Cerium doped lutetium yttrium orthosilicate

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2016-04-11 to 2016-06-24

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2016

Report date:

2016

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

adopted 24 Feb1987

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Cerium doped lutetium yttrium orthosilicate

EC Number:

941-731-3

Molecular formula:

Lu2(1-x)Y2xSiO5:Ce, 0

IUPAC Name:

Cerium doped lutetium yttrium orthosilicate

Test material form:

solid

Specific details on test material used for the study:

- Name: Lyso
- Chemical Name: Cerium doped Lutetium Yttrium Orthosilicate
- EC No.: 941-731-3
- Batch No.: C14-193
- Expiry date: not applicable
- Physical state: solid (crystal)
- Colour: Colourless
- Purity: theoretical composition based on starting materials: 81.25% Lu2O3, 13.51% SiO2, 5.2% Y2O3 and 0.039% CeO2
- Molecular weight: 440.7 g/mol
- Stability in water at room temperature: stable
- Storage Conditions: at room temperature

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
The test item was used as delivered by the sponsor. In order to ensure good skin contact, it was moistened with the vehicle.

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, 97633 Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: no
- Age at study initiation: males: 9-10 weeks old; females: 12-13 weeks old
- Weight at study initiation: males: 227-258 g; females: 201-216 g
- Fasting period before study: no
- Housing: The animals were kept individually in IVC cages, type III H, polysulphone cages on Altromin saw fibre bedding
- Diet (e.g. ad libitum): Altromin 1324 maintenance diet, ad libitum
- Water (e.g. ad libitum): ad libitum: tap water, sulphur acidified to a pH value of approximately 2.8 (drinking water, municipal residue control, microbiological controls at regular intervals)
- Acclimation period: at least five days under laboratory conditions

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 55 ± 10
- Air changes (per hr): 10 x
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Type of coverage:

semiocclusive

Vehicle:

water

Details on dermal exposure:

TEST SITE
- Area of exposure: dorsal area of the trunk
- % coverage: approx. 10 of the body surface
- Type of wrap if used: gauze-dressing and non-irritating tape, both fixes with an additional dressing in a suitable manner.

REMOVAL OF TEST SUBSTANCE
- At the end of the exposure period the residual test item was removed using water.

TEST MATERIAL
- Amount(s) applied: single dose of 2000 mg/kg body weight

VEHICLE
- Aqua ad injectiabilia (AlleMan Pharma, lot no. 505651, expiry date: 30/04/2018). This vehicle was chosen due to its non-irritating characteristics.

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: A careful clinical examination was made several times on the day of dosing (at least once during the first 30 minutes and with special attention given during the first 4 hours post-dose). Thereafter, the animals were observed for clinical signs once daily until the end of the observation period.
- Frequency of weighing: The animals were weighed on day 1 (prior to the application) and on days 8 and 15
- Necropsy of survivors performed: Yes, at the end of the observation period the animals were sacrificed with an overdosage of pentobarbital injected intraperitoneally at a dosage of 250-400 mg/kg bw. All animals were subjected to gross necropsy and examined macroscopically for gross pathological changes.

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

no indication of skin irritation up to the relevant limit dose level

Mortality:

No mortality has occurred during and after the treatment of the test animals with Cerium doped Lutetium Yttrium Orthosilicate.

Clinical signs:

other: No specific clinical signs of toxicity were recorded.

Gross pathology:

With the exception of acute injection of blood vessels in the abdominal region, which is due to the euthanasia injection, no specific gross pathological changes were recorded for any animal.

Any other information on results incl. tables

Table 1: Absolute Body Weights in g and Body Weight Gain in %

Test Group	Animal No.	Dose (mg/kg bw)	Body weight (g) on Day			BW gain in Comparison to Day 1 (%)
			Day 1	Day 8	Day 15	Day 15
Males	21	2000	258	279	304	18
	22		238	267	300	26
	23		235	261	284	21
	24		227	243	263	16
	25		242	263	282	17
Females	26	2000	201	200	205	2
	27		206	205	207	0
	28		208	204	211	1
	29		216	219	220	2
	30		212	210	206	-3

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of the present study, a single dermal application of the test item to rats at the limit dose of 2000 mg/kg body weight was associated with no mortality and neither signs of toxicity nor signs of skin irritation. Thus, the LD50 is considered to exceed 2000 mg/kg bw.

Executive summary:

In an acute dermal toxicity study conducted according to OECD 402, groups of young adult Wistar rats (5 male/5 female) were dermally exposed to Cerium doped Lutetium Yttrium Orthosilicate in water for 4 hours at dose of 2000 mg/kg bw. Animals then were observed for 14 days. No mortality occurred during the test period. Further, there were no treatment related clinical signs and necropsy findings. The slight weight loss might be secondary to the dressing and toxicological relevance of this finding cannot clearly be concluded. Based on the results, the LD50 can be considered to exceed 2000 mg/kg bw.