Registration Dossier

Administrative data

Description of key information

No reliable results are available for acute toxicity of synthetic rutile. Therefore, read-across is proposed to available data on TiO2.
Acute toxicity, oral:
LD50 > 5000mg/kg bw
Acute toxicity, inhalation:
LC50 > 6.82mg/L (MMAD=1.55 µm, GSD=1.70 µm)
Acute toxicity, dermal:
Conduct of an acute dermal toxicity study is unjustified as inhalation of the substance is considered as major route of exposure and physicochemical properties and dermal absorption data of the substance do not suggest a significant rate of absorption through the skin (cf. Annex VIII section 8.5 Column 2 of regulation (EC) 1907/2006).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2006-05-10 to 2006-08-01
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study; no GLP compliance statement.
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
GLP compliance:
no
Test type:
up-and-down procedure
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
other: Crl:CD(SD)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, North Carolina
- Age at study initiation: 9-11 weeks
- Fasting period before study: 16-18 hours
- Housing: All animals were housed singly in stainless steel, wire-mesh cages suspended above cage boards.
- Diet: ad libitum; PMI® Nutrition International, LLC Certified Rodent LabDiet® 5002
- Water: ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-26
- Humidity (%): 30-70
- Photoperiod: 12-hour light/dark cycle
No further details are given.
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
Individual dose volumes were calculated using the fasted body weights obtained prior to dosing. The rats were dosed at a volume of 10 ml per kg of body weight. The dosing suspensions were stirred prior to and throughout the dosing procedure. A single oral dose of H-27416, suspended in deionised water, was administered by oral gavage to one fasted fasted female rat each.
Doses:
175, 550 and 1750 mg/kg and three fasted female rats at a dose of 5000 mg/kg
No. of animals per sex per dose:
6 rats: 1 or 3 rats per dose
Control animals:
not specified
Details on study design:
The rats were dosed one at a time at a minimum of 48-hour intervals.
Observations for mortality and signs of illness, injury, or abnormal behavior were made daily throughout the study. The rats were observed for clinical signs at the beginning of fasting, just before dosing (test day 0), once during the first 30 minutes after dosing and 2 more times on the day of dosing, and once each day thereafter. The rats were weighed on test days –1, 0, 7, and 14. On test day 14, the surviving rats were euthanized and necropsied to detect grossly observable evidence of organ or tissue damage or dysfunction. The rats were anesthetised by carbon dioxide and euthanised by exsanguination.
Statistics:
A software package (A0T425StatPgm)a was used to determine the dose progression and to calculate the LD50.
Preliminary study:
no data
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Mortality:
No deaths occurred.
Clinical signs:
The rat dosed at 1750 mg/kg and the three rats dosed at 5000 mg/kg exhibited grey colored feces beginning the day after dosing and up to 5 days after dosing.
Body weight:
No biologically important body weight loss occurred after dosing.
Gross pathology:
No gross lesions were present in the rats at necropsy.
Other findings:
no
Interpretation of results:
practically nontoxic
Remarks:
Migrated information for the tested doses Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of this study, the oral LD50 for titanium dioxide (sample: H-27416) was greater than 5000 mg/kg for female rats.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
5 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Read across concept

Synthetic rutile consists primarily of a titanate phase (solid solution) most of which is titanium in an oxidised form. Upon ingestion, a low rate of dissolution in the GI tract is assumed, based on the experimental verified inertness of the material. Any material being released from Synthetic rutile under physiological conditions will be in the form of ionic titanium, which is similarly the case for titanium dioxide, thus read-across from repeated dose oral toxicity data on titanium dioxide is considered feasible without any restrictions.

Furthermore, transformation/dissolution testing according to “OECD 29 Environmental Health and Safety Publications, Series on testing and assessment, Guidance document on transformation/ dissolution of metals and metal compounds in Aqueous media” has shown that synthetic rutile compared to titanium dioxide has a similar release rate of titanium ions (please refer to the respective entry under the endpoint water solubility).

The conduct of an acute inhalation toxicity study is unjustified as inhalation of the substance is considered negligible, based on the outcome of the dustiness testing according to method EN 15051/ DIN 33897-2, as reported under section particle size distribution (granulometry). The results demonstrate that synthetic rutile has a limited ability to be inhaled by humans: 0.025 % of airborne material is estimated to be inhalable, whereas about 0.002 % or less of inhaled material is predicted to be deposited in the pulmonary region (PU), i.e. respirable fraction. The material deposited in the tracheobronchial (TB) and the extrathoracic region (Head) may be assumed to be cleared to the GI tract (i.e., by mucociliary escalation and subsequent swallowing).

Several animal studies on acute oral exposure are available, conducted according to OECD guidelines 401, 420, 425 or according to state of the art methodology at that time. They indicate that oral LD50 is in excess of 25000 mg/kg bw in rats. However, the study selected as key study reports a LD50 > 5000mg/kg bw in rats which will be used further for the human health hazard assessment.

There are no reliable reports whatsoever on acute dermal toxicity in the public domain. However, the conduct of an acute dermal toxicity study is unjustified as ingestion of the substance is considered as major route of exposure and physico-chemical properties and dermal absorption data of the substance do not suggest a significant rate of absorption through the skin (cf. Annex VIII section 8.5 Column 2 of regulation (EC) 1907/2006).

Justification for classification or non-classification

Acute oral toxicity

The reference Finlay, C. (2006) is considered as the key study for acute oral toxicity and will be used for classification. Rats were dosed at 175, 550, 1750 and 5000 mg/kg orally via gavage. During the conduct of the study no mortalities occurred, no biologically important body weight loss occurred after dosing, and no gross lesions were present in the rats at necropsy.

LD50 oral, rat > 5,000 mg/kg bw

The classification criteria acc. to regulation (EC) 1272/2008 as acutely toxic are not met since the ATE is above 2000mg/kg body-weight, hence no classification required.

It is considered that these conclusions can be read across to Synthetic Rutile.

 

Specific target organ toxicant (STOT) – single exposure: oral

The classification criteria acc. to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – single exposure, oral are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value, oral for a Category 1 classification of 300 mg/kg bw and at the guidance value, oral for a Category 2 classification of 2000 mg/kg bw. No classification required.

It is considered that these conclusions can be read across to Synthetic Rutile.

Acute inhalation toxicity and Specific target organ toxicant (STOT) – single exposure: inhalation

The conduct of an acute inhalation toxicity study is unjustified as inhalation of the substance is considered negligible, based on the outcome of the dustiness testing according to method EN 15051/ DIN 33897-2, as reported under section particle size distribution (granulometry). The results demonstrate that synthetic rutile has a limited ability to be inhaled by humans: 0.025 % of airborne material is estimated to be inhalable, whereas about 0.002 % or less of inhaled material is predicted to be deposited in the pulmonary region (PU), i.e. respirable fraction. The material deposited in the tracheobronchial (TB) and the extrathoracic region (Head) may be assumed to be cleared to the GI tract (i.e., by mucociliary escalation and subsequent swallowing).

It is considered that these conclusions can be read across to Synthetic Rutile.