Registration Dossier

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
8 September 2004 to 22 September 2004
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP-Guideline study. Read across from an analogue substance.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report Date:
2005

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
other: Japan MAFF, Notification No. 12 Nousan-8147
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Lanthanum carbonate
- Molecular formula (if other than submission substance): La2(CO3)3*8H2O
- Molecular weight (if other than submission substance): 601.98 g/mol
- Physical state: white powder
- Percentages of components: 42.9% La, Carbonate/CO3: 26.7% , "free capillary water": 6.8%
- Analytical purity: > 99.5%
- Lot/batch No.: MB-04/016
- Storage condition of test material: room temperature/darkness

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan-Winkelmann GmbH, Borchen, Germany
- Strain: Wistar, Hsd Cpb:WU (SPF)
- Age at study initiation: approx. 2 months
- Weight at study initiation: control: 189.6 ± 5.1 g (males), 174.4 ± 2.7 g (females); 5000 g/m3: 185.2 ± 10.4 g (males), 167.0 ± 5.0 g (females)
- Fasting period before study: no information available
- Housing: single in conventional Makrolon Type IIIh cages; cages were changed twice a week while unconsumed feed and water bottles were changed once a week
- Diet (e.g. ad libitum): standard fixed-formula diet for mouse and rat: KLIBA 3883 (= NAFAG9441 pellets from PROVIMI KLIBA SA, Kaiseraugst, Switzerland), ad libitum
- Water (e.g. ad libitum): municipal tap water, ad libitum
- Acclimation period: at least 5 d, to the animal room conditions


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 40 - 70
- Air changes (per hr): approx. 10 air changes per hour
- Photoperiod (hrs dark / hrs light): 12:12

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
other: no vehicle
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Plexiglass exposure tubes applying a directed-flow nose-only exposure principle
- Exposure chamber volume: internal volume about 3.8 L (inner diameter of aluminium inhalation chamber: 14 cm, height 25 cm)
- Method of holding animals in test chamber: individual restrainer
- Method of conditioning air: compressed air (28 L air/min.) was supplied by Boge compressors and was conditioned (i.e. freed from water, dust and oil) automatically by a VIA compressed air dryer.
- System of generating particulates/aerosols: Test substance was aerolised using a Wright-Dust-Feeder, continuous dynamic generation of test atmosphere, which was forced through openings in the inner concentric cylinders directly towards the rats breathing zone (one segment was suitable to accomodate 20 rats at the perimeter location). Steady state of test atmosphere generation was attained wthin approx. 1 min. of exposure (t99% = 4.6 X chamber volume/flow rate). At each exposure port an adaequate air flow rate was provided, so that twice the respiratory minute volume of rats (1.4 L/min.) is exceeded. A process control system established a secured PC internal study protocol which determined all basic physical inhalation chamber operating parameters for the study.
- Method of particle size determination: Analysis via an Andersen cascade impactor (gravimetric analysis of individual impactor stages (glass plates)
- Treatment of exhaust air: purified via cotton-wool and HEPA filters
- Temperature and humidity, pressure in air chamber:
control: T = 21.2 °C, rel humidity = 42.4% , inlet air flow = 15 L/min., exhaust air flow = 13 L/min.
5000 mg/m3: T = 21.5°C, rel. humidity = 31.1%, inlet air flow = 28 L/min., exhaust air flow = 25 L/min.

TEST ATMOSPHERE
- Brief description of analytical method used:
Nominal concentrations were not calculated since this would have required a derangment of the dust generating system and gravimetric determination of the weight of the reservoir containing the test substance before and after exposure is rather inaccurate.
Actual concentrations: determined by gravimetrical analysis (glass-fiber filter). After sampling, filters were dried for 15 min. Chamber samples were taken in the vicinity of the breathing zone. Optimally, three samples per exposure day were collected. The plausibility of collected volumes was always controlled by additional measurements of the flow-rate over time.

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: see endpoint study record chapter 4.5 (Pauluhn, Wright-Dust-Feeder, 2004, RL2, Particle size distribution (Granulometry)
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): MMAD = 7.19 µm, GSD = 2.11
Analytical verification of test atmosphere concentrations:
yes
Remarks:
(gravimetrical analysis)
Duration of exposure:
4 h
Concentrations:
5928 mg/m3 (measured)
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: body weights were measured before exposure, on days 3 and 7, and weekly thereafter; clinical signs: several times on the day of exposure and at least once daily thereafter.
- Necropsy of survivors performed: yes, gross pathological examination with particular references to changes related to the respiratory tract.
- Other examinations performed (individual records for each animal):
Clinical signs: changes in the skin and fur, eyes, mucus membranes, respiratory, circulatory, autonomic and central nervous system and somatomotor activity and behaviour pattern. Particular attention was directed to observations of tremors, convulsions, salivation, diarrhea, lethargy, somnolence and prostration. No specific assessment was performed during exposure while animals were restrained.
The following reflexes were tested: visual placing response and grip strength on wire mesh, abdominal muscle tone, corneal and pupillary reflexes, pinnal reflex, righting reflex, tail-pinch response, startle reflex with respect to behavioural changes stimulated by sounds (finger snapping) and touch (back)
Rectal temperatures: measured shortly after cessation of exposure (approx. within 0.5 h after the end of exposure) using a digital thermometer with rectal probe for rats.
Statistics:
Body weights and physiological data were statistically evaluated using the ANOVA procedure.
Necrospy findings were evaluated using the pair-wise Fisher test after R x C chi-squared test.

Results and discussion

Effect levelsopen allclose all
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5 928 mg/m³ air (nominal)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: original value according to the test susbtance lanthanumcarbonate-octahydrate
Sex:
male/female
Dose descriptor:
LC50
Effect level:
4 509 mg/m³ air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: recalculated value according to the test substance lanthanum carbonate
Mortality:
Mortality did not occur in any group
Clinical signs:
other: Control: all rats tolerated the exposure without specific signs 5928 g/m3: slight laboured breathing patterns on day 0 in 1 out of 5 males and 2 out of 5 females, slight piloerection on day 1 in 1 out of 5 females.
Body weight:
Comparisons between the control and the exposure groups revealed isolated significant changes in body weights, however, they are considered of no toxicological significance.
Gross pathology:
All animals sacrificed at the end of the observation period: Essentially all rats of the exposure group showed macroscopic alterations of the lung. The most prominent changes included gray-red dislocations and no collapse of the lung upon opening the thoracic cavity (consolidation). After necropsy, the lungs from some rats were cut and whitish, highly viscous deposits were observed.
Other findings:
Reflex measurements:
In comparison to the rats of the control group, none of the rats of the exposure group exhibited a change in reflexes.

Rectal temperatures:
Control: 37.6 °C (males) and 37.7 °C (females); 5000 mg/m3: 36.7 °C (males) and 36.5 °C (females). Values for standard deviation not given, only shown in a figure.
Statistical comparisons between the control and the exposure group did not reveal significant changes in body temperatures.

Any other information on results incl. tables

Atmosphere characterisation:

 

Date of exposure

Sampled volume (L) / flow rate (L/min.)

Target concentration (mg/m3 air)

Gravimetric concentrations (mg/m3 air)

Mean concentration (mg/m3 air)

Group 1 (Control)

18.08.2009

n.a.

-

0

n.a.

Group 2

08.09.2004

10/4

5000

5780

6990

5310

5630

5928

n.a. not applicable

Body weights:

Group 1: control males (all data in g):

 

Post exposure day (d)

animal

0

3

7

14

1

192

201

232

267

2

189

204

240

281

3

181

200

234

279

4

193

213

257

310

5

193

212

249

288

mean

189.6

206.0

242.4

285.0

STD

5.1

6.1

10.5

15.9

Group 2: 5000 mg/m3 males (all data in g):

 

Post exposure day (d)

animal

0

3

7

14

11

184

199

228

264

12

191

204

233

277

13

185

195

218

247

14

197

213

245

290

15

169

182

216

255

mean

185.2

198.6

228.0

266.6

STD

10.4

11.5

11.8

17.2

Group 3: control females (all data in g):

 

Post exposure day (d)

animal

0

3

7

14

6

173

173

183

191

7

174

177

187

195

8

176

173

184

198

9

175

173

187

191

10

169

171

182

190

mean

173.4

173.4

184.6

193.0

STD

2.7

2.2

2.3

3.4

Group 4: 5000 mg/m3 females (all data in g):

 

Post exposure day (d)

animal

0

3

7

14

16

175

175

184

195

17

162

163

167

177

18

168

175

183

189

19

166

164

171

196

20

164

166

175

187

mean

167.0

168.6

176.0

188.8

STD

5.0

5.9

7.4

7.6

Body weight gain (all data in g):

 

Post exposure day (d)

 

3

7

14

Group 1: control males

mean

16.4

36.4

42.6

STD

4.6

4.8

6.8

Group 2: 5000 mg/m3 males

mean

13.4

29.4

38.6

STD

2.3

4.2

6.5

Group 3: control females

mean

0.0

11.2

8.4

STD

2.5

1.6

3.6

Group 4: 5000 mg/m3 females

mean

1.6

7.4

12.8

STD

3.4

2.1

7.2

Gross necropsy findings:

Individual findings/male rats (significant differences, P = 0.004):

 

Animal no.

Sacrificed after

Pathology findings

Control

1-5

14 d

No observable findings

5000 mg/m3

11

14 d

Lung: less collapsed, gray-red, isolated whitish areas

12

14 d

Lung: less collapsed, gray-red, isolated whitish areas

13

14 d

Lung: less collapsed, gray-red

14

14 d

Lung: less collapsed, gray-red, isolated whitish areas

15

14 d

Lung: less collapsed, gray-red, isolated whitish areas; incisive teeth missing

Individual findings/female rats (significant differences, P = 0.004):

 

Animal no.

Sacrificed after

Pathology findings

Control

6-10

14 d

No observable findings

5000 mg/m3

16

14 d

Lung: gray-red

17

14 d

Lung: gray-red

18

14 d

Lung: gray-red

19

14 d

Lung: less collapsed, gray-red

20

14 d

Lung: gray-red

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute inhalation LC50 of Lanthanum carbonate to male and female Wistar rats was found to be > 5928 mg/m^3
Executive summary:

Because data were not available concerning the toxicity of dineodymium tricarbonate to wistar rats via the inhalation route, the toxicity of a closely related compound, Lanthanum carbonate, was utilized to estimate this toxicity.

The study was performed according to OECD Guideline 403, EU Method B.2, EPA OPPTS 870.1300 and Japan MAFF, Notification No. 12 Nousan-8147, and to GLP standard.

The acute inhalation LC50 of Lanthancarbonate-octahydrate to male and female Wistar rats was found to be > 5928 mg/m3