 8-oxoguanine in rat lung tissue, 

induction of gene mutations in the Ames assay or chromosomal aberrations in vitro in Chinese hamster 

ovary cells. The International Agency for Research on Cancer (IARC) in 2010 concluded that in vivo

studies have shown enhanced micronucleus formation in bone marrow and peripheral blood 

lymphocytes of intraperitoneally instilled mice. Increased HPRT mutations were seen in lung epithelial 

cells isolated from titanium dioxide instilled rats. In another study no enhanced oxidative DNA damage 

was observed in lung tissue of rats that were intratracheally instilled with titanium dioxide. The results 

of most in vitro genotoxicity studies with titanium dioxide were negative. 

IARC concluded that titanium dioxide was possibly carcinogenic to humans (Group 2B) on the 

basis of an inhalation carcinogenicity study in rats (Heinrich et al. 1995). However, IARC also concluded 

that titanium dioxide did not induce tumors by oral, intraperitoneal or subcutaneous routes of exposure 

in rats or mice. In a Bioassay of titanium dioxide performed by the National Cancer Institute (NCI), 

groups of 50 rats of each sex and 50 mice of each sex were administered titanium dioxide in the diet at 

25,000 or 50,000 ppm (or mg/kg) for 103 weeks. They concluded that under the conditions of the 

bioassay, titanium dioxide was not carcinogenic by the oral route for Fischer 344 rats or B6C3F1 mice.A 

chronic dietary study administration of titanium dioxide coated mica at 0, 1, 2 and 5% in Fischer 344 

rats for 130 weeks showed no toxicological or carcinogenic effects (Bernard et al., 1990).

Based on the physiochemical properties of titanium dioxide, it is believed to be stable and 

persistent in the environment. Titanium minerals are very abundant in the Earth’s crust and therefore a 

background level of exposure to titanium dioxide will need to be taken into account throughout the 

assessment. Ecotoxicity studies also showed that titanium dioxide is practically non-toxic to freshwater 

fish, invertebrates and algae on an acute toxicity bases. Due to low absorption through oral and dermal 

routes, terrestrial exposure of titanium dioxide as an inert ingredient in pesticide formulations to non 

target organisms is thought to be of little concern.

The available toxicity studies on titanium dioxide via oral route of exposure clearly demonstrate 

lack of toxicity. The several studies in mice, rats, dogs, cats, rabbits and other species of varying

durations do not indicate toxicity at very high doses (e.g. 50,000 ppm dietary exposure for two years in 

rats). No end point of concern via oral route of exposure has been identified in the available database. 

Therefore, dietary exposure was not conducted. This conclusion is in agreement with the World Health 

Organization (WHO) Committee on Food Coloring Materials had determined that no ADI need be set for 

the use of titanium dioxide based on the range of acute, sub-acute and chronic toxicity assays, all 

showing low mammalian toxicity. Similarly, no significant toxicity of titanium dioxide is expected via the 
5

dermal route of exposure. All currently registered uses of titanium dioxide as an inert ingredient in 

lambda-cyhalothrin, and all anticipated uses of titanium dioxide as an inert ingredient in napropamide 

formulations, do not include residential applications. Therefore no residential risk assessment was 

performed. The available inhalation studies indicate that the primary toxicity of titanium dioxide is due 

to deposition of the inhaled particles and also suggest possible carcinogenic effects due to prolong 

exposure. The occupational inhalation exposure assessment was not conducted based on its requested 

use pattern and no direct exposure to titanium dioxide particles is expected in pesticide napropamide

formulations (less than 5% in formulations). The actual environmentally anticipated exposures of 

titanium dioxide based on the use patterns of products that would contain titanium dioxide are orders 

of magnitude less than that allowed by the Occupational Safety and Health Administration’s

(OSHA)Permissible Exposure Limit (PEL).

Regulatory Recommendation

Taking into consideration all available information on titanium dioxide, EPA concludes that there 

is a reasonable certainty that no harm will result to the general population when titanium dioxide is 

used as an inert ingredient. The establishment of an exemption from tolerance for food use for residues 

of titanium dioxide when used as an inert ingredient (UV protectant) applied to growing crops in 

pesticide formulations containing the active ingredient napropamide at no more than 5.0% by weight of 

the formulation can be considered safe under section 408 of the FFDCA. This approval granted only for 

the use of micronized form of titanium dioxide and nano sized is prohibited.

2. BACKGROUND

United Phosphorus, Inc. submitted a petition (PP 1E7918) requesting an amendment of a tolerance 

exemption for a food use inert ingredient, titanium dioxide (CAS Reg. No. 13463-67-7), when used as an 

inert ingredient (UV protectant) in microencapsulated formulations of the insecticide lambdacyhalothrin at no more than 3.0% by weight of the formulation (40 CFR § 180.1195). United Phosphorus, 

Inc. wishes to amend 40 CFR § 180.1195 to include the use of titanium dioxide as an inert ingredient 

(UV-stabilizer) at no more than 5% in pesticide formulations containing the active ingredient 

napropamide. Napropamide is a systemic herbicide formulated as an emulsifiable concentrate, wettable 

powder, granule, and suspension concentrate. Application methods include aerial, ground boom, handheld sprayers, granular application and chemigation. Napropamide is registered for use on cranberries, 

strawberries, tomatoes, peppers, tobacco, nut trees, small fruits, vegetables, field-grown nursery stock, 

liner stock, dichondra, and container-grown ornamentals.

Titanium dioxide has two exemptions from the requirement of a tolerance 40 CFR § 180.920 

pesticide formulations applied to growing crops as a pigment/colorant in plastic bags used to wrap 

bananas, colorant on seeds for planting and 40 CFR § 180.930 pesticide formulations applied to animals

as a pigment/colorant in animal tags . A Food Quality Protection Act (FQPA) reassessment was 

performed on titanium dioxide in June 2005 for these two exemptions from a tolerance. Some of the 

background, conclusions and discussion will be carried over into this document. Titanium dioxide is also 
6

approved for use as a colorant in food (21 CFR § 73.575), in drugs (21 CFR § 73.1575), and in cosmetics 

(21 CFR § 73.2575; 21 CFR § 73.3126). There has also been a previous exemption, also listed above, from 

requirement of a tolerance for residues in or on growing crops, when used as an inert ingredient (UV 

protectant) in microencapsulated formulations of the insecticide lambda-cyhalothrin at no more than 

3.0% by weight or the formulations (40 CFR § 180.1195) which was established in March 1998 and 

therefore not included in the 2005 FQPA tolerance reassessment.

Titanium dioxide is a naturally occurring mineral found predominately in ilmenite (FeTiO3) and rutile 

(titanium dioxide) forms. Titanium itself is one of the most abundant elements in the earth’s crust. It is 

mined in Australia, South Africa, Canada and the United States. Titanium dioxide is manufactured in high 

purity (>99%) and is available as microsized or nanosized particles. The registrant specifically and 

repeatedly states that they will be using only microsized pigmentary grade titanium dioxide particles 

with size range from 0.25 μm (250 nm) to 80 μm (80,000 nm). While there are open literature sources 

which discuss the toxicity of nanosized titanium dioxide particles, only studies which contributed useful 

information regarding microsized titanium dioxide particles are referenced herein.

3. SUMMARY OF USES

Titanium dioxide is a widely used inorganic white pigment that is produced from mined sources of 

titanium. Titanium dioxide pigments are white inorganic pigments used primarily in the production of 

paints, printing inks, paper and plastic products. Titanium dioxide is also used in many white or colored 

products including foods, cosmetics, UV skin protection products, ceramics, fibers, and rubber products.

It is also used as an inert ingredient in pesticide formulations as previously mentioned above. 

4. PHYSICAL AND CHEMICAL PROPERTIES

Table 1. Physical and Chemical Properties of Titanium Dioxide

Parameter Value Source

Structure ChemIDplusLite

CAS # 13463-67-7 ChemIDplusLite

Molecular Weight (g/mol) 79.865 ChemIDplusLite

Physical State Solid ChemIDplusLite

Color White Registrant Submission

Odor Odorless Registrant Submission

pH Not applicable. Practically insoluble 

in water.
7

Melting Point (in °C) 1843 HSDB 2005

Boiling Point (in °C) Not applicable to solids.

Density (in kg/m3at 25°C) 3.5 (anatase) – 4.2 (rutile) The Merck Index

Dissociation Constant (pKa) Not applicable. Titanium dioxide 

contains no chemical functional 

group that readily dissociates.

Particle size, fiber length, and 

diameter distribution

Median particle size > 100 nm (nonnano)Registrant Submission

Vapor Pressure (in hPa at 25°C) Not applicable.

Partition Coefficient (Kow) Not applicable.

Water Solubility (in mg/L at 

20°C)

Insoluble in water, hyudrochloric, 

dilute sulfuric and organic solvents. 

Dissolves slowly in hydrofluoric acid 

hot concentrated sulfuric acid.

The Merck Index, IPCS 

1993

Henry’s Law Constant (in atm 

m

3

/mole at 25°C)

Not applicable.

5. HUMAN HEALTH ASSESSMENT

5.1 Summary of Toxicity Data

Acute Toxicity Summary

All studies summarized in table below are from MRID 48587801 and include only open 

literature studies. It cannot be confirmed whether the studies followed U.S. EPA guideline or 

not therefore all submitted studies under this MRID are assumed to be non-guideline 

studies.

Table 2. Summary of Acute Toxicity Data for Titanium Dioxide

Parameter Toxicity Value Toxicity 

Category

Reference 

(MRID: 48587801)

Acute Oral LD50, Rat >5000 mg/kg IV Warheir, D., Hoke, R., 

Finlay, C. et al. 2007 (open 

literature)

Acute Oral LD50, 

Mice

>5000 mg/kg IV Wang, J., Zhou, G., Chen, C. 

et al. 2007 (open 

literature)

Acute Inhalation 

NOAEL, Rat

10 mg/kg N/A Warheir, D., Hoke, R., 

Finlay, C. et al. 2007 (open 

literature)

Eye Irritation, 

Rabbit

Conjunctival redness from 24 

to 48 hrs after instillation.

III Warheir, D., Hoke, R., 

Finlay, C. et al. 2007 (open 

literature)

Acute Dermal No skin irritations were IV Warheir, D., Hoke, R., 
8

Irritation, Rabbit observed. Finlay, C. et al. 2007 (open 

literature)

Skin Sensitization, 

LLNA

Product is not a sensitizer Not a 

Sensitizer

Warheir, D., Hoke, R., 

Finlay, C. et al. 2007 (open 

literature)

Acute Oral

In an acute oral toxicity study (Warheir, D., Hoke, R., Finlay, C. et al 2007) a single dose of 

ultrafine particle type C (uf-C) TiO2 (80:20 ratio of anatase:rutile titanium dioxide; particle 

size 0.140 μm) suspended in water was administered by gavage to one female (fasted; 

species unspecified) rat each at a dose of 175, 550 or 1750 mg/kg and to three females 

(fasted) at a dose of 5000 mg/kg. The study was run according to the acute oral toxicity testup and down procedure. The rats were observed for mortality, clinical signs of toxicity and 

body weight effects for 14 days. A complete necropsy was performed on each rat at the 

time of sacrifice. There were no mortalities. The only clinical sign observed was grey feces. 

There were no effects on body weights nor were there any gross findings. The oral LD50 of 

uf-C titanium dioxide was >5000 mg/kg.

In another acute oral toxicity study (Wang, J., Zhou, G., Chen, C. et al. 2007), ultrafine 

titanium dioxide particles (0.155 μm; >99% pure) suspended in 0.5% hydroxypropyl 

methylcellulose K4M were administered by gavage to CD-1 (ICR) 9 male and 8 female mice 

at a dose of 5000 mg/kg. Two different nanosized particles were also examined in this study 

for comparative purposes; however, the results are not summarized herein. Two weeks 

after the single dose all mice were sacrificed. All mice survived the 14 day period. Body 

weights and liver, spleen and kidney weights were unaffected. None of the serum 

parameters evaluating liver toxicity, nephrotoxicity and cardiac toxicity were affected by 

treatment. The livers of male and female mice examined microscopically had hydrospic 

degeneration around the central vein and spotty hepatocytic necrosis. Upon microscopic 

examination the heart, lung, testes, ovary and spleen had no findings. The LD50 was greater 

than 5000 mg/kg/day.

Acute Inhalation

In a acute inhalation study (Warheit, D., Hoke, R., Finlay, C. et al. 2007), groups of 

Crl:CD(SD)IGS BR male rats were intratracheally instilled titanium dioxide formulations at 

doses of 0, 2 or 10 mg/kg. The particles were suspended in saline. Twenty-four hours, one 

week and 1 and 3 months after instillation, 8 rats/ time point were sacrificed. The lungs of 4 

rats/time point were assessed using both bronchoalveolar biomarkers and the lungs of the 

other 4 rats were examined for histopathology/cell proliferation. 

The numbers of cells recovered by bronchoalveolar lavage from the lungs of the titanium 

dioxide exposed groups were not significantly different from the controls at any time point 

after exposure. At 2 mg/kg, H-11,567 and H-11,569 produced a short-term pulmonary 
9

inflammatory response as shown by an increase in the numbers and percentage of 

bronchoaveolar lavage neutrophils at the 24 hour time point. The same inflammatory 

response was also observed at 24 hours in all groups exposed to 10 mg/kg. Exposures to 10 

mg/kg H-l 1,567 and H-l 1,569 produced a more sustained lung inflammatory response 

which persisted to the one month time point for H-11,569 and to three months for H11,567.

Examination of the bronchoaveolar lavage fluid from the H-11,565 and H-11,566 groups 

treated at 10 mg/kg revealed an increase in lactate dehydrogenase values at the 24 hour 

time point that were not observed at the later time points. Exposures to H-11,569 produced 

significant increases in lactate dehydrogenase values at the one week time point. The H11,567 formulation produced a sustained increase in this parameter through the one month 

time point. Transient significant increase in bronchoaveloar fluid microprotein values were 

observed in the lungs of the 10 mg/kg H-11,566 and H-11.568 at the 24 hour time point, but 

did not persist. H-11,569 produced a significant increase in microprotein at 1 week. H11,567 caused sustained increased in lung permeability endpoints through one week post 

exposure. No increase in alkaline phosphatase values or in BrdU lung cell proliferation rates 

in parenchymal cells was observed.

Microscopic examination of the lungs of the rats instilled with the titanium dioxide 

formulations revealed no significant morphological differences between the formulations. 

The lung tissues had particle-laden macrophages at bronchoalveolar junctions following 

instillation. There were no other findings. The NOAEL was 10 mg/kg for the 99% TiO21% cooxidized Al2O3, the least formulated material.

In a acute lung instillation toxicity study (Ogami, A., Morimoto, Y., Myojo, T. et al. 2007), 

titanium dioxide was intratracheally administered into the lungs of 25 male Wistar rats at 

dose of 2 mg per 0.4 mL of saline. The control group received only saline. Five rats were 

sacrificed at each of five time points for examination of lung tissue: 3 days, one week, one 

month, three months and six months after instillation. Titanium dioxide was one of several 

materials tested. Other test materials included silicon carbide whiskers, potassium 

oxtatanate whiskers, crystalline silica and crocidolite asbestos. Only the data generated on 

titanium dioxide will be summarized herein.

Titanium dioxide was intratracheally administered into the lungs of 25 male Wistar rats at 

dose of 2 mg per 0.4 ml of saline. The control group received only saline. Five rats per 

sacrificed at each of five time points for examination of lung tissue: 3 days, one week, one 

month, three months and six months after instillation. The particle size of the titanium 

dioxide used was 1.5 μm (GSD = 1.8). Lung inflammation and collagen deposition rate were 

scored. Paraffin sections of the left lung were stained with hematoxylin-eosin and by the van 

Gieson method. Lung inflammation was scored by placing a 300-point grid over each lung 

image (focusing mainly on the alveoli with five images/lung) on a computer screen. 
10

Pulmonary inflammation was examined by the point counting method. The percentage of 

the areas of inflammation excluding air spaces in the lung parenchyma was calculated. The 

results were categorized into four grades and the score was determined. To evaluate the 

extent of fibrosis, digital images were taken and analyzed by the point counting method. 

The percentage of collagen deposits for each section was calculated. The collagen 

deposition rate was equal to the number of collagen (red) points in parenchyma divided by 

the total number of points in the lung parenchyma.

The inflammation score for titanium dioxide at 3 days and 1 week after exposure was 

statistically higher than the control group. After one month no significant difference was 

observed between the titanium dioxide group and the control group. Titanium dioxide had 

similar scores to the control group for collagen deposition.

Acute Eye Irritation

In an acute eye irritation study (Warheit, D., Hoke, R., Finlay, C. et al. 2007), uf-C TiO2 (80:20 

ratio of anatase:rutile titanium dioxide; particle size ~0.140 μm) was evaluated for eye 

irritation in New Zealand white rabbits. Approximately 57 mg of uf-C TiO2 was instilled into 

one eye of each animal. The eye remained unwashed. One animal was treated initially. No 

server irritation occurred, so an additional two rabbits were treated. The eyes were 

evaluated at 1, 24, 48 and 72 hours following instillation. The test material caused 

conjuctival redness (score 1 or 2) of all three rabbits. There was no corneal involvement as 

determined by fluorescent staining. The treated eyes were normal 24 or 48 hours after 

instillation. 

Acute Dermal Irritation

In an acute dermal irritation study (Warheit, D., Hoke, R., Finlay, C. et al. 2007) uf-C TiO2

(80:20 ratio of anatase:rutile titanium dioxide; particle size ~0.140 μm) was evaluated for 

dermal irritation in new Zealand white rabbits. A single dose of 0.5 g uf-C TiO2 was applied 

to the shaved back after being moistened with 0.25mL of distilled water. The application 

area was covered with a 2-ply gauze square held in place with non-irritating tape and 

covered with porous tape (semi-occlusive)., After the four hours expose period, the test 

substance was removed and the sites were evaluated by the Draize scoring system at 1, 24, 

48 and 72 hours after removal. No skin irritation was observed during the study. Uf-C TiO2

was not a skin irritant under the conditions of this study.

Skin Sensitization

In a skin sensitization study (Warheit, D., Hoke, R., Finlay, C. et al. 2007) uf-C TiO2 (80:20 

ratio of anatase:rutile titanium dioxide; particle size ~0.140 μm) was evaluated for dermal 

sensitization in the local lymph node assay in mice. Five groups of five female CBA/JHsd 

mice were dosed for three consecutive days with 0% (vehicle), 5%, 25%, 50% or 100% 

titanium dioxide. A positive control (hexylcinnamaldehyde) group was also run. On the 5th

day of the study, 3H-thymidine was injected into the tail vein of each mouse, and the mice 
11

were sacrificed 5 hours later. Cell proliferation in the draining auricular lymph nodes of the 

mice was evaluated. A stimulation index (SI) was derived for each group. A response was 

considered positive if the SI was ≥3.0. Stimulation indices of less than 3.0 were obtained for 

the titanium dioxide treated groups. The positive control produced the expected positive 

response. UF-C TiO2 was not a dermal sensitizer in the mouse local lymph node assay.

28-Day Repeated Dose Oral Toxicity Study

In a subchronic oral toxicity study (West, B. Wyzan, H., 1963), two groups of 10 male and 10 

female rats were given 0 or 10 percent (approximately 100,000 ppm) N.F. grade TiO2 in 

their diet for 30-34 days. No treatment related effects were observed in this study. 

90-Day Oral Toxicity Study-Rat/Mouse (NCI study summarize results)

In a National Cancer Institute (NCI) 90-day oral toxicity study on rats and mice, 10 males and 

10 females of each species were administered titanium dioxide at doses of 6,250, 12,500, 

25,000, 50,000, or 100,000 ppm. Ten males and 10 females of each species also received 

basal diets. In both studies, rats and mouse, there were no deaths and dosed animals had 

mean body weight gains that were comparable to those of the controls. No gross or 

microscopic pathology was found that could be related to the administration of the test 

chemical in either the rats or the mice at doses up to 100,000 ppm (equal to 5000 

mg/kg/day in rats). 

In another three month subchronic toxicity study (Vernetti-Blina, 1928), three groups of two 

dogs were given orally 0.05, 0.1 and 0.15 g of titanium dioxide. Every five days the dose was 

increased by the same amounts. One dog of each group was kept for one month, the other 

for two months. No toxic effects were seen in dogs.

A third, three month subchronic toxicity study (Bernard et al. 1990) was conducted on 

albino rats fed diets containing 0, 1.0, 3.16 and 10% titanium dioxide coated-mica (TCM). No 

compound related effects on behavior, growth, food consumption or mortality were 

observed. Organs and tissues showed neither consistent gross changes nor histopathological 

changes that could be attributed to dietary administration of TCM.

Chronic Oral Toxicity Study-Rat/Mouse (NCI study summarize results)

Groups of 50 rats of each sex and 50 mice of each sex were administered titanium dioxide in 

the diet at one of two doses, either 25,000 or 50,000 ppm (approximately 1250 mg/kg/day 

and 2500 mg/kg/day respectively) for 103 weeks. Matched controls consisted of 50 

untreated rats of each sex and 50 untreated mice of each sex. All surviving rats and mice 

were killed at 104 weeks. 

Administration of the titanium dioxide had no appreciable effect on the mean body weights 

of rats or mice of either sex. With the exception of white feces, there was no other clinical 
12

sign that was judged to be related to the administration of titanium dioxide. Survival of the 

rats and male mice at the end of the bioassay was not affected by the test chemical; 

mortality in female mice was dose related. 

In another chronic oral toxicity study (Lehmann & Herget, 1927), two guinea-pigs, two 

rabbits, two cats and one dog were fed technical grade titanium dioxide for 390 days. The 

dog received 9g/day, rabbits and cats, 3 g/day, and guinea pigs 0.6 g/day. No signs of 

systemic toxicity were observed in these animals.

Developmental Toxicity

No study submitted.

Reproductive Toxicity (summary taken from MRID 48587801)

In a nonguideline male reproductive parameter evaluation study (El-Sharkawy, N., Hamza, S. 

and Abou-Zeid, E. 2010), Male albino rats (180 to 200g; 6/group) were placed on diets 

containing 0, 1 and 2% titanium dioxide for a period of 65 days. Body weights were recorded 

at study initiation and at study termination. Clinical signs of toxicity were monitored. Serum 

levels of testosterone, nitrite, superoxide dismutase activity, glutathione reductase activity 

and malondialdehyde levels. The cauda epididymis was minced in saline and examined for 

sperm motility, sperm cell concentration, sperm abnormalities and live % spermatozoa. The 

testis, seminal vesicle and liver were fixed for histopathological examination.

At study termination various reproductive parameters were examined along with body 

weights and clinical signs of toxicity. Depression, anorexia and white feces were noted in the 

titanium dioxide treated groups (incidence not shown). Body weights were statistically 

significantly decreased in both treated groups compared to the control: 14.6% decrease at 

the low dose and 14% at the high dose. Sperm motility was depressed at both dosage levels 

but the decrease was statistically significant at the high dose only. Sperm cell concentration, 

sperm viability and serum testosterone levels were statistically decreased and the number 

of sperm abnormalities were statistically increased at both titanium dioxide concentrations 

tested. Malondialdehyde levels were unaffected by treatment; however, glutathione 

reductase and superoxide dismutase activities, and nitrite levels were statistically increased 

at both dosage levels compared to control levels.

Macroscopically, the seminal vesicles of the treated rats showed hypertrophy at the low 

dose and atrophy at the high dose. Microscopically, the lining of the seminal vesicle of all 

rats fed 1% titanium dioxide had hyperplastic changes with little or absence of secretion 

"beside edema of trabiculae" while at 2% titanium dioxide, there was a reduction in number 

and size of the epithelial cell lining of the tubuloaveolar glands. At the low dose, the 

seminiferous tubules revealed mild spermatogenesis with congested interstitial blood 

vessels with endotheliosis. Thickened tunica albuginea with degenerated spermatogonial 

cell layers and spermatocytes with the absence of spermatogenesis were also observed 
13

particularly at the high dose. Microscopic examination of the liver revealed hepatocytic 

degenerative changes which varied from vacuolar and hydropic degeneration to cell death 

at the low dose and increased in severity to mainly steatosis of the hepatic cells as the high 

dose. A NOAEL was not observed in this study. However a LOAEL was observed at 1% 

titanium dioxide in the diet which is equivalent to approximately 500 mg/kg/day. However, 

this male rate reproductive parameter study did not specify the particle size of the titanium 

dioxide used which may be micro or nano. 

There was another open literature male mouse reproductive parameter study (Guo, LL. 

2009) reported which was conducted with nano-sized titanium dioxide that produced a 

LOAEL of 500 mg/kg/day and a NOAEL of 200 mg/kg/day based on decreases in the liver, 

heart and kidneys weights, and a significant increase in serum biochemical parameters such 

as ALT, ALT/AST and BUN (P <0.05). The 500 mg/kg/day group also showed significantly 

reduced sperm density and motility, increased sperm abnormality and germ cell apoptosis 

but no obvious pathological changes in the liver, kidney, spleen, testis and epididymis. Due 

to the similarities in toxicity between this these two reproductive parameter studies, the 

male rat reproductive parameter study was likely also conducted with nano-sized titanium 

dioxide and will not be used for risk assessment purposes of microsized titanium dioxide. 

Genetic Toxicity (summary taken from MRID 48587801)

In an In Vitro Sister Chromatid Exchange Assay and In Vitro Micronucleus Assay (Turkez, H. 

2008), Titanium dioxide was tested for its potential to induce sister-chromatid exchanges 

(SCE) and micronuclei formation in human whole blood cultures. Blood cultures were 

treated with 0, 1, 2, 3, 5, 7.5 or 10 uM titanium dioxide. The formation of SCE and 

micronuclei were examined in the blood lymphocytes. SCE were increased in a dose-related 

manner at titanium dioxide concentrations of 2 uM and above. Micronuclei were increased 

at titanium dioxide concentrations of 5 uM and above. When tested in the presence of 

either boric acid or borax, the titanium dioxide response was significantly reduced in both 

assays.

In a DNA damage: formation of 8-oxoguanine study (Rehn, B., Seiler, F., Rehn, S. et al 2002), 

female Wistar rats (5/group) were exposed by instillation to a single dose of 0.15, 0.3, 0.6, 

and 1.2 mg of titanium dioxide P25 (untreated, hydrophilic surface) or titanium dioxide T805 

(silanized, hydrophobic surface) particles, suspended in 0.2 ml of physiological saline 

containing with 0.25% lecithin. The controls were instilled with the vehicle or with a single 

dose of 0.6 mg quartz DQ12 as a positive control. The rats were euthanized 90 days after 

instillation. Eight micron frozen sections of the left lobe of the lung stored at -80 degrees C. 

The sections were used for immunohistochemical detection of 8-oxoguanine (8-oxoGua) by 

a polyclonal antibody in the DNA of individual lung cells. The fluorescence intensity of 500 

individual cells per animal was determined. The genotoxic effects in the lung of two types of 

commercially available titanium dioxide at low doses relevant to the working environment 

were examined. Although, the companies supplying the titanium dioxide particles claimed 
14

their particle size was 20 nm, electron microscopy demonstrated that the particles were 

aggregated and agglomerated. Sonication was not successful in breaking up the particles to 

a size of 20 nm. In the quartz-exposed animals ninety days after exposure, a significant 

increase in the amount of 8-oxoGua in the DNA of lung cells was detected. In contrast, 

animals exposed to TiO2 P25 or TiO2 T805 the amount of 8-oxoGua as a marker of DNA 

damage, was at the level of the control.

In an In Vitro Micronucleus Assay and the Comet Assay (Falck, G., Lindberg, H., Suhonen, S. 

et al. 2009), various forms of titanium dioxide in human bronchial epithelial BEAS 2B cells 

were tested using the Comet assay and the cytokinesis-block micronucleus test. Rutile 

(nanosize) titanium dioxide stated to be 99.5% pure but found to contain <5% SiO2 as a 

coating (particle size 10 x 40 nm), rutile (fine) titanium dioxide oxide (99.9% pure; particle 

size <5 jam) and anatase titanium dioxide nanopowder (99.7% pure; particle size <25 nm) 

were tested. Actual particle size was determined by transmission electron microscopy. 

Concentrations tested were 1 to 100 μg/cm2, which were selected based on preliminary 

cytotoxicity test. The Comet assay was conducted twice. The titanium dioxide forms were 

dispersed as agglomerates with an average size ranging from 3.8 pm (fine rutile) to 5.5 μm 

(nanosized anatase) as determined by transmission electron microscopy. The dispersions 

also contained nanosized particles. All three forms caused DNA damage in the Comet assay. 

Nanosized anatase and fine rutile showed similar induction of DNA damage. Nanosized 

rutile was less effective. However, none of the titanium dioxide forms produced a potent 

response. Only nanosized anatase induced micronuclei in BEAS 28B cells after 72 hours, but 

not at 24 and 48 hours. There was no dose response and there was only a doubling at the 

two doses that were positive for inducing micronuclei.

In an In Vitro Comet Assay (Karlsson, H., Gustafsson, J., Cronholm, P. et al. 2009), nano- and 

microsized particles of titanium dioxide were used on human alveolar type-II-like epithelial 

cells (A594 cells). The cells were exposed to 40 and 80 μg/ml of each particle size for four 

hours. To measure DNA damage as single strand breaks and alkali labile sites, the alkaline 

version of the Comet assay was used. To investigate oxidative DNA lesions mainly oxidized 

purines, the FormamidoPyrimidine DNA Glycosylase enzyme was added. Thirty-five cells in 

duplicate were analyzed. DNA damage was measured by as percent DNA in the tail. Particle 

size was determined to be an average of 63 nm for the nanosized titanium dioxide particles 

and 1 μm for the microsized titanium dioxide particles. A significant increase in DNA damage 

was observed for both nano- and microsized titanium dioxide particles at 80 μg/mL. At 40 

μg/mL, both particle sized caused an increase in DNA damage; however, the increase was 

significant with the microsized titanium dioxide particles, only.

In a Bacterial Reverse Mutation Test (Warheit, D., Hoke, R., Finlay, C. et al. 2007), Uf-C TiO2

(80:20 ratio of anatase.rutile titanium dioxide; particle size ~0.140 μm) was tested in the 

bacterial reverse mutation (Ames) test using the plate incorporation method. Titanium 

dioxide was tested in Salmonella tester strains TA98, TA100, TA1535 and TA1537 and 
15

Escherichia coli strain WP2uvrA both in the presence and absence of metabolic activation 

(Arochlor induced rat liver). The vehicle was sterile water. Dosage levels tested were 100, 

333, 1000, 333 and 5000 μg/plate. The appropriate positive controls were used. Uf-C TiO2

did not produce a positive response in any of the test strains either in the presence or 

absence of metabolic activation.

In an In Vitro mammalian Chromosome Aberration Test (Warheit, D., Hoke, R., Finlay, C. et 

al. 2007), Uf-C TiO2 (80:20 ratio of anatase:rutile titanium dioxide; particle size -0.140 μm) 

was tested for chromosomal aberrations in vitro in Chinese hamster ovary cells in the 

presence and absence of metabolic activation (Aroclor-induced rat liver S9). The vehicle was 

Milli-Q water. Cytogenetic evaluations of structural aberrations and numerical aberrations 

were conducted in 200 cells in metaphase at 750, 1250 and 2500 μg/mL for the 4 hour non 

activated test; at 62.5, 125 and 250 μg/mL for the 4 hour activated test; and at 25, 50 and 

100 μg/mL for the 20 hour non-activated test. The appropriate positive controls were 

included. Uf-C TiO2 did not produce structural or numerical aberrations under the conditions 

of this study.

Carcinogenicity

In a bioassay of titanium dioxide performed by the National Cancer Institute (NCI 1979), 

groups of 50 rats of each sex and 50 mice of each sex were administered titanium dioxide in 

the diet at one of two doses, either 25,000 or 50,000 ppm (approximately 1,250 mg/kg/day 

and 2,500 mg/kg/day respectively), for 103 weeks and then observed for 1 additional week. 

A control group consisted of 50 untreated rats of each sex and 50 untreated mice of each 

sex. 

Administration of the titanium dioxide had no appreciable effect on the mean body weights 

of rats or mice of either sex. The only exception was the presence of white feces. No other 

clinical signs were observed to be related to the administration of titanium dioxide. In the 

female rats, C-cell adenomas or carcinomas of the thyroid occurred at incidences that were 

dose related but were not high enough to be of significance. Therefore these tumors were 

not considered to be related to the administration of the test chemical.

In the male and female mice, no tumors occurred in dosed groups at incidences that were 

significantly higher than those for corresponding control groups. It was concluded that 

under the conditions of the bioassay, titanium dioxide was not carcinogenic by the oral 

route for Fischer 344 rats or B6C3F1 mice. 

(Summary taken from MRID 48587801)

In a carcinogenicity study (IARC 2010), IARC summarized the available animal data on 

titanium dioxide as follows:
16

Pigmentary and ultrafine titanium dioxide were tested for 

carcinogenicity by oral administration in mice and rats, by inhalation in 

rats and female mice, by intratracheal administration in hamsters and 

female rats and mice, by subcutaneous injection in rats by 

intraperitoneal administration in male mice and female rats.

In one inhalation study, the incidence of benign and malignant lung 

tumours was increased in female rats. In another inhalation study, the 

incidences of lung adenomas were increased in the high-dose groups of 

male and female rats. Cystic keratinizing lesions that were diagnosed as 

squamous-cell carcinomas but re-evaluated as nonneoplastic pulmonary 

keratinizing cysts were also observed in the high-dose groups of female 

rats. Two inhalation studies in rats and one in female mice were 

negative.

Intratracheally instilled female rats showed an increased incidence of 

both benign and malignant lung tumours following treatment with two 

types of titanium dioxide. Tumour incidence was not increased in 

intratracheally instilled hamsters and female mice. Oral, subcutaneous 

and intraperitoneal administration did not produce a significant 

increase in the frequency of any type of tumour in mice or rats.

From these data, IARC concluded that there is sufficient evidence in experimental animals 

for the carcinogenicity of titanium dioxide however there is inadequate evidence in humans 

for the carcinogenicity of titanium dioxide. The overall conclusion was that titanium dioxide 

is possibly carcinogenic to humans (Group 2B) based on the inhalation study (Heinrich et al. 

1995). However IARC also states that titanium dioxide is a poorly soluble low toxicity (PSLT) 

particle, which can elicit overloading of lung clearance, chronic inflammation, and lung 

tumors in rats following prolonged exposure at sufficiently high concentrations of particles. 

The tumors present in the lungs may have been a localized fibrogenic effect caused by 

overloading the lungs with titanium dioxide particles. IARC also concluded that titanium 

dioxide did not induce tumors by oral, intraperitoneal or subcutaneous routes of exposure 

in rats or mice.

Dermal Absorption

No dedicated study was submitted for dermal absorption but based on anecdotal findings in 

other submitted studies; it can be assumed that the titanium dioxide particles (nonnanosized) are too large to be absorbed through the skin. The World Health Organization 

(WHO) reported at the Joint FAO/WHO Expert Committee on Food Additives 1969 (JECFA 

1969) that the compound is very insoluble and showed no significant absorption.
17

28-Day Inhalation Toxicity (summary taken from MRID 48587801)

In a 28-day inhalation toxicity study (Warheit, D., Brock, W., Lee, K et al. 2005), twenty-five 

male Chr:CD rats/group were exposed to one of six formulations of titanium dioxide for six 

hours per day, give days a week for a total of 20 exposures. A control group of 15 male rats 

were exposed to air only. Ten rats per group were subjected to a clinical laboratory 

evaluation (hematology, clinical chemistry and urinalysis) following the 20th exposure and 

five/group subjected to a clinical laboratory evaluation after a 14 day recovery period. Urine 

aminolevulinic acid concentrations and blood aminolevulinic acid dehydrase activity were 

also determined. Histopathology was conducted on the organs/tissues of five rats/ group on 

the last day of exposure and at 14 days and three, six and 12 months after exposure. 

Weights of the heart, liver, lungs, spleen, testis and thymus were recorded.

The exposure concentrations were determined gravimetrically. The particle size (mass 

medium diameter) ranged from 1.3 to 1.8 μm among the size formulations. Body weight 

was reduced in the H-11,567 titanium dioxide formulation group but was similar to the 

control group's body weight after the recovery period. No significant effects were observed 

with the other titanium dioxide formulations. The only notable clinical finding was lung 

noises in two rats (day 8 and 11, respectively) in the H-11,567 treated group; however, this 

finding was absent by study day 15. Four mortalities occurred during the study: two in the 

control group and one in the H-11,565 treated group and one in the H-11,566 treated group.

Neutrophils were significantly elevated in the H-11,564 (high dose only), H-11,566, H11,567, H-11,568 and H-11,569 treated groups. These values remained elevated after the 

14-day recovery period. No other significant findings were seen in the hematology, clinical 

chemistry and urinalysis parameters analyzed. Histological evaluation of the lungs of rats 

exposed to the titanium dioxide formulations had dust-laden alveolar macrophages which is 

consistent with the elevation in the observed number of neutrophils (see discussion below).

The mean absolute and relative lung weights of rats exposed to the six titanium dioxide 

formulations, except for the low dose H-11,565 group, were statistically elevated when 

compared to the control group. The lung weights remained elevated after the 4-week 

recovery period through the 12 month recovery period, except for the H-11,564 treated rats 

at both concentrations tested. The mean lung weight was still elevated at the high dose 

when compared to the control group.

At the end of the four-week exposure period, the inhaled dust particles of all test groups 

were heavily concentrated with the bronchioles, alveolar ducts and alveoli. The dust 

particles were mostly phagocytized by the intra-alveolar macrophages. In addition, dust cell 

accumulation and alveolar cell hyperplasia were observed in all rats exposed to H-11,564 at 

both test concentrations. A marked reduction in dust cells and alveolar cell proliferation was 

observed at the end of the 14 day and three month recovery periods; however, dust cells 

were still observed at the six and twelve month recovery periods.
18

Rats exposed to H-11,567 and H-11,569 exhibited hyperplasia of the type II pneumocytes 

and disintegration of dust cells at the three month recovery period. The hyperplasia 

persisted to the 12 month recovery period. Light collagen deposition which represents a 

fibrogenic response was observed in the H-11,567 treated group. H-11,564, H-11,565, H11,566, H-11,568 and H-11,569 exhibited slight alveolar cell hyperplasia at the end of the 

four week exposure. No effects on collagen deposition were observed.

The study authors concluded that except for H-11,567 which exhibited a slight fibrogenic 

response, the titanium dioxide formulations caused lung changes consistent with a nuisance 

dust.

90-Day Inhalation Toxicity (summary taken from MRID 48587801)

In a 90-day inhalation toxicity study (Bermudez, E., Mangum, J., Wong, B. et al. 2004), the 

comparative toxicity of ultrafine titanium dioxide particles was examined in female 

B3C3F1/CrlBR mice, CDF (F344)/CrlBr rats and Lak:LVG (SYR)BR hamsters by inhalation 

exposure for 13 weeks, 6 hours/day, 5 days/week. Groups of 25 animals for each species 

and time point where used. The animals were sacrificed after 13 weeks of exposure and at 

4, 13, 26 or 52 (49 for hamsters) after exposure had terminated. Dosage levels tested were 

0, 0.5, 2 or 10 mg/m3. Lung burden of titanium dioxide was determined in the combined 

right lung lobes and in the lung-associated lymph nodes. Left lung lobes were used to assess 

lung cell proliferation and histopathological end points. The inflammatory status of the lung 

was assessed at each time point using a separate group of animals subjected to 

bronchoalveolar lavage. Lavage fluid was assayed for lactate dehydrogenase and total 

protein and the differential cytology of recovered cells.

The mass median aerodynamic diameter particle size was determined to be 1.29 μm for 

hamsters, 1.45 μm for mice and 1.44 μm for rats. Mean measured concentrations of 

titanium dioxide were 0.54, 2.2 and 10.8 mg/m3for mice, 0.52, 2.1 and 10.5 mg/m3for rats 

and 0.53, 2.1 and 10.7 mg/m3for hamsters. Treatment related mortality was limited to mice 

(data not presented). The report states that body weight gain was depressed in mice and 

rats at the end of the exposure period and that body weight loss occurred in hamsters, but 

body weight data were not presented. Titanium dioxide burdens were equivalent at all 

exposure concentrations for rats and mice; however, lung burdens in hamsters were 2 to 5 

fold lower than those of rats and mice. Lung burdens decreased in the lung with time in all 

three species and the decreases were dose dependent. Lymph node titanium dioxide 

burden increased with time post exposure.

Statistically significant changes in the cytological profile of the cells recovered by lavage 

were limited to the mice, rats and hamsters in the high-dose group. Mice had significantly 

elevated numbers of macrophages, neutrophils and lymphocytes at the end of the exposure 

period which remained elevated until the 52 week recovery period. The same parameters 

were significantly affected in rats, but returned to normal at the 26 week recovery period. 
19

Only the percentage of neutrophils was increased in hamsters. Data were presented for the 

10 mg/m3group. Total protein and LDH were unaffected in hamsters, but increases were 

observed in mice and rats at the high dose. Terminal bronchiolar cell replication was 

statistically increased at the end of the exposure period in mice (high dose), rats (mid and 

high dose) and hamsters (high dose). Values returned to control levels by week 4 post 

exposure in rats and mice and in hamsters by week 13. Alveolar cell replication was 

statistically increased in rats at the mid- and high dose levels and returned to control levels 

at the 26 week post exposure period.

In rats, changes in the lungs at the low dose were restricted to the appearance of particles 

within alveolar macrophages and very minimal changes in the patterns of alveolar 

macrophage accumulation in the lungs. Lesions in the mid-dose group were minimal to mild 

in severity and consisted primarily of particle-laden macrophage accumulation and 

aggregation in subpleural regions and in centriacinar zones. These findings were associated 

with minimal hypertrophy and hyperplasia of type II alveolar epithelial cells. At the high 

dose in rats, there were progressively more severe epithelial proliferative changes, including 

metaplastic changes in the centriacinar region associated with particle burden. No lesions 

were seen in the low and mid-dose mice. At the high dose, there was little epithelial change 

and the lesions consisted primarily of aggregations of heavily particle-laden macrophages 

concentrated in centriacinar sites. Only alveolar and interstitial macrophages containing 

particles and occasional aggregation of particle-laden macrophages at the high dose were 

seen in hamsters.

There were also treatment related mortalities. Four mice died during exposure phase of the 

study. Four more mice and seven rats died in post exposure phase. Hamsters had the 

greatest morbidity and mortality at 35 in the post exposure phase but the authors believe 

this was due to age-related conditions such as chronic renal disease. No control groups were 

used. 

The study authors concluded that "[t]aken together, the species differences observed in this 

study reflect the outcome of previously reported chronic exposures to poorly soluble 

particulates for each species and suggest that susceptibility of the rat, under pulmonary 

overload conditions, to the induction of lung tumors by these materials has underlying 

components of dosimetry and biological response". The lowest NOAEL was 2.1 mg/m3found 

for rats. However due to the uncertainty and lack of data pertaining to the effects which 

constituted the LOAEL, this study is not used for inhalation exposure risk assessment 

purposes.

Subchronic, Reproductive and Genetic Toxicity Summary

Table 3. Subchronic, Reproductive and Genetic Toxicity Data Summary.
20

TOX PROFILE: Titanium Dioxide

Guideline No./Study 

Type

Dose levels (ppm or 

mg/kg bw/day)

MRID No./Ref. 

(year)*

Results

870-3050 Repeated 

Dose 28-Day Oral 

Toxicity Study in 

Rodents (nonguideline)

10% (100,000 ppm) 

TiO2 for 30-34 days

West, B. Wyzan, 

H. (1963)

No treatment related effects were observed.

870-3100 90-Day 

Oral Toxicity in Rats 

(non-guideline)

0, 1.0, 3.16 & 10% 

TiO2 for 90 days

Bernard B.K. et al 

(1990)

No compound related effects on behavior, growth, 

food consumption or mortality were observed. Organs 

and tissues showed neither consistent gross changes 

nor histopathological changes that could be attributed 

to dietary abministration of titanium coated mica.

870-3150 90-Day 

Oral Toxicity in 

Nonrodents (nonguideline)

0.05, 0.1 and 0.15g 

TiO2 for 1 or 2 

months (Dogs)

Vernetti-Blina 

(1928)

No toxic effects were seen in dogs.

870-3100 90-Day 

Oral Toxicity in 

rats/mice (nonguideline)

6,250, 12,500, 

25,000, 50,000 or 

100,000 ppm 

NCI Bioassay of 

Titanium Dioxide 

(1979)

No mortality and mean body weight gains similar to 

controls. No gross or microscopic pathology was found 

pertaining to test chemical in rats or mice.

870-4100 Chronic 

Oral Toxicity in 

rats/mice (nonguideline)

25,000 or 50,000 

ppm

NCI Bioassay of 

Titanium Dioxide 

(1979)

No evidence of toxicity based on growth rate, 

mortality or other clinical signs for either dosed rats or 

mice after 104 weeks.

870-4100 Chronic 

Toxicity (nonguideline)

1 dog & 2 rabbits 

(9g/day), 2 cats 

(3g/day), 2 guinea 

pigs (0.6g/day) for 

390 days

Lehmann & 

Herget (1927)

No signs of systemic toxicity were observed in these 

animals.

870.3800 

Reproductive Toxicity 

in rats (nonguideline)

0, 1 and 2% TiO2 for 

65 days. 

(500mg/kg.day and 

1000mg/kg/day)

MRID 48587801

El-Sharkawwy, N., 

Hamza, S., and 

Abou-Zeid, E. 

(2010)

The LOAEL was 1% titanium dioxide in the diet which is 

approximately 500 mg/kg/day. This is 1/2 times the 

limit dose. Not clear on TiO2 particle size, most likely 

nanosized.

870.4200 

Carcinogenicity –

Oral (non-guideline)

25,000 ppm and 

50,000 ppm for 103 

weeks.

NCI Bioassay of 

Titanium Dioxide 

(1979)

Titanium dioxide was not carcinogenic by the oral 

route for Fischer 344 rats or B6C3F1 mice.

870.4200 

Carcinogenicity –

Inhalation (nonguideline)

Average of 10mg/m3 

for 2 years

IARC (2010) Inadequate evidence in humans for the carcinogenicity 

of TiO2 and there is sufficient evidence in experimental 

animals for the carcinogenicity of TiO2. TiO2 is possibly 

carcinogenic to humans.

870.5000 In Vitro

Sister Chromatid 

Exchange Assay/ In 

Vitro Micronucleus 

Assay (non-guideline)

0, 1, 2, 3, 5, 7.5 or 10 

μM.

MRID 48587801

Turkez, H. (2008)

Sister-chromatid exchanges (SCE) were increased in a 

dose-related manner at conc. of 2 μM and above.

Micronuclei were increase at TiO2 conc. of 5 μM and 

above.

870.5000 DNA 

Damage: Formation 

of 8-Oxoguanine in 

rats(non-guideline)

Single dose of 0.15, 

0.3, 0.6, and 1.2 mg 

suspended in 0.2 mL 

of saline containing 

0.25% lecithin.

MRID 48587801

Rehn, B., Seiler, F., 

Rehn, S. et al. 

(2002)

Animals exposed to TiO2 showed no difference in the 

amount of 8-oxoGua than the control.

870.5375 In Vitro

Micronucleus Assay 

and Comet Assay 

(non-guideline)

Rutile (nanosize), 

Rutile (fine) and 

Anatase nanopowder 

Conc. 1- 100 μg/cm2

MRID 48587801

Falck, G., 

Lindberg, H., 

Suhonen, S. et al. 

All three forms caused DNA damage in the Comet 

assay. None produced a potent response. Only 

nanosized anatase induced micronuclei in BEAS 28B 

cells after 72 hours but not at 24 or 48 hours.
21

(2009)

870.5100 Bacterial 

Reverse Mutation 

Test (non-guideline)

100, 333, 1000, 333 

and 5000 μ/plate.

MRID 48587801

Warheit, D., Hoke, 

R., Finlay, C. et al 

(2007)

Uf-C TiO2 did not produce a positive response in any of 

the test strains either in the presence or absence of 

metabolic activation.

870.5375 In Vitro 

Mammalian 

Chromosome 

Aberration Test (nonguideline)

750, 1250 and 2500 

μg/mL 4 hour nonactivated test.

62.5, 125 and 250 

μg/mL 4 hour active 

test.

25, 50 and 100 

μg/mL 20 hour nonactivated test.

MRID 48587801

Warheit, D., Hoke, 

R., Finlay, C. et al. 

(2007)

Uf-C TiO2 did not produce structural or numerical 

aberrations under the conditions of the study.

870.3465 28-Day 

Inhalation Toxicity in 

rats (non-guideline)

85% to 99% TiO2 MRID 48587801

Warheit, D., 

Brock, W., Lee, K 

et al. (2005)

Except for rats exposed to 85%, which exhibited a 

slight fibrogenic response, the TiO2 formulations 

caused lung changes consistent with a nuisance dust.

870.3465 90-Day 

Inhalation toxicity in 

rats, mice, hamsters 

(non-guideline)

0, 0.5, 2 or 10 mg/m3 MRID 48587801

Bermudez, E., 

Mangum, J., 

Wong, B. et al 

(2004)

The LOAEL was assumed to be 2.1 mg/m3for rats. 

However there are not enough details in the study on 

the effects to the animals to use this LOAEL for risk 

assessment purposes.

5.2 Toxicity Endpoint Selection

The available toxicity studies on titanium dioxide via oral route of exposure clearly 

demonstrate lack of toxicity. The several studies in mice, rats, dogs, cats, rabbits and other 

species of varying durations do not indicate toxicity at very high doses (e.g. 50,000 ppm 

dietary exposure for two years in rats). No endpoint of concern via the oral route of 

exposure has been identified in the available database. Therefore, a dietary exposure

assessment was not conducted. This conclusion is in agreement with the World Health 

Organization (WHO) Committee on Food Coloring Materials determination that no ADI 

need be set for the use of titanium dioxide based on the range of acute, sub-acute and 

chronic toxicity assays, all showing low mammalian toxicity. Similarly, no significant toxicity 

of titanium dioxide is expected via the dermal route of exposure. All currently registered 

uses of titanium dioxide as an inert ingredient in lambda-cyhalothrin, and all anticipated 

uses of titanium dioxide as an inert ingredient in napropamide formulations, do not include 

residential applications. Therefore no residential risk assessment was performed. The 

available inhalation studies indicate that the primary toxicity of titanium dioxide is due to 

deposition of the inhaled particles and also suggest possible carcinogenic effects due to 

prolong exposure. An occupational inhalation exposure assessment was not conducted 

based on the fact that the formulation type and use patterns of products that contain 

titanium dioxide do not result in direct exposure to titanium dioxide particles by mixers, 

loaders and applicators of pesticides as well as post application (reentry) exposure).
22

6. EXPOSURE ASSESSMENT

Titanium dioxide is currently approved for use in a significant number of pharmaceutical, 

cosmetic, industrial and food products. Therefore, the potential for aggregate exposure 

from dietary and non-dietary routes does exist for titanium dioxide. While it is difficult to 

develop a precise estimate of total human exposure to titanium dioxide, its low toxicity at 

relatively high doses indicate that expected exposures are likely to be of low toxicological 

concern. The acute and chronic dietary (food and water) exposure assessments were not 

conducted because no endpoint of concern has been identified in the available database.

6.1 Cancer.

Carcinogenicity via Oral Route:

Based on the National Cancer Institute (NCI) (1979) carcinogenicity study on male and 

female mice, tumors did not occur at incidences that were significantly higher than 

those for corresponding control groups when dosed at 25,000 or 50,000 ppm over 104 

weeks via oral administration. However in female rats, C-cell adenomas or carcinomas 

of the thyroid occurred at incidences that were dose related but were not high enough 

to meet the level required by the Bonferroni criterion. Thus, these tumors of the thyroid 

were not considered to be related to the administration of the test chemical. They 

concluded that under the conditions of the bioassay, titanium dioxide was not 

carcinogenic by the oral route for Fischer 344 rats or B6C3F1 mice.

The International Agency for Research on Cancer (IARC) review for titanium dioxide also 

concluded that oral, subcutaneous and intraperitoneal administration did not produce a 

significant increase in the frequency of any type of tumor in mice or rats. 

An oral cancer risk assessment for titanium dioxide was not performed based on the 

results of carcinogenicity studies in mice and rats, and conclusions by the IARC.

Carcinogenicity via Inhalation Route:

The IARC review on titanium dioxide concluded that there may be some evidence of 

carcinogenicity via inhalation however these effects may be attributable to overloading 

of lung clearance and chronic inflammation following prolonged exposure at high 

particle concentrations of titanium dioxide.

Occupational exposure to titanium dioxide may occur via the inhalation route; however 

any concern for carcinogenicity is addressed by health-protective exposure levels 

established by under the Occupational Safety and Health Administration’s (OSHA) 

Permissible Exposure Limit (PEL) for titanium dioxide. OSHA does not regulate titanium 

dioxide as a carcinogen. The OSHA permissible exposure limit for titanium dioxide is 15 

mg/m3, as total dust, expressed as an 8-hour time-weighted average. These 
23

concentration levels far exceed actual expected occupational exposure concentrations

of titanium dioxide n pesticide formulations Therefore, an inhalation cancer risk 

assessment for occupational exposure was not conducted and there are no occupational 

risks of concern

7. RESIDENTIAL EXPOSURE/RISK PATHWAY

Based on the use patterns of products that would contain 5% titanium dioxide by weight in 

pesticide formulations containing the active ingredient napropamide, there are no uses that 

would be applied in and/or around the home or in a way which would results in residential 

exposures, therefore a residential exposure risk assessment is not required and there are no 

residential risks of concern.

8. AGGREGATE RISK AND DETERMINATION OF SAFETY

In examining aggregate exposure, FFDCA section 408 directs EPA to consider available 

information concerning exposures from the pesticide residue in food and all other nonoccupational exposures, including drinking water from ground water or surface water and 

exposure through pesticide use in gardens, lawns, or buildings (residential and other indoor 

uses). FFDCA section 408 provides that EPA shall also apply an additional tenfold margin of 

safety for infants and children in the case of threshold effects in calculating a dose level that 

to account for pre- and post-natal toxicity and the completeness of the database unless EPA 

determines that a different margin of safety will be safe for infants and children. Margins of 

safety are incorporated into EPA risk assessments either directly through the use of margin 

of exposure analysis or through using uncertainty (safety) in calculating a dose level that 

poses no appreciable risk to humans. 

Titanium dioxide has two exemptions from the requirement of a tolerance:, 40 CFR § 

180.920 pesticide formulations applied to growing crops and 40 CFR § 180.930 pesticide 

formulations applied to animals. Titanium dioxide is also approved for use as a colorant in 

food (21 CFR § 73.575), in drugs (21 CFR § 73.1575), and in cosmetics (21 CFR § 73.2575; 21 

CFR § 73.3126). There has also been a previous exemption from requirement of a tolerance 

for residues in or on growing crops, when used as an inert ingredient (UV protectant) in 

microencapsulated formulations of the insecticide lambda-cyhalothrin at no more than 3.0% 

by weight or the formulations (40 CFR § 180.1195).

8.1 Acute Aggregate Risk
24

There was no hazard attributable to a single exposure seen in the toxicity database for 

titanium dioxide; therefore, an acute aggregate risk assessment is not required.

8.2 Short-Term/Intermediate-Term Aggregate Risk

The short-term and intermediate-term aggregate risk includes chronic dietary exposures 

to food and drinking water and short- or intermediate-term residential exposures. There 

are currently no active registrations for titanium dioxide as used under the existing and 

proposed tolerance exemptions that may result in residential exposures. Chronic 

dietary risk was not assessed due to the absence of any hazards identified in the toxicity 

database. Therefore short-term and Intermediate-term aggregate risks for titanium 

dioxide are considered not of concern. 

8.3 Long-Term Aggregate Risk

The long-term aggregate risk includes chronic dietary exposures to food and drinking 

water only. There are currently no active registrations for titanium dioxide as used 

under the existing and proposed tolerance exemptions that may result in residential 

exposures. Chronic dietary risk was not assessed due to the absence of any hazards 

identified in the toxicity database. Therefore, long-term (chronic) aggregate risks for 

titanium dioxide are not expected to be of concern.

9. OCCUPATIONAL EXPOSURE/RISK PATHWAY

The Agency has considered uses of products that would contain titanium dioxide at 5% of 

formulation with napropamide and has determined that there may be a concern for 

occupational exposure.

9.1 Handler Risk

Occupational dermal and inhalation exposure is expected to be low because of personal 

protective equipment requirements associated with the use of pesticide products 

containing napropamide and lambda-cyhalothrin. However due to the classification of 

titanium dioxide as possibly carcinogenic to humans by IARC, there is a potential 

concern for cancer risk via inhalation exposure by workers. However, worker inhalation 

exposures to titanium dioxide, based on the considered uses of products that would 

contain titanium dioxide at 5% in napropamide formulations, are orders of magnitude 

less than levels associated with increased tumor incidence in animal studies and as well 

as occupational exposure levels allowed by the Occupational Safety and Health 
25

Administration (OSHA) or The American Conference of Governmental Industrial 

Hygienists (ACGIH). The OSHA Permissible Exposure Limit (PEL) for General Industry (29 

CFR 1910.1000) is set to 15 mg/m3TWA. The ACGIH Threshold Limit Value (TLV) is 10 

mg/m3TWA and OSHA does not classify titanium dioxide as a human carcinogen. 

9.2 Occupational Post Application Risk

Inhalation exposures are not typically considered for occupational post-application 

scenarios because inhalation exposures generally account for a negligible percentage of 

the overall body burden for most pesticide chemicals. Therefore occupational post 

application exposure is not expected to be of concern.

10. CUMULATIVE EXPOSURE

Cumulative effects from substances with a common mechanism of toxicity, Section 

408(b)(2)(D)(v) of Federal Food, Drug and Cosmetic Act (FFDCA) requires that, when 

considering whether to establish, modify, or revoke a tolerance, the Agency consider 

“available information” concerning the cumulative effects of a particular pesticide’s residues 

and “other substances that have a common mechanism of toxicity.”

EPA has not found a common mechanism of toxicity with any other substances. Titanium 

dioxide for the purposes of this tolerance action is assumed to not have a common 

mechanism of toxicity with other substances. For information regarding EPA’s efforts to 

determine which chemicals have a common mechanism of toxicity and to evaluate the 

cumulative effects of such chemicals, see EPA’s website at 

http://www.epa.gov/pesticides/cumulative. 

11. ENVIRONMENTAL FATE CONSIDERATIONS

Titanium dioxide is a stable inorganic compound that is insoluble in water. Titanium dioxide

is naturally occurring and is found in both sediments and soils. Titanium dioxide is a solid at 

environmentally relevant temperatures and pressures and is therefore not expected to 

volatilize into the atmosphere. 

12. ECOTOXICITY

In an acute toxicity to freshwater fish study (Warheit, D., Hoke, R., Finlay, C. et al. 2007), fine 

(99% titanium dioxide and 1% alumina; particle size ~0.380 μm) and ultrafine titanium 

dioxide (90% titanium dioxide, 7% alumina and 1% amorphous silica; 80:20 ratio of 
26

anatase:rutile; particle size 0.140 μm) was determined in rainbow trout (Oncorhynchus 

mykiss). There was no mortality in the test at the end of 96 hours. The 96 hour LC50 for both 

titanium dioxide test materials was > 100 mg/L. Titanium dioxide is considered practically 

nontoxic to freshwater fish on acute bases.

In an acute toxicity to freshwater invertebrate study (Warheit, D., Hoke, R., Finlay, C. et al. 

2007), fine (99% titanium dioxide and 1% alumina; particle size ~0.380 μm) and ultrafine 

titanium dioxide (90% titanium dioxide, 7% alumina and 1% amorphous silica; 80:20 ratio of 

anatase:rutile; particle size 0.140 μm) was determined in Daphnia magna under static, 

unaerated test conditions. The 48 hour EC50 based on nominal concentrations for both 

titanium dioxide test materials was > 100 mg/L. Titanium dioxide is considered practically 

nontoxic to freshwater invertebrates on acute bases.

In an acute toxicity to green algae study (Warheit, D., Hoke, R., Finlay, C. et al. 2007), fine 

(99% titanium dioxide and 1% alumina; particle size ~0.380 μm) and ultrafine titanium 

dioxide (90% titanium dioxide, 7% alumina and 1% amorphous silica; 80:20 ratio of 

anatase:rutile; particle size 0.140 μm) was determined in green algae species 

Pseudokirchneriella subcapitata static test conditions. The algae 72 hour EC50 values (95% 

fiducial limits) based on inhibition of growth and healthy cell counts were 16 (12-22) mg/L

for fine titanium dioxide particles and 21 (16-26) mg/L for ultrafine particles. The 72 hours 

EC50 values (95% fiducial limits) for growth rate based on nominal concentrations and 

healthy cell counts were 61 (52-72) mg/L for fine particles and 87 (83-91) mg/L for ultrafine 

particles.

Based on the 2005 FQPA reassessment of titanium dioxide, there was an acute aquatic 

toxicity study available from 2002 ECOTOX database. The one cited was a fathead minnow 

study which produced a LC50 > 1000 mg/L which supports the conclusion that titanium 

dioxide is practically nontoxic to freshwater fish on an acute bases. 

Based on the three studies submitted for acute fish toxicity, acute invertebrate toxicity and 

algal toxicity titanium dioxide and the study cited form the 2005 FQPA reassessment, 

titanium dioxide may be classified as practically non-toxic to aquatic organisms. Based on 

the insoluble nature of titanium dioxide in water and the low acute toxicity of titanium 

dioxide to freshwater fish, there are no non-target aquatic species risk concerns resulting 

from the use of titanium dioxide as an inert ingredient. Based on the lack of absorption data 

that was identified in the toxicological effects in the animal testing, there are very low risks 

for non-target terrestrial organisms resulting from the use of titanium dioxide being used as 

an inert ingredient. 

13. ENVIRONMENTAL JUSTICE STATEMENT
27

Potential areas of environmental justice concerns, to the extent possible, were considered 

in this human health risk assessment, in accordance with U.S. Executive Order 12898, 

"Federal Actions to Address Environmental Justice in Minority Populations and Low-Income 

Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, IIAB estimates 

risks to population subgroups from pesticide exposures that are based on patterns of that 

subgroup’s food and water consumption, and activities in and around the home that involve 

pesticide use in a residential setting. Extensive data on food consumption patterns are 

compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and 

are used in pesticide risk assessments for all registered food uses of a pesticide. These data 

are analyzed and categorized by subgroups based on age, season of the year, ethnic group, 

and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, 

specialized subgroups and exposure assessments are performed when conditions or 

circumstances warrant. Whenever appropriate, non-dietary exposures based on home use 

of pesticide products and associated risks for adult applicators and for toddlers, youths, and 

adults entering or playing on treated areas post application are evaluated. Further 

considerations are currently in development as OPP has committed resources and expertise 

to the development of specialized software and models that consider exposure to 

bystanders and farm workers as well as lifestyle and traditional dietary patterns among 

specific subgroups.

14. RISK CHARACTERIZATION

The petitioner, United Phosphorus Inc., submitted a request (Petition # 1E7918) to the EPA 

for an amendment of an existing tolerance exemption for the food use inert ingredient, 

titanium dioxide (CAS Reg. No. 13463-67-7) when used as a pesticide in or on growing crops 

as an inert ingredient (UV protectant) in microencapsulated formulations of the insecticide 

lambda-cyhalothrin at no more than 3.0% by weight of the formulation (40 CFR § 180.1195

to include the use of titanium dioxide as an inert ingredient (UV-stabilizer) at no more than 

5% in napropamide pesticide formulations. The acute toxicity of titanium dioxide is very 

minimal. There were no acute toxicological end points of concern identified in the acute 

toxicity database. Subchronic and chronic oral toxicity studies performed on rats and mice 

up to 50,000 ppm and over 2 years showed no toxicity. There were no guideline 

reproductive or developmental studies submitted or in the database. Genotoxicity results 

were mixed and inconclusive. It was concluded that titanium dioxide was not carcinogenic 

via the oral route however there are concerns via inhalation. The tumors present in the 

lungs may have been a localized fibrogenic effect caused by overloading the lungs with high 

concentrations of titanium dioxide particles over a prolonged period. IARC also concluded 
28

that titanium dioxide did not induce tumors by oral, intraperitoneal or subcutaneous routes 

of exposure in rats or mice.

The acute and chronic dietary (food and water) exposure assessments were not conducted 

because no endpoint of concern has been identified in the available database. Based on the 

use products that would contain 5% titanium dioxide by weight in pesticide formulations 

containing the active ingredient napropamide, there are no uses that would be applied in 

and/or around the home or in a way which would results in residential exposures, therefore 

a residential exposure risk assessment is not required and there are no residential risks of 

concern. There was also no aggregate risk assessments performed since there was no single 

exposure, dietary or drinking water endpoints of concern. Titanium dioxide is a stable 

inorganic compound that is insoluble in water. Titanium dioxide is a solid at environmentally 

relevant temperatures and pressures and is therefore not expected to volatilize into the 

atmosphere. Based on the insoluble nature of titanium dioxide in water and the low acute 

toxicity of titanium dioxide to freshwater fish, there are no non-target aquatic species risk 

concerns resulting from the use of titanium dioxide as an inert ingredient. Based on the lack 

of absorption data that was identified in the toxicological effects in the animal testing, there 

are very low risks for non-target terrestrial organisms resulting from the use of titanium 

dioxide being used as an inert ingredient.

Taking into consideration all available information on titanium dioxide, EPA concludes that 

there is a reasonable certainty that no harm will result to the general population when 

titanium dioxide is used as an inert ingredient. The establishment of an exemption from 

tolerance for food use for residues of titanium dioxide when used as an inert ingredient (UV 

protectant) applied to growing crops in pesticide formulations containing the active 

ingredient napropamide at no more than 5.0% by weight of the formulation can be 

considered safe under section 408 of the FFDCA. This approval granted only for the use of 

micronized form of titanium dioxide and nano sized is prohibited.

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