Tetrasodium enneatitanium icosaoxide hydrate

Endpoint summary

Description of key information

Acute toxicity: 
Acute (single dose, fixed dose method) Oral (gavage) Toxicity Study, Rat (Wistar strain) f - (GLP, OECD Guideline 420, EU Method B1 bis): LD50 >2000 mg/kg bw (actual dose received) (female). 
Acute (24-hour, fixed dose method) Dermal (semiocclusive) Toxicity Study (Limit Test), Rat (Wistar Strain) m/f - (GLP, OECD Guideline 402, EU method B3): LD50 >2000 mg/kg bw (actual dose received) (male/female) 

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

4.11.2014-3.12.2014

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

The study was performed by following the recommended method (OECD Guideline for Testing of Chemicals No 420 “Acute Oral Toxicity - Fixed Dose Method” (2001) and Method B1 bis Acute Toxicity (Oral) of Commission Regulation (EC) No. 440/2008 ) and GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Version / remarks:

2001

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)

Version / remarks:

(EC) No. 440/2008

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Certificate is as an attachment to the study report

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories UK Ltd., Oxon, UK.
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: 157 - 186 g
- Fasting period before study: Overnight
- Housing: The animals were housed in groups of up to four in suspended solid-floor polypropylene cages furnished with woodflakes.
- Diet (e.g. ad libitum): 2014C Teklad Global Rodent diet supplied by Harlan Laboratories UK Ltd., Oxon, UK
- Water (e.g. ad libitum): tap water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25 °C
- Humidity (%): 30 to 70%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

arachis oil

Remarks:

Arachis oil BP was used because the test item did not dissolve/suspend in distilled water.

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 30 mg/ml or 200 mg/ml
- Amount of vehicle (if gavage): 10 ml/kg
- Justification for choice of vehicle: Arachis oil BP was used because the test item did not dissolve/suspend in distilled water.

MAXIMUM DOSE VOLUME APPLIED: 10 ml

Doses:

In the absence of data regarding the toxicity of the test item, 300 mg/kg was chosen as the starting dose
- Dose level (mg/kg: 300 mg/kg
- Concentration (mg/ml): 30
- Dose volume (ml/kg): 10

In the absence of toxicity at a dose level of 300 mg/kg, five additional animals was treated as follows:
- Dose level (mg/kg): 2000
- Concentration (mg/ml): 200
- Dose Volume (ml/kg): 10

No. of animals per sex per dose:

Dose 300 mg/kg: 1 female
Dose 2000 mg/kg: 5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations were made half, 1, 2, and 4 hours after dosing and then daily for fourteen days. Morbidity and mortality checks were made twice daily. Individual body weights were recorded on Day 0 (the day of dosing) and on Days 7 and 14.
- Necropsy of survivors performed: yes.
- Other examinations performed: Clinical signs and body weight. Gross necropsy, including external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded.

Statistics:

The test item was classified according to Annex 3 of the OECD Guidelines for Testing of Chemicals No. 420 "Acute Oral Toxicity - Fixed Dose Method" (adopted 17 December 2001)

Evaluation of data included identification of the number of animals that died during the study (or that were killed for humane reasons), and determination of the nature, severity, onset and duration of the toxic effects. If possible, the signs of evident toxicity were described. Evident toxicity refers to the toxic effects of sufficient severity that administration of the next higher dose level could result in development of severe signs of toxicity and probable mortality. Effects on body weights and abnormalities noted at necropsy were also identified.
Using the mortality data obtained, an estimate of the acute oral median lethal dose (LD50) of the test item was made.

Preliminary study:

The sighting study included administering a dose of 300 mg/kg of test item to a female. At the absence of any signs of toxicity, a female was dosed with 2000 mg/kg of test item. At the absence of any signs of toxicity, four females were administered 2000 mg/kg test item.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There was no mortality (see table 1, Any other information on results incl. tables).

Clinical signs:

other: No signs of systemic toxicity were noted during the observation period (see table 1, Any other information on results incl. tables).

Gross pathology:

No abnormalities detected at necropsy (see table 3, Any other information on results incl. tables.)

Other findings:

No effects were noted.

Table 1. Individual Clinical Observations and Mortality Data

Dose level (mg/kg	Animal number and sex	Effects Noted After Dosing (Hours)				Effects Noted During Period After Dosing (Days)
		0.5	1	2	4	1	2	3	4	5	6	7	8	9	10	11	12	13	14
300	1-0 F	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	2-0 F	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	3-0 F	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	3-1 F	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	3-2 F	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	3-3 F	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

Table 2. Individual Body Weights and Body Weight Changes

Dose level (mg/kg	Animal number and sex	Body weight (g) a Day			Body Weight Gain (g) During Week
		0	7	14	1	2
300	1-0 F	170	189	197	19	8
2000	2-0 F	166	185	205	19	20
	3-0 F	167	186	198	19	12
	3-1 F	157	174	193	17	19
	3-2 F	176	184	189	8	5
	3-3 F	186	199	206	13	7

Table 3. Individual Necropsy Findings.

Dose level (mg/kg	Animal number and sex	Time of Death	Macroscopic Observations
300	1-0 F	Killed day 14	No abnormalities detected
2000	2-0 F	Killed day 14	No abnormalities detected
	3-0 F	Killed day 14	No abnormalities detected
	3-1 F	Killed day 14	No abnormalities detected
	3-2 F	Killed day 14	No abnormalities detected
	3-3 F	Killed day 14	No abnormalities detected

Interpretation of results:

GHS criteria not met

Remarks:

According to GHS, the substance is unclassified.

Conclusions:

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 2000 mg/kg body weight (Globally Harmonized Classification System - Unclassified).

Executive summary:

The toxicity of the test item was studied through a sighting test on one Wistar Rat with a starting dose of 300 mg/kg. As the starting dose induced no signs of toxicity, the dose was increased to 2000 mg/kg. As the Wistar Rat showed no signs of toxicity, four more rats were administered 2000 mg/kg of test item. After a 14 day observation period the lives of the rats were terminated.

There were no deaths and no signs of systemic toxicity were noted during the observation period. All animals showed expected gains in body weight over the observation period. No abnormalities were noted at necropsy.

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 2000 mg/kg body weight (Globally Harmonized Classification System - Unclassified).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The study is a GLP compliant and was performed by following the recommended method (OECD Guideline for Testing of Chemicals No 420 “Acute Oral Toxicity - Fixed Dose Method” (2001) and Method B1 bis Acute Toxicity (Oral) of Commission Regulation (EC) No. 440/2008). It has a Klimisch score of 1.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

20.4.2015-4.5.2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

The test was performed according to recommended test Guidelines (OECD Guideline for the Testing of Chemicals No. 402 “Acute Dermal Toxicity” (adopted 24 February 1987) and Method B3 Acute Toxicity (Dermal) of Commission Regulation (EC) No. 440/2008) and GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

Adopted 24.2.1987

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Version / remarks:

(EC) No. 440/2008

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

The certificate is as an attachment to the study report

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories UK Ltd., Oxon, UK.
- Age at study initiation: 8 to 12 weeks
- Weight at study initiation: males 251 - 274 g, females 208-224 g
- Fasting period before study: No
- Housing: The animals were housed in suspended solid floor polypropylene cages furnished with woodflakes.
- Diet (e.g. ad libitum): 2014C Teklad Global Rodent diet supplied by Harlan Laboratories UK Ltd., Oxon, UK
- Water (e.g. ad libitum): tap water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25
- Humidity (%): 30 to 70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Vehicle:

arachis oil

Remarks:

arachis oil BP,

Details on dermal exposure:

TEST SITE
- Area of exposure: Back and flanks
- % coverage: 10% of the total body surface area
- Type of wrap if used: A piece of surgical gauze was placed over the treatment area and semi-occluded with a piece of self-adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): After the 24-Hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with arachis oil BP to remove any residual test item.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg
- Constant volume or concentration used: yes
- For solids, paste formed: yes

VEHICLE
- Amount(s) applied (volume or weight with unit): The test item was moistened with Arachis oil BP

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5 females and 5 males

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed for deaths or overt signs of toxicity 30 minutes, 1, 2 and 4 hours after dosing and subsequently once daily for 14 days.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, dermal reactions, mortality

Statistics:

Data evaluations included the relationship, if any, between the exposure of the animal to the test item and the incidence and severity of all abnormalities including behavioral and clinical observations, gross lesions, body weight changes, mortality and any other toxicological effects.

Using the mortality data obtained, an estimate of the acute dermal median lethal dose (LD50) of the test item was made.

Preliminary study:

Five female and five male rats were treated with 2000 mg/kq bw test item moistened with Arachis Oil BP. The treatment lasted 24 h. The observation period was 14 days.

There were no deaths, signs of systemic toxicity or dermal irritation.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths (see Table 1, Any other infromation on results incl. tables).

Clinical signs:

other: There were no signs of systemic toxicity (see Table 1, Any other infromation on results incl. tables).

Gross pathology:

No abnormalities were noted at necropsy (see Table 3, Any other infromation on results incl. tables).

Other findings:

Dermal Reactions:
Very slight erythema and very slight edema were observed on days three and four in one female. There were no signs of dermal irritation in the remaining animals (see Tables 4 and 5, Any other infromation on results incl. tables).

Table 1 Individual Clinical Observations and Mortality Data

Dose level (mg/kg)	Animal number	Effects Noted After Dosing (Hours)				Effects Noted During Period After Dosing (Days)
	and sex	0.5	1	2	4	1	2	3	4	5	6	7	8	9	10	11	12	13	14
2000	1-0 M	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	1 -1 M	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	1 -2 M	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	1 -3 M	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	1 - 4 M	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	2 - 0 F	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	2 - 1 F	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	2 - 2 F	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	2 - 3 F	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	2 - 4 F	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

Table 2 Individual Body Weights and Body Weight Changes

Dose Level mg/kg	Animal Number and Sex	Body Weight (g) at Day			Weight Change (g) During Week
		0	7	14	1	2
2000	1-0 Male	263	279	304	16	25
	1-1 Male	274	293	326	19	33
	1-2 Male	255	273	293	18	20
	1-3 Male	264	282	309	18	27
	1-4 Male	251	258	281	7	23
	2-0 Female	224	227	232	3	5
	2-1 Female	213	213	216	0	3
	2-2 Female	212	207	213	-5	6
	2-3 Female	211	210	215	-1	5
	2-4 Female	208	207	217	-1	10

Table 3 Individual Necropsy Findings

Dose Level mg/kg	Animal Number and Sex	Time of Death	Macroscopic Observations
2000	1-0 Male	Killed Day 14	No abnormalities detected
	1-1 Male	Killed Day 14	No abnormalities detected
	1-2 Male	Killed Day 14	No abnormalities detected
	1-3 Male	Killed Day 14	No abnormalities detected
	1-4 Male	Killed Day 14	No abnormalities detected
	2-0 Female	Killed Day 14	No abnormalities detected
	2-1 Female	Killed Day 14	No abnormalities detected
	2-2 Female	Killed Day 14	No abnormalities detected
	2-3 Female	Killed Day 14	No abnormalities detected
	2-4 Female	Killed Day 14	No abnormalities detected

Table 4 Individual Dermal Reactions - Males

Dose level (mg/kg)	Animal number	Observation			Effects Noted After Initiation of Exposure (Days)
	and sex		1	2	3	4	5	6	7	8	9	10	11	12	13	14
2000	1-0 M	Erythema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
		Edema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
		Other	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	1 - 1 M	Erythema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
		Edema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
		Other	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	1 - 2 M	Erythema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
		Edema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
		Other	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	1 - 3 M	Erythema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
		Edema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
		Other	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	1 - 4 M	Erythema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
		Edema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
		Other	0	0	0	0	0	0	0	0	0	0	0	0	0	0

Table 5 Individual Dermal Reactions - Females

Dose level (mg/kg)	Animal number	Observation			Effects Noted After Initiation of Exposure (Days)
	and sex		1	2	3	4	5	6	7	8	9	10	11	12	13	14
2000	2-0 F	Erythema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
		Edema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
		Other	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	2 - 1 F	Erythema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
		Edema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
		Other	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	2 - 2 F	Erythema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
		Edema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
		Other	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	2 - 3 F	Erythema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
		Edema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
		Other	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	2 - 4 F	Erythema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
		Edema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
		Other	0	0	0	0	0	0	0	0	0	0	0	0	0	0

Interpretation of results:

GHS criteria not met

Remarks:

According to GHS, the substance is unclassified.

Conclusions:

The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg body weight. Therefore the test item is not classified as acutely toxic via the skin.

Executive summary:

The study was performed to assess the acute dermal toxicity of the test item in the Wistar strain rat.

A group of ten animals (five males and five females) was given a single, 24 hour, semi-occluded dermal application of the test item to intact skin at a dose level of 2000 mg/kg body weight. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy.

Mortality. There were no deaths.

Clinical Observations. There were no signs of systemic toxicity.

Dermal Irritation. Very slight erythema and very slight edema were observed on days three and four in one female. There were no signs of dermal irritation in the remaining animals.

Body Weight. Four females showed body weight loss or no gain in body weight during the first week with expected gain in body weight during the second week. The remaining animals showed expected gains in body weight over the study period.

Necropsy. No abnormalities were noted at necropsy.

The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The study is a GLP compliant and was performed by following the recommended method (OECD Guideline for Testing of Chemicals No 402 “Acute Dermal Toxicity” (adopted 24 February 1987) and Method B3 Acute Toxicity (Dermal) of Commission Regulation (EC) No. 440/2008). It has a Klimisch score of 1.

Additional information

There are no data gaps in acute toxicity. Even though there is no human data available on the hazards of the substance for acute toxicity, there is no reason to believe that the observed results in the acute oral toxicity (fixed dose method) study and the acute dermal toxicity (limit test) study in the Wistar strain rats would not be relevant to humans.

No severe adverse effects were observed in either the acute oral toxicity study or the acute dermal toxicity study, with LD50 -values found to be greater than 2000 mg/kg body weight in both studies.

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 2000 mg/kg body weight. The test item is therefore not classified as acutely toxic via the oral route according to the CLP Regulation (2008/1272/EC).

 

The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat (male/female) was found to be greater than 2000 mg/kg body weight. The test item is therefore not classified as acutely toxic via the skin according to the CLP Regulation (2008/1272/EC).

Justification for selection of acute toxicity – oral endpoint
Only one study available

Justification for selection of acute toxicity – inhalation endpoint
Study technically not feasible: the inhalation route of exposure is not relevant for the substance, as the particle size of the substance is so large that it excludes any likely exposure through inhalation, and the calculated vapour pressure of the substance is very low. Therefore the test for studying acute toxicity through inhalation was not performed.

Justification for selection of acute toxicity – dermal endpoint
Only one study available

Justification for classification or non-classification

No severe adverse effects were observed in either the acute oral toxicity study or the acute dermal toxicity study in rats. Both the acute oral median lethal dose (LD50) and the acute dermal median lethal dose (LD50) of the test item in rats were found to be greater than 2000 mg/kg body weight. Therefore the substance is not classified as acutely toxic via the skin or the oral route according to the Globally Harmonized Classification System and the CLP Regulation (2008/1272/EC).