### TITLE PAGE

STUDY TITLE

Report

C obalt Lithium Manganese Nickel oxide

- Subchronic 90

- day inhalation study in Wistar rats dust exposure

TEST GUIDELINE(S)

OECD - Guideline method 413 Commission Regulation (EC) No 440/2008

U.S. EPA OPPTS Guidelines 870.3465

AUTHOR(S)

STUDY COMPLETION DATE

16 Sep 2013

TEST FACILITY

TEST FACILITY PROJECT IDEN TIFICATION

SPONSOR

P AR T I OF III (REPORT SECTION AND SUMMARY TABLES)

This document contains manufacturing and trade secrets of the Sponsor(s). It is the property of the Sponsor(s) and may be use d only for that purpose for which it was intended by the Sponsor(s). Every other or additional use, exploitation, reproduction, pub lication or submission to other parties require the written permission of the Sponsor(s), with the exception of regulatory ag encies acting within the limits of their administrative authority.



### Page 1 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors **This document is the property of the sponsor and may be used only for that purpose intended by the sponsor. The use of these studies/documents for regulatory, registration or other commercial purposes, including but not limited to**  **Registration, Evaluation, Authorization and Restriction of Chemical Substances (REACH), without the express written permission of the sponsor is unauthorized and strictly prohibited.**  

### EPA-HQ-OPPT-2009-0922

SANITIZED

### Page 2 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 4 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### CONTRIBUTORS TO THE STUDY / SUPERVISORY LABORATO RY PERSONNEL

Head of Experimental Toxicology and Ecology:

Study director:

Clinical Pathology:

Pathology:

Data processing:

Statistics:

Analytical Chemistry:

Quality Assurance Unit (QAU):

Coordination QAU:

Inhalation Toxicology:

Clinical Chemistry:

Pathology:

Page 6 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### GLP CERTIFICATE (FROM THE COMPETENT AUTH ORITY)

Page 8 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### CONTENTS

TITLE PAGE

STATEMENT OF NO DATA CONFIDENTIALITY CLAI MS

GLP COMPLIANCE STATE MENT

FLAGGING CRITERIA

SIGNATURE PAGE

CONTRIBUTORS TO THE STUDY / SUPERVISORY LABORATO RY PERSONNEL

STATEMENT OF THE QUA LITY ASSURANCE UNIT GLP CERTIFICATE (FROM THE COMPETENT AUTHORITY)

CONTENTS

1. SUMMARY

2. INTRODUCTION

2.1. OBJECTIVES

2.2. SELECTION OF CONCENTRATIONS

2.3. TEST GUIDELINES

2.4. TIME SCHEDULE

2.5. RETENTION OF RECORDS

2.6. ANIMAL WELFARE

3. MATERIALS AND METHOD S

3.1. TEST ITEM

3.2. TEST SYSTEM

3.3. HOUSING AND DIET

3.4. TEST GROUPS AND TARG ET CONCENTRATIONS

3.5. GENERATION OF THE IN HALATION ATMOSPHERES

3.6. ANALYSES

3.6.1. Calculation of nominal concentrations

3.6.2. Determination of atmospheric concentrations

3.6.2.1. Sampling for gravimetric analyses

3.6.2.2. Gravimetrical method of analyses

3.6.2.3. Real time mo nitoring of constancy of concentrations

3.6.3. Particle size analysis

3.6.3.1. Definitions

3.6.3.2. Equipment, sampling and method of determination

3.6.3.3. Particle size analysis by Aerodynamic Particle Sizer (APS)

3.6.4. Food analyses

3.6.5. Drinking water analyses

3.6.6. Bedding and enrichment analyses

Page 9 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 3.7. EXPERIMENTAL PROCEDU RE

3.7.1. Acclimatization and exposure period

3.7.2. Exposure systems; exposure of the animals

3.7.3. Measurements of the exposure conditions

3.8. CLINICAL EXAMINATION S

3.8.1. Mortality

3.8.2. Clinical observations

3.8.3. Detailed clinical observation (DCO)

3.8.4. Body weight data

3.8.5. Food consumption

3.8.6. Ophthalmology

3.8.7. Functional observational battery

3.8.8. Motor activity measurements (MA)

3.9. CLINICAL PATHOLOGY

3.9.1. Hematology

3.9.2. Clinical chemistry

3.10. PATHOLOGY

3.10.1. Organ weights

3.10.2. Organ/tissue fixation

3.10.3. Histopathology

3.11. STATISTICS

4. RESULTS

4.1. ANALYSES

4.1.1. Measurements of atmosphere parameters and operation conditions

4.1.1.1. Concentration measurements in the exposure system

4.1.1.2. Measurements concerning operation conditions

4.1.1.3. Results of the particle size analyses

4.1.2. Food analyses

4.1.3. Drinking water analyses

4.1.4. Bedding and enrichment analyses

4.2. CLINICAL EXAM INATIONS

4.2.1. Mortality

4.2.2. Clinical observations

4.2.3. Detailed clinical observations

4.2.4. Body weight data

4.2.5. Food consumption

4.2.6. Ophthalmology

4.2.7. Functional observational battery

4.2.8. Motor activity

Page 10 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 4.3. CLINICAL PATHOLOGY

4.3.1. Hematology

4.3.2. Clinical chemistry

4.4. PATHOLOGY

4.4.1. Main Groups

4.4.1.1. Weight parameters

4.4.1.2. Gross lesions

4.4.1.3. Histopathology

4.4.2. Recovery Groups

4.4.2.1. Weight parameters

4.4.2.2. Gross lesions

4.4.2.3. Histopathology

5. DISCUSSION

6. CONCLUSION

7. REFERENCES

8. LIST OF ABBREVIATION S

8.1. CLINICAL EXAMINATION S

8.2. ANALYTICAL DATA AND EXPOSURE PARAMETERS

8.3. CLINICAL PATHOLOGY

8.4. PATHOLOGY

Page 11 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### INCIDENCE AND SUMMARY TABLES

CLINICAL EXAMINATIONS (Mean values and Summary tables) Table

Summary - Clinical Observation
Male animals IA -1
Female animals IA -2

Detailed clinical observation s report
Male animals IA -3 - IA -5
Female animals IA

- 6 - IA -8

Summary Body Weights
Male animals IA -9 - IA

- 12
Female animals IA

- 13 - IA

- 16

Summary Changes Body W eight s Male animals IA

- 17 - IA

- 19
Female animals IA

- 20 - IA

- 22

Food consumption
Male animals IA

- 23 - IA

- 25
Female animals IA

- 26 - IA

- 27

Ophthalmological Findings
Male animals IA

- 28
Female animals IA

- 29

Functional observational battery IA -30 - IA

- 45

Motor activity IA

- 46 - IA

- 49

CLINICAL PATHOLOGY (Mean values and Summary tables)

Red blood cell + coagulation parameters IB 1 – IB 4 White blood cell parameters IB 5 – IB 8 Enzymes IB 9 – IB 12
Substrates IB 13 – IB 16 Electrolytes + minerals IB 17 – IB 20

Page 12 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### PATHOLOGY (Mean values and Summary tables)

Absolute weights - mean values (male), (main groups) IC

- 1 - IC -2 Absolute weights - mean values (female), (main groups) IC -3 - IC -4 Relative weights - mean values (male), (main groups) IC

- 5 - IC -6 Relative weights - mean values (female), (main groups) IC -7 - IC -8 Incidence of gross lesions (main groups) IC -9
Incidence of all microscopic findings (main groups) IC

- 10 - IC

- 13 Incidence and grading of microscopic findings in target organs (main groups) IC

- 14 - IC

- 15

Absolute weights - mean values (male), (recovery groups) IC

- 16 - IC

- 17 Absolute weights - mean values (female), (recovery groups) IC

- 18 - IC

- 19 Relative weights - mean values (male), (recovery groups) IC

- 20 - IC

- 21 Relative weights - mean values (female), (recovery groups) IC

- 22 - IC

- 23
Incidence of gross lesions (recovery groups) IC

- 24 Incidence of all microscopic findings (recovery groups) IC

- 25 Incidence and grading of microscopic findings in target organs (recovery groups) IC

- 26

MEASUREMENTS OF EXPOSURE PARAMETERS (Summary table)

Exposure P arameters ID -1

Page 13 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### PART II: INDIVIDUAL TABLES AND FIGURES

CLINICAL EXAMINATIONS (Individual values) Table

Individual Signs By Interval – Clinical Observation
Male animals IIA

- 1 - IIA

- 29
Female animals IIA

- 30 - IIA

- 57

Detailed clinical observation s report
Male animals IIA

- 58 - IIA

- 59
Female animals IIA

- 60 - IIA

- 61

Individual Body W eight s Male animals IIA

- 62 - IIA

- 68
Female animals IIA

- 69 - IIA

- 75

Individual Food consumption Per Animal Per Day
Male animals IIA

- 76 - IIA

- 79
Female animals IIA

- 80 - IIA

- 83

Ophthalmological Findings
Male animals IIA

- 84 - IIA

- 86
Female animals IIA

- 87 - IIA

- 89

Functional observational battery IIA

- 90 - IIA

- 117

Motor activity IIA

- 11 8 - IIA

- 12 5

CLINICAL PATHOLOGY (Individual values)

Red blood cell + coagulation parameters IIB 1 – I IB 10 White blood cell parameters IIB 11 – IIB 20 Enzymes IIB 21 – IIB 30
Substrates IIB 31 – IIB 40 Electrolytes + minerals IIB 41 – IIB 50

PATHOLOGY (Individual values)

Absolute weights IIC

- 1 - IIC

- 24 Relative weights IIC

- 25 - IIC

- 48 Single animal sheet IIC

- 49 - IIC

- 115

Page 14 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### MEASUREMENTS OF EXPOSURE PARAMETERS

Exposure parameters (Daily Means) IID

- 1 - IID -4 Particle size analysis (Individual measurements) IID

- 5 - IID

- 48

Page 15 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### PART III: SUPPLEMENT

Analysis of the test substance

H istorical cont rol data of clinical pathology testing

Functional Observational Battery (FOB) Detailed description of examinations, ranking and documentation procedures

Page 16 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

## 1. SUMMARY

To evaluate the toxicity profile of Cobalt Lithium Manganese Nickel oxide ( BATMA) after inhalation exposure, groups of ten male and ten female Wistar rats per test group were exposed nose

- only to dynamic atmosphere of BATMA for 6 hours per day on 5 consecu tive days per week for 3 months ( 90

- day study). To enable dust atmosphere generation, the test material was milled prior to the study. The target concentrations were 0.2, 1 and 5 mg/m 3 . A concurrent control group was exposed to conditioned air. For adaptation to the experimental conditions all animals were kept in glass restraining tubes identical to those used in the main study and were exposed nose

- only to fresh air on two days before start of the exposure period. To detect reversibility of the effects, r ecovery group animals (5 male and 5 female
animals per group ) were exposed to high concentration. A concurrent control group was exposed to conditioned air. The recovery period was 4 weeks.

Clinical observation was performed at least three times on exposure days and once a day during the other days. Body weight and food consumptions were determined for all animals. Detailed clinical observation was performed three times (prior to start, at midterm and against the end of the exposure). Ophthalmological examinations were performed from the main group animals prior to exposure and towards the end of the exposure. Functional observation battery and motor activity test were performed on study day 90.

After the last exposure or at the end of the 4 week recovery period , blood was sampled from main group animals, hematology and clinical chemistry parameters were determined. The animals were then subjected to gross necropsy (including macroscopic examination of the major internal organs and collection of organ weight data ). Histological examinations were performed according to respective test guidelines.

Results:

As shown in table 1, the targeted atmospheric concentrations were maintained well throughout the whole study. Control animals were exposed to conditioned air. The following study means of concentrations were determined by gravimetrical analysis

.

Table 1 : Study means and standard deviations of test substance concentrations and particle
size distribution

Test

group Target
concentration (mg/m3) Measured concentration (mg/m3) Mass median aerodynamic diameter (μm) Mean SD
1 0.2 0.2 5 0. 17 2.0 to 3.9

2 1 1.42 0. 42 2.5 to 5.7

3 5 5.10 1.2 4 3.0 to 4.0

Concerning clinical observation, body weight development and clinical pathology, no
treatment

- related, adverse effects were observed up to 5 mg/m3.

Page 17 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### The following substance

- related adverse effects were observed in the lungs :

Test group 3 (5 mg/m3, m ain Groups )

• Increased absolute and relative lung weights in males and females

• Cellular debris, alveolar in all male and female animals graded slight to moderate in males and slight to marked in female animals

• Histiocytosis, alveolar in all male and female anima ls graded minimal to slight in both

sex es

• Inflammation, multifocal in all male animals graded minimal to moderate and 1 female
animal (graded minimal)

• Infiltrates, inflammatory cell in all male ( graded minimal to slight) and female animals (graded minimal )

• Mucus in all male and female animals graded minimal to slight in males and minimal to
severe in females

• Regeneration, alveolar epithelium in 5/10 males and 6/10 females graded minimal to slight in males and minimal in females

• Emphysema in 2/10 males

• Reduced number, clara cells in all male and female animals graded severe in male animals and slight to severe in females

• Degeneration, bronchial epithelial cells in all male and female animals graded minimal
in both sexes

• Metaplasia, mucoid, bronchial in 5/10 female animals graded m inimal to slight

• Obliteration, bronchial in 2/10 female animals graded minimal to slight

Test group 3 ( 5 mg/m3 , r ecovery Group)

• Increased absolute and relative lung weights in males and females

• Cellular debris, alveolar in all male and female animals gra ded minimal to moderate in males and minimal to slight in female animals

• Histiocytosis,alveolar in all male and female animals graded moderate in both sexes

• Inflammation, multifocal in all male and female animals graded minimal to slight

• Infiltrates, inflammatory cell in all male and female animals graded minimal to slight in
both sexes

• Mucus in all male and female animals graded minimal to severe in males and minimal
to moderate in females

• Regeneration, alveolar epithelium in all male and female animals graded minimal to moderate in males and minimal to slight in females

Test group 2 (1 mg/m3)

• Increased absolute and relative lung weights in males and females

• Cellular debris, alveolar in all male and female animals graded minimal to mod erate in males and minimal to slight in female animals

• Histiocytosis,alveolar in all male and female animals graded minimal in both sexes

• Inflammation, multifocal in 7/10 male animals and 9/10 female animals graded minimal

• Infiltrates, inflammatory cell in all male and female animals graded minimal

Page 18 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### • Mucus in all male and female animals graded minimal to severe in males and minimal
to moderate in females

• Regeneration, alveolar epithelium in 4/10 females graded minimal

• Emphysema in 3/10 females

• Reduced number, clara cells in all male and female animals graded minimal or
moderate in male animals and minimal to severe in females

• Degeneration, bronchial epithelial cells in all male and female animals graded minimal
in both sexes

• Metaplasia, mucoid, bronchial in 2/10 female animals graded minimal

Test group 1 (0.2 mg/m3)

• Increased absolute and relative lung weights in males and females

• Cellular debris, alveolar in all male and female animals graded minimal to slight in
mal es and minimal to moderate in female animals

• Histiocytosis,alveolar in all male and female animals graded slight to moderate in
males and minimal to moderate in females

• Inflammation, multifocal in 9/10 male animals and 2/10 female animals graded minimal
to slight in both sexes

• Infiltrates, inflammatory cell in all male and female animals graded minimal in males and minimal to slight in females

• Mucus in all male and female animals graded slight to moderate in males and minimal to slight in females

• Regeneration, alveolar epithelium in 5/10 males and 6/10 females graded minimal in
males and minimal or moderate in females

• Emphysema in 1/10 males

• Reduced number, clara cells in 4/10 male animals graded minimal to slight

• Degeneration, bronchial epithelial cells in 3/10 male animals graded minimal

• Metaplasia, mucoid, bronchial in 4/10 female animals graded minimal to slight

Conclusion Inhalation exposure of 0.2, 1 and 5 mg/m 3 

### Cobalt Lithium Manganese Nickel oxide for 90 days (65 exposures) caused clearly treatment

- related histological changes in lung

. The effects were not fully reversible within 4 weeks recovery period. A No Observed Adverse Effect Concentration (NOAEC) could not be established under the current study condition.

Based on the data of clinical observation, body weight, food consumption, clinical chemistry, hematology and histological examinations, there was no indication for any systemic toxicity. Therefore, the NOAEC for systemic toxicity is 5 mg/m3 under the current study condition.

Page 19 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

## 2. INTRODUCTION

2.1. OBJECTIVES

Aim of the study is the characterization of the toxicity profile of Cobalt Lithium Manganese
Nickel oxide including target organs and determination of a No Observed Adverse Effect
Concentra tion (NOAEC) after 3 months exposure to dusts

.

2.2. SELECTION OF CONCENT RATIONS

The concentrations to be tested in this study were selected based on the results of the 14

- day range finding study.

In the range finding study, inhalation exposure to 50 mg/m3 test substance caused death of 16 of the 22 rats after 2 exposures. Clinical signs of toxicity comprised accelerated and intermittent respiration, piloerection, pale skin, hypothermia. Two animals that showed abdominal position, poor general state / convulsion were sacrificed moribund. They were counted as deaths. Histopathological examination of the dead animals revealed severe alveolar damage as the cause of death. In the surviving animals of this group, which were
sacrificed after a 3

- week recovery period, a minimal bronchial epithelial degeneration/regeneration was observed. Clinically, the surviving animals recovered very fast and were free of clinical signs of toxicity 4 days after termination of the exposure. The body weights of survivors were significantly lower than the controls on study day 4 but reached the control level on study day 6. The recovery of the surviving animals and the minimal morphological change in the histopathology demonstrated the reversibility of the effects on the bronchial epithe lium. Focal necrosis and squamous metaplasia in the olfactory epithelium, bronchial epithelial degeneration/ regeneration, lympho

- reticular hyperplasia in mediastinal and tracheobronchial lymph - nodes, inflammation of the trachea, and squamous metaplasia of the larynx were also noted in animals exposed to 50 mg/m3 test substance.

At 2 and 10 mg/m3, no clinical signs of toxicity were noted; mean body weight was comparable with the controls. In the lavage fluid, counts of neutrophils and lymphocytes were
si gnificantly increased, accompanied by increased total protein and activity of several enzymes, indicative of inflammatory responses. All these changes were almost fully reversible within the recovery period of 3 weeks. Histologically, concentration

- related changes were observed in nasal cavity, lymph nodes (mediastinal and tracheobronchial) and trachea. Focal necrosis in the olfactory epithelium and bronchial epithelial degeneration/regeneration were still present at the low concentration of 2 mg/m3, though with less incidence and severity than at 10 mg/m3.

Based on these data, we choose the following concentration for the 90

- day inhalation study:

5 mg/m3: as the high concentration causing adverse effect 1 mg/m3: as the mid concentration causing som e effect 0.2 mg/m3: as the low concentration and the expected no adverse effect concentration

Page 20 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 2.3. TEST GUIDELINES

The study was conducted according to/ based on the following test guidelines:

• Organization for Economic Cooperation and Development (OECD), OECD Guidelines for Testing of Chemicals, Section 4: Health Effects, No. 413 “Sub

- Chronic Inhalation Toxicity:
90

- day Study” adopted 07 September 2009.

• Commission Regulation (EC) No 440/2008 of 30 May 2008 laying down test methods pursuant to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), Part
B .29 : Methods for the determination of toxicity and other health eff ects: Sub -chronic
inhalation toxic ity study 90

- day repeated inhalation dose study using rodent species No.
L142

• US Environmental Protection Agency (EPA), OPPTS Guidelines Section 870.3465 90

- Day Inhalation Toxicity, EPA 712 -C- 98

- 204, August 1998

2.4. TIME SCHEDULE

Test dates: Study initiatio n date: 20 March 2012 Experimental starting date (Arrival of test animals): 20 March 2012

Experimental completion date (check the raw data for its completeness): 30 Jan 2013

Page 21 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### The study was performed according to the following time table:

Table 2 : S tudy timetable

Date Study day Study section / Examination

Male Animals Female Animals

20 March 2012

- 15/

- 16 Arrival of the animals (age: 7 weeks); experimental starting date

02 April 2012 03 April 2012 -2 Start of pre

- exposure 02 April 2012 03 April 2012

- 2 Ophthalmology

04 April 2012 05 April 2012 0 DCO

04 April 2012 05 April 2012 0 Start of exposure period

05 April 2012 06 April 2012 1 Urine

17 May 2012 18 May 2012 43 DCO

23 May 2012 24 May 2012 49 Urine

26 June 2012 27 June 2012 83 Ophthalmology

27 June 2012 28 June 2012 84 Urine

28 June 2012 29 June 2012 85 DCO

03 July 2012 04 July 2012 90 FOB, MA

04 July 2012 05 July 2012 91 End of exposure period = last exposure day

05 July 2012 06 July 2012 92 Blood sampling*, necropsy*, start of clinical and pathological examination of the main group
animals

05 July 2012 06 July 2012 92 Start of recovery period

03 August 2012 121/120 Blood sampling*, necropsy*, start of clinical and pathological examination of the recovery group
animals

* = Before blood sampling and necropsy food will be withdrawn from the animals overnight (about 16

- 20 hours)



### .

Page 22 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 2.5. RETENTION OF RECORDS

GLP

- relevant records and materials are stored at for at least the period of time specified in the GLP principles. Details concerning responsibilities or locations of archiving can be seen from the respective SOPs and from the raw data.

All blood samples for clinical e xamination are disposed two years after the finalization of the study.

All urine samples for clinical examination are disposed three years after the finalization of the study.

2.6. ANIMAL WELFARE

This study was performed in an laboratory in accordance with the

.

Page 23 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

## 3. MATERIALS AND METHOD S

3.1. TEST ITEM

The technical material provided by the sponsor was coarse. No dust aerosol could be generated. Therefore, the technical material wa s micronized to achieve respirable particles.
The test item (= test substance) refer to the micronized material. The micronized material analyses were characterized at

Name of test substa nce: Cobalt Lithium Manganese Nickel oxide

Test substance No.:

Batch No.:

CAS No.: 182442

- 95 -1

Purity /composition : See report as attached in part III

Homogeneity: Given

Storage stability: The stability of the test substance under storage conditions over the test period was guaranteed by the

sponsor , and the sponsor holds this responsibility.

ADDITIONAL TEST SUBSTANCE INFORMATION

Synonyms: Cobalt Lithium Manganese Nickel oxide

Physical state/ Appearance: Solid / black

Storage conditions: Room temperature

The Sponsor is responsible for compliance for all test substance information and their storage, except for those test substance investigations commissioned by the test faci lity.

More details of the test substance can be found in the Part III of this report and in the raw
data.

Page 24 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 3.2. TEST SYSTEM

Test species and strain: Wistar rats, Crl:WI(Han)

Reason for selection of the test species: Rats were selected since this rodent species is recommended in the respective test guidelines.
Wistar rats were selected since there is extensive experience available in the laboratory with this strain of
rats.

Age when supplied; sex: about 7 weeks, male and female

Supplier: Charles River Laboratories, Research Models and Services,

Arrival in the testing facility: 20 March 2012

Identification: The animals were identified individually by tattooing the respect ive animal number into the ears

The female animals were nulliparous and non

- pregnant.

Only animals free from clinical signs of disease were used for the study.

Page 25 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 3.3. HOUSING AND DIET

The rats were housed together (up to 5 animals per cage) in Polysulfon cages (H- Temp [ PSU ]) supplied by TECNIPLAST, Hohenpeißenberg, Germany (floor area about 2065 cm 2 

### ). Bedding in the Polycarbonate cages were Type Lignocel fibres, dust- free wooden bedding was used in this study (the present supplier is documented in the raw data)

. For enrichment wooden gnawing blocks (Typ NGM E

- 022), supplied by Abedd ® 

### Lab. and Vet. Service GmbH, Vienna, Austria, were added.

The animals were kept in fully air

- conditioned rooms in which a temperature in the range of
20 - 24°C and relative hu midity in the range of 30 - 70% were ensured by means of a central
air

- conditioning system. 15 air changes per hour.

A light/dark rhythm of 12 hours was maintained:

• 06.00 a.m. - 06.00 p.m. light

• 06.00 p.m. - 06.00 a.m. dark

Deviations f rom these ranges did not occur. The room was completely disinfected using a disinfector ("AUTEX", fully automatic, formalin

ammonia

- based terminal disinfector) before the start of the study. The floor and the walls were cleaned once a week with water containing an appropriate disinfectant.

The animals were maintained on mouse/rat laboratory diet “GLP”, 10 mm pellets (Provimi Kliba SA, Kaiseraugst, Basel Switzerland) and tap water ad libitum.

Details of the feed batch used are available in the raw data.

Page 26 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 3.4. TEST GRO UPS AND TARGET CONCE NTRATIONS

Test groups, target concentrations and allocation of animals in the groups are presented in the following tables.

Table 3 : Main groups (males)

Test group Concentration (mg/m 3 ) 1 No. of animals Animal No.

0 0 10 1

- 10

1 0.2 10 11

- 20

2 1 10 21

- 30

3 5 10 31

- 40



### Table 4 : Main groups (females)

Test group Concentration (mg/m 3 ) 1 No. of animals Animal No.

0 0 10 41

- 50

1 0.2 10 51

- 60

2 1 10 61

- 70

3 5 10 71

- 80



### In order to check for any reversibility, progression or delay of toxic effects the following

recovery groups were used. The recovery group animal s we re observed for 4 weeks after the exposure period.

Table 5 : Recovery groups (males)

Test group Concentration (mg/m 3 ) 1 No. of animals Animal No.

0 0 5 81

- 85

3 5 5 86

- 90



### Table 6 : Recovery groups (females)

Test group Concentration (mg/m 3 ) 1 No. of animals Animal No.

0 0 5 91

- 95

3 5 5 96

- 100

1 test substance concentration



### Page 27 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 3.5. GENERATION OF THE INHALATION ATMOSPHER ES

Generator systems:

• Solid particle generators (brush

- generator; )

• Mixing tube

Generation procedure:

The test substance was used unchanged.

For each concentration the dust aerosol was generated with the dust generator and

compre ssed air inside a mixing tube mixed with conditioned dilution air and passed into the inhalation system. Conditioned supply air is activated charcoal filtered air conditioned to
about 50% ± 20% relative humidity and 22°C ± 2°C. C ompressed air is filtered air pressurized to about 6 bar.

The following substance flow and air flows were scheduled:

Table 7 : Scheduled exposure parameters

Test

group Substance
flow (g/h) Supply air compressed (m3/h) Supply air
conditioned (m3/h) Supply air 2 * (m3/h) Exhaust air (m3/h) Exhaust air 2 # ( out of the mixing tube ) (m3/h)

0

- - 5. 7

– 6

. 3

- 5

. 1

- 5

. 7

- 1 0.1

– 1. 2 1

. 2

- 1

. 8 4.2

– 4. 8 2.5

– 4. 8 5

. 1

- 5

. 7 2.5

– 4. 8

2 0

. 5

– 2

. 5 1

. 2

- 1

. 8 4. 2

– 4

. 8

- 5

. 1

- 5

. 7

- 3 2.5

– 12. 5 1

. 2

- 1

. 8 4.2

– 4. 8

- 5

. 1

– 5

. 7

- * conditioned air to the mixing tube, part of dilution system
# air out of the mixing tube, part of dilution system



### Page 28 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Figure 1: Generator system

Test group 1:

Test Group 2 – 3:

Page 29 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 3.6. ANALYSES

3.6.1. Calculation of nominal concentrations

In test groups 2 and 3, the nominal concentration was calculated from the study means of the
substance flow and the supply air flows used during exposure to generate the respective
concentrations.

In test group 1 nominal concentration was not determined because dilution system was used to achieve the low target concentration of 0.2 mg/m3. The nominal concentration in this group was not comparable to those determined in the other groups and did not r eflect the generation efficiency. As the nominal concentration is not of significance to the analytically measured one, it is not determined for this group.

3.6.2. D etermination of atmospheric concentrations

Principle:

The concentrations of the inhalation atmospheres were analyzed by gravimetry in test groups
1 - 3

.

Details were described in Part II.

Daily means were calculated based on the measured samples per concentration and exposure. From the daily mean values of each concentration, mean concentrati ons and standard deviations for the entire study were derived.

In these groups, the constancy of concentrations in the inhalation system s we re continuously monitored using scattered light photometers.

The analyses were carried out at

3.6.2.1. Sampling for gravimetric analyses

Equipment

• Internal probe diameter: 7 mm

• Filter: MN 85/90 BF (d = 4.7 cm)

• Vacuum pump (Millipore Corporation, Billerica, MA 01821, USA )

• Balance: Sartorius M3P

- 000V001 (Sa r torius AG, Göttingen, Germany)

Page 30 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Sampling:

• Sampling velocity:

• Flow rate of sampling:

• Sample volumes:

• Test group 1:

• Test group 2:

• Test group 3: 1.25
3

180
180

90 or 180 m/s
L/min

L

L

L

• Sampling site:

• Sampling frequency: immediately adjacent to the animals' noses at a separate spare port as a rule, three samples per exposure and concentration group

3.6.2.2. Gravimetrical method of analyses

A preweighed filte r was placed into the filter holder. By means of a vacuum compressed air pump a defined volum e of the dust was drawn through the filter.

The dust concentration in mg/m3 was calculated from the difference between the weight of the preweighed filter and the weight of the filter after sampling , w ith reference to the sample
volume of the inhalation atmos phere.

3.6.2.3. Real time monitoring of constancy of concentrations

Scattered light photometers (VisGuard

, Sigrist

, Ennetbürgen, Switzerland) in test groups 1

- 3 were used to continuously monitor the constancy of concentrations of test substance dusts in the inhalation systems. The data were recorded by the automated measuring system.

3.6.3. Particle size analysis

3.6.3.1. Definitions

• EACD 50%(effective aerodynamic cutoff diameter 50%) defines the separation characteristic of each impactor stage. 50% of particles with the EACD given are deposited in the pertinent impactor stage; the remainder has reached one of the following stages.

• MMAD(mass median aerodynamic diameter) is the calculated aerodynamic diameter which divides the size distribution in half when measured by mass.

• Geometrical standard deviation (GSD) is the ratio of the estimated 84 percentile to the
50 percentile and indicates the slope of the cumulative particle size distribution curve.

3.6.3.2. Equipment, sampling and method of determination

The particle size analysis was carried out with a cascade impactor.

Page 31 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Equipment for particle size analysis:

• Stack sampler Marple 298 (New Star Environmental, Inc., Roswell, Georgia 30075, USA )

• Vacuum compressed air pump (Millipore Corporation , Billerica, MA 01821, USA )

• Limiting orifice 3 L/min (Millipore Corporation, Billerica, MA 01821, USA )

• Samp ling probe internal diameter 7 mm Balance Sartorius M3P

- 000V001 and LC 1201S

- 00MS (Sa r torius AG, Göttingen, Germany)

Sampling for particle size an alyses:

Preweighed m etal collecting discs and a backup particle filter were placed in to the cascade impactor: O ne sample was taken in each concentration per week at a sampling velocity of 1.25 m/sec. from the breathing zones of the animals.

Table 8 Sample numbers and volumes for particle size measurement by casecade impactor

Test group Number of samples Sample Volume (L)

1 15 720 or 990

2 15 720

3 15 720 or 630

Method of analysis:
Gr avimetrical determination analyses

The amount of dust deposited by each stage in mg was calculated from the difference between the weight of the metal collecting and backup filter before and after sampling.

The deposits in the probe and the wall losses in the impactor were also determined as difference of the total mass increase of the impactor and the sum of masses on the collecting discs and backup filter.

Evaluation:

The calculation of the particle size distribution was carried out in on the basis of mathematical methods for evaluating particle measurements (DIN 66141: Darstellung von Korngrößenverteilungen and DIN 661 61: Partikelgrößenanalyse, Beuth

- Ver trieb GmbH, Berlin und Köln, Germany ).

Page 32 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 3.6.3.3. Particle size analysis by Aerodynamic Particle Sizer (APS)

Particle s ize distribution in the test atmospheres was measured by TSI APS 3321 . Mass Median Aerodynamic Diameter (MMAD) and Geometric Standard Deviation (GSD) is obtained directly by the equipment used (TSI APS 3321).

Frequency: 3 repeats per test group

3.6.4. Food analyses

The food used in the study was assayed for chemical as well as for microbiological
contaminants.

3.6.5. Drinki ng water analyses

The drinking water is regularly assayed for chemical contaminants by the municipal
authorities of as well as for the presence of microorganisms by a co ntract laboratory.

3.6.6. Bedding and enrichment analyses

The bedding and enrichment are regularly assayed for contaminants (chlorinated hydrocarbons and heavy metals).

Page 33 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 3.7. EXPERIMENTAL PROCEDU RE

3.7.1. Acclimatization and exposure period

The animals were delivered and subjected immediately to the acclimatization period in which they were adapted to the surroundings.

Prior to the pre

- exposure period, the animals were distributed according to weight among the individual test groups, separated by sex. The weight variation of the animals used did not

exceed ± 20 percent of the mean weight of each sex. The list of randomization instructions was compiled with a computer.

For each neurofunctional test and motor activity measurement, separate randomization lists were created. The list of randomization instructions were compiled with a computer

3.7.2. Exposure systems; exposure of the animals

Head

- nose exposure systems

The inhalation atmosphere was maintained inside aerodynamic exposure consisting of a cylindrical inhalation chamber made of stainless steel sheeting and cone

- shaped outlets and inlets. The rats were restrained in glass exposure tubes. Their snouts projected into the inhalation chamber and thus they inhaled the aerosol. The exposure systems were located in
exhaust hoods in an air conditioned room.

Two inhalation systems are used. Prior to exposure, to adjust the animals to the exposure condition, INA 120 ( V ≈ 155 L, ) was used

. During subs tance exposure, INA 60 (V ≈ 90 L, was used.

Exposures

The head

- nose exposure technique was preferably selected for this dust inhalation study to minimize fur contamination of the animals with the substance, which cannot be avoided during whole

- body exposure. Fur contamination may lead to an additional dermal and oral uptake (animals preen as their fur becomes contaminated). Thus an estimation of an nominal dose, taken up by the animals and its correlation to a toxic effect becomes more difficult

.

Furthermore, by using the dynamic mode of operation with a low

- volume chamber, the equilibrium characteristic of this exposure technique is favorable: t 99 

### (the time to reach 99% of the final target concentration) is shorter as compared to whole

- body chambers with a higher chamber volume.

A positive pressure was maintained inside the exposure systems by adjusting the air flow of the exhaust air system. This ensured that the aerosol in the breathing zones of the animals was not diluted by laboratory air.

Page 34 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### In order to accustom the animals to exposure they were treated with supply air under conditions comparable to exposure on two days before start of exposure ( pre

- exposure period). Then all test groups were exposed for 6 hours on each workday over a time pe riod suitable to reach 65 exposures.

The animals did not have access to water or feed during the exposure.

Figure 2 : Exposure system

Page 35 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 3.7.3. Measurements of the exposure conditions

Recording of exposure parameters was performed according to the following table.

Table 9 : Recording of exposure parameters

Exposure parameters Determination method Recording Test Group 1 Supply air (conditioned) Rotameter three times per exposure Supply air (compressed) orifice plate with differential pressure measurement automated system

Supply air (conditioned) to the mixing tube Rotameter three times per exposure

Exhaust air orifice plate with differential pressure measurement automated system

Exhaust air
out of the mixing tube Rotameter three times per exposure

Chamber humidity Dielectric probe (Testo) automated system Chamber temperature Thermosensor automated system
Real time concentration
surveillance Scattered light photometers automated system

Test Group 2 and 3 Supply air (conditioned) orifice plate with differential pressure measurement automated system

Supply air (compressed) orifice plate with differential pressure measurement automated system

Exhaust air orifice plate with differential

pressure measurement automated system

Chamber humidity Dielectric probe (Testo) automated system Chamber temperature Thermosensor automated system
Real time concentration
surveillance Scattered light photometers automated system

No surveillance of the oxygen content in the inhalation system was performed. The air change within the inhalation systems was judged to be sufficient to prevent oxygen depletion by the breathing of the animals and the concentrations of the test substance used could not have a substantial influence on oxygen partial pressure.

Page 36 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Principles of recording with the automated measuring system:

Each parameter was measured at appropriate measuring points using suitable measuring equipment (sensors, orifice plates etc.). The measurements were standardized (0 - 20 or
4 - 20 mA) and transferred to instrumentation consoles. There, the measured values were displayed in an analogous way (where this is provided for) and some were used as actual value for regulating the specific parameter.

In addition, the measured values were scanned every 10 seconds, converted from analog to digital, transferred to a personal computer, displayed on its screen, and saved on hard disk. The computer checked the arriving values against preset threshold values, displayed warnings if violations of thresholds occurred and recorded the start and the end of threshold violations for each measured parameter affected. After the end of each exposure all data gathered during this exposure were backed up on optical media.

Daily pr otocols were prepared from the recorded values using suitable software. The protocols include start and stop times of exposure and possible threshold violations, and daily means of each parameter. The records saved on optical media and the printed daily re cords are considered as raw data. Relevant disturbances are reported under “Results”.

Page 37 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 3.8. CLINICAL EXAMINATION S

3.8.1. Mortality

The animals were examined for evident signs of toxicity or mortality twice a day (in the morning and in the late afternoon) on working days and once a day (in the morning) on Saturdays, Sundays and public holidays.

3.8.2. Clinical observations

The clinical condition of the test animals was recorded once daily during the pre

- exposure period and on post

- exposure observation days and at least 3 t imes per day (before, during and after exposure) on exposure days.

During exposure only a group wise examination was possible.

3.8.3. Detailed clinical observation (DCO)

All animals will be subjected to detailed clinical observations outside their cages once before the beginning of the administration period (day 0), at midterm and against the end of the exposure period. For observation, the animals will be removed from their cages and placed in a standard arena (50 x 37.5 x 25 cm). The scope of examinations and the scoring of the findings that are observed will be based on the current index of findings in PDS ToxData ® and includes but is not limited to the following parameters listed:

1. abnormal behavior during handling
2. fur
3. skin
4. posture
5. salivation
6. respiration
7. a ctivity/arousal level
8. tremors
9. convulsions
10. abnormal movements
11. impairment of gait
12. lacrimation
13. palpebral closure
14. exophthalmus
15. feces (appearance/consistency)
16. urine
17. pupil size

Page 38 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 3.8.4. Body weight data

The body weight of the animals was determined at the start of the pre

- exposure , at the start of the exposure period and then, as a rule, once a week as well as prior to gross necropsy. As a rule, the animals were weighed at the same time of the day.

Body weight change was calculated as the difference between body weight on Monday and Friday of the same week. Group means were derived from the individual differences.

3.8.5. Food consumption

Food consumption was determined weekly and calculated as mean food consump tion in grams per animal and day.

The animals were maintained in social

- housing cages, with 5 animals per cage, during the whole study period. Therefore, the food consumption was determined cage

- wise. The food consumption per animal and day was calculated by dividing food consumption of the day of a respective cage by the 5 animals per cage. As the animals of each test group 1 and 2 were housed in only two cages per sex, no statistical evaluation of food consumption is possible.

3.8.6. Ophthalmology

Before the start of the exposure period (day -2 ) the eyes of all main group animals, and at the end of the study (day 83 ) the eyes of the animals of test group 0 (control group) and test

group 3 (high concentration) were examined for any changes in the refracting medi a with an ophthalmoscope (HEINE Optotechnik, Herrsching, Germany ) after administration of a mydriatic (Mydrum, Chauvin ankerpharm GmbH, Rudolstadt, Germany).

Page 39 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 3.8.7. Functional observational battery

A functional observation battery (FOB) was carried out on the assigned animals (see section 3.4.). There is no exposure of the concerning animals.

At least one hour before the start of the FOB the animals were transferred singly to Polycarbonate cages (floor area about 800 cm 2 

### ). The cages were placed in the racks in a randomized order (randomization based upon animals number). Drinking water was provided ad libitum whereas no food was offered during the measurements.

The FOB started with passive observations, without disturbing the animals, followed by removal from home cage, and open field observations in a standard arena. Thereafter, sensorimotor tests and reflex tests were conducted. The examinations were carried out by trained technicians which performed positive control studies as part of their training. Another technician documented all findings and values obtained. The findings were ranked according to the degree of severity, if applicable.

(A more detailed description of the method, the ranking and documentation system can be found in Part III (Supplement).)

Home cage observations:

The animals were observed in their closed home cages; any disturbing activities (touch ing the cage or rack, noise) were avoided during these examinations in order not to influence the
behav ior of the animals. Attention was paid to:

1. posture
2. tremor
3. convulsions
4. abnormal movements
5. impairment of gait

Open field observations:

The animals were transferred to a standard arena (50 x 50 cm with sides of 25 cm high) and
observed for at least 2 minut es. Following parameters were examined:

1. behavior when removed from cage
2. fur
3. skin
4. salivation
5. nasal discharge
6. lacrimation
7. eyes/pupil size
8. posture
9. palpebral closure
10. respiration
11. tremors

Page 40 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 12. convulsions
13. abnormal movements/ stereotypies
14. impairment of gait
15. activity/arousal level
16. feces (number of fecal pellets/appearance/consistency) within two minutes
17. urine (amount/color) within two minutes
18. number of rearings within two minutes

Sensorimotor Tests/Reflexes:

The animals were removed from the open field and subjected to following sensorimotor or
reflex tests:

1. approach response
2. touch response
3. vision ("visual placing response")
4. pupillary reflex
5. pinna reflex
6. audition ("startle response")
7. coordination of movements ("righting response")
8. behavior during "handling"
9. vocalization
10. pain perception ("tail pinch")
11. grip strength of forelimbs
12. grip strength of hindlimbs
13. landing foot

- splay test

3.8.8. Motor activity measurements (MA)

Motor activity was measured on the same day and with the same animals as FOB was performed. The mea sure ment was performed in the dark using the TSE Labmaster System ( TSE Systems GmbH, Bad Homburg, Germany ) w ith 18 infrared beams per cage. During the measurement the animals were kept in Polycarbonate cages with wire covers from Ehret, Emmendingen (floor area about 800 cm 2 

### ) and small amounts of absorbent material. The animals were put into the cages in a randomized order. The measurements started at about
14:00 p.m. The numbers of beam interrupts were counted over 12 intervals, each lasting
5 minutes. Measurement did not commence at the same instant for all cages; the period of assessment for each animal started when the first beam was interrupted by pushing the cage into the rack (staggered start). Measurements ended exactly 60 minutes thereafter. During
the measurements the animals received no food and no water.

Page 41 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 3.9. CLINICAL PATHOLOGY

In the morning blood was taken from the retro

- bulbar venous plexus from fasted animals. The animals were anaesthetized using isoflurane (Isoba®, Essex GmbH Munich, Germany). The blood sampling procedure and subsequent analysis of blood and serum samples were carried out in a randomized sequence.

The assays of blood and serum parameters were performed under internal laboratory quality
control conditions with reference controls to assure reliable test results.

The results of clinical pathology examinations were expressed in International System (SI)
units

.

The following examinations were carried out in 10 animals per test group and sex at the end

o f the administration period and in 5 animals per sex of the control and highest dose group at the end of the recovery period

.

3.9.1. Hematology

The following parameters were determined in blood with EDTA -K 3 

### as anticoagulant using a particle counter (Advia 120 model; Bayer, Fernwald, Germa ny):

Page 42 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Table 10 : Hematology p arameters and methods

Parameter Unit Method References Leukocyte count (WBC) giga/L cytochemistry coupled with flow cytometry Erythrocyte count (RBC) tera/L flow cytometric laserlight scattering Hemoglobin (HGB) mmol/L cyanmethemoglobin method; according to ICSH

Hematocrit (HCT) L/L calculation: MCV x erythrocytes Mean corpuscular
volume (MCV) fL RBC/PLT method; mean of
RBC volume distribution curve (histogram) Operator’s Guide for Advia 120 System

Mean corpuscular hemoglobin (MCH) fmol calculation:

hemoglobin erythrocytes Mean corpuscular hemoglobin
concentration (MCHC) mmol/L calculation:

hemoglobin
hematocrit

Platelet count (PLT) giga/L flow cytometric laserlight scattering
Differential blood
count % and giga/L cytochemistry coupled with flow cytometry Reticulocytes (RET) % cytochemistry coupled with flow cytometry



### Furthermore, blood smears were prepared and stained according to WRIGHT without being evaluated, because of non

- ambiguous results of the differential blood cell counts measured by the automated instrument. (reference: Hematology: Principles and Procedures, 6 th 

### Edition, Brown AB, Lea & Febiger, Philadelphia , 1993, page 101).

Clotting tests were carried out using a ball coagulometer (AMAX destiny plus model; Trinity biotech, Lemgo, Germany).

Table 11 : Clotting test and methods

Parameter Unit Method References

Prothrombin time (Hepato Quick’s test) (HQT) seconds citrated blood with calcium thromboplastin Fischer, M. and Falkensammer, Ch.,
Klin. Wschr. 86 , 577

- 583 (1974)



### Page 43 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 3.9.2. Clinical chemistry

An automatic analyzer (Hitachi 917; Roche, Mannheim, Germany) was used to examine the clinicochemical parameters

Table 12 : Clinical chemistry p arameters and methods

Enzyme (systematic name and system number) Unit Method, wave

length and measuring temperature References

Alanine aminotransferase (ALT) (L

- alanine: 2

- oxoglutarate aminotransferase; EC 2.6.1.2.) μkat/L kinetic UV test,
340 nm; 37°C Recommendations of the German Society for Clinical Chemistry:
"Standardization of methods for determining enzyme activities in biological liquids". Aspartate aminotransferase (AST) (L

- aspartate: 2

- oxoglutarate aminotransferase; EC 2.6.1.1.) μkat/L kinetic UV test,
340 nm; 37°C J. Clin. Chem. Clin. Biochem. 8 , 658

- 660 (1970);
J. Clin. Chem. Clin. Biochem. 9 , 464

- 465 (1971);
J. Clin. Chem. Clin. Biochem. 10

, 182

- 192 (1972) Alkaline phosphatase (ALP) (orthophosphoric acid monoester phosphohydrolase; EC 3.1.3.1.) μkat/L kinetic color test,
415 nm, 37°C Roche working instructions

γ

- Glutamyltransferase (GGT) ( γ

- glutamyl) peptide: aminoacid

- γ

glutamyl

- transferase;
EC 2.3.2.2.) nkat/L kinetic color test,
415 nm, 37°C Szasz, G. et al.,
J. Clin. Chem. Clin. Biochem. 12 , 228 (1974) Roche working instructions



### Page 44 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsBlood Chemistry
Parameter Unit Method References

Sodium (NA) mmol/L

Potassium (K) mmol/L ion selective electrodes (ISE) Hitachi 917

- working instructions

Chloride (CL) mmol/L

Inorganic phosphate (INP) mmol/L molybdate reaction Henry, R.J. in: "Clinical Chemistry", Harper and Row Publishers, New York (1974); Roche working instructions
Calcium (CA) mmol/L o

- cresolphthalein complex without deproteinization Ray Sarkar, B.C. and Chauhan, U.P.S.,
Anal. Biochem. 20 , 155 (1967); Roche working instructions

Urea (UREA) mmol/L enzymatic determination with the urease/ glutamate dehydro

genase method Neumann, U. and Ziegenhorn, J.: XVI, Nordiska kongressen for klinisk kemi och klinisk fysiologi 1977, Oulu, Finland; Roche working instructions
Creatinine (CREA) μ mol/L kinetic Jaffé method without deproteinization Bartels, H. et al., Clin. Chim. Acta 37 , 193 (1972); Roche working instructions
Glucose (GLUC) mmol/L hexokinase/glucose

- 6

- phosphate dehydrogenase method Schmidt, F.H., Klin. Wschr. 39 , 1244

- 1247 (1961); Roche working instructions

Total bilirubin (TBIL) μmol/L DPD method Wahlefeld, A.W. et al., Scand. J. Clin. Lab.
Invest. 29 , Suppl. 126 (1972) Abstract 11.12; Roche working instructions Total protein (TPROT) g/L biuret method Weichselbaum, T.E., Amer. J. Clin. Path.
10 , 40 (1946); Roche working instructions

Albumin (ALB) g/L bromocresol green method Doumas et al., Clin. Chim. Acta 31 , 87 (1971); Roche working instructions
Globulins (GLOB) g/L difference between total protein
and albumin Triglycerides (TRIG) mmol/L enzymatic color test with lipase esterase/ glycerokinase/ glycerol

3- phosphate oxidase/4

- amino

phenazone mod. method by Wahlefeld, A.W., in "Methoden der enzymatischen Analyse" [Methods of enzymatic analysis] (Bergmeyer, H.U., ed.) Vol. II, 3rd ed., Verlag Chemie Weinheim, GERMANY, pp.
1878

- 1882 (1974); Roche working
instructions
Cholesterol (CHOL) mmol/L enzymatic determination with
cholesterol esterase/ cholesterol
oxidase/4

- amino

- phenazone (CHOD

- PAP method) Siedel, J. et al., J. Clin. Chem. Clin.
Biochem. 19 , 838 (1981); Roche working
instructions



### Page 45 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 3.10. PATHOLOGY

The animals were sacrificed under pentobarbitone anesthesia by exsanguination from the abdominal aorta and vena cava. The exsanguinated animals were necropsied and assessed by gross patholog y.

3.10.1. Organ weights

The following weights were determined in all animals sacrificed on schedule:

1. Anesthetized animals
2. Adrenal glands
3. Brain
4. Epididymides
5. Heart
6. Kidneys
7. Liver
8. Lung
9. Ovaries
10. Spleen
11. Testes
12. Thymus
13. Thyroid glands
14. Uterus

3.10.2. Organ/tissue fixation

The following organs or tissues were fixed in 4% buffered formaldehyde solution or in
modified Davidson’s solution:

1. All gross lesions
2. Adrenal glands
3. Aorta
4. Bone marrow (femur)
5. Brain with olfactory bulb
6. Cecum
7. Colon
8. Duodenum
9. Epididymides
10. Esophagus
11. Extraorbital lacrimal gland
12. Eyes with optic nerve and eyelid
13. Femur with knee joint
14. Harderian glands
15. Heart
16. Ileum

Page 46 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 17. Jejunum
18. Kidneys
19. Larynx
20. Liver
21. Lung
22. Lymph nodes (tracheobronchial, mediastinal and mesenteric lymph nodes)
23. Mammary gland (male + female)
24. Nose (nasal cavity)
25. Ovaries
26. Pharynx
27. Pancreas
28. Parathyroid glands
29. Pituitary gland
30. Prostate
31. Rectum
32. Salivary glands (mandibular and sublingual glands)
33. Sciatic nerve
34. Seminal vesicles
35. Skeletal muscle
36. Skin
37. Spinal cord (cervical, thoracic and lumbar cord)
38. Spleen
39. Sternum with marrow
40. Stomach (forestomach and glandular stomach)
41. Teeth
42. Testes (modified Davidson’s solution)
43. Thymus
44. Thyroid glands
45. Tongue
46. Trachea
47. Ureter
48. Urethra
49. Urinary bladder
50. Uterus

Page 47 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 3.10.3. Histopathology

Fixation was followed by histotechnical processing, examination by light microscopy and assessment of findings according to the table below:

Table 13 : Histological examination of main group animals (F1)

Organs Test group

0 1 2 3

1. All gross lesions A2 A2 A2 A2

2. Adrenal glands A1 A1

3. Aorta A1 A1

4. Brain A1 A1

5. Bone marrow (femur) A1 A1

6. Cecum A1 A1

7. Colon A1 A1

8. Duodenum A1 A1

9. Epididymides A1 A1

10. Esophagus A1 A1

11. Eyes with optic nerve A1 A1

12. Extraorbital lacrimal gland A1 A1

13. Femur with knee joint A1 A1

14. Harderian gland A1 A1

15. Heart A1 A1

16. Ileum A1 A1

17. Jejunum A1 A1

18. Kidneys A1 A1

19. Larynx (3 levels) * 

### A1 A1 A1 A1

20. Liver A1 A1

21. Lung A1 A1 A1 A1

22. Lymph nodes (tracheobronchial, mediastinal and mesenteric lymph nodes) A1 A1

23. Mammary gland (female) A1 A1

24. Nasal cavity (4 levels) † 

### A1 A1 A1 A1

25. Ovaries A1 A1

26. Pancreas A1 A1

* One level does include the base of the epiglottis.
† One level includes the nasopharyngeal duct; the 4 levels allow adequate examination of the squamous, transitional, respiratory and olfactory epithelium, and the draining lymphatic tissue (NALT).



### Page 48 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Organs Test group

0 1 2 3

27. Pharynx A1 A1

28. Parathyroid glands A1 A1

29. Pituitary gland A1 A1

30. Prostate A1 A1

31. Rectum A1 A1

32. Salivary glands (mandibular and sublingual glands) A1 A1

33. Sciatic nerve A1 A1

34. Seminal vesicles A1 A1

35. Skeletal muscle A1 A1

36. Skin A1 A1

37. Spinal cord (cervical, thoracic and lumbar cord) A1 A1

38. Spleen A1 A1

39. Sternum with marrow A1 A1

40. Stomach (forestomach and glandular stomach) A1 A1

41. Teeth A1 A1

42. Testes A1 A1

43. Thymus A1 A1

44. Thyroid glands A1 A1

45. Trachea * 

### A1 A1 A1 A1

46. Urinary bladder A1 A1

47. Uterus A1 A1

* One transverse section and one longitudinal section through the carina of the bifurcation of the extrapulmonary bronchi.



### Page 49 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Table 14 : Histological examination of recovery group (R1)

Organs Test group

0 3

1. All gross lesions A2 A2

2. Larynx (3 levels) * 

### A1 A1

3. Lung A1 A1

4. Nasal cavity (4 levels) † 

### A1 A1

5. Trachea ‡ 

### A1 A1



### A = Hematoxylin and eosin (H&E) stain

1 = All animals/test group 2 = All animals affected/test group

A correlation between gross lesions and histopathological findings was attempted.

Peer review

Due to histological findings, after completion of the histopathological assessment by the study pathologist an internal peer review of all test groups in main and recovery groups of lung , larynx level I and II and nasal cavity level I and II in animals of both sexes was performed by Results presented in the report reflect the consensus opinion of the study pathologist and the peer review patholo gist.

* One level does include the base of the epiglottis.
† One level includes nasopharyngeal duct; the 4 levels allow adequate examination of the squamo us, transitional, respiratory and olfactory epithelium, and the draining lymphatic tissue (NALT).
‡ One transverse section and one longitudinal section through the carina of the bifurcation of the extrapulmonary
bronchi.



### Page 50 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 3.11. STATISTICS

Means, medians and standard deviations of each test group were calculated for several parameters (see tables). Further statistical analyses were performed according to following
tables . Details were explained in the summary tables in PART I :

Table 15 : Statistical analyses

Parameter Statistical test markers in
the tables References

Body weight, body weight change, food consumption, A com parison of each group with the control group was performed using DUNNETT's test (two

- sided) for the hypothesis of equal means * for p < 0.05
** for p < 0.01 DUNNETT, C.W. (1955): A multiple comparison procedure for comparing several treatments with a control. JASA,
Vol. 50, 1096 – 1121

DUNNETT, C.W. (1964). New tables for multiple comparisons with a control. Biometrics, Vol. 20, 482 – 491

Feces, rearing, grip strength length forelimbs, grip strength length hindlimbs, foot

splay test, motor activity

Blood parameters (with bidirectional changes) Non

- parametric one

- way analysis using KRUSKAL

WALLIS test (two

- sided).If the resulting p

- value was equal or less than 0.05, a pairwise comparison of each dose group with the control group was performed using
Wilcoxon

- test (two

- sided) for the equal medians * for p < 0.05
** for p < 0.01 SIEGEL, S. (1956):
Non

- parametric statistics for the behavioural
sciences. McGraw

- Hill New York

Blood parameters ( with unidirectional changes ) Pairwise comparison of each dose group with the control group using the WILCOXON

test (one

- sided) with
Bonferroni

- Holm adjustment for the hypothesis of equal
medians * for p < 0.05

** for p < 0.01 Holm (19 71 ): A Simple Sequentially Rejective Multiple Test Procedure. Scand. J. Statist. 6, 65

- 70

Weight of the
anesthetized
animals and
absolute and relative organ weights Non

- parametric one

- way analysis using KRUSKAL

WALLIS test (two

- sided). If the resulting p

- value was equal or less than 0.05, a pairwise comparison of each dose group with the control group was performed using
WILCOXON

- test (two

- sided) for the equal medians * for p ≤ 0.05

** for p ≤- 0.01 HETTMANNSPERGER, T.P. (1984): Statistical Inference based on Ranks, John Wiley & Sons New York, 132

- 140

. International Mathematical and Statistical Libraries, Inc., 2500 Park West Tower One, Houston, Texas 77042

- 3020, USA, nakl

- 1 - nakl -3
MILLER, R.G. (1981): Simultaneous Statistical Inference, Springer

- Verlag New York Inc., 165

- 167

NIJENHUIS, A. and S.W. WILF (1978): Combinatorial Algorithms, Academic Press,
New York, 32

- 33



### Page 51 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

## 4. RESULTS

Throughout the sections of the report, when intergroup differences are referred to as "significant " it implies that the differences have attained statistical significance (p ≤ 0.05) when compared with the control group.

4.1. ANALYSES

4.1.1. Measurements of atmosphere parameters and operation conditions

Detailed results of the measurements of concentrations and operation conditions can be
found in Part II.

Details of the particle size analyses are given in Part II.

Individual values may be found in the record sheets and are kept with the raw data.

4.1.1.1. Concentration measurements in the exposure system

(Tables ID

- 1, IID

- 1 - IID -4)

Table 16 : Study means and standard deviations of test substance concentrations

Test group Target concentration (mg/m3) Measured concentration (mg/m3) Nominal
concentration (mg/m3) Mean SD

0

- 1 0.2 0.2 5 0. 17

- 2 1 1.42 0. 42 12.4

3 5 5.10 1.2 4 14.7

Page 52 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Figure 3 : Time course of daily concentrations

Real time surveillance of the inhalation atmospheres with scattered light photometers generally proved the constancy of each concentration throughout the daily exposures. Examples of recorder protocols are depicted in the figure below (original protocols a re archived with the raw data). 0 2 4 6 8 10 12 14 16 18 20

1 6 11 16 21 26 31 36 41 46 51 56 61 66Measured concentrations [mg/m3]



### Exposure numbers

Test group 1 (0.2 mg/m3) Test group 2 (1 mg/m3) Test group 3 (5 mg/m3)



### Page 53 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Figure 4 : Examples of concentration real time records

Test group 1

Test group 2

Page 54 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Test group 3

Figure 5 : Examples of concentration real time records showing variations

Test group 2

Page 55 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Test group 3

Real time surveillance of the inhalation atmospheres with scattered light photometers showed some variations of concentration during daily exposure, reflecting the variation found for the study means (examples of recorder protocols see APPENDIX, original protocols are archived with the raw data).

Page 56 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 4.1.1.2. Measurements concerning operation conditions

(Tables ID

- 1, IID

- 1 - IID -4)

The air flows were constantly maintained in the desired range. An air change of a bout
67 times per hour can be calculated by dividing the supply air flow through the volume of each inhalation system.

Daily m ean s of relative humidities in the inhalation systems ranged between 34.0 and
63.7 %. Daily m ean s of temperatures in the inhalation systems ranged between 21.0 and
23.8 °C.

4.1.1.3. Results of the particle size analyses

(Tables ID

- 1, IID -5 - IID

- 48 )

All measurements of particle size resulted in MMADs between 2 .0 and 5.7 μm with GSDs
between 1.9 and 4.4

. In most cases, the calculated mass fractions of particles below 3 μm

ae rodynamic size ranged between 29.5 and 66.4 %. One measurement in test group 2 showed large MMAD of 5.7, and a fraction of only 19.8 % were < 3 μm. We considered this value as a single event. The generated dust aerosols were generally within respirable range. The casecade impactor measurement was confirmed by APS.

In t he following table the MMAD/GSD by cascade impactor ( Tables IID

- 5 - IID

- 48 in Part II)
and APS are presented:

Table 17 Particle size distributions measured by different devices

Test groups 1 2 3 Target concentration (mg/m 3 

### ) 0.2 1 5 MMAD (μm) / GSD 2.8 / 2. 3
3.4 / 2. 2
3.7 / 2.2
3.0 / 2.4
2.5 / 2.7
3.8 / 2.3
2.3 / 2.1
2.0 / 2.7
3.0 / 2.2
2.6 / 3.1
2.4 / 3.0
2.0 / 3.2
3.4 / 3.0
3.3 / 4.4
3.9 / 2.3 5.7 / 2.1
4.8 / 2. 3
3.3 / 2.6
2.5 / 1.9
4.2 / 2.2
4.0 / 2.1
3.8 / 2.1
3.1 / 2.0
3.8 / 2.4
4.0 / 2.1
3.2 / 2.5
3.4 / 2.3
2.7 / 3.1
2.9 / 2.8
4.1 / 2.1 3 .7 / 2.3
3 .9 / 2.2
3.4 / 2.4
3.6 / 2.4
3.5 / 2.4
4.0 / 2.1
3.6 / 2.2
3.4 / 2.3
3.4 / 2.3
3.7 / 2.3
3.5 / 2.3
3.7 / 2.2
3.2 / 2.5
3.5 / 2.0
3.0 / 2.4

APS 3321: MMAD (μm) / GSD 3. 30 / 1. 78
3.87 / 1. 93
3.11 / 1.97 3.37 / 1. 90
3.59 / 1. 99
3.70 / 2.03 2.77 / 1. 66
2.79 / 1. 88
3.00 / 1.86



### Page 57 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 4.1.2. Food analyses

On the basis of duration of use and the analytical findings with respect to chemical and microbiological contaminants the food was found to be suitable. Fed. Reg. Vol. 44, No. 91 of 9 May 1979, p. 27354 (EPA), served as a guideline for maximum tolerable ch emical contaminants. The number of microorganisms did not exceed 1*10 5 

### /g food. Individual results
are to be found in the archives of

4.1.3. Drinking water analyses

On the basis of the analytical findings the drinking water was found to be suitable.
served as a guideline for maximum tolerable contaminants. Individual results are to be found in

4.1.4. Bedding and enrichment analyses

On the basis of the analytical findings the bedding and the enrichment are found to be suitable. Levels given in Lab. Animal, Nov

- Dec 1979, pp. 24

- 33, served as a guideline for
maximum tol erable contaminants. Individual results are to be found in

Page 58 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 4.2. CLINICAL EXAMINATION S

Summary Tables of the results can be found in Part I (Tables IA

- 1 - IA

- 49 ); individual values
are to be f ound in Part II (Tables IIA

- 1 - IIA

- 12 5 ).

4.2.1. Mortality

No deaths were recorded throughout the study.

4.2.2. Clinical observations

(Summary tabl es IA

- 1 - IA -2 in Part I and individual value tables IIA

- 1 - IIA

- 57 in Part II)

All male animals did not show any clinical signs of toxicity throughout the study. In female animals reduced fur care was observed in individuals of test group 2 (2 of the 10 females) and group 3 (3 of the 15 females).

4.2.3. Detailed clinical observations

(Summary table s IA

- 3 – IA -8 in Part I and individual value tables IIA

- 58 - IIA

- 61 in Part II)

The detailed clinical observations did not reveal any abnormalities in all male and female animals of test groups.

4.2.4. Body weight data

(Summary tables IA -9 - IA

- 22 in Part I and Individual values tables IIA

- 62 - IIA

- 75 in Part II)

Body weight:

The mean body weights of the male and female animals exposed to test substance were not statistically significantly different from the control group 0 throughout the study

.

Page 59 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Figure 6 : Body weight development of male animals before and during exposure period

Figure 7 : Body weight development of male animals during recovery period

Page 60 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Figure 8: Body weight development of female animals before and during exposure period

Figure 9 : Body weight development of female animals during recovery period

Page 61 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Body weight change

The body weight changes of all exposed fe male animals were comparable to the controls throughout the study

.

The following statistically significant body weight changes were observed in exposed male
animals:

From study day

- 2 to 0: group 2 From study day 0 to 2: group 1, group 2 and group 3 From study day 12 to 16: group 3 From study day 54 to 58: group 2 From study day 61 to 65: group 2 From study day 82 to 86: group 2 and 3

The reduced body weight gain in test group 2 from study day

- 2 to 0 is clearly not substance

related, because the exposure did not start at the measurement time point. From study day 0 to 2 body weight gains of all exposed groups are reduced when compared with the control. Because this change is transient and there is not concentration

- response relationship, this finding is considered to be incidental.

During the exposure period, the body weight gains of test group 2 and 3 were marginally lower than those of the control, though not statistically sig nificant in most cases. Therefore, the significances in body weight gain of test groups 2 and 3 might be related to the exposure. The findings are considered to be not adverse because there was no concentration

- response relationship, and the reduction ( max imum

- 2.3 %) was so minimal.

4.2.5. Food consumption

(Summary tables IA

- 23 - IA

- 27 in Part I and individual value tables IIA

- 76 - IIA 83 in Part II)

No substance

- related changes of food consumption were observed during the whole study period.

4.2.6. Ophthalmology

(Summary tables IA

- 28 - IA

- 29 in Part I and individual value tables IIA

- 84 - IIA 89 in Part II)

Spontaneous findings such as remainders of the pupillary membrane or corneal stippling were observed in several animals of all test groups and the control group without any

concen tration

- response relationship.

The individual ophthalmologic findings are archived with the raw data.

Page 62 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 4.2.7. Functional observational battery

(Summary tables IA

- 30 - IA

- 45 in Part I and individual value tables IIA

- 90 - IIA

- 11 7
in Part I I)

On the day of the performance of the Functional Observation Battery, the animals were not exposed to the test sub s tances.

Deviations from "zero values" were obtained in several animals. However, as most findings were equally distributed between treated groups and controls, were without a dose

- response relationship or occurred in single animals only, these observations were considered to have
been incidental. Besides this, the following findings were observed and have to be assessed individually:

Observations on day 90 :

No substance

- related findings were observed.

Home cage observations: (Males see table IA

- 30 and Females see table IA

- 37 )

No substance

- related findings were observed.

Open field observations: (Males see tables IA

- 31 – IA

- 34 and Females see tables IA

- 38 – IA

- 41 )

No substance

- related findings were observed.

Sensorimotor tests/reflexes: (Males see tables IA

- 35 – IA

- 36 and Females see tables IA

- 42 – IA

- 43 )

No substance

- related findings were observed.

4.2.8. Motor activity

(Summary tables IA

- 46 - IA

- 49 in Part I and individual value tables IIA

- 118 - IIA

- 125 in Part II)

Regarding the overall motor activity as well as single intervals, no test substance

- related
deviations were noted for male and female rats.

Page 63 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Figure 10 : Motor activity of male animals

Figure 11 : Motor activity of female animals

Page 64 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 4.3. CLINICAL PATHOLOGY

Summary tables of the results are given in the Appendix of PART I; individual valu es are given in Part B of PART II.

4.3.1. Hematology

(Tables IB 1 – IB 4 Red blood cell + coagulation parameters ) (Tables IB 5 – IB 8 White blood cell parameters )

No treatment

- related , adverse changes among hematological parameters were observed.

After the 4

- weeks recovery period , in males of test group 3 (5 mg/m 3 

### ), hemoglobin and hematokrit values as well as in females of the same dose group red blood cell (RBC) counts were higher compared to controls. However, all values were within historical control ranges (males: hemoglobin 9.0

- 9.8 mmol/L, hematokrit 0.396

- 0.448 L/L; females: RBC 7.28

- 8.25 Tera/L, PART III, Supplement) and therefore, the alterations were regarded as incidental and
not treatment

- related.

After the recovery in females of test group 3 (5 mg/m 3 

### ), absolute and relative neutrophil counts were increased and correspondingly, relative lymphocyte counts were decreased.
Total white blood cell counts were not changed in this group and there was no change in the differential blood cell counts during the 3 months administration period. Therefore, the higher neutrophil counts after the recovery period were regarded as maybe treatment

- related, but
not adverse.

4.3.2. Clinical chemistry

(Tables IB 9 – IB 12 Enzymes) (Tables IB 13 – IB 16 Substrates ) (Tables IB 17 – IB 20 Electrolytes + minerals )

No treatment

- related , adverse changes among clinical chemistry p arameters were observed.

After the recovery period in males of test group 3 (5 mg/m 3 

### ), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were higher compared to controls. The ALT mean was at the border of the historical control range and the AST mean was slightly above this range (ALT 0.46

- 0.94 μkat/L; AST 1.37

- 2.29 μkat/L, PART III, Supplement). The AST mean in test group 3 was 36 % higher compared to that of the study control, which was regarded as a marginal elevation. Neither any change of liver enzyme
activities nor any altered other clinical chemistry parameter occurred during the administration phase. Even after the recovery period no other liver parameter (total proteins, albumin, cholesterol, triglycerides, prothrombin time, bilirubin) apart from both mentioned l iver enzymes was altered. Therefore, these higher liver enzyme activities after the recovery period were regarded as treatment

- related, but not adverse.

Page 65 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### After the recovery period in males of test group 3 (5 mg/m 3 

### ), potassium levels were higher compared to controls, but the values were within the historical control range (potassium 4.35

- 4.82 mmol/L, PART III, Supplement) and therefore, this alteration was regarded as incidental
and not treatment

- related.

Page 66 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 4.4. PATHOLOG Y

Summary tables of the results are to be found in Part C of PART I; individual tables can be
found in Part C of PART II.

4.4.1. Main Groups

4.4.1.1. Weight parameters

(Tables IC 1 – IC 8)

Absolute weights When compared to the control group 0 (set to 100%), the mean absolute weights of the lung were significantly increased in all test groups ( statistically significant changes printed in bold ):

Table 18 Relative increase of absolute lung weight

Male animals Female animals Test group ( mg/m3 ) 1 (0.2 ) 2 (1 ) 3 (5) 1 (0.2 ) 2 (1 ) 3 (5) 

### Lung 154%** 187%** 199%** 152%** 158 %** 190% p <= 0.01



### All other mean absolute weight parameters did not show significant differences when compared to the control group 0.

Relative organ weights When compared to the control group 0 (set to 100%), the mean relative weights of the lung were significantly increased in all test groups ( statistically significant changes printed in bold):

Table 19 Relative increase of relative l ung weight

Male animals Female animals Test group ( mg/m3 ) 1 (0.2 ) 2 (1 ) 3 (5) 1 (0.2 ) 2 (1 ) 3 (5) 

### Lung 147%**  186%** 205%** 148%** 16 0 %** 191% p <= 0.01



### All other mean relative weight parameters did not show significant differences when compared to the control group 0.

The increased lung weights in males and females (absolute and relative) of all treated test groups were regarded to be treatment

- related.

Page 67 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 4.4.1.2. Gross lesions

(Table IC 9)

Treatment

- related foci were noted on the lung of animals of all treated test groups with an
incidence as shown in the table below:

Table 20 Gross lesions

Lung Male animals Female animals Test group ( mg/m3 ) 0 (0) 1 (0.2 ) 2 (1 ) 3 (5) 

### 0 (0) 1 (0.2 ) 2 (1 ) 3 (5) 

### Animals per group 10 10 10 10 10 10 10 10
Focus 3 8 10 1 7 10

All other findings occurred individually. They were considered to be incidental or spontaneous in origin and without any relation to treatment

4.4.1.3. Histopathology

(Tables IC 10 – IC 15)

Target organs were the larynx, level I and lung.

Larynx, level I
Treatment - related findings in the larynx were epithelial alteration characterized by s light modification of epithelial cells (i.e., three to four cell layers, focally flattened and stratified

, indicating beginning metaplastic transformation ) and minimal squamous metaplasia (characterized by three to four cell layers of flattened, stratified epithelium with no signs of
keratinization and only affecting the epiglottis ) as described in Kaufmann et al., 2009.
Incidence and grading were recorded as shown in the table below:

Table 21 Incidence and grading of histological findings in larynx

Larynx, level I Male animals Female animals Test group ( mg/m3 ) 0 (0) 1 (0.2 ) 2 (1 ) 3 (5) 

### 0 (0) 1 (0.2 ) 2 (1 ) 3 (5) 

### Animals per group 10 10 10 10 10 10 10 10 Epithelial alteration 6 9 8 1 3 8 8

• Grade 1 6 9 8 1 3 8 8 Metaplasia,

squamous 1 1

• Grade 1 1 1

Page 68 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Lung

There were numerous treatment – related findings in alveoli and bronchi, diagnostic terms are explained below.

** Alveoli**
Cellular debris : thin (2 μm) strands of eosin o philic tissue interpreted as necrotic alveolar septae , sometimes coiled , admixed with polygonal eosi nophilic cell – shaped debris Histiocytosis: Increase in alveolar macrophages which sometimes form aggregates and have foamy cytoplasm Inflammation, multifocal: Foci of pyogranulomatous inflammation with cellular debris and
alveolar necrosis Infiltrates, inflammatory cells : Inflammatory cell infiltrates without evident tissue damage
Mucus : Blue

- grey granular material in bronchi and alveoli Regeneration of alveolar epithelium: Type II pneum o cyte activation characterized by cuboidal
to flattened cells with g ranular to foamy basophilic cytoplasm Emphysema : Tearing of alveolar septae

**Bronchi**
Reduced number of clara cells : reduction of number of dome shaped Clara c ells in bronchi of
treated animals Degeneration, bronchial epithelial cells : Bronchial epithelial cells variably flattened with loss of cilia, and basophilic cytoplasm Metaplasia, mucoid, bronchial: increased number of goblet cells in bronchi Obliteration, bronchial : tissue strands partially obliterating the bronchial lumen
Test m aterial, bronchial: dark small particles with a diameter of less 1μm and interpreted as
test material

Table 22 Incidence and grading of histological findings in lung

Lung Male animals Female animals Test group ( mg/m3 ) 0 (0) 1 (0.2) 2 (1) 3 (5) 

### 0 (0) 1 (0.2) 2 (1) 3 (5) 

### Animals per group 10 10 10 10 10 10 10 10 Cellular debris,
alveolar 10 10 10 10 10 10

• Grade 1 4 2 3 2

• Grade 2 6 5 6 6 8 6

• Grade 3 3 4 1 3

• Grade 4 1 Histiocytosis,alveolar 10 10 10 10 10 10

• Grade 1 10 5 4 10 6

• Grade 2 9 5 5 4

• Grade 3 1 1

Page 69 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Lung Male animals Female animals Test group ( mg/m3 ) 0 (0) 1 (0.2) 2 (1) 3 (5) 

### 0 (0) 1 (0.2) 2 (1) 3 (5) 

### Animals per group 10 10 10 10 10 10 10 10 Inflammation, (m)f 9 7 10 2 9 1

• Grade 1 8 7 2 1 9 1

• Grade 2 1 7 1

• Grade 3 1 Infiltrates, inflammatory cell 2 10 10 10 10 10 10

• Grade 1 2 10 10 7 7 10 10

• Grade 2 3 3
Mucus 10 10 10 10 10 10

• Grade 1 1 1 5 1 6

• Grade 2 6 2 9 5 6 2

• Grade 3 4 6 3 1

• Grade 4 1 1 Regeneration, alveolar epithelium 5 5 6 4 6

• Grade 1 5 4 5 4 6

• Grade 2 1

• Grade 3 1 Emphysema 1 2 3

• present 1 2 3 Reduced number,
clara cells 4 10 10 10 10

• Grade 1 3 2 2

• Grade 2 1 2 2

• Grade 3 8 4 2

• Grade 4 10 2 6 Degeneration, bronchial epithelial
cells 3 10 10 10 10

• Grade 1 3 10 10 10 10 Metaplasia, mucoid,
bronchial 4 2 5

• Grade 1 3 2 3

• Grade 2 1 2 Obliteration,
bronchial 2

• Grade 1 1

• Grade 2 1 Test material,
bronchial 1 1

• Present 1 1

Page 70 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### All other findings occurred either individually or were biologically equally distributed over control and treatment groups. They were considered to be incidental or spontaneous in origin and without any relation to treatment.

4.4.2. Recovery Groups

4.4.2.1. Weight parameters

(Tables IC 16 – IC 23)

Absolute weights When compared to the control group 0 (set to 100%), the mean absolute weights of the lung were significantly increased in test group 3 ( statistically significant changes printed in bold ):

Table 23 Relative changes of absolute lung weight

Male animals Female animals Test group ( mg/m3 ) 3 (5) 3 (5) 

### Lung 211%** 221% p <= 0.01



### Relative organ weights When compared to the control group 0 (set to 100%), the mean relative weights of the lung were significantly increased in test group 3 ( statistically significant changes printed in bold):

Table 24 Relative changes of relative lung weight

Male animals Female animals Test group ( mg/m3 ) 3 (5) 3 (5) 

### Lung 215%**  215%** **p <= 0.01



### All other mean relative weight parameters did not show significant differences when compared to the control group 0. The increased lung weights in males and females (absolute and relative) of test group 3 were regarded to be treatment

- related.

Page 71 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 4.4.2.2. Gross lesions

(Table IC 24)

Treatment

- related findings were noted in the lung of recovery animals

Table 25 Gross lesions

Lung Male animals Female animals Test group ( mg/m3 ) 0 (0) 3 (5) 

### 0 (0) 3 (5) 

### Animals per group 5 5 5 5
Focus 5 5

All other findings occurred individually. They were considered to be incidental or spontaneous in origin and without any relation to treatment.

4.4.2.3. Histopathology

(Tables IC 25 - IC 26)

Larynx, level I

Laryngeal epithelial alteration was only present in 2/5 female animals recovering from 5 mg/m3 indicating recovery from this finding in most animals.

Table 26 Incidence and grading of histological findings in larynx

Larynx, level I Male animals Female animals Test group ( mg/m3 ) 0 (0) 3 (5) 

### 0 (0) 3 (5) 

### Animals per group 5 5 5 5 Epithelial alteration 2

• Grade 1 2

Lung

Findings in the lung alveoli persisted in recovery animals; notably, there was a higher grade of alveolar histiocytosis in animals recovering from 5 mg/m3. Findings in bronchi were no longer detected after the recovery period.

Page 72 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Table 27 Incidence and grading of histological findings in lung

Lung Male animals Female animals Test group ( mg/m3 ) 0 (0) 3 (5) 

### 0 (0) 3 (5) 

### Animals per group 5 5 5 5 Cellular debris, alveolar 5 5

• Grade 1 2 1

• Grade 2 2 4

• Grade 3 1 Histiocytosis,alveolar 5 5

• Grade 3 5 5 Inflammation, (m)f 5 5

• Grade 1 3 2

• Grade 2 2 3 Infiltrates, inflammatory cell 5 1 5

• Grade 1 3 1 3

• Grade 2 2 2
Mucus 5 5

• Grade 1 1 1

• Grade 2 3

• Grade 3 2 1

• Grade 4 2 Regeneration, alveolar epithelium 5 5

• Grade 1 3 2

• Grade 2 1 3

• Grade 3 1 Emphysema 1

• present 1

Page 73 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

## 5. DISCUSSION

During the exposure period, the target concentrations were maintained as constant and stable as could be provided with dust aerosol generation techniques in the concentration range tested. Particle size distribution measurement demonstrated that the aeroso ls were respirable for rats.

Concerning clinical observation, body weight development and clinical pathology, no
treatment

- related, adverse effects were observed up to 5 mg/m3.

Regarding pathology, target organs were larynx, level I and the lung.

Laryngeal epithelial alteration in most male and female animals of all treated test groups (0.2, 1, 5 mg/m3) and minimal squamous metaplasia without inflammation in one male animal each of test groups 2 and 3 (1 and 5 mg/m3) were regarded as non

- adverse as recommended in Kaufmann et al., 2009. There was recovery from this finding as the incidence in recovery groups (2/5) was lower than in main test groups (8/10) in females and it was absent in male animals recovering from 5 mg/m3.

The absolute and relative lung weights of animals of all treated groups were significantly higher than controls showing a dose dependent increase from 154%/152% (male/female) in test group 1 (0.2 mg/m3) to 199%/190% (male/female) in test group 3 (5 mg/m3). In animals recovering from 5 mg/m3, lung weights were even higher with absolute weights of 211%/221% (male/female) and relative weights of 215% in both sexes. The weight increase was considered to be related to the histologically observed accumulation of fluid (mucus) and
inflamm ation/inflammatory cells including histiocytes in the lung parenchyma, which also correlates to foci observed on macroscopic examination.

Histologically, the lung of animals of all treated test groups (0.2, 1, 5 mg/m3) showed a range of alveolar and bronchial findings indicating inflammatory to degenerative and regenerative reactions to inhalation of the test substance. All animals of all treated test groups showed findings in the alveolar region in the lung, while findings in bronchi were present in all a nimals of test groups 2 and 3 (1 and 5 mg/m3, respectively) but less in animals in test group 1 (0.2 mg/m3). Apart from cellular debris in alveoli which tended to increase with dose and the number of clara cells in bronchi (decreasing number with dose), findings showed no clear
dose – response. Comparing main test group 3 (5 mg/m3) animals with recovery animals, lung weights were increased in animals recovering from 5 mg/m3, and there was less debris and mucus and more histiocytes in alveoli of those animals. This reflects an increased clearance reaction in recovery animals. Findings in bronchi were no longer present in recovery animals indicating complete regeneration.

Findings in alveoli and bronchi of main group animals and in alveoli in recovery animal s were regarded as adverse. All other findings recorded were considered to be incidental in nature
and not related to treatment.

Page 74 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

## 6. CONCLUSION

Inhalation exposure of 0.2, 1 and 5 mg/m 3 

### Cobalt Lithium Manganese Nickel oxide for 90 days (65 exposures) caused clearly treatment

- related histological changes in lung

. The effects were not fully reversible within 4 weeks recovery period. A No Observed Adverse Effect Concentration (NOAEC) could not be established under the current study condition.

Based on the data of clinical observation, body weight, food consumption, clinical chemistry, hematology and histological examinations, there was no indication for any systemic toxicity. Therefore, the NOAEC for systemic toxicity is 5 mg/m3 under the current study cond ition.



## 7. REFERENCES

Kaufmann W, Bader R, Ernst H, Harada T, Hardisty J, Kittel B, Kolling A, Pino M, Renne R, Rittinghausen S, Schulte A, Wöhrmann T, Rosenbruch M. 1 st 

### international ESTP expert workshop: "Larynx squamous metaplasia". A re

- consideration of morphology and diagnostic approaches in rodent studies and its relevance for human risk assessment. Exp Toxicol
Pathol. 2009

. Nov;61(6):591

- 603.

Page 75 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

## 8. LIST OF ABBREVIATION S

The following list contains abbreviations and definitions generally used in reports for this study type. This report will not necessarily use all expressions listed below.

8.1. CLINICAL EXAMINATION S

AE = after exposure

a.m. = ante meridiem (before noon)

anm = animal
BE = before exposure
BW = body weight

cm = centimeter
d = day
D = Dunett ́s test , two sided
DE = during exposure
f / F = female
food cons. = food consumption
food eff = food efficiency
FST = foot

- splay test

g = gram GS F = grip strength forelimbs
GS H = grip strength hindlimbs
h = hour
Interr. = interrupts
Interv. = intervall
m / M = male mg/m3; mg/m**3 = milligram per cubicmeter

mm = millimeter
N = number of animals or samples

n = Student’s test (two

- sided)
NC = not calculable
NOAEC = No observed adverse effect concentration

p = significance level

p.m. = post meridiem (after noon)
REAR = rearing
SPF = specific pathogen free
SD = standard deviation %dev = per cent deviation % = per cent

- = not detected

The gradings in tables IA

- 30 – IA

- 43 are explained in the description of FOB in Part III.

Page 76 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 8.2. ANALYTICAL DATA AND EXPOSURE PARAMETERS

b = intercept from linear regression
d = diameter
EACD = effective aerodynamic cutoff diameter
GSD = Geometrical standard deviation
h = hour
INA = H ead

- nose inhalation system
IKA = Whole

- body inhalation system
L = liter
L/min = liter per minute
L/h = liter per hour

ppm = parts per million

m = slope of linear regression line (lnEACD versus probit of cumulative mass distribution)
m/s = meter per second
mL = milliliter
mL/h = milliliter per hour
m3 /h = cubicmeter per hour

mg = milligram mg/L = milligram per liter mg/h = milligram per hour mg/m 3 

### = milligram per cubicmeter

μm = micrometer
MMAD = mass median aerodynamic diameter 50%
Pa = Pascal
r2 = squared correlation coefficient of regression
RF = backup particle filter (for german term “Restfilter”)
SD = standard deviation
V = volume
v/v = volume per volume % = per cent °C = degree Celsius
%RH = per cent relative humidity

Page 77 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 8.3. CLINICAL PATHOLOGY

SD = standard deviation
N = number of values

HEMATOLOGY:

WBC = white blood cells (leukocytes)
RBC = red blood cells (erythrocytes)
HGB = hemoglobin
HCT = hematocrit
MCV = mean corpuscular volume
MCH = mean corpuscular hemoglobin
MCHC = mean corpuscular hemoglobin concentration
PLT = platelets
RETI = reticulocytes
NEUT = polymorphonuclear neutrophils
LYMPH = lymphocytes
MONO = monocytes EOS = eosinophils
BASO = basophils
LUC = large unstained cells
NEUTA = polymorphonuclear neutrophils (absolute)
LYMPHA = lymphocytes (absolute)
MONOA = monocytes (absolute)
EOSA = eosinophils (absolute)
BASOA = basophils (absolute)
LUCA = large unstained cells (absolute)
ANISO = anisocytosis
MICRO = microcytosis
MACRO = macrocytosis
VAR = anisochromasia
HYPO = hypochromasia
HYPER = hyperchromasia HQT = prothrombin time (Hepato Quick's test)

CLINICAL CHEMISTRY:

ALT = alanine aminotransferase
AST = aspartate aminotransferase
ALP = alkaline phosphatase
SGGT = serum

- γ

- glutamyltransferase
NA = sodium
K = potassium

Page 78 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### CL = chloride
INP = inorganic phosphate
CA = calcium
UREA = urea CREA = creatinine
GLUC = glucose
TBIL = total bilirubin
TPROT = total protein
ALB = albumin
GLOB = globulins
TRIG = triglycerides
CHOL = cholesterol
MG = magnesium
TBA = bile acids

ACUTE PHASE PROTEINS:

HAPT = haptoglobinr
A2M = α 2

- macroglobulin

BRONCHOALVEOLAR LAVAGE:

BALTCN = total cell number
BALMPH = macrophages
BALLY = lymphocytes
BALPMN = polymorphonuclear neutrophils
BALEO = eosinophils
BALMO = monocytes
BALATY = atypical cells
GGT = γ

- glutamyltransferase
MTP = total protein
LDH = lactate dehydrogenase
ALP = alkaline phosphatase
NAG = N

- acetyl

- β

- D

- glucosaminidase

CYTOKINES IN BAL

MCP

- 1 = monocyte chemoattractant protein

- 1
IL

- 8 = Cytokine

- induced neutrophil chemoattractant

- 1
M

- CSF = Macrophage colony stimulating factor
OSP = Osteopontin

Page 79 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### CYTOKINES IN LUNG TISSUE

IL

- 1α = interleukin 1α
TNF α = tumor necrosis factor

- alpha

UNITS:

mmol/L = millimole/liter μmol/L = micromole/liter
nmol/L = nanomole/liter ng/mL = nanogram/milliliter pg/mL = pictogram/milliliter g/L, G/L = gram/liter
L/L = liter/liter
% = per cent fmol = femtomole = 10 - 15 

### mole
fL = femtoliter = 10 - 15 

### liter
tera/L = tera/liter = 10 12 

### /liter giga/L = giga/liter = 10 9 

### /liter μkat/L = microkatal/liter
nkat/L = nanokatal/liter
PPM = parts per million mg/kg = mg/kilogram μL = microliter
ML = mL(milliliter)

Page 80 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 8.4. PATHOLOGY

KEY TO THE ABBREVIATIONS USED IN TABLES IC and IIC

F1 = final sacrifice groups

g = weight determination in grams

M = male animals (under sex); mean value (on weight level)

mg = weight determination in milligrams

μg = microgram

n = number of values measured for the determination of mean value and
standard deviation

SD = standard deviation

% = percentage related to the reference weight in relative organ weight
calculations

% dev = deviation in organ or body weight in % when compared to control

Codes used at finding level:

The codes are used for a grading system which takes into consideration either the severity or the number or the size of a microscopic finding.

severity number size

grade 1 minimal very few very small

grade 2 slight, mild few small

grade 3 moderate moderate number; several moderate size

grade 4 marked; severe many large

grade 5 massive; extreme extensive number extensive size



### Whenever a grading was not used, the microscopic finding was indicated to be present (P).

Page 81 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsIA- 1StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary - Clinical ObservationSex:Male- Phase:In-lifeG 0 / MTest group 0G 1 / MTest group 1G 2 / MTest group 2G 3 / MTest group 3day -2 [06:00 - 18:00] -> day 121 [06:00 - 18:00]Animals examinedN 15101015deadsacrificed scheduledN 15 10 10 15% 100.0100.0100.0100.0normalNADN 15 10 10 15% 100.0100.0100.0100.0



### Page 82 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsIA- 2StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary - Clinical ObservationSex:Female- Phase:In-lifeG 0 / FTest group 0G 1 / FTest group 1G 2 / FTest group 2G 3 / FTest group 3day -2 [06:00 - 18:00] -> day 120 [06:00 - 18:00]Animals examinedN 15101015Animals with signsN0 0 2 3% 0.0 0.0 20.0 20.0deadsacrificed scheduledN 15 10 10 15% 100.0 100.0 100.0 100.0furreduced fur careN0 0 2 3% 0.0 0.0 20.0 20.0normalNADN 15 10 10 15% 100.0 100.0 100.0 100.0



### Page 83 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsIA- 3StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary - Clinical ObservationSex:Male- Phase:In-lifeG 0 / MTest group 0G 1 / MTest group 1G 2 / MTest group 2G 3 / MTest group 3day 0 [DCO] -> [DCO]Animals examinedN15101015normalNADN 15 10 10 15%100.0100.0100.0100.0



### Page 84 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsIA- 4StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary - Clinical ObservationSex:Male- Phase:In-lifeG 0 / MTest group 0G 1 / MTest group 1G 2 / MTest group 2G 3 / MTest group 3day 43 [DCO] -> [DCO]Animals examinedN15101015normalNADN 15 10 10 15%100.0100.0100.0100.0



### Page 85 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsIA- 5StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary - Clinical ObservationSex:Male- Phase:In-lifeG 0 / MTest group 0G 1 / MTest group 1G 2 / MTest group 2G 3 / MTest group 3day 85 [DCO] -> [DCO]Animals examinedN15101015normalNADN 15 10 10 15%100.0100.0100.0100.0



### Page 86 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsIA- 6StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary - Clinical ObservationSex:Female- Phase:In-lifeG 0 / FTest group 0G 1 / FTest group 1G 2 / FTest group 2G 3 / FTest group 3day 0 [DCO] -> [DCO]Animals examinedN15101015normalNADN 15 10 10 15%100.0100.0100.0100.0



### Page 87 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsIA- 7StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary - Clinical ObservationSex:Female- Phase:In-lifeG 0 / FTest group 0G 1 / FTest group 1G 2 / FTest group 2G 3 / FTest group 3day 43 [DCO] -> [DCO]Animals examinedN15101015normalNADN 15 10 10 15%100.0100.0100.0100.0



### Page 88 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsIA- 8StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary - Clinical ObservationSex:Female- Phase:In-lifeG 0 / FTest group 0G 1 / FTest group 1G 2 / FTest group 2G 3 / FTest group 3day 85 [DCO] -> [DCO]Animals examinedN15101015normalNADN 15 10 10 15%100.0100.0100.0100.0



### Page 89 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Dunnett test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statisticsn=DUNNETTIA- 9StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary Body Weights - BW / Body Weights [g]Sex:Male- Phase:In-lifeG 0 / MTest group 0G 1 / MTest group 1G 2 / MTest group 2G 3 / MTest group 3day -2MeanS.d.N266.010.515n269.112.210267.18.910266.09.715day 0MeanS.d.N258.910.415n265.211.510264.812.810261.79.215day 2MeanS.d.N259.812.115n261.012.610260.413.910256.712.615day 5MeanS.d.N272.413.115n274.014.210271.415.410261.914.015day 9MeanS.d.N271.013.315n273.214.610270.618.510261.616.115day 12MeanS.d.N277.914.115n283.717.210281.920.810270.516.515day 16MeanS.d.N280.715.915n285.220.010281.524.310267.717.215day 19MeanS.d.N290.816.115n297.421.110292.123.710280.118.715day 23MeanS.d.N292.318.215n300.522.010291.727.810279.119.315day 26MeanS.d.N303.117.315n310.323.010302.927.310290.319.915day 30MeanS.d.N303.217.915n308.924.410301.631.110287.921.915



### Page 90 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Dunnett test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statisticsn=DUNNETTIA- 10StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary Body Weights - BW / Body Weights [g]Sex:Male- Phase:In-lifeG 0 / MTest group 0G 1 / MTest group 1G 2 / MTest group 2G 3 / MTest group 3day 33MeanS.d.N310.016.915n317.225.210310.929.410298.721.215day 37MeanS.d.N311.017.315n317.325.810311.732.010297.322.515day 40MeanS.d.N320.816.915n327.625.410321.931.810307.822.615day 44MeanS.d.N321.516.915n326.925.210322.034.710308.123.115day 47MeanS.d.N328.217.915n334.526.510329.534.110317.023.115day 51MeanS.d.N327.822.015n334.025.410327.335.910316.124.715day 54MeanS.d.N336.921.515n343.625.710337.536.210326.325.415day 58MeanS.d.N336.921.815n343.526.710333.838.010324.026.915day 61MeanS.d.N344.522.315n352.528.010342.738.410333.726.415day 65MeanS.d.N342.023.415n351.227.710334.937.310328.627.915day 68MeanS.d.N348.222.815n358.830.010346.539.110338.227.515



### Page 91 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Dunnett test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statisticsn=DUNNETTIA- 11StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary Body Weights - BW / Body Weights [g]Sex:Male- Phase:In-lifeG 0 / MTest group 0G 1 / MTest group 1G 2 / MTest group 2G 3 / MTest group 3day 72MeanS.d.N347.723.215n359.130.910346.341.410336.128.615day 75MeanS.d.N354.024.315n366.931.510353.641.010344.128.215day 79MeanS.d.N350.121.415n361.734.810350.845.610339.129.415day 82MeanS.d.N356.824.515n370.132.710359.143.610347.329.315day 86MeanS.d.N356.425.015n367.631.710353.945.110342.330.015day 89MeanS.d.N362.125.715n373.231.910362.145.510350.429.815day 92MeanS.d.N345.331.715n347.830.310337.144.510334.133.315



### Page 92 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Dunnett test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statisticsn=DUNNETTIA-12StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary Body Weights - BW / Body Weights [g]Sex:Male- Phase:In-lifeG 0 / MTest group 0G 3 / MTest group 3day 93MeanS.d.N372.933.95n360.921.15day 96MeanS.d.N376.834.05n362.120.15day 100MeanS.d.N389.136.25n376.221.45day 103MeanS.d.N394.837.45n385.420.55day 107MeanS.d.N399.539.65n390.119.05day 110MeanS.d.N404.840.75n395.120.85day 114MeanS.d.N412.044.15n402.322.25day 117MeanS.d.N414.944.45n407.821.95day 121MeanS.d.N401.542.05n391.322.05



### Page 93 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Dunnett test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statisticsn=DUNNETTIA- 13StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary Body Weights - BW / Body Weights [g]Sex:Female- Phase:In-lifeG 0 / FTest group 0G 1 / FTest group 1G 2 / FTest group 2G 3 / FTest group 3day -2MeanS.d.N179.35.815n181.05.510179.78.010180.38.315day 0MeanS.d.N177.26.915n180.17.810177.66.210178.77.215day 1MeanS.d.N174.27.415n175.610.810171.68.010177.68.415day 4MeanS.d.N181.58.615n182.98.010181.05.610181.07.615day 8MeanS.d.N180.57.915n183.68.010180.76.610180.38.315day 11MeanS.d.N184.46.515n189.17.010184.19.910186.19.815day 15MeanS.d.N185.67.015n190.27.910183.410.110184.911.015day 18MeanS.d.N190.46.415n194.07.510190.48.710191.510.915day 22MeanS.d.N189.96.515n194.48.710190.18.210192.311.315day 25MeanS.d.N195.48.415n199.910.110195.38.010198.29.815day 29MeanS.d.N194.48.515n199.111.010194.27.210197.110.715



### Page 94 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Dunnett test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statisticsn=DUNNETTIA-14StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary Body Weights - BW / Body Weights [g]Sex:Female- Phase:In-lifeG 0 / FTest group 0G 1 / FTest group 1G 2 / FTest group 2G 3 / FTest group 3day 32MeanS.d.N197.69.015n202.58.610199.47.910201.89.715day 36MeanS.d.N198.49.815n202.99.610200.07.910201.69.815day 39MeanS.d.N205.010.115n208.18.410202.410.510206.810.915day 43MeanS.d.N204.310.515n207.29.210201.811.310204.811.115day 46MeanS.d.N207.88.715n211.08.210208.610.410209.310.215day 50MeanS.d.N205.99.515n209.38.410205.810.810205.510.414day 53MeanS.d.N209.111.715n214.110.310211.49.510212.310.215day 57MeanS.d.N208.211.215n212.111.610208.78.510210.410.515day 60MeanS.d.N210.611.415n214.110.310212.59.210214.29.815day 64MeanS.d.N208.311.815n213.910.010209.69.410211.110.015day 67MeanS.d.N213.411.915n219.08.910211.612.210216.111.315



### Page 95 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Dunnett test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statisticsn=DUNNETTIA- 15StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary Body Weights - BW / Body Weights [g]Sex:Female- Phase:In-lifeG 0 / FTest group 0G 1 / FTest group 1G 2 / FTest group 2G 3 / FTest group 3day 71MeanS.d.N212.711.615n217.110.410210.211.110214.212.215day 74MeanS.d.N216.610.015n220.710.410215.910.010218.012.515day 78MeanS.d.N215.310.715n220.710.210213.49.310216.013.415day 81MeanS.d.N217.512.115n224.111.710218.29.310220.210.115day 85MeanS.d.N213.910.615n217.514.310211.59.810213.512.615day 88MeanS.d.N216.811.715n224.210.710217.58.610219.611.915day 92MeanS.d.N204.512.215n204.610.210196.88.710206.715.815



### Page 96 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Dunnett test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statisticsn=DUNNETTIA- 16StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary Body Weights - BW / Body Weights [g]Sex:Female- Phase:In-lifeG 0 / FTest group 0G 3 / FTest group 3day 95MeanS.d.N216.211.35n224.010.45day 99MeanS.d.N225.911.35n233.111.85day 102MeanS.d.N228.711.95n236.110.15day 106MeanS.d.N231.811.35n237.310.25day 109MeanS.d.N233.514.85n239.912.45day 113MeanS.d.N233.415.25n239.113.45day 116MeanS.d.N235.313.55n242.013.75day 120MeanS.d.N222.310.85n227.710.65



### Page 97 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Dunnett test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statisticsd = day; n=DUNNETTIA- 17StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary Changes Body Weights - BW / Body Weights [g]Sex:Male- Phase:In-lifeG 0 / MTest group 0G 1 / MTest group 1G 2 / MTest group 2G 3 / MTest group 3d -2 -> 0MeanS.d.N-7.13.415n-3.95.210-2.35.810*-4.33.615d 0 -> 2MeanS.d.N1.05.315n-4.24.610*-4.41.910*-5.05.215**d 5 -> 9MeanS.d.N-1.44.415n-0.72.210-0.84.010-0.45.715d 12 -> 16MeanS.d.N2.84.915n1.54.110-0.55.610-2.73.815**d 19 -> 23MeanS.d.N1.53.815n3.13.110-0.46.210-1.14.215d 26 -> 30MeanS.d.N0.03.715n-1.43.010-1.45.710-2.43.715d 33 -> 37MeanS.d.N1.03.515n0.13.3100.83.310-1.43.615d 40 -> 44MeanS.d.N0.75.715n-0.72.3100.13.9100.21.915d 47 -> 51MeanS.d.N-0.46.115n-0.52.410-2.23.810-0.93.015d 54 -> 58MeanS.d.N0.04.015n0.04.210-3.73.410*-2.33.015d 61 -> 65MeanS.d.N-2.52.415n-1.32.910-7.97.310**-5.13.015



### Page 98 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Dunnett test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statisticsn=DUNNETT; d = dayIA- 18StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary Changes Body Weights - BW / Body Weights [g]Sex:Male- Phase:In-lifeG 0 / MTest group 0G 1 / MTest group 1G 2 / MTest group 2G 3 / MTest group 3d 68 -> 72MeanS.d.N-0.52.515n0.32.010-0.23.610-2.13.215d 75 -> 79MeanS.d.N-3.96.015n-5.26.310-2.86.210-4.94.315d 82 -> 86MeanS.d.N-0.44.215n-2.53.210-5.33.910**-5.02.515**



### Page 99 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Dunnett test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statisticsd = day; n=DUNNETTIA- 19StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary Changes Body Weights - BW / Body Weights [g]Sex:Male- Phase:In-lifeG 0 / MTest group 0G 3 / MTest group 3d 89 -> 93MeanS.d.N2.22.65n2.63.85d 96 -> 100MeanS.d.N12.33.45n14.13.55d 103 -> 107MeanS.d.N4.72.95n4.73.55d 110 -> 114MeanS.d.N7.23.45n7.22.95



### Page 100 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Dunnett test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statisticsd = day; n=DUNNETTIA-20StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary Changes Body Weights - BW / Body Weights [g]Sex:Female- Phase:In-lifeG 0 / FTest group 0G 1 / FTest group 1G 2 / FTest group 2G 3 / FTest group 3d -2 -> 0MeanS.d.N-2.13.415n-0.95.010-2.23.110-1.65.015d 0 -> 1MeanS.d.N-3.04.815n-4.55.910-5.95.610-1.15.315d 4 -> 8MeanS.d.N-1.02.315n0.72.110-0.31.810-0.72.915d 11 -> 15MeanS.d.N1.23.515n1.13.010-0.71.710-1.12.315d 18 -> 22MeanS.d.N-0.51.815n0.42.010-0.21.0100.82.115d 25 -> 29MeanS.d.N-1.11.715n-0.81.510-1.12.410-1.12.215d 32 -> 36MeanS.d.N0.82.015n0.42.4100.57.010-0.31.815d 39 -> 43MeanS.d.N-0.73.015n-0.92.710-0.62.310-2.04.015d 46 -> 50MeanS.d.N-1.92.115n-1.72.110-2.72.010-2.82.914d 53 -> 57MeanS.d.N-1.02.915n-2.03.110-2.72.010-1.92.415d 60 -> 64MeanS.d.N-2.31.815n-0.23.110-2.92.010-3.22.615



### Page 101 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Dunnett test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statisticsn=DUNNETT; d = dayIA-21StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary Changes Body Weights - BW / Body Weights [g]Sex:Female- Phase:In-lifeG 0 / FTest group 0G 1 / FTest group 1G 2 / FTest group 2G 3 / FTest group 3d 67 -> 71MeanS.d.N-0.72.215n-1.92.610-1.42.710-1.92.215d 74 -> 78MeanS.d.N-1.31.915n0.02.210-2.52.210-2.02.715d 81 -> 85MeanS.d.N-3.63.415n-6.76.510-6.77.210-6.76.215



### Page 102 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Dunnett test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statisticsd = day; n=DUNNETTIA- 22StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary Changes Body Weights - BW / Body Weights [g]Sex:Female- Phase:In-lifeG 0 / FTest group 0G 3 / FTest group 3d 88 -> 92MeanS.d.N-1.40.85n1.02.75d 95 -> 99MeanS.d.N9.77.45n9.03.25d 102 -> 106MeanS.d.N3.11.55n1.21.65d 109 -> 113MeanS.d.N-0.11.95n-0.84.05



### Page 103 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Dunnett test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statisticsd = day; n=DUNNETTIA-23StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary Food Consumption Per Animal Per Day [g/d]Sex:Male- Phase:In-lifeG 0 / MTest group 0G 1 / MTest group 1G 2 / MTest group 2G 3 / MTest groupd 5 -> 9Mean [g]S.d.N23.01.13n22.10.62X24.01.12X22.62.63d 12 -> 16Mean [g]S.d.N23.20.73n22.40.02X23.50.72X21.81.43d 19 -> 23Mean [g]S.d.N23.20.63n22.81.22X22.60.62X22.32.03d 26 -> 30Mean [g]S.d.N24.20.23n23.00.32X23.61.12X22.92.43d 33 -> 37Mean [g]S.d.N23.10.33n22.40.42X23.10.02X21.62.83d 40 -> 44Mean [g]S.d.N22.00.93n21.40.42X21.60.62X21.22.33d 47 -> 51Mean [g]S.d.N20.72.23n20.12.92X20.23.02X20.44.93d 54 -> 58Mean [g]S.d.N22.41.13n22.71.02X22.30.42X21.62.33d 61 -> 65Mean [g]S.d.N22.30.93n23.20.32X21.80.32X21.31.93d 68 -> 72Mean [g]S.d.N21.41.33n23.10.62X22.40.32X22.01.63



### Page 104 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Dunnett test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statisticsn=DUNNETT; d = dayIA-24StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary Food Consumption Per Animal Per Day [g/d]Sex:Male- Phase:In-lifeG 0 / MTest group 0G 1 / MTest group 1G 2 / MTest group 2G 3 / MTest group 3d 75 -> 79Mean [g]S.d.N21.31.23n22.10.42X21.80.32X20.71.83d 82 -> 86Mean [g]S.d.N19.41.73n19.12.52X17.62.52X18.43.13d 89 -> 91Mean [g]S.d.N21.20.82X21.20.42X20.90.22X20.40.62X



### Page 105 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsd = dayIA-25StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary Food Consumption Per Animal Per Day [g/d]Sex:Male- Phase:In-lifeG 0 / MTest group 0G 3 / MTest group 3d 89 -> 93Mean [g]N22.3121.71d 96 -> 100Mean [g]N22.4122.31d 103 -> 107Mean [g]N22.1122.01d 110 -> 114Mean [g]N23.3123.21d 117 -> 120Mean [g]N23.6123.11



### Page 106 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Dunnett test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statisticsd = day; n=DUNNETTIA-26StudyToxData© System 3.0Subchronic 90-day inhalation studyin Wistar ratsdust exposureSummary Food Consumption Per Animal Per Day [g/d]Sex:Female- Phase:In-lifeG 0 / FTest group 0G 1 / FTest group 1G 2 / FTest group 2G 3 / FTest group 3d 4 -> 8Mean [g]S.d.N15.41.53n16.20.32X15.70.52X14.61.13d 11 -> 15Mean [g]S.d.N15.50.33n15.90.12X15.40.82X15.21.53d 18 -> 22Mean [g]S.d.N16.11.03n16.40.32X15.80.62X16.31.53d 25 -> 29Mean [g]S.d.N16.10.83n16.40.12X16.41.12X16.31.63d 32 -> 36Mean [g]S.d.N16.11.13n16.10.12X16.01.22X16.01.23d 39 -> 43Mean [g]S.d.N15.70.93n15.80.12X16.21.82X15.51.33d 46 -> 50Mean [g]S.d.N13.62.43n13.82.82X14.23.52X14.22.83d 53 -> 57Mean [g]S.d.N15.20.73n15.80.42X17.00.12X15.81.63d 60 -> 64Mean [g]S.d.N15.40.73n16.10.22X16.20.62X15.61.33d 67 -> 71Mean [g]S.d.N15.20.73n15.60.72X15.90.62X15.41.33d 74 -> 78Mean [g]S.d.N14.81.23n15.60.42X15.31.32X15.41.33d 81 -> 85Mean [g]S.d.N11.33.33n13.03.42X13.14.22X11.34.13d 88 -> 91Mean [g]S.d.N14.91.32X15.11.12X14.70.82X15.10.92X



### Page 107 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsd = dayIA-27StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary Food Consumption Per Animal Per Day [g/d]Sex:Female- Phase:In-lifeG 0 / FTest group 0G 3 / FTest group 3d 88 -> 92Mean [g]N14.8117.31d 95 -> 99Mean [g]N15.6117.21d 102 -> 106Mean [g]N15.2116.41d 109 -> 113Mean [g]N14.8116.31d 116 -> 119Mean [g]N15.0116.51



### Page 108 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsTable IA - 28INCIDENCE OF OPHTHALMOLOGICAL FINDINGSmale animalsday -2day 83group 0 group 1 group 2 group 3 group 0 group 30 mg/m3 0.2 mg/m3 1 mg/m3 5 mg/m3 0 mg/m3 5 mg/m3Number of animals examined 10 10 10 10 10 10Without ophthalmological findings0100 00remainder of the pupillary membrane2230 00corneal stippling 10 9 10 10 10 10



### Page 109 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsTable IA - 29INCIDENCE OF OPHTHALMOLOGICAL FINDINGSfemale animalsday -2day 83group 0 group 1 group 2 group 3 group 0 group 30 mg/m3 0.2 mg/m3 1 mg/m3 5 mg/m3 0 mg/m3 5 mg/m3Number of animals examined 10 10 10 10 10 10Without ophthalmological findings1021 01remainder of the pupillary membrane2423 22corneal stippling9 8 7 8 10 9



### Page 110 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsProject No.:Table IA -30Mean values day 90male animalstest group 0 test group 1 test group 2 test group 3HOME CAGE OBSERVATIONRankN=10N=10N=10N=10posture- animal is sitting or laying05578- animal is standing or moving15532- squatting posture20000- abdominal position30000- abdominal position with splayed limbs40000- lateral position50000- oblique head posture60000- opisthotonus70000tremors- no tremors010101010- slight tremors10000- moderate tremors20000- severe tremors30000convulsions- no convulsions010101010- slight convulsions10000- moderate convulsions20000- severe convulsions30000abnormal movements- no abnormalities010101010- manege movements10000- head shaking20000- excessive cleaning30000- frequent chewing40000impairment of gait- animal is not walking during observation05578- no impairment of gait15532- stiff gait20000- slight impairment of coordination, unsteady gait30000- moderate impairment of coordination, shuffling gait40000- severe impairment of coordination, dragging of the hindlimbs50000- severe impairment of coordination, with splayed limbs60000- animal is unable to walk (abdominal or lateral position)70000other findings010101010FUNCTIONAL OBSERVATIONAL BATTERY



### Page 111 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsProject No.:Table IA -31Mean values day 90male animalstest group 0 test group 1 test group 2 test group 3OPEN FIELD OBSERVATIONSRankN=10N=10N=10N=10behavior when removed from cage- animal is tense, but it shows no resistance against handling010101010- animal shows a slight resistance against the handling10000- animal shows no resistance against the handling but appears indifferent20000- animal is difficult to handle, it shows aggressiveness30000- animal is very difficult to handle, it shows severe aggressiveness40000fur- nothing abnormal detected010101010- discolored fur10000- urine staining of anogenital region20000- piloerection30000- alopecia40000- reduced care on fur50000skin- nothing abnormal detected010101010- discolored skin10000- reddening20000- paleness30000- dehydration (exsiccosis)40000- hypothermia (skin is cold during handling)50000- lesion(s)60000- crust(s)70000salivation- no salivation010101010- slight salivation (area around the mouth is moist)10000- moderate salivation (wet mouth)20000- severe salivation (mouth very wet, wet paws)30000nose discharge- no discharge, dry nose010101010- clear discharge10000- reddish discharge20000FUNCTIONAL OBSERVATIONAL BATTERY



### Page 112 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsProject No.:Table IA -32Mean values day 90male animalstest group 0 test group 1 test group 2 test group 3OPEN FIELD OBSERVATIONSRankN=10N=10N=10N=10lacrimation- no lacrimation010101010- slight lacrimation10000- moderate lacrimation20000- severe lacrimation30000eyes/pupil size- nothing abnormal detected, pupils contracted at room light010101010- chromodacryorrhea10000- exophthalmos20000- pupils dilated30000- abnormal shape of pupils40000- oblique eye posture50000- opacity60000- cataract70000posture- animal is sitting or laying00000- animal is standing or moving110101010- squatting posture20000- abdominal position30000- abdominal position with splayed limbs40000- lateral position50000- oblique head posture60000- opisthotonus70000palpebral closure- nothing abnormal detected010101010- eyelid(s) slight closure10000- eyelid(s) half closure20000- eyelid(s) permanent closure30000FUNCTIONAL OBSERVATIONAL BATTERY



### Page 113 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsProject No.:Table IA -33Mean values day 90male animalstest group 0 test group 1 test group 2 test group 3OPEN FIELD OBSERVATIONSRankN=10N=10N=10N=10respiration- nothing abnormal detected010101010- respiration labored10000- gasping/respiratory sounds20000- respiration accelerated30000- respiration irregular40000tremors- no tremors010101010- slight tremors10000- moderate tremors20000- severe tremors30000convulsions- no convulsions010101010- slight convulsions10000- moderate convulsions20000- severe convulsions30000abnormal movements/stereotypics- no abnormalities010101010- manege movements10000- head shaking20000- excessive cleaning30000- frequent chewing40000impairment of gait- animal is not walking during observation00000- no impairment of gait1 10 10 10 10- stiff gait20000- slight impairment of coordination, unsteady gait30000- moderate impairment of coordination, shuffling gait40000- severe impairment of coordination, dragging of the hindlimbs50000- severe impairment of coordination, with splayed limbs60000- animal is unable to walk (abdominal or lateral position)70000FUNCTIONAL OBSERVATIONAL BATTERY



### Page 114 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsProject No.:Table IA - 34Mean values day 90male animalstest group 0 test group 1 test group 2 test group 3OPEN FIELD OBSERVATIONSRankN=10N=10N=10N=10activity/arousal level- normal exploration of the area010101010- reduced exploration of the area10000- severe reduced exploration of the area, animal apathetic20000- increased exploration of the area, sudden or jerky movements30000- hyperactivity40000feces- no defecation during observation period01091010- feces without abnormalities10100- discolored feces20000- crumbly feces30000- soft feces40000- muicid feces50000- diarrhea60000urine- no urination during observation period09788- urine without abnormalities (some wet areas on the filter paper)11322- discoloration of urine20000- polyuria (great wet areas on the filter paper)30000FUNCTIONAL OBSERVATIONAL BATTERY



### Page 115 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsProject No.:Table IA - 35Mean values day 90male animalstest group 0 test group 1 test group 2 test group 3SENSORIMOTOR TESTS/REFLEXESRankN=10N=10N=10N=10approach response- no reaction010101010- approaching to object10000- escape reaction20000- aggressive reaction and attacking of object30000touch response- no reaction010101010- orientation to the stimulus10000- escape after touch20000- aggressive reaction and attacking of object30000- reaction to the stimulus but no ability to localize (e.g. turning to wrong side)40000vision- nothing abnormal detected (grasping with forelimbs)0 10 10 10 10- no grasping10000pupillary reflex- nothing abnormal detected, physiological adaptation of the pupil to light0 10 10 10 10- retarded adaptation of the pupil to light10000- no adaptation of the pupil to light, pupils permanently contracted20000- no adaptation of the pupil to light, pupils permanently dilated30000pinna reflex- immediate response to the stimulus010101010- no response to the stimulus10000audition- nothing abnormal detected, immediate normal response to the stimulus010 10 10 10- no response10000- increased response20000- hyperreaction30000coordination of movements- nothing abnormal detected, immediate righting response010101010- retarded righting response10000- fails to turn into upright position, animal stays in lateral position20000- no righting response, animal stays in dorsal position30000FUNCTIONAL OBSERVATIONAL BATTERY



### Page 116 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsProject No.:Table IA - 36Mean values day 90male animalstest group 0 test group 1 test group 2 test group 3SENSORIMOTOR TESTS/REFLEXESRankN=10N=10N=10N=10behavior during handling- normal behavior, easy to handle, animal is tense, but it shows no resistance0 10 10 10 10- very easy to handle, animal is limply hanging in the hand10000- slightly difficult to handle, animal shows a slight resistance against handling20000- difficult to handle, animal shows a severe resistance against handling30000vocalization- no or only sporadic vocalizations when touched010101010- very frequent vocalizations when touched10000- vocalizations always when touched20000- vocalization without touching30000pain perception- nothing abnormal detected, immediate response to the stimulus0 10 10 10 10- weak or retarded reaction to the stimulus10000- no response to the stimulus20000- hyperreaction to the stimulus30000other findings010 10 10 10FUNCTIONAL OBSERVATIONAL BATTERY



### Page 117 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsProject No.:Table IA - 37Mean values day90female animalstest group 0 test group 1 test group 2 test group 3HOME CAGE OBSERVATIONRank N=10 N=10 N=10 N=10posture- animal is sitting or laying06344- animal is standing or moving14766- squatting posture20000- abdominal position30000- abdominal position with splayed limbs40000- lateral position50000- oblique head posture60000- opisthotonus70000tremors- no tremors 0 10 10 10 10- slight tremors10000- moderate tremors20000- severe tremors30000convulsions- no convulsions 0 10 10 10 10- slight convulsions10000- moderate convulsions20000- severe convulsions30000abnormal movements- no abnormalities 0 10 10 10 10- manege movements10000- head shaking20000- excessive cleaning30000- frequent chewing40000impairment of gait- animal is not walking during observation06344- no impairment of gait14766- stiff gait20000- slight impairment of coordination, unsteady gait30000- moderate impairment of coordination, shuffling gait40000- severe impairment of coordination, dragging of the hindlimbs50000- severe impairment of coordination, with splayed limbs60000- animal is unable to walk (abdominal or lateral position)70000other findings010101010FUNCTIONAL OBSERVATIONAL BATTERY



### Page 118 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsProject No.:Table IA - 38Mean values day90female animalstest group 0 test group 1 test group 2 test group 3OPEN FIELD OBSERVATIONSRank N=10 N=10 N=10 N=10behavior when removed from cage- animal is tense, but it shows no resistance against handling 0 10 10 10 10- animal shows a slight resistance against the handling10000- animal shows no resistance against the handling but appears indifferent20000- animal is difficult to handle, it shows aggressiveness30000- animal is very difficult to handle, it shows severe aggressiveness40000fur- nothing abnormal detected0101087- discolored fur10000- urine staining of anogenital region20000- piloerection30000- alopecia40000- reduced care on fur50023skin- nothing abnormal detected 0 10 10 10 10- discolored skin10000- reddening20000- paleness30000- dehydration (exsiccosis)40000- hypothermia (skin is cold during handling)50000- lesion(s)60000- crust(s)70000salivation- no salivation 0 10 10 10 10- slight salivation (area around the mouth is moist)10000- moderate salivation (wet mouth)20000- severe salivation (mouth very wet, wet paws)30000nose discharge- no discharge, dry nose 0 10 10 10 10- clear discharge10000- reddish discharge20000FUNCTIONAL OBSERVATIONAL BATTERY



### Page 119 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsProject No.:Table IA - 39Mean values day90female animalstest group 0 test group 1 test group 2 test group 3OPEN FIELD OBSERVATIONSRank N=10 N=10 N=10 N=10lacrimation- no lacrimation 0 10 10 10 10- slight lacrimation10000- moderate lacrimation20000- severe lacrimation30000eyes/pupil size- nothing abnormal detected, pupils contracted at room light 0 10 10 10 10- chromodacryorrhea10000- exophthalmos20000- pupils dilated30000- abnormal shape of pupils40000- oblique eye posture50000- opacity60000- cataract70000posture- animal is sitting or laying00000- animal is standing or moving 1 10 10 10 10- squatting posture20000- abdominal position30000- abdominal position with splayed limbs40000- lateral position50000- oblique head posture60000- opisthotonus70000palpebral closure- nothing abnormal detected 0 10 10 10 10- eyelid(s) slight closure10000- eyelid(s) half closure20000- eyelid(s) permanent closure30000FUNCTIONAL OBSERVATIONAL BATTERY



### Page 120 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsProject No.:Table IA - 40Mean values day90female animalstest group 0 test group 1 test group 2 test group 3OPEN FIELD OBSERVATIONSRank N=10 N=10 N=10 N=10respiration- nothing abnormal detected 0 10 10 10 10- respiration labored10000- gasping/respiratory sounds20000- respiration accelerated30000- respiration irregular40000tremors- no tremors 0 10 10 10 10- slight tremors10000- moderate tremors20000- severe tremors30000convulsions- no convulsions 0 10 10 10 10- slight convulsions10000- moderate convulsions20000- severe convulsions30000abnormal movements/stereotypics- no abnormalities 0 10 10 10 10- manege movements10000- head shaking20000- excessive cleaning30000- frequent chewing40000impairment of gait- animal is not walking during observation00000- no impairment of gait1 10 10 10 10- stiff gait20000- slight impairment of coordination, unsteady gait30000- moderate impairment of coordination, shuffling gait40000- severe impairment of coordination, dragging of the hindlimbs50000- severe impairment of coordination, with splayed limbs60000- animal is unable to walk (abdominal or lateral position)70000FUNCTIONAL OBSERVATIONAL BATTERY



### Page 121 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsProject No.:Table IA - 41Mean values day90female animalstest group 0 test group 1 test group 2 test group 3OPEN FIELD OBSERVATIONSRank N=10 N=10 N=10 N=10activity/arousal level- normal exploration of the area010101010- reduced exploration of the area10000- severe reduced exploration of the area, animal apathetic20000- increased exploration of the area, sudden or jerky movements30000- hyperactivity40000feces- no defecation during observation period 0 10 10 10 10- feces without abnormalities10000- discolored feces20000- crumbly feces30000- soft feces40000- muicid feces50000- diarrhea60000urine- no urination during observation period08896- urine without abnormalities (some wet areas on the filter paper)12214- discoloration of urine20000- polyuria (great wet areas on the filter paper)30000FUNCTIONAL OBSERVATIONAL BATTERY



### Page 122 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsProject No.:Table IA - 42Mean values day90female animalstest group 0 test group 1 test group 2 test group 3SENSORIMOTOR TESTS/REFLEXESRank N=10 N=10 N=10 N=10approach response- no reaction 0 10 10 10 10- approaching to object10000- escape reaction20000- aggressive reaction and attacking of object30000touch response- no reaction 0 10 10 10 10- orientation to the stimulus10000- escape after touch20000- aggressive reaction and attacking of object30000- reaction to the stimulus but no ability to localize (e.g. turning to wrong side)40000vision- nothing abnormal detected (grasping with forelimbs)0 10 10 10 10- no grasping10000pupillary reflex- nothing abnormal detected, physiological adaptation of the pupil to light0 10 10 10 10- retarded adaptation of the pupil to light10000- no adaptation of the pupil to light, pupils permanently contracted20000- no adaptation of the pupil to light, pupils permanently dilated30000pinna reflex- immediate response to the stimulus 0 10 10 10 10- no response to the stimulus10000audition- nothing abnormal detected, immediate normal response to the stimulus0 10 10 10 10- no response10000- increased response20000- hyperreaction30000coordination of movements- nothing abnormal detected, immediate righting response010101010- retarded righting response10000- fails to turn into upright position, animal stays in lateral position20000- no righting response, animal stays in dorsal position30000FUNCTIONAL OBSERVATIONAL BATTERY



### Page 123 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsProject No.:Table IA - 43Mean values day90female animalstest group 0 test group 1 test group 2 test group 3SENSORIMOTOR TESTS/REFLEXESRank N=10 N=10 N=10 N=10behavior during handling- normal behavior, easy to handle, animal is tense, but it shows no resistance0 10 10 10 10- very easy to handle, animal is limply hanging in the hand10000- slightly difficult to handle, animal shows a slight resistance against handling20000- difficult to handle, animal shows a severe resistance against handling30000vocalization- no or only sporadic vocalizations when touched010101010- very frequent vocalizations when touched10000- vocalizations always when touched20000- vocalization without touching30000pain perception- nothing abnormal detected, immediate response to the stimulus0 10 10 10 10- weak or retarded reaction to the stimulus10000- no response to the stimulus20000- hyperreaction to the stimulus30000other findings0 10 10 10 10FUNCTIONAL OBSERVATIONAL BATTERY



### Page 124 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Kruskal-Wallis + Wilcoxon test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statisticsk=KRUSKAL-WALLISIA-44StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary Functional Observation BatterySex:Male- Phase:In-lifeG 0 / MTest group 0G 1 / MTest group 1G 2 / MTest group 2G 3 / MTest group 3Feces[N]day 90MeanS.d.N0010k011000100010Rearing[N]day 90MeanS.d.N8410k741084109310GS F[Newton]day 90MeanS.d.N4.30.710k4.10.5104.20.7103.80.710GS H[Newton]day 90MeanS.d.N3.50.610k3.50.4103.90.4103.30.610FST[cm]day 90MeanS.d.N9.80.910k9.51.6109.11.3109.71.010



### Page 125 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Kruskal-Wallis + Wilcoxon test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statisticsk=KRUSKAL-WALLISIA-45StudyToxData© System 3.0Subchronic 90-day inhalation study in Wistar ratsdust exposureSummary Functional Observation BatterySex:Female- Phase:In-lifeG 0 / FTest group 0G 1 / FTest group 1G 2 / FTest group 2G 3 / FTest group 3Feces[N]day 90MeanS.d.N0010k001000100010Rearing[N]day 90MeanS.d.N17510k155101261015510GS F[Newton]day 90MeanS.d.N3.80.710k3.70.8104.20.8104.00.510GS H[Newton]day 90MeanS.d.N3.30.610k2.90.4102.90.4102.90.410FST[cm]day 90MeanS.d.N8.50.910k8.20.9108.41.3108.70.610



### Page 126 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors**TABLE IA - 4 6** **ect Number GROUP MEANS MOTOR ACTIVITY DAY 90 PRINT DATE 19JUL12** **M A L E S Interv. 1 Interv. 2 Interv. 3 Interv. 4 Interv. 5 Interv. 6 Interv. 7 Interv. 8** **Beam Beam Beam Beam Beam Beam Beam Beam Interr. Interr. Interr. Interr. Interr. Interr. Interr. Interr.** **0 / M M 815.8 643.4 253.0 72.4 54.5 24.1 24.7 4.7** **SD 249.9 229.4 152.4 98.8 83.3 25.3 30.1 5.5 N 10 10 10 10 10 10 10 10** **1 / M M 819.8 569.5 115.0 18.7 10.8 18.3 17.9 8.2** **SD 192.5 197.4 45.9 26.1 9.4 28.9 22.0 9.4 N 10 10 10 10 10 10 10 10** **2 / M M 868.5 637.8 355.1 29.4 12.9 12.2 15.1 14.3** **SD 239.3 195.1 465.0 44.4 19.8 17.8 20.4 10.8 N 10 10 10 10 10 10 10 10** **3 / M M 938.2 728.5 254.5 78.9 62.0 35.1 30.9 22.6** **SD 245.0 245.5 85.4 90.8 77.5 57.3 40.1 47.9 N 10 10 10 10 10 10 10 10** **-------------------------------------------------------------------------------------------------------------------------****Kruskal-Wallis + Wilcoxon-tests (two-sided): * p<=0.05; ** p<=0.01 (Statistical unit = Animal)**



### Page 127 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors**TABLE IA - 4 7** **ect Number GROUP MEANS MOTOR ACTIVITY DAY 90 PRINT DATE 19JUL12** **M A L E S Interv. 9 Interv.10 Interv.11 Interv.12 Interv.1-12** **Beam Beam Beam Beam Sum Interr. Interr. Interr. Interr. Interr.** **0 / M M 16.6 17.5 18.9 22.0 1967.6** **SD 26.2 23.0 21.4 30.4 558.4 N 10 10 10 10 10** **1 / M M 17.1 15.3 10.9 11.6 1633.1** **SD 21.1 29.3 10.7 12.0 303.8 N 10 10 10 10 10** **2 / M M 12.4 14.2 16.3 19.4 2007.6** **SD 16.7 18.3 19.3 16.4 659.2 N 10 10 10 10 10** **3 / M M 14.3 26.2 36.6 34.9 2262.7** **SD 25.3 36.9 49.6 53.4 399.3 N 10 10 10 10 10** **-------------------------------------------------------------------------------------------------------------------------****Kruskal-Wallis + Wilcoxon-tests (two-sided): * p<=0.05; ** p<=0.01 (Statistical unit = Animal)**



### Page 128 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors**TABLE IA - 4 8** **ect Number GROUP MEANS MOTOR ACTIVITY DAY 90 PRINT DATE 19JUL12** **F E M A L E S Interv. 1 Interv. 2 Interv. 3 Interv. 4 Interv. 5 Interv. 6 Interv. 7 Interv. 8** **Beam Beam Beam Beam Beam Beam Beam Beam Interr. Interr. Interr. Interr. Interr. Interr. Interr. Interr.** **0 / F M 891.7 619.9 341.8 121.4 56.8 36.6 26.7 11.4** **SD 327.9 156.0 112.4 74.1 68.0 77.6 43.2 14.1 N 10 10 10 10 10 10 10 10** **1 / F M 1144.7 632.9 365.3 193.2 89.5 21.1 12.6 17.4** **SD 292.7 280.0 204.0 157.8 114.6 29.5 18.3 16.6 N 10 10 10 10 10 10 10 10** **2 / F M 1055.8 581.8 300.7 122.7 37.7 19.4 34.1 10.3** **SD 296.3 190.1 107.3 142.2 41.3 26.0 63.0 8.2 N 10 10 10 10 10 10 10 10** **3 / F M 921.9 584.4 345.8 147.1 83.4 26.8 18.1 20.2** **SD 178.9 213.5 190.4 120.7 136.2 43.4 31.1 26.8 N 10 10 10 10 10 10 10 10** **-------------------------------------------------------------------------------------------------------------------------****Kruskal-Wallis + Wilcoxon-tests (two-sided): * p<=0.05; ** p<=0.01 (Statistical unit = Animal)**



### Page 129 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors**TABLE IA - 4 9** **ect Number GROUP MEANS MOTOR ACTIVITY DAY 90 PRINT DATE 19JUL12** **F E M A L E S Interv. 9 Interv.10 Interv.11 Interv.12 Interv.1-12** **Beam Beam Beam Beam Sum Interr. Interr. Interr. Interr. Interr.** **0 / F M 15.3 17.4 40.1 25.0 2204.1** **SD 16.9 17.9 80.0 23.7 368.7 N 10 10 10 10 10** **1 / F M 25.4 41.4 16.7 58.2 2618.4** **SD 26.6 67.8 21.1 70.8 886.1 N 10 10 10 10 10** **2 / F M 69.4 84.7 51.8 64.7 2433.1** **SD 148.8 128.4 110.2 78.1 615.5 N 10 10 10 10 10** **3 / F M 7.9 11.3 18.2 48.6 2233.7** **SD 10.4 8.9 21.0 95.7 627.8 N 10 10 10 10 10** **-------------------------------------------------------------------------------------------------------------------------****Kruskal-Wallis + Wilcoxon-tests (two-sided): * p<=0.05; ** p<=0.01 (Statistical unit = Animal)**



### Page 130 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Kruskal-Wallis + Wilcoxon test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics k=KRUSKAL-WALLIS IB 1

Study 12-Nov-2012 11:13

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats
dust exposure
Red blood cell + coagulation parameters

Sex: Male - Phase: In-life

G 0 / M Test group 0 G 1 / M Test group 1 G 2 / M Test group 2 G 3 / M Test group 3

RBC [tera/L] day 92 Mean S.d.
N
Median 8.97
0.35

10
8.91 k 8.93
0.91

10
9.13 8.79
0.50

10
8.75 8.74
0.46

10
8.62

HGB [mmol/L] day 92 Mean S.d.
N
Median 9.1
0.3
10
9.1 k 9.1
0.5
10
9.4 9.2
0.3
10
9.2 9.2
0.2
10
9.3

HCT [L/L] day 92 Mean S.d.
N
Median 0.441
0.015
10
0.442 k 0.439
0.032
10
0.452 0.440
0.014
10
0.440 0.443
0.011
10
0.444

MCV [fL] day 92 Mean S.d.
N
Median 49.2
2.0
10
49.0 k 49.4
2.5
10
48.7 50.1
2.1
10
49.7 50.7
2.4
10
50.9

MCH [fmol] day 92 Mean S.d.
N
Median 1.01
0.05

10
1.00 k 1.03
0.06

10
1.00 1.04
0.05

10
1.02 1.06
0.05

10
1.06

MCHC [mmol/L] day 92 Mean S.d.
N
Median 20.58
0.24

10
20.61 k 20.85
0.48

10
20.74 20.82
0.29

10
20.91 20.88
0.23

10
20.97

RET [%] day 92 Mean S.d.
N
Median 1.8
0.3
10
1.8 k 1.7
0.6
10
1.5 1.6
0.2
10
1.6 1.6
0.3
10
1.7

PLT [giga/L] day 92 Mean S.d.
N
Median 691
76
10
689 k 707
32

9
702 695
57 10
688 648
84
10
666

HQT [sec] day 92 Mean S.d.
N
Median 37.2
2.5
10
37.1 k 37.4
2.1
10
37.7 37.7
1.7
10
36.9 37.9
2.2
10
37.7



### Page 131 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Kruskal-Wallis + Wilcoxon test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics k=KRUSKAL-WALLIS IB 2

Study Nov-2012 11:13

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats
dust exposure
Red blood cell + coagulation parameters

Sex: Female - Phase: In-life

G 0 / F Test group 0 G 1 / F Test group 1 G 2 / F Test group 2 G 3 / F Test group 3

RBC [tera/L] day 92 Mean S.d.
N
Median 7.91
0.48

10
8.01 k 8.03
0.25

10
7.98 8.17
0.40

10
8.24 8.06
0.54

10
8.04

HGB [mmol/L] day 92 Mean S.d.
N
Median 8.7
0.3
10
8.7 k 8.8
0.3
10
8.8 8.9
0.4
10
8.9 8.9
0.4
10
8.8

HCT [L/L] day 92 Mean S.d.
N
Median 0.416
0.012
10
0.417 k 0.420
0.010
10
0.420 0.423
0.021
10
0.419 0.422
0.023
10
0.420

MCV [fL] day 92 Mean S.d.
N
Median 52.7
2.2
10
52.2 k 52.3
1.3
10
52.4 51.9
2.4
10
52.2 52.4
2.3
10
51.7

MCH [fmol] day 92 Mean S.d.
N
Median 1.11
0.05

10
1.10 k 1.09
0.03

10
1.08 1.09
0.05

10
1.10 1.10
0.05

10
1.08

MCHC [mmol/L] day 92 Mean S.d.
N
Median 20.99
0.24

10
20.91 k 20.88
0.21

10
20.83 21.01
0.42

10
20.97 21.01
0.36

10
21.09

RET [%] day 92 Mean S.d.
N
Median 1.9
0.3
10
2.0 k 2.1
0.3
10
2.0 1.8
0.6
10
1.9 2.0
0.4
10
2.0

PLT [giga/L] day 92 Mean S.d.
N
Median 701
113

10
752 k 811
74

9
847 709
108

10
730 737
132

10
690

HQT [sec] day 92 Mean S.d.
N
Median 33.6
1.5
10
33.2 k 33.7
2.3

9
33.7 33.4
2.1
10
33.3 34.6
1.8
10
34.5



### Page 132 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Wilcoxon test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics x=WILCOX IB 3

Study 12-Nov-2012 11:23

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats
dust exposure
Red blood cell + coagulation parameters

Sex: Male - Phase: In-life

G 0 / M Test group 0 G 3 / M Test group 3

RBC [tera/L] day 121 Mean S.d.
N
Median 8.24
0.43
5 8.39 x 8.26
0.47
5 8.50

HGB [mmol/L] day 121 Mean S.d.
N
Median 8.8
0.3

5 8.9 x 9.2
0.1

5 9.2 *

HCT [L/L] day 121 Mean S.d.
N
Median 0.419
0.011
5 0.426 x 0.433
0.005
5 0.432 *

MCV [fL] day 121 Mean S.d.
N
Median 50.9
2.1

5 50.8 x 52.6
2.8

5 51.6

MCH [fmol] day 121 Mean S.d.
N
Median 1.07
0.03
5 1.07 x 1.11
0.07
5 1.10

MCHC [mmol/L] day 121 Mean S.d.
N
Median 21.03
0.34
5 21.13 x 21.19
0.21
5 21.28

RET [%] day 121 Mean S.d.
N
Median 1.9
0.3

5 1.8 x 2.0
0.2

5 1.9

PLT [giga/L] day 121 Mean S.d.
N
Median 651
59

5 659 x 674
76

5 681

HQT [sec] day 121 Mean S.d.
N
Median 39.3
2.9

5 38.5 x 38.6
1.5

5 38.2



### Page 133 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Wilcoxon test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics x=WILCOX IB 4

Study 12-Nov-2012 11:22

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats
dust exposure
Red blood cell + coagulation parameters

Sex: Female - Phase: In-life

G 0 / F Test group 0 G 3 / F Test group 3

RBC [tera/L] day 120 Mean S.d.
N
Median 7.67
0.23
5 7.82 x 7.98
0.15
5 8.00 *

HGB [mmol/L] day 120 Mean S.d.
N
Median 8.6
0.4

5 8.5 x 8.8
0.3

5 9.0

HCT [L/L] day 120 Mean S.d.
N
Median 0.407
0.019
5 0.407 x 0.417
0.013
5 0.424

MCV [fL] day 120 Mean S.d.
N
Median 53.1
1.3

5 53.7 x 52.3
1.0

5 52.7

MCH [fmol] day 120 Mean S.d.
N
Median 1.12
0.04
5
1.14 x 1.11
0.03
5
1.11

MCHC [mmol/L] day 120 Mean S.d.
N
Median 21.17
0.20
5 21.15 x 21.13
0.28
5 21.26

RET [%] day 120 Mean S.d.
N
Median 2.4
0.5

5
2.4 x 2.0
0.5

5 1.9

PLT [giga/L] day 120 Mean S.d.
N
Median 749
92

3
754 x 644
30

5 637

HQT [sec] day 120 Mean S.d.
N
Median 33.6
2.0

3
33.5 x 34.7
2.5

5 35.2



### Page 134 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Kruskal-Wallis + Wilcoxon test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics k=KRUSKAL-WALLIS IB 5

Study 12-Nov-2012 11:11

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats
dust exposure
White blood cell parameters

Sex: Male - Phase: In-life

G 0 / M Test group 0 G 1 / M Test group 1 G 2 / M Test group 2 G 3 / M Test group 3

WBC [giga/L] day 92 Mean S.d.
N
Median 5.06
1.11

10
4.95 k 5.11
1.23

10
4.62 5.01
0.92

10
4.96 4.88
1.01

10
4.77

NEUTA [giga/L] day 92 Mean S.d.
N
Median 1.10
0.31

10
1.20 k 1.39
0.26

10
1.38 1.28
0.37

10
1.22 1.35
0.47

10
1.29

LYMPHA [giga/L] day 92 Mean S.d.
N
Median 3.75
1.00

10
3.50 k 3.49
1.10

10
3.05 3.53
0.66

10
3.56 3.31
0.85

10
3.05

MONOA [giga/L] day 92 Mean S.d.
N
Median 0.09
0.02

10
0.10 k 0.10
0.02

10
0.10 0.10
0.03

10
0.08 0.09
0.03

10
0.09

EOSA [giga/L] day 92 Mean S.d.
N
Median 0.10
0.04

10
0.10 k 0.10
0.03

10
0.09 0.07
0.02

10
0.07 0.08
0.03

10
0.07

BASOA [giga/L] day 92 Mean S.d.
N
Median 0.01
0.01

10
0.01 k 0.01
0.01

10
0.01 0.01
0.00

10
0.01 0.01
0.01

10
0.01

LUCA [giga/L] day 92 Mean S.d.
N
Median 0.02
0.01

10
0.02 k 0.02
0.01

10
0.02 0.02
0.01

10
0.02 0.03
0.02

10
0.03

NEUT [%] day 92 Mean S.d.
N
Median 22.1
6.1
10
23.6 k 28.1
5.9
10
26.8 25.4
4.8
10
25.6 27.8
7.1
10
28.3

LYMPH [%] day 92 Mean S.d.
N
Median 73.5
6.6
10
72.3 k 67.5
5.9
10
68.0 70.6
5.3
10
70.3 67.8
7.4
10
67.3

MONO [%] day 92 Mean S.d.
N
Median 1.8
0.4
10
1.9 k 2.0
0.4
10
1.9 1.9
0.7
10
1.8 1.9
0.4
10
2.0

EOS [%] day 92 Mean S.d.
N
Median 1.9
0.7
10
1.8 k 1.8
0.7
10
1.8 1.4
0.3
10
1.3 1.6
0.4
10
1.4

BASO [%] day 92 Mean S.d.
N
Median 0.3
0.1
10
0.3 k 0.2
0.1
10
0.2 0.3
0.1
10
0.3 0.3
0.1
10
0.3

LUC [%] day 92 Mean S.d.
N
Median 0.4
0.2
10
0.3 k 0.4
0.1
10
0.4 0.3
0.1
10
0.3 0.5
0.3
10
0.5



### Page 135 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Kruskal-Wallis + Wilcoxon test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics k=KRUSKAL-WALLIS IB 6

Study 12-Nov-2012 11:11

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats
dust exposure
White blood cell parameters

Sex: Female - Phase: In-life

G 0 / F Test group 0 G 1 / F Test group 1 G 2 / F Test group 2 G 3 / F Test group 3

WBC [giga/L] day 92 Mean S.d.
N
Median 3.20
0.62

10
3.01 k 3.48
0.75

10
3.37 3.48
0.88

10
3.37 3.42
0.95

10
3.08

NEUTA [giga/L] day 92 Mean S.d.
N
Median 0.67
0.18

10
0.68 k 0.90
0.24

10
0.78 0.97
0.29

10
1.02 0.96
0.40

10
0.81

LYMPHA [giga/L] day 92 Mean S.d.
N
Median 2.38
0.62

10
2.46 k 2.42
0.65

10
2.25 2.37
0.80

10
2.29 2.31
0.83

10
2.29

MONOA [giga/L] day 92 Mean S.d.
N
Median 0.06
0.02

10
0.06 k 0.06
0.01

10
0.06 0.06
0.02

10
0.06 0.06
0.02

10
0.06

EOSA [giga/L] day 92 Mean S.d.
N
Median 0.06
0.01

10
0.06 k 0.06
0.02

10
0.06 0.07
0.04

10
0.06 0.07
0.04

10
0.06

BASOA [giga/L] day 92 Mean S.d.
N
Median 0.01
0.01

10
0.01 k 0.01
0.01

10
0.01 0.01
0.01

10
0.01 0.01
0.01

10
0.01

LUCA [giga/L] day 92 Mean S.d.
N
Median 0.01
0.00

10
0.01 k 0.02
0.01

10
0.01 0.01
0.00

10
0.01 0.01
0.00

10
0.01

NEUT [%] day 92 Mean S.d.
N
Median 21.7
7.8
10
21.3 k 26.4
6.0
10
27.4 28.6
8.0
10
30.8 29.1
13.9

10
27.0

LYMPH [%] day 92 Mean S.d.
N
Median 73.7
8.2
10
74.9 k 69.1
6.3
10
67.5 67.2
8.5
10
65.7 66.3
14.4

10
68.7

MONO [%] day 92 Mean S.d.
N
Median 1.9
0.6
10
1.9 k 1.9
0.4
10
2.0 1.7
0.4
10
1.6 1.8
0.6
10
1.8

EOS [%] day 92 Mean S.d.
N
Median 1.9
0.5
10
1.9 k 1.8
0.4
10
1.7 1.9
0.8
10
1.8 2.0
0.7
10
2.0

BASO [%] day 92 Mean S.d.
N
Median 0.4
0.2
10
0.3 k 0.4
0.2
10
0.3 0.3
0.2
10
0.2 0.4
0.2
10
0.3

LUC [%] day 92 Mean S.d.
N
Median 0.4
0.1
10
0.3 k 0.4
0.2
10
0.4 0.3
0.2
10
0.3 0.3
0.1
10
0.2



### Page 136 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Wilcoxon test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics x=WILCOX IB 7

Study 12-Nov-2012 11:24

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats
dust exposure
White blood cell parameters

Sex: Male - Phase: In-life

G 0 / M Test group 0 G 3 / M Test group 3

WBC [giga/L] day 121 Mean S.d.
N
Median 4.23
0.94
5 4.61 x 5.39
0.68
5 5.82

NEUTA [giga/L] day 121 Mean S.d.
N
Median 1.04
0.18
5 1.04 x 1.43
0.33
5 1.49

LYMPHA [giga/L] day 121 Mean S.d.
N
Median 3.01
0.75
5 3.41 x 3.72
0.62
5 3.73

MONOA [giga/L] day 121 Mean S.d.
N
Median 0.08
0.02
5 0.07 x 0.10
0.03
5 0.09

EOSA [giga/L] day 121 Mean S.d.
N
Median 0.07
0.01
5 0.08 x 0.10
0.06
5 0.07

BASOA [giga/L] day 121 Mean S.d.
N
Median 0.02
0.01
5 0.02 x 0.02
0.01
5 0.02

LUCA [giga/L] day 121 Mean S.d.
N
Median 0.01
0.01
5 0.01 x 0.02
0.01
5 0.02

NEUT [%] day 121 Mean S.d.
N
Median 25.0
2.8

5 25.2 x 26.6
5.7

5 29.6

LYMPH [%] day 121 Mean S.d.
N
Median 70.8
3.1

5 70.4 x 69.0
6.5

5 65.5

MONO [%] day 121 Mean S.d.
N
Median 1.9
0.4

5
1.7 x 1.9
0.6

5 1.6

EOS [%] day 121 Mean S.d.
N
Median 1.7
0.3

5 1.6 x 1.8
1.0

5
1.4

BASO [%] day 121 Mean S.d.
N
Median 0.4
0.2

5 0.4 x 0.4
0.2

5 0.4

LUC [%] day 121 Mean S.d.
N
Median 0.2
0.1

5 0.3 x 0.4
0.2

5 0.4



### Page 137 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Wilcoxon test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics x=WILCOX IB 8

Study 12-Nov-2012 11:24

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats
dust exposure
White blood cell parameters

Sex: Female - Phase: In-life

G 0 / F Test group 0 G 3 / F Test group 3

WBC [giga/L] day 120 Mean S.d.
N
Median 3.79
0.42
5 3.70 x 3.81
0.93
5 3.69

NEUTA [giga/L] day 120 Mean S.d.
N
Median 0.60
0.14
5 0.69 x 1.28
0.40
5
1.22 **

LYMPHA [giga/L] day 120 Mean S.d.
N
Median 3.01
0.48
5 2.85 x 2.35
1.01

5 2.49

MONOA [giga/L] day 120 Mean S.d.
N
Median 0.07
0.03
5 0.06 x 0.08
0.01
5 0.08

EOSA [giga/L] day 120 Mean S.d.
N
Median 0.06
0.02
5 0.06 x 0.07
0.03
5 0.06

BASOA [giga/L] day 120 Mean S.d.
N
Median 0.02
0.01
5 0.02 x 0.01
0.00
5 0.01

LUCA [giga/L] day 120 Mean S.d.
N
Median 0.02
0.01
5 0.02 x 0.01
0.01
5 0.01

NEUT [%] day 120 Mean S.d.
N
Median 16.3
4.7

5 18.9 x 35.6
17.3

5 30.0 **

LYMPH [%] day 120 Mean S.d.
N
Median 79.1
4.4

5 76.1 x 59.5
17.8

5 65.7 **

MONO [%] day 120 Mean S.d.
N
Median 1.9
0.5

5 1.6 x 2.1
0.5

5
2.4

EOS [%] day 120 Mean S.d.
N
Median 1.7
0.6

5 1.6 x 2.0
0.9

5
1.7

BASO [%] day 120 Mean S.d.
N
Median 0.6
0.2

5 0.5 x 0.4
0.2

5 0.4

LUC [%] day 120 Mean S.d.
N
Median 0.4
0.2

5 0.5 x 0.4
0.1

5 0.4



### Page 138 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Kruskal-Wallis + Wilcoxon test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics k=KRUSKAL-WALLIS IB 9

Study 12-Nov-2012 11:16

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats
dust exposure
Enzymes

Sex: Male - Phase: In-life

G 0 / M Test group 0 G 1 / M Test group 1 G 2 / M Test group 2 G 3 / M Test group 3

ALT [μkat/L] day 92 Mean S.d.
N
Median 0.87
0.16

10
0.91 k 0.85
0.21

10
0.80 0.85
0.11

10
0.83 0.85
0.16

10
0.90

AST [μkat/L] day 92 Mean S.d.
N
Median 2.15
0.57

10
2.03 k 1.97
0.46

10
1.97 2.00
0.49

10
1.99 2.08
0.60

10
1.90

ALP [μkat/L] day 92 Mean S.d.
N
Median 1.13
0.23

10
1.08 k 1.17
0.28

10
1.19 1.17
0.20

10
1.16 1.14
0.27

10
1.05
GGT_C [nkat/L] day 92 Mean S.d.
N
Median 0
0
10
0 k 0
0
10
0 0
0
10
0 0
0
10
0



### Page 139 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Kruskal-Wallis + Wilcoxon test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics k=KRUSKAL-WALLIS; v=KRUSKAL-WALLIS-WILCOX IB 10

Study 12-Nov-2012 11:16

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats
dust exposure
Enzymes

Sex: Female - Phase: In-life

G 0 / F Test group 0 G 1 / F Test group 1 G 2 / F Test group 2 G 3 / F Test group 3

ALT [μkat/L] day 92 Mean S.d.
N
Median 0.62
0.11

10
0.57 k 0.72
0.17

10
0.71 0.64
0.10

10
0.61 0.64
0.10

10
0.65

AST [μkat/L] day 92 Mean S.d.
N
Median 2.30
0.69

10
2.21 k 2.51
0.77

10
2.40 2.46
1.25

10
2.19 2.26
0.25

10
2.23

ALP [μkat/L] day 92 Mean S.d.
N
Median 0.58
0.14

10
0.52 v 0.55
0.09

10
0.55 0.71
0.16

10
0.67 0.67
0.13

10
0.65
GGT_C [nkat/L] day 92 Mean S.d.
N
Median 0
0
10
0 k 0
0
10
0 0
0
10
0 0
0
10
0



### Page 140 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Wilcoxon test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics x=WILCOX IB 11

Study 12-Nov-2012 11:26

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats
dust exposure
Enzymes

Sex: Male - Phase: In-life

G 0 / M Test group 0 G 3 / M Test group 3

ALT [μkat/L] day 121 Mean S.d.
N
Median 0.84
0.11
5 0.88 x 0.97
0.04
5 0.99 *

AST [μkat/L] day 121 Mean S.d.
N
Median 2.15
0.46
5 1.92 x 2.93
0.62
5 2.68 *

ALP [μkat/L] day 121 Mean S.d.
N
Median 1.11
0.14
5
1.12 x 1.17
0.25
5 1.30
GGT_C [nkat/L] day 121 Mean S.d.
N
Median 0
0
5 0 x 0
0
5 0



### Page 141 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Wilcoxon test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics x=WILCOX IB 12

Study 12-Nov-2012 11:26

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats
dust exposure
Enzymes

Sex: Female - Phase: In-life

G 0 / F Test group 0 G 3 / F Test group 3

ALT [μkat/L] day 120 Mean S.d.
N
Median 0.69
0.21
5 0.55 x 0.53
0.07
5 0.53

AST [μkat/L] day 120 Mean S.d.
N
Median 3.18
2.03
5 1.97 x 2.05
0.22
5 2.03

ALP [μkat/L] day 120 Mean S.d.
N
Median 0.46
0.13
5 0.50 x 0.49
0.13
5 0.44
GGT_C [nkat/L] day 120 Mean S.d.
N
Median 0
0
5 0 x 0
0
5 0



### Page 142 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Kruskal-Wallis + Wilcoxon test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics k=KRUSKAL-WALLIS IB 13

Study 12-Nov-2012 11:17

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats
dust exposure

Substrates

Sex: Male - Phase: In-life

G 0 / M Test group 0 G 1 / M Test group 1 G 2 / M Test group 2 G 3 / M Test group 3

UREA [mmol/L] day 92 Mean S.d.
N
Median 6.77
0.44

10
6.79 k 6.03
0.80

10
6.12 6.21
0.65

10
6.16 6.53
0.74

10
6.39

CREA [ μ mol/L] day 92 Mean S.d.
N
Median 51.7
2.7
10
51.2 k 50.4
2.2
10
50.2 48.8
3.8
10
50.5 52.1
2.9
10
52.0

GLUC [mmol/L] day 92 Mean S.d.
N
Median 6.10
0.68

10
6.11 k 6.18
0.83

10
5.83 6.03
0.78

10
6.09 5.62
0.70

10
5.34

TBIL [μmol/L] day 92 Mean S.d.
N
Median 1.76
0.44

10
1.75 k 1.90
0.50

10
1.85 1.90
0.37

10
1.98 1.86
0.41

10
1.94

TPROT [g/L] day 92 Mean S.d.
N
Median 64.48
2.77

10
63.80 k 64.15
2.66

10
64.90 64.77
1.62

10
64.56 63.73
2.57

10
64.14

ALB [g/L] day 92 Mean S.d.
N
Median 39.68
1.32

10
39.77 k 39.38
1.46

10
39.50 39.24
0.69

10
39.19 39.28
0.98

10
39.25

GLOB [g/L] day 92 Mean S.d.
N
Median 24.80
1.92

10
24.30 k 24.77
1.58

10
24.80 25.53
1.49

10
25.41 24.45
1.70

10
25.02

CHOL [mmol/L] day 92 Mean S.d.
N
Median 1.77
0.40

10
1.83 k 1.84
0.28

10
1.84 1.81
0.31

10
1.71 1.80
0.21

10
1.85

TRIG [mmol/L] day 92 Mean S.d.
N
Median 0.85
0.48

10
0.75 k 0.94
0.29

10
0.96 0.96
0.31

10
0.89 0.87
0.36

10
0.83



### Page 143 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Kruskal-Wallis + Wilcoxon test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics k=KRUSKAL-WALLIS IB 14

Study 12-Nov-2012 11:17

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats
dust exposure

Substrates

Sex: Female - Phase: In-life

G 0 / F Test group 0 G 1 / F Test group 1 G 2 / F Test group 2 G 3 / F Test group 3

UREA [mmol/L] day 92 Mean S.d.
N
Median 7.70
0.31

10
7.67 k 7.74
0.69

10
7.96 7.81
0.75

10
8.02 7.70
0.84

10
7.84

CREA [ μ mol/L] day 92 Mean S.d.
N
Median 60.3
3.3
10
60.2 k 61.6
4.6
10
62.8 61.1
4.4 10
60.8 60.6
4.1
10
60.2

GLUC [mmol/L] day 92 Mean S.d.
N
Median 5.12
0.57

10
5.08 k 4.91
0.69

10
4.65 4.76
0.36

10
4.78 4.90
0.57

10
4.92

TBIL [μmol/L] day 92 Mean S.d.
N
Median 2.12
0.41

10
2.13 k 2.14
0.60

10
2.00 2.31
0.51

10
2.40 2.27
0.55

10
2.23

TPROT [g/L] day 92 Mean S.d.
N
Median 64.48
3.01

10
63.74 k 64.37
3.24

10
64.19 64.12
2.87

10
63.45 64.63
3.30

10
64.48

ALB [g/L] day 92 Mean S.d.
N
Median 40.92
1.53

10
40.66 k 40.36
2.22

10
39.85 39.92
2.17

10
40.11 40.54
2.13

10
41.02

GLOB [g/L] day 92 Mean S.d.
N
Median 23.56
1.79

10
23.76 k 24.02
1.41

10
23.91 24.20
1.52

10
24.46 24.09
2.31

10
24.09

CHOL [mmol/L] day 92 Mean S.d.
N
Median 1.33
0.39

10
1.21 k 1.28
0.45

10
1.27 1.21
0.29

10
1.27 1.33
0.35

10
1.33

TRIG [mmol/L] day 92 Mean S.d.
N
Median 0.46
0.12

10
0.45 k 0.47
0.17

10
0.42 0.47
0.12

10
0.43 0.53
0.13

10
0.55



### Page 144 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Wilcoxon test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics x=WILCOX IB 15

Study 12-Nov-2012 11:27

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats
dust exposure

Substrates

Sex: Male - Phase: In-life

G 0 / M Test group 0 G 3 / M Test group 3

UREA [mmol/L] day 121 Mean S.d.
N
Median 5.51
0.70
5 5.60 x 6.12
0.43
5 6.12

CREA [mmol/L] day 121 Mean S.d.
N
Median 51.8
4.5

5 53.7 x 53.2
2.3

5 53.4

GLUC [mmol/L] day 121 Mean S.d.
N
Median 6.39
0.49
5 6.47 x 6.64
0.83
5 6.55

TBIL [μmol/L] day 121 Mean S.d.
N
Median 1.50
0.31
5 1.43 x 1.38
0.33
5 1.36

TPROT [g/L] day 121 Mean S.d.
N
Median 60.67
1.63

5 61.11 x 61.25
1.20

5 61.44

ALB [g/L] day 121 Mean S.d.
N
Median 37.15
0.99
5 36.77 x 36.42
0.89
5 36.00

GLOB [g/L] day 121 Mean S.d.
N
Median 23.52
1.21

5 23.46 x 24.83
1.19

5 24.23

CHOL [mmol/L] day 121 Mean S.d.
N
Median 1.36
0.17
5 1.31 x 1.36
0.13
5 1.39

TRIG [mmol/L] day 121 Mean S.d.
N
Median 0.96
0.23
5 1.09 x 1.03
0.19
5 1.05



### Page 145 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Wilcoxon test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics x=WILCOX IB 16

Study 12-Nov-2012 11:28

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats
dust exposure

Substrates

Sex: Female - Phase: In-life

G 0 / F Test group 0 G 3 / F Test group 3

UREA [mmol/L] day 120 Mean S.d.
N
Median 7.77 0.79
5 7.88 x 7.29
0.85
5 7.58

CREA [mmol/L] day 120 Mean S.d.
N
Median 62.6
2.3

5 62.8 x 60.7
3.9

5 60.9

GLUC [mmol/L] day 120 Mean S.d.
N
Median 5.72
0.75
5 5.70 x 5.18
0.09
5 5.19

TBIL [μmol/L] day 120 Mean S.d.
N
Median 2.34
0.70
5 2.15 x 1.92
0.62
5 2.18

TPROT [g/L] day 120 Mean S.d.
N
Median 65.64
3.41
5 65.75 x 64.01
3.87
5 65.26

ALB [g/L] day 120 Mean S.d.
N
Median 41.90
1.65

5 41.92 x 41.18
2.18
5 42.32

GLOB [g/L] day 120 Mean S.d.
N
Median 23.73
1.87

5 23.21 x 22.83
2.03
5 23.45

CHOL [mmol/L] day 120 Mean S.d.
N
Median 1.02
0.28
5 1.01 x 1.18
0.26
5 1.23

TRIG [mmol/L] day 120 Mean S.d.
N
Median 0.53
0.20
5 0.47 x 0.54
0.16
5 0.47



### Page 146 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Kruskal-Wallis + Wilcoxon test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics k=KRUSKAL-WALLIS IB 17

Study 12-Nov-2012 11:18

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats
dust exposure
Electrolytes + minerals

Sex: Male - Phase: In-life

G 0 / M Test group 0 G 1 / M Test group 1 G 2 / M Test group 2 G 3 / M Test group 3

NA [mmol/L] day 92 Mean S.d.
N
Median 145.4
1.7
10
145.3 k 144.8
1.3
10
144.5 144.9
1.1
10
144.9 145.6
1.6
10
145.6

K [mmol/L] day 92 Mean S.d.
N
Median 4.60
0.18

10
4.62 k 4.55
0.19

10
4.50 4.68
0.13

10
4.68 4.68
0.24

10
4.62

CL [mmol/L] day 92 Mean S.d.
N
Median 104.7
1.7
10
104.8 k 104.0
2.1
10
104.1 104.0
1.1
10
104.3 104.8
1.6
10
104.5

INP [mmol/L] day 92 Mean S.d.
N
Median 1.56
0.20

10
1.59 k 1.56
0.18

10
1.54 1.69
0.12

10
1.73 1.60
0.14

10
1.52

CA [mmol/L] day 92 Mean S.d.
N
Median 2.54
0.05

10
2.52 k 2.54
0.04

10
2.54 2.56
0.07

10
2.55 2.54
0.07

10
2.55



### Page 147 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Kruskal-Wallis + Wilcoxon test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics k=KRUSKAL-WALLIS IB 18

Study 12-Nov-2012 11:18

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats
dust exposure
Electrolytes + minerals

Sex: Female - Phase: In-life

G 0 / F Test group 0 G 1 / F Test group 1 G 2 / F Test group 2 G 3 / F Test group 3

NA [mmol/L] day 92 Mean S.d.
N
Median 143.1
1.8
10
142.7 k 143.4
1.3
10
143.4 143.8
1.2
10
143.7 143.4
1.2
10
143.4

K [mmol/L] day 92 Mean S.d.
N
Median 4.02
0.36

10
4.00 k 4.15
0.32

10
4.14 4.00
0.33

10
4.01 4.12
0.34

10
4.05

CL [mmol/L] day 92 Mean S.d.
N
Median 103.6
2.4
10
102.8 k 103.8
1.4
10
103.9 103.6
1.3
10
103.4 104.4
1.5
10
104.4

INP [mmol/L] day 92 Mean S.d.
N
Median 1.32
0.23

10
1.31 k 1.22
0.14

10
1.21 1.40
0.21

10
1.39 1.31
0.19

10
1.28

CA [mmol/L] day 92 Mean S.d.
N
Median 2.50
0.08

10
2.49 k 2.45
0.09

10
2.48 2.48
0.08

10
2.49 2.50
0.06

10
2.50



### Page 148 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Wilcoxon test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics x=WILCOX IB 19

Study 12-Nov-2012 11:20

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats
dust exposure
Electrolytes + minerals

Sex: Male - Phase: In-life

G 0 / M Test group 0 G 3 / M Test group 3

NA [mmol/L] day 121 Mean S.d.
N
Median 145.1
1.1

5 145.1 x 144.2
0.8

5 144.3

K [mmol/L] day 121 Mean S.d.
N
Median 4.37
0.08
5 4.34 x 4.72
0.22
5 4.66 *

CL [mmol/L] day 121 Mean S.d.
N
Median 104.2
1.4

5 104.3 x 104.2
1.1

5 104.5

INP [mmol/L] day 121 Mean S.d.
N
Median 1.54
0.16
5 1.51 x 1.62
0.18
5 1.67

CA [mmol/L] day 121 Mean S.d.
N
Median 2.45
0.04
5 2.45 x 2.46
0.08
5 2.45



### Page 149 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsStatistic Profile = Wilcoxon test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics x=WILCOX IB 20

Study 12-Nov-2012 11:21

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats
dust exposure
Electrolytes + minerals

Sex: Female - Phase: In-life

G 0 / F Test group 0 G 3 / F Test group 3

NA [mmol/L] day 120 Mean S.d.
N
Median 142.5
1.1

5 142.3 x 143.4
0.9

5 143.2

K [mmol/L] day 120 Mean S.d.
N
Median 4.22
0.43
5
4.44 x 4.00
0.21
5 4.05

CL [mmol/L] day 120 Mean S.d.
N
Median 102.7
1.1

5 102.3 x 103.4
1.5

5 103.3

INP [mmol/L] day 120 Mean S.d.
N
Median 1.37
0.25
5 1.29 x 1.35
0.17
5 1.37

CA [mmol/L] day 120 Mean S.d.
N
Median 2.55
0.06
5 2.57 x 2.52
0.10
5 2.50



### Page 150 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 151 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 152 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 153 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 154 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 155 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 156 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 157 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 158 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 159 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 160 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 161 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 162 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 163 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 164 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 165 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 166 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 167 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 168 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 169 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 170 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 171 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 172 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 173 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 174 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 175 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 176 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsExposure Parameters
Inhalation Laboratory · Proj. No.: Table ID - 1 Study Summary of Means of Chamber Parameters ± Standard Deviation (SD)Supply airSDSupply airinto the dilutiontubeSDCompressed airSDExhaust airSDExhaust airfrom the dilutiontubeSDChambertemperatureSDChamberhumiditySDSubstance flowConcentration ofsubstanceSD

[m3/h] [°C] [%RH] [mg/h] [mg/m3]

Test Group 0 Study Mean 6.0 0.0 - - - - 5.4 0.0 - - 22.3 1.1 53.5 4.9 - - -

Test Group 1 Study Mean 4.5 0.0 4.0 0.2 1.5 0.0 5.6 0.0 4.0 0.2 22.9 0.1 47.8 3.7 20.3 0.25 0.17

Test Group 2 Study Mean 4.5 0.0 - - 1.5 0.0 5.5 0.1 - - 21.5 0.1 49.9 4.0 74.5 1.42 0.42

Test Group 3 Study Mean 4.5 0.0 - - 1.6 0.0 5.5 0.1 - - 22.7 0.2 38.2 2.7 89.9 5.10 1.24

Date Particle Size Analyses Test Group 1 MMAD

GSD

Fraction of particles < 3 μm [%]
Test Group 2 MMAD

GSD

Fraction of particles < 3 μm [%]
Test Group 3 MMAD

GSD

Fraction of particles < 3 μm [%]

Date Particle Size Analyses Test Group 1 MMAD

GSD

Fraction of particles < 3 μm [%]
Test Group 2 MMAD

GSD

Fraction of particles < 3 μm [%]
Test Group 3 MMAD

GSD

Fraction of particles < 3 μm [%]

Date Particle Size Analyses Test Group 1 MMAD

GSD

Fraction of particles < 3 μm [%]
Test Group 2 MMAD

GSD

Fraction of particles < 3 μm [%]
Test Group 3 MMAD

GSD

Fraction of particles < 3 μm [%] [m3/h] [m3/h] [m3/h]

04 Apr 2012 10 Apr 2012 11 Apr 2012

2.8 3.4 05 Apr 2012

3.5 3.9 53.5 43.2

2.7 - -

3.7 -

- 34.9 2.1 -

-

-

- 39.9 02 May 2012 08 May 2012

- 07 May 2012

2.3

2.3 - 3.8 2.2

2.5 3.3

2.6 2.3 1.9 - 4.8 2.2

2.1

3.7 49.3 -

29.5 46.5

- 61.2

- 39.9

-

2.2 42.1 2.3

40.3 37.0 2.2 2.3 19.8 5.7

-

21 May 2012 23 May 2012

3.0 - - -

-

- 3.6

- -

2.0 15 May 2012 -

12 Jun 2012

2.6 2.4 04 Jun 2012 30 May 2012 2.4

38.7

- -
3.4 55.5 66.4 63.7

3.8 - 49.7

2.4 -

3.8 4.0 3.1 2.1 -

- 3.2

- -

37.6 48.0 2.0 3.1

- - - 2.1 3.7

-

44.0 2.4 3.4 - 30 Apr 2012

-

- 16 Apr 2012

3.0

- 2.7 2.4 19 Apr 2012 24 Apr 2012 01 May 2012

- - - - -

32.8 -

43.3 23 Apr 2012

40.0 - 2.2

- 2.3 2.1 2.5

-

2.2 4.2 - 57.2

-

-

- -

2.1 -

4.0 4.0 -

34.3 - -

2.3 3.5 -

3.2 3.0 35.6 -

63.5

43.4 - -

-

47.6 2.5 57.7 2.4

11 Jun 2012

2.0

- - 3.6

19 Jun 2012 20 Jun 2012 2.2

40.8 -

25 Jun 2012 03 Jul 2012

37.9 - 3.9 - 02 Jul 2012 39.9 - 3.4 -

44.5 2.3 2.3 3.7

45.2 - - -

- 3.4 -

- 3.4

47.8 3.0 2.3

- - 3.3 26 Jun 2012

43.4 - 42.6

- - 4.4 2.3

- - - 2.1 - 4.1

53.9 2.8 - 2.7 - 2.9 - 3.1 -

3.2 33.7

- - - 51.4

49.9 - 2.4 - 3.0 - 3.5

-

- - 2.5 2.0

47.8 41.7 -



### Page 177 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### STUDY TITLE

Report

Cobalt Lithium Manganese Nickel oxide

- Subchronic 90

- day inhalation study in Wistar rats dust exposure

TEST FACILITY

TEST FACILITY PROJECT IDEN TIFICATION

PART II OF III ( TABLES SECTION, INDIVIDUAL VALUES )

This document contains manufacturing and trade secrets of the Sponsor(s). It is the property of the Sponsor(s) and may be use d only for that purpose for which it was intended by the Sponsor(s). Every other or additional use, exploitation, reproduction, pub lication or submission to other parties require the written permission of the Sponsor(s), with the exception of regulatory ag encies acting within the limits of their administrative authority.



### Page 178 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### CONTENTS OF PART II (TABLES SECTION; INDIVIDUAL VALUES)

TITL E PAGE

TABLE OF CONTENTS

CLINICAL EXAMINATIONS (Individual values) Table

Individual Signs By Interval – Clinical Observation
Male animals IIA

- 1 - IIA

- 29
Female animals IIA

- 30 - IIA

- 57

Detailed clinical observation s report
Male animals IIA

- 58 - IIA

- 59
Female animals IIA

- 60 - IIA

- 61

Individual Body W eight s Male animals IIA

- 62 - IIA

- 68
Female animals IIA

- 69 - IIA

- 75

Individual Food Consumption Per Animal Per Day
Male animals IIA

- 76 - IIA

- 79
Female animals IIA

- 80 - IIA

- 83

Ophthalmological Findings
Male animals IIA

- 84 - IIA

- 86
Female animals IIA

- 87 - IIA

- 89

Functional observational battery IIA

- 90 - IIA

- 117

Motor activity IIA

- 118 - IIA

- 125

CLINICAL PATHOLOGY (Individual values)

Red blood cell + coagulation parameters II B 1 – I IB 10 White blood cell parameters IIB 11 – IIB 20 Enzymes IIB 21 – IIB 30
Substrates IIB 31 – IIB 40 Electrolytes + minerals IIB 41 – IIB 50

PATHOLOGY (Individual values)

Absolute weights IIC

- 1 - IIC

- 24 Relative weights IIC

- 25 - IIC

- 48 Single animal sheet IIC

- 49 - IIC

- 115

Page 179 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### MEASUREMENTS OF EXPOSURE PARAM ETERS

Exposure parameters (Daily Means) IID

- 1 - IID -4 Particle size analysis (Individual measurements) IID

- 5 - IID

- 48

Page 180 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 181 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 182 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 183 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 184 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 185 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 186 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 187 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 188 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 189 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 190 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 191 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 192 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 193 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 194 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 195 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 196 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 197 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 198 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 199 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 200 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 201 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 202 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 203 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 204 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 205 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 206 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 207 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 208 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 209 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 210 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 211 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 212 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 213 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 214 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 215 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 216 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 217 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 218 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 219 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 220 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 221 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 222 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 223 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 224 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 225 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 226 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 227 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 228 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 229 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 230 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 231 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 232 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 233 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 234 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 235 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 236 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 237 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 238 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 239 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 240 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 241 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 242 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 243 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 244 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 245 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 246 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 247 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 248 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 249 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 250 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 251 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 252 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 253 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 254 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 255 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 256 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 257 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 258 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 259 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 260 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 261 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 262 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 263 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 264 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 265 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 266 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 267 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 268 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 269 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 270 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 271 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 272 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 273 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 274 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 275 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 276 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 277 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 278 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 279 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 280 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 281 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 282 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 283 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 284 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 285 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 286 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 287 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 288 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 289 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 290 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 291 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 292 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 293 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 294 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 295 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 296 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 297 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 298 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 299 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 300 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 301 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 302 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 303 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 304 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 305 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 306 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 307 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 308 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 309 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 310 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 311 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 312 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 313 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 314 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 315 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 316 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 317 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 318 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 319 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 320 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 321 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 322 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 323 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 324 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 325 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 326 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 327 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 328 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 329 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 330 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 331 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 332 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 333 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 334 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 335 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 336 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 337 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 338 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 339 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 340 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 341 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 342 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 343 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 344 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 345 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 346 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 347 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 348 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 349 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 350 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 351 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 352 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 353 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 354 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 355 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 356 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 357 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 358 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 359 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 360 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 361 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 362 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 363 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 364 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 365 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 366 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 367 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 368 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 369 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 370 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 371 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 372 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 373 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 374 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 375 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 376 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 377 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 378 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 379 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 380 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 381 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 382 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 383 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 384 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 385 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 386 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 387 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 388 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 389 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 390 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 391 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 392 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 393 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 394 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 395 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 396 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 397 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 398 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 399 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 400 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 401 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 402 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 403 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 404 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 405 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 406 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 407 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 408 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 409 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 410 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 411 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 412 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 413 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 414 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 415 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 416 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 417 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 418 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 419 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 420 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 421 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 422 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 423 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 424 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 425 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 426 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 427 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 428 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 429 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 430 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 431 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 432 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 433 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 434 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 435 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 436 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 437 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 438 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 439 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 440 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 441 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 442 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 443 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 444 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 445 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 446 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 447 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 448 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 449 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 450 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 451 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 452 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 453 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 454 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 455 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 456 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 457 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 458 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 459 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 460 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 461 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 462 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 463 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 464 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 465 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 466 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 467 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 468 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 469 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 470 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsExposure Parameters (Daily Means) Table IID - 1 Inhalation Laboratory · Test Group 0

Date Study day

males Exposure No. Study day

females Exposure No.

mean S.D. mean S.D. mean S.D. mean S.D. Wed 04 Apr 2012 0 1 -1 6.0 0.0 5.4 0.0 50.1 0.5 21.2 0.2 Thu 05 Apr 2012 1 2 0 1 6.0 0.0 5.4 0.0 49.6 0.4 21.2 0.1 Fri 06 Apr 2012 2 3 1 2 6.0 0.0 5.4 0.0 48.8 0.2 21.4 0.1 Sat 07 Apr 2012 3 2 Sun 08 Apr 2012 4 3 Mon 09 Apr 2012 5 4 4 3 6.0 0.0 5.4 0.0 49.2 0.4 21.1 0.0 Tue 10 Apr 2012 6 5 5 4 6.0 0.0 5.4 0.0 48.9 0.3 21.3 0.2 Wed 11 Apr 2012 7 6 6 5 6.0 0.0 5.4 0.0 49.5 0.2 21.2 0.1 Thu 12 Apr 2012 8 7 7 6 6.0 0.0 5.4 0.0 48.6 0.3 21.2 0.2 Fri 13 Apr 2012 9 8 8 7 6.0 0.0 5.4 0.0 49.5 0.3 21.1 0.1 Sat 14 Apr 2012 10 9 Sun 15 Apr 2012 11 10 Mon 16 Apr 2012 12 9 11 8 6.0 0.0 5.4 0.0 49.8 0.4 21.1 0.0 Tue 17 Apr 2012 13 10 12 9 6.0 0.0 5.4 0.0 49.7 0.4 21.1 0.1 Wed 18 Apr 2012 14 11 13 10 6.0 0.0 5.4 0.0 48.9 0.2 21.2 0.1 Thu 19 Apr 2012 15 12 14 11 6.0 0.0 5.4 0.0 49.2 0.4 21.3 0.1 Fri 20 Apr 2012 16 13 15 12 6.0 0.0 5.4 0.0 46.7 4.8 21.0 0.0 Sat 21 Apr 2012 17 16 Sun 22 Apr 2012 18 17 Mon 23 Apr 2012 19 14 18 13 6.0 0.0 5.4 0.0 48.8 0.3 21.2 0.1 Tue 24 Apr 2012 20 15 19 14 6.0 0.0 5.4 0.0 48.6 0.2 21.3 0.2 Wed 25 Apr 2012 21 16 20 15 6.0 0.0 5.4 0.0 49.1 0.3 21.1 0.0 Thu 26 Apr 2012 22 17 21 16 6.0 0.0 5.4 0.0 48.7 0.1 21.1 0.1 Fri 27 Apr 2012 23 18 22 17 6.0 0.0 5.4 0.0 48.6 0.3 21.2 0.1 Sat 28 Apr 2012 24 23 Sun 29 Apr 2012 25 24 Mon 30 Apr 2012 26 19 25 18 6.0 0.0 5.4 0.0 54.3 4.5 21.1 0.0 Tue 01 May 2012 27 20 26 19 6.0 0.0 5.4 0.0 49.0 1.0 21.4 0.2 Wed 02 May 2012 28 21 27 20 6.0 0.0 5.4 0.0 58.8 0.2 21.2 0.2 Thu 03 May 2012 29 22 28 21 6.0 0.0 5.4 0.0 48.8 0.2 21.3 0.2 Fri 04 May 2012 30 23 29 22 6.0 0.0 5.4 0.0 49.6 0.2 21.1 0.1 Sat 05 May 2012 31 30 Sun 06 May 2012 32 31 Mon 07 May 2012 33 24 32 23 6.0 0.0 5.4 0.0 49.0 0.4 21.3 0.1 Tue 08 May 2012 34 25 33 24 6.0 0.0 5.4 0.0 48.9 0.4 21.4 0.2 Wed 09 May 2012 35 26 34 25 6.0 0.0 5.4 0.0 58.2 0.4 21.1 0.0 Thu 10 May 2012 36 27 35 26 6.0 0.0 5.4 0.0 60.4 1.5 21.3 0.1 Fri 11 May 2012 37 28 36 27 6.0 0.0 5.4 0.0 60.2 1.4 21.5 0.2 Sat 12 May 2012 38 37 Sun 13 May 2012 39 38 Mon 14 May 2012 40 29 39 28 6.0 0.0 5.4 0.0 50.0 0.7 21.4 0.1 Tue 15 May 2012 41 30 40 29 6.0 0.0 5.4 0.0 49.6 0.2 21.4 0.2 Wed 16 May 2012 42 31 41 30 6.0 0.0 5.4 0.0 50.0 0.3 21.1 0.1 Thu 17 May 2012 43 32 42 31 6.0 0.0 5.4 0.0 50.1 0.5 21.2 0.1 Fri 18 May 2012 44 33 43 32 6.0 0.0 5.4 0.0 50.2 0.5 23.7 0.1 Sat 19 May 2012 45 44 Sun 20 May 2012 46 45 Mon 21 May 2012 47 34 46 33 6.0 0.0 5.4 0.0 55.5 0.5 23.7 0.1 Tue 22 May 2012 48 35 47 34 6.0 0.0 5.4 0.0 57.4 0.7 23.4 0.1 Wed 23 May 2012 49 36 48 35 6.0 0.0 5.4 0.0 60.7 1.5 23.4 0.2 Thu 24 May 2012 50 37 49 36 6.0 0.0 5.4 0.0 59.5 2.7 23.5 0.3 Fri 25 May 2012 51 38 50 37 6.0 0.0 5.4 0.0 51.6 1.6 23.1 0.1 Sat 26 May 2012 52 51 Sun 27 May 2012 53 52 Mon 28 May 2012 54 39 53 38 6.0 0.0 5.4 0.0 49.7 1.1 23.1 0.1 Tue 29 May 2012 55 40 54 39 6.0 0.0 5.4 0.0 50.5 1.2 23.2 0.0 Wed 30 May 2012 56 41 55 40 6.0 0.0 5.4 0.0 57.9 1.3 23.0 0.2 Thu 31 May 2012 57 42 56 41 6.0 0.0 5.4 0.0 57.1 1.1 23.0 0.1

Fri 01 Jun 2012 58 43 57 42 6.0 0.0 5.4 0.0 51.8 0.8 23.1 0.1
Sat 02 Jun 2012 59 58
Sun 03 Jun 2012 60 59

Mon 04 Jun 2012 61 44 60 43 6.0 0.0 5.4 0.0 51.2 0.8 23.5 0.1

Tue 05 Jun 2012 62 45 61 44 6.0 0.0 5.4 0.0 50.5 0.7 23.3 0.2

Wed 06 Jun 2012 63 46 62 45 6.0 0.0 5.4 0.0 52.4 2.3 23.0 0.1

Thu 07 Jun 2012 64 47 63 46 6.0 0.0 5.4 0.0 57.6 0.5 22.9 0.1

Fri 08 Jun 2012 65 48 64 47 6.0 0.0 5.4 0.0 55.2 4.9 23.2 0.0
Sat 09 Jun 2012 66 65
Sun 10 Jun 2012 67 66

Mon 11 Jun 2012 68 49 67 48 6.0 0.0 5.4 0.0 56.9 2.2 23.4 0.0

Tue 12 Jun 2012 69 50 68 49 6.0 0.0 5.4 0.0 54.8 2.7 23.3 0.2

Wed 13 Jun 2012 70 51 69 50 6.0 0.0 5.4 0.0 57.5 0.6 23.6 0.1

Thu 14 Jun 2012 71 52 70 51 6.0 0.0 5.4 0.0 53.6 1.3 23.2 0.2

Fri 15 Jun 2012 72 53 71 52 6.0 0.0 5.4 0.0 53.1 1.1 23.6 0.1
Sat 16 Jun 2012 73 72
Sun 17 Jun 2012 74 73

Mon 18 Jun 2012 75 54 74 53 6.0 0.0 5.4 0.0 60.3 0.9 23.4 0.1

Tue 19 Jun 2012 76 55 75 54 6.0 0.0 5.4 0.0 60.2 0.8 23.3 0.1

Wed 20 Jun 2012 77 56 76 55 6.0 0.0 5.4 0.0 61.2 0.8 23.5 0.3

Thu 21 Jun 2012 78 57 77 56 6.0 0.0 5.4 0.0 60.2 0.9 23.5 0.2

Fri 22 Jun 2012 79 58 78 57 6.0 0.0 5.4 0.0 50.8 1.5 23.2 0.1
Sat 23 Jun 2012 80 79
Sun 24 Jun 2012 81 80

Mon 25 Jun 2012 82 59 81 58 6.0 0.0 5.4 0.0 50.3 1.2 23.3 0.2

Tue 26 Jun 2012 83 60 82 59 6.0 0.0 5.4 0.0 51.5 1.1 23.6 0.2

Wed 27 Jun 2012 84 61 83 60 6.0 0.0 5.4 0.0 58.8 0.6 23.5 0.1

Thu 28 Jun 2012 85 62 84 61 6.0 0.0 5.4 0.0 60.9 0.8 23.5 0.2

Fri 29 Jun 2012 86 63 85 62 6.0 0.0 5.4 0.0 62.0 1.9 23.8 0.2
Sat 30 Jun 2012 87 86
Sun 01 Jul 2012 88 87

Mon 02 Jul 2012 89 64 88 63 6.0 0.0 5.4 0.0 62.1 0.9 23.4 0.2
Tue 03 Jul 2012 90 FOB 89 64 6.0 0.0 5.4 0.0 59.8 1.0 22.4 0.1

Wed 04 Jul 2012 91 65 90 FOB 6.0 0.0 5.4 0.0 61.1 0.5 22.6 0.1

Thu 05 Jul 2012 92 91 65 6.0 0.0 5.4 0.0 63.7 1.1 22.4 0.1

Study mean 68 Exposures 6.0 0.0 5.4 0.0 53.5 1.0 22.3 0.1
S.D. 0.0 0.0 4.9 1.1

Study mean - males 65 Exposures 6.0 0.0 5.4 0.0 53.3 1.0 22.3 0.1
S.D. 0.0 0.0 4.7 1.1

Study mean - females 65 Exposures 6.0 0.0 5.4 0.0 53.5 1.0 22.3 0.1

S.D. 0.0 0.0 4.8 1.1 [m3/h] [m3/h] [%RH] [°C] Supply air

Conditioned Exhaust air Chamber humidity Chamber temperature



### Page 471 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsExposure Parameters (Daily Means) Table IID - 2 Inhalation Laboratory · Test Group 1

Date Study day

males Exposure No. Study day

females Exposure No. Substance

flow

[mg/h]

mean S.D. mean S.D. mean S.D. mean S.D. mean S.D. mean S.D. mean S.D. mean mean S.D. Wed 04 Apr 2012 0 1 -1 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 43.9 0.6 22.9 0.3 26.91 0.28 0.22 Thu 05 Apr 2012 1 2 0 1 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 44.7 0.4 22.9 0.1 23.06 0.40 0.16 Fri 06 Apr 2012 2 3 1 2 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 44.9 1.1 23.0 0.2 23.06 0.19 0.04 Sat 07 Apr 2012 3 2 Sun 08 Apr 2012 4 3 Mon 09 Apr 2012 5 4 4 3 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 45.1 0.9 22.7 0.2 23.06 0.23 0.14 Tue 10 Apr 2012 6 5 5 4 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 44.7 1.3 22.8 0.2 23.06 0.25 0.10 Wed 11 Apr 2012 7 6 6 5 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 44.7 1.1 22.8 0.2 23.06 0.18 0.19 Thu 12 Apr 2012 8 7 7 6 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 44.2 1.1 23.0 0.3 21.81 0.31 n.a. Fri 13 Apr 2012 9 8 8 7 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 45.0 0.9 22.8 0.2 21.81 0.10 0.02 Sat 14 Apr 2012 10 9 Sun 15 Apr 2012 11 10 Mon 16 Apr 2012 12 9 11 8 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 44.6 1.2 23.0 0.3 21.91 0.36 0.47 Tue 17 Apr 2012 13 10 12 9 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 44.0 1.5 22.9 0.2 21.91 0.26 0.08 Wed 18 Apr 2012 14 11 13 10 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 44.9 0.9 22.8 0.2 21.91 0.35 0.23 Thu 19 Apr 2012 15 12 14 11 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 44.7 1.3 22.9 0.2 13.39 0.48 0.19 Fri 20 Apr 2012 16 13 15 12 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 42.2 3.3 22.8 0.1 7.3 0.18 0.10 Sat 21 Apr 2012 17 16 Sun 22 Apr 2012 18 17 Mon 23 Apr 2012 19 14 18 13 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 44.4 1.4 23.0 0.3 2.47 0.52 0.31 Tue 24 Apr 2012 20 15 19 14 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 44.5 1.1 22.9 0.2 2.47 0.21 0.10 Wed 25 Apr 2012 21 16 20 15 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 44.6 1.5 22.8 0.2 2.47 0.14 0.20 Thu 26 Apr 2012 22 17 21 16 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 44.1 1.0 22.9 0.2 2.47 0.09 0.04 Fri 27 Apr 2012 23 18 22 17 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 43.6 0.8 22.9 0.2 14.79 0.09 0.02 Sat 28 Apr 2012 24 23 Sun 29 Apr 2012 25 24 Mon 30 Apr 2012 26 19 25 18 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 48.5 3.3 23.0 0.3 24.65 0.06 0.02 Tue 01 May 2012 27 20 26 19 4.5 0.0 3.8 0.35 1.5 0.0 5.6 0.0 3.8 0.35 44.0 2.0 23.0 0.4 49.4 0.07 0.04 Wed 02 May 2012 28 21 27 20 4.5 0.0 3.8 0.35 1.5 0.0 5.6 0.0 3.8 0.35 50.0 0.9 22.8 0.3 38.72 0.54 0.21 Thu 03 May 2012 29 22 28 21 4.5 0.0 4.0 0.0 1.5 0.0 5.5 0.0 4.0 0.0 44.0 1.1 22.9 0.3 26.7 0.13 0.03 Fri 04 May 2012 30 23 29 22 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 44.5 1.5 22.9 0.3 26.7 0.46 0.14 Sat 05 May 2012 31 30 Sun 06 May 2012 32 31 Mon 07 May 2012 33 24 32 23 4.5 0.0 4.0 0.0 1.5 0.0 5.5 0.0 4.0 0.0 44.2 1.2 23.0 0.3 16.02 0.33 0.04 Tue 08 May 2012 34 25 33 24 4.5 0.0 4.0 0.0 1.5 0.0 5.5 0.0 4.0 0.0 44.4 1.0 22.9 0.2 10.68 0.14 0.12 Wed 09 May 2012 35 26 34 25 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 50.4 0.9 22.8 0.2 24.03 0.12 0.10 Thu 10 May 2012 36 27 35 26 4.5 0.0 4.0 0.0 1.5 0.0 5.5 0.0 4.0 0.0 52.5 1.5 22.9 0.2 34.71 0.35 0.41 Fri 11 May 2012 37 28 36 27 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 52.6 1.5 23.0 0.2 16.02 0.46 0.17 Sat 12 May 2012 38 37 Sun 13 May 2012 39 38 Mon 14 May 2012 40 29 39 28 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 46.4 1.2 22.8 0.1 16.02 0.43 0.30 Tue 15 May 2012 41 30 40 29 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 45.8 1.9 23.0 0.3 16.02 0.34 0.11 Wed 16 May 2012 42 31 41 30 4.5 0.0 4.2 0.4 1.5 0.0 5.6 0.0 4.2 0.4 47.4 1.9 22.9 0.2 2.67 1.15 0.86 Thu 17 May 2012 43 32 42 31 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 46.2 1.7 22.8 0.1 26.7 0.15 0.02 Fri 18 May 2012 44 33 43 32 4.5 0.0 4.2 0.4 1.5 0.0 5.6 0.0 4.2 0.4 47.4 1.8 23.0 0.2 2.67 0.15 0.12 Sat 19 May 2012 45 44 Sun 20 May 2012 46 45 Mon 21 May 2012 47 34 46 33 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 51.6 4.0 23.0 0.3 33.91 0.08 0.08 Tue 22 May 2012 48 35 47 34 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 50.6 3.6 22.7 0.2 64.09 0.22 0.11 Wed 23 May 2012 49 36 48 35 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 54.1 3.7 23.0 0.3 13.35 0.48 0.17 Thu 24 May 2012 50 37 49 36 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 53.4 3.4 22.9 0.2 40.05 0.12 0.06 Fri 25 May 2012 51 38 50 37 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 45.1 1.7 23.0 0.2 40.05 0.19 0.16 Sat 26 May 2012 52 51 Sun 27 May 2012 53 52 Mon 28 May 2012 54 39 53 38 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 45.4 0.9 22.8 0.1 40.05 0.35 0.28 Tue 29 May 2012 55 40 54 39 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 45.9 1.1 22.7 0.2 40.05 0.23 0.13 Wed 30 May 2012 56 41 55 40 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 50.8 3.1 22.9 0.2 40.05 0.28 0.18 Thu 31 May 2012 57 42 56 41 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 49.6 3.2 23.0 0.2 40.05 0.12 0.09

Fri 01 Jun 2012 58 43 57 42 4.5 0.0 4.5 0.4 1.5 0.0 5.6 0.0 4.5 0.4 48.2 1.7 22.8 0.2 21.36 0.46 0.39

Sat 02 Jun 2012 59 58

Sun 03 Jun 2012 60 59

Mon 04 Jun 2012 61 44 60 43 4.5 0.0 4.7 0.0 1.5 0.0 5.6 0.0 4.7 0.0 48.6 1.4 22.8 0.3 13.35 0.37 0.08

Tue 05 Jun 2012 62 45 61 44 4.5 0.0 4.2 0.4 1.5 0.0 5.6 0.0 4.2 0.4 46.6 1.5 22.9 0.2 13.35 0.27 0.07

Wed 06 Jun 2012 63 46 62 45 4.5 0.0 4.0 0.0 1.5 0.0 5.5 0.0 4.0 0.0 45.2 1.6 22.7 0.2 13.35 0.18 0.09

Thu 07 Jun 2012 64 47 63 46 4.5 0.0 4.0 0.0 1.5 0.0 5.5 0.0 4.0 0.0 51.6 2.8 22.7 0.1 13.35 0.20 0.07

Fri 08 Jun 2012 65 48 64 47 4.5 0.0 4.0 0.0 1.5 0.0 5.5 0.0 4.0 0.0 49.5 4.6 22.7 0.1 13.35 0.30 0.13

Sat 09 Jun 2012 66 65

Sun 10 Jun 2012 67 66

Mon 11 Jun 2012 68 49 67 48 4.5 0.0 4.0 0.0 1.5 0.0 5.5 0.0 4.0 0.0 48.7 3.2 23.0 0.3 2.67 0.20 0.06

Tue 12 Jun 2012 69 50 68 49 4.5 0.0 4.0 0.0 1.5 0.0 5.5 0.0 4.0 0.0 47.5 2.2 22.9 0.2 2.67 0.14 0.09

Wed 13 Jun 2012 70 51 69 50 4.5 0.0 4.0 0.0 1.5 0.0 5.5 0.0 4.0 0.0 50.7 3.4 22.8 0.2 2.67 0.14 0.02

Thu 14 Jun 2012 71 52 70 51 4.5 0.0 4.0 0.0 1.5 0.0 5.5 0.0 4.0 0.0 47.0 2.3 22.8 0.2 2.67 0.22 0.12

Fri 15 Jun 2012 72 53 71 52 4.5 0.0 4.0 0.0 1.5 0.0 5.5 0.0 4.0 0.0 47.9 1.3 22.8 0.2 2.67 0.11 0.04

Sat 16 Jun 2012 73 72

Sun 17 Jun 2012 74 73

Mon 18 Jun 2012 75 54 74 53 4.5 0.0 4.0 0.0 1.5 0.0 5.5 0.0 4.0 0.0 52.5 2.6 23.0 0.2 2.67 0.18 0.13

Tue 19 Jun 2012 76 55 75 54 4.5 0.0 4.0 0.0 1.5 0.0 5.5 0.0 4.0 0.0 51.5 3.4 23.1 0.3 2.67 0.23 0.05

Wed 20 Jun 2012 77 56 76 55 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 55.1 3.4 22.9 0.3 13.35 0.08 0.02

Thu 21 Jun 2012 78 57 77 56 4.5 0.0 3.5 0.0 1.5 0.0 5.6 0.0 3.5 0.0 51.3 2.9 22.9 0.2 58.75 0.11 0.06

Fri 22 Jun 2012 79 58 78 57 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 44.0 1.3 23.1 0.3 24.03 0.25 0.13

Sat 23 Jun 2012 80 79

Sun 24 Jun 2012 81 80

Mon 25 Jun 2012 82 59 81 58 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 43.8 1.3 23.0 0.3 5.34 0.18 0.06

Tue 26 Jun 2012 83 60 82 59 4.5 0.0 3.5 0.5 1.5 0.0 5.6 0.0 3.5 0.5 44.5 1.5 23.0 0.2 32.04 0.10 0.02

Wed 27 Jun 2012 84 61 83 60 4.5 0.0 3.8 0.3 1.5 0.0 5.6 0.0 3.8 0.3 50.7 1.5 23.0 0.2 120.16 0.47 0.29

Thu 28 Jun 2012 85 62 84 61 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 54.5 3.0 23.1 0.3 2.67 0.14 0.08

Fri 29 Jun 2012 86 63 85 62 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 55.3 3.1 23.1 0.3 2.67 0.15 0.07

Sat 30 Jun 2012 87 86

Sun 01 Jul 2012 88 87

Mon 02 Jul 2012 89 64 88 63 4.5 0.0 4.3 0.3 1.5 0.0 5.5 0.0 4.3 0.3 52.4 2.2 23.1 0.3 2.67 0.14 0.07

Tue 03 Jul 2012 90 FOB 89 64 4.5 0.0 4.4 0.0 1.5 0.0 5.6 0.0 4.4 0.0 52.8 2.8 22.5 0.3 2.67 0.16 0.08

Wed 04 Jul 2012 91 65 90 FOB 4.5 0.0 4.3 0.3 1.5 0.0 5.6 0.0 4.3 0.3 53.9 3.3 22.6 0.3 2.67 0.08 0.02

Thu 05 Jul 2012 92 91 65 4.5 0.0 4.0 0.0 1.5 0.0 5.6 0.0 4.0 0.0 55.6 2.8 22.6 0.3 2.67 0.26 0.21

Study mean 68 Exposures 4.5 0.0 4.0 0.1 1.5 0.0 5.6 0.0 4.0 0.1 47.8 1.9 22.9 0.2 20.3 0.25 0.14

S.D. 0.0 0.2 0.0 0.0 0.2 3.7 0.1 19.3 0.17

Study mean - males 65 Exposures 4.5 0.0 4.0 0.1 1.5 0.0 5.6 0.0 4.0 0.1 47.6 1.9 22.9 0.2 20.8 0.25 0.14

S.D. 0.0 0.2 0.0 0.0 0.2 3.6 0.1 19.3 0.17

Study mean - females 65 Exposures 4.5 0.0 4.0 0.1 1.5 0.0 5.6 0.0 4.0 0.1 47.8 1.9 22.9 0.2 20.4 0.25 0.14

S.D. 0.0 0.2 0.0 0.0 0.2 3.6 0.1 19.5 0.17 n.a. not applicable, because only two concentrations were measured on that day. Chamber temperature Concentration of substance

[°C] [mg/m3] [m3/h] [m3/h] [m3/h] [%RH] [m3/h] [m3/h] Supply air 1 Supply air 2

into the

dilution tube Exhaust air 2

from the dilution

tube Chamber humidity Compressed

air Exhaust air 1



### Page 472 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsExposure Parameters (Daily Means) Table IID - 3 Inhalation Laboratory · Test Group 2

Date Study day

males Exposure No. Study day

females Exposure No. Substance

flow

[mg/h]

mean S.D. mean S.D. mean S.D. mean S.D. mean S.D. mean mean S.D. Wed 04 Apr 2012 0 1 -1 4.5 0.0 1.5 0.0 5.4 0.0 45.7 0.9 21.3 0.4 226.51 0.59 0.37 Thu 05 Apr 2012 1 2 0 1 4.5 0.0 1.5 0.1 5.4 0.0 46.2 0.8 21.5 0.2 2306.28 0.96 1.12 Fri 06 Apr 2012 2 3 1 2 4.5 0.0 1.5 0.0 5.4 0.0 46.1 1.1 21.5 0.3 71.57 2.04 1.08 Sat 07 Apr 2012 3 2 Sun 08 Apr 2012 4 3 Mon 09 Apr 2012 5 4 4 3 4.5 0.0 1.5 0.0 5.4 0.0 46.3 1.2 21.3 0.3 71.57 1.03 0.57 Tue 10 Apr 2012 6 5 5 4 4.5 0.0 1.5 0.0 5.4 0.0 46.2 1.5 21.4 0.4 71.57 1.40 0.34 Wed 11 Apr 2012 7 6 6 5 4.5 0.0 1.5 0.0 5.4 0.0 46.4 1.0 21.4 0.4 71.57 1.49 0.19 Thu 12 Apr 2012 8 7 7 6 4.5 0.0 1.5 0.0 5.4 0.0 46.2 1.1 21.4 0.3 71.57 1.64 0.61 Fri 13 Apr 2012 9 8 8 7 4.5 0.0 1.5 0.0 5.4 0.0 46.7 0.9 21.3 0.3 63.16 1.05 0.11 Sat 14 Apr 2012 10 9 Sun 15 Apr 2012 11 10 Mon 16 Apr 2012 12 9 11 8 4.5 0.0 1.5 0.0 5.4 0.0 46.4 1.1 21.5 0.3 72.28 0.60 0.22 Tue 17 Apr 2012 13 10 12 9 4.5 0.0 1.5 0.0 5.4 0.0 45.8 1.5 21.4 0.2 72.28 1.08 0.48 Wed 18 Apr 2012 14 11 13 10 4.5 0.0 1.5 0.0 5.4 0.0 46.7 0.8 21.3 0.3 72.28 1.12 0.69 Thu 19 Apr 2012 15 12 14 11 4.5 0.0 1.5 0.0 5.4 0.0 46.5 2.0 21.5 0.3 72.28 0.77 0.38 Fri 20 Apr 2012 16 13 15 12 4.5 0.0 1.5 0.0 5.4 0.0 44.0 3.0 21.4 0.2 72.28 1.55 1.12 Sat 21 Apr 2012 17 16 Sun 22 Apr 2012 18 17 Mon 23 Apr 2012 19 14 18 13 4.5 0.0 1.5 0.0 5.4 0.0 46.0 1.3 21.7 0.4 73.33 1.93 0.58 Tue 24 Apr 2012 20 15 19 14 4.5 0.0 1.5 0.0 5.4 0.0 46.2 1.3 21.5 0.3 73.33 1.43 1.00 Wed 25 Apr 2012 21 16 20 15 4.5 0.0 1.5 0.0 5.4 0.0 46.4 1.5 21.4 0.4 73.33 0.55 0.19 Thu 26 Apr 2012 22 17 21 16 4.5 0.0 1.5 0.0 5.4 0.0 46.1 0.9 21.5 0.2 73.33 0.81 0.43 Fri 27 Apr 2012 23 18 22 17 4.5 0.0 1.5 0.0 5.4 0.0 46.2 3.7 21.7 0.4 73.33 1.67 0.85 Sat 28 Apr 2012 24 23 Sun 29 Apr 2012 25 24 Mon 30 Apr 2012 26 19 25 18 4.5 0.0 1.5 0.0 5.4 0.0 50.0 3.4 21.7 0.4 73.33 1.66 1.07 Tue 01 May 2012 27 20 26 19 4.5 0.0 1.5 0.0 5.4 0.0 46.3 1.9 21.7 0.4 73.33 2.78 3.03 Wed 02 May 2012 28 21 27 20 4.5 0.0 1.5 0.0 5.4 0.0 52.7 1.2 21.4 0.3 73.33 1.65 0.42 Thu 03 May 2012 29 22 28 21 4.5 0.0 1.5 0.0 5.4 0.0 46.0 1.2 21.6 0.4 73.33 1.63 0.20 Fri 04 May 2012 30 23 29 22 4.5 0.0 1.5 0.0 5.4 0.0 46.4 1.6 21.7 0.4 73.33 1.29 0.12 Sat 05 May 2012 31 30 Sun 06 May 2012 32 31 Mon 07 May 2012 33 24 32 23 4.5 0.0 1.5 0.0 5.4 0.0 46.0 1.2 21.5 0.4 73.33 1.94 0.33 Tue 08 May 2012 34 25 33 24 4.5 0.0 1.5 0.0 5.4 0.0 46.2 1.0 21.3 0.3 73.33 1.93 1.07 Wed 09 May 2012 35 26 34 25 4.5 0.0 1.5 0.0 5.4 0.0 52.3 1.1 21.3 0.3 73.33 1.59 0.20 Thu 10 May 2012 36 27 35 26 4.5 0.0 1.5 0.0 5.4 0.0 54.8 1.3 21.3 0.3 73.33 1.62 0.26 Fri 11 May 2012 37 28 36 27 4.5 0.0 1.5 0.0 5.4 0.0 55.0 1.4 21.5 0.3 73.33 1.47 0.82 Sat 12 May 2012 38 37 Sun 13 May 2012 39 38 Mon 14 May 2012 40 29 39 28 4.5 0.0 1.5 0.0 5.4 0.0 48.0 1.1 21.5 0.3 73.33 1.52 0.68 Tue 15 May 2012 41 30 40 29 4.5 0.0 1.5 0.0 5.4 0.0 47.7 2.0 21.6 0.3 73.33 1.34 0.40 Wed 16 May 2012 42 31 41 30 4.5 0.0 1.5 0.0 5.4 0.0 48.3 2.1 21.5 0.3 73.33 1.70 0.38 Thu 17 May 2012 43 32 42 31 4.5 0.0 1.5 0.0 5.5 0.1 48.7 1.5 21.2 0.2 73.33 1.69 0.33 Fri 18 May 2012 44 33 43 32 4.5 0.0 1.5 0.0 5.6 0.0 48.2 0.9 21.5 0.4 73.33 1.20 0.38 Sat 19 May 2012 45 44 Sun 20 May 2012 46 45 Mon 21 May 2012 47 34 46 33 4.5 0.0 1.5 0.0 5.6 0.0 54.6 3.6 21.6 0.3 73.33 1.49 0.15 Tue 22 May 2012 48 35 47 34 4.5 0.0 1.5 0.0 5.5 0.0 53.9 2.7 21.4 0.3 73.33 1.29 1.07 Wed 23 May 2012 49 36 48 35 4.5 0.0 1.5 0.0 5.5 0.0 56.5 3.5 21.6 0.5 73.33 1.13 0.10 Thu 24 May 2012 50 37 49 36 4.5 0.0 1.5 0.0 5.5 0.0 55.9 3.2 21.6 0.4 73.33 1.21 0.49 Fri 25 May 2012 51 38 50 37 4.5 0.0 1.5 0.0 5.6 0.0 47.6 2.0 21.8 0.3 73.33 1.28 0.33 Sat 26 May 2012 52 51 Sun 27 May 2012 53 52 Mon 28 May 2012 54 39 53 38 4.5 0.0 1.5 0.0 5.6 0.0 47.5 1.1 21.5 0.2 73.33 1.13 0.81 Tue 29 May 2012 55 40 54 39 4.5 0.0 1.5 0.0 5.6 0.0 47.6 1.1 21.2 0.2 73.33 0.54 0.20 Wed 30 May 2012 56 41 55 40 4.5 0.0 1.5 0.0 5.5 0.0 53.0 3.4 21.5 0.4 79.99 1.56 0.21 Thu 31 May 2012 57 42 56 41 4.5 0.0 1.5 0.0 5.5 0.0 52.1 3.5 21.5 0.3 79.99 1.71 0.86

Fri 01 Jun 2012 58 43 57 42 4.5 0.0 1.5 0.0 5.6 0.0 48.5 1.5 21.3 0.3 79.99 1.85 0.46
Sat 02 Jun 2012 59 58
Sun 03 Jun 2012 60 59

Mon 04 Jun 2012 61 44 60 43 4.5 0.0 1.5 0.0 5.6 0.0 49.4 1.8 21.5 0.4 79.99 1.39 0.82

Tue 05 Jun 2012 62 45 61 44 4.5 0.0 1.5 0.0 5.5 0.0 48.5 1.1 21.4 0.3 79.99 1.43 0.13

Wed 06 Jun 2012 63 46 62 45 4.5 0.0 1.5 0.0 5.6 0.0 47.4 1.9 21.3 0.3 79.99 1.66 0.32

Thu 07 Jun 2012 64 47 63 46 4.5 0.0 1.5 0.0 5.5 0.0 53.8 2.9 21.4 0.2 79.99 1.72 0.20

Fri 08 Jun 2012 65 48 64 47 4.5 0.0 1.5 0.0 5.5 0.0 51.8 5.0 21.5 0.2 79.99 1.82 0.85
Sat 09 Jun 2012 66 65
Sun 10 Jun 2012 67 66

Mon 11 Jun 2012 68 49 67 48 4.5 0.0 1.5 0.0 5.5 0.0 50.4 3.1 21.7 0.4 79.99 1.79 0.28

Tue 12 Jun 2012 69 50 68 49 4.5 0.0 1.5 0.0 5.5 0.0 49.8 2.1 21.5 0.3 79.99 1.36 0.23

Wed 13 Jun 2012 70 51 69 50 4.5 0.0 1.5 0.0 5.6 0.0 53.1 3.5 21.5 0.3 79.99 1.48 0.44

Thu 14 Jun 2012 71 52 70 51 4.5 0.0 1.5 0.0 5.6 0.0 49.5 2.5 21.5 0.3 79.99 2.35 0.19

Fri 15 Jun 2012 72 53 71 52 4.5 0.0 1.5 0.0 5.5 0.0 50.0 1.5 21.5 0.2 79.99 1.80 0.60
Sat 16 Jun 2012 73 72
Sun 17 Jun 2012 74 73

Mon 18 Jun 2012 75 54 74 53 4.5 0.0 1.5 0.0 5.5 0.0 55.0 2.5 21.7 0.2 79.99 1.72 1.23

Tue 19 Jun 2012 76 55 75 54 4.5 0.0 1.5 0.0 5.5 0.0 54.0 3.6 21.8 0.4 79.99 1.66 0.62

Wed 20 Jun 2012 77 56 76 55 4.5 0.0 1.5 0.0 5.5 0.0 58.3 3.7 21.5 0.3 79.99 1.68 0.22

Thu 21 Jun 2012 78 57 77 56 4.5 0.0 1.5 0.0 5.5 0.0 55.4 2.9 21.5 0.3 79.99 1.72 0.57

Fri 22 Jun 2012 79 58 78 57 4.5 0.0 1.5 0.0 5.6 0.0 46.6 1.5 21.6 0.3 79.99 1.28 0.21
Sat 23 Jun 2012 80 79
Sun 24 Jun 2012 81 80

Mon 25 Jun 2012 82 59 81 58 4.5 0.0 1.5 0.0 5.6 0.0 46.5 1.1 21.3 0.3 79.99 1.33 0.26

Tue 26 Jun 2012 83 60 82 59 4.5 0.0 1.5 0.0 5.5 0.0 47.4 0.9 21.5 0.2 79.99 1.51 1.40

Wed 27 Jun 2012 84 61 83 60 4.5 0.0 1.5 0.0 5.6 0.0 53.1 1.6 21.5 0.2 79.99 1.21 0.14

Thu 28 Jun 2012 85 62 84 61 4.5 0.0 1.5 0.0 5.5 0.0 57.4 3.1 21.6 0.3 79.99 0.70 0.36

Fri 29 Jun 2012 86 63 85 62 4.5 0.0 1.5 0.0 5.5 0.0 58.3 3.4 21.7 0.3 79.99 1.35 0.37
Sat 30 Jun 2012 87 86
Sun 01 Jul 2012 88 87

Mon 02 Jul 2012 89 64 88 63 4.5 0.0 1.5 0.0 5.5 0.0 55.1 3.2 21.4 0.4 59.31 1.25 0.52
Tue 03 Jul 2012 90 FOB 89 64 4.5 0.0 1.5 0.0 5.5 0.0 54.6 3.2 21.2 0.5 59.31 1.08 0.30
Wed 04 Jul 2012 91 65 90 FOB 4.5 0.0 1.5 0.0 5.5 0.0 55.8 3.0 21.3 0.4 59.31 1.22 0.55

Thu 05 Jul 2012 92 91 65 4.5 0.0 1.5 0.0 5.5 0.0 58.0 2.6 21.4 0.4 59.31 0.69 0.33

Study mean 68 Exposures 4.5 0.0 1.5 0.0 5.5 0.0 49.9 2.0 21.5 0.3 74.5 1.42 0.53
S.D. 0.0 0.0 0.1 4.0 0.1 5.4 0.42

Study mean - males 65 Exposures 4.5 0.0 1.5 0.0 5.5 0.0 49.7 2.0 21.5 0.3 74.9 1.44 0.54
S.D. 0.0 0.0 0.1 3.9 0.1 4.7 0.41

Study mean - females 65 Exposures 4.5 0.0 1.5 0.0 5.5 0.0 49.9 2.0 21.5 0.3 74.7 1.44 0.54

S.D. 0.0 0.0 0.1 4.0 0.1 5.1 0.41 Chamber humidity Chamber temperature

[mg/m3] Concentration of substance

[%RH] [°C] [m3/h] Supply air Compressed

air Exhaust air

[m3/h] [m3/h]



### Page 473 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsExposure Parameters (Daily Means) Table IID - 4 Inhalation Laboratory · Test Group 3

Date Study day

males Exposure No. Study day

females Exposure No. Substance

flow

[mg/h]

mean S.D. mean S.D. mean S.D. mean S.D. mean S.D. mean mean S.D. Wed 04 Apr 2012 0 1 -1 4.5 0.0 1.5 0.2 5.4 0.0 35.8 1.4 22.3 0.5 68.29 3.04 0.49 Thu 05 Apr 2012 1 2 0 1 4.5 0.0 1.6 0.0 5.4 0.0 35.0 0.8 22.9 0.2 685.84 7.71 4.31 Fri 06 Apr 2012 2 3 1 2 4.5 0.0 1.6 0.0 5.4 0.0 35.4 0.8 22.8 0.2 266.23 9.50 7.62 Sat 07 Apr 2012 3 2 Sun 08 Apr 2012 4 3 Mon 09 Apr 2012 5 4 4 3 4.5 0.0 1.6 0.0 5.4 0.0 35.8 0.7 22.5 0.2 266.23 6.26 1.74 Tue 10 Apr 2012 6 5 5 4 4.5 0.0 1.6 0.0 5.4 0.0 35.3 1.1 22.8 0.4 133.12 7.39 1.40 Wed 11 Apr 2012 7 6 6 5 4.5 0.0 1.6 0.0 5.4 0.0 35.5 1.0 22.6 0.3 101.17 6.03 0.49 Thu 12 Apr 2012 8 7 7 6 4.5 0.0 1.6 0.0 5.4 0.0 35.6 1.3 22.7 0.4 79.18 9.33 6.96 Fri 13 Apr 2012 9 8 8 7 4.5 0.0 1.6 0.0 5.4 0.0 35.8 0.8 22.6 0.3 67.87 5.76 0.21 Sat 14 Apr 2012 10 9 Sun 15 Apr 2012 11 10 Mon 16 Apr 2012 12 9 11 8 4.5 0.0 1.6 0.0 5.4 0.0 35.4 0.9 22.8 0.3 76.46 2.33 1.07 Tue 17 Apr 2012 13 10 12 9 4.5 0.0 1.6 0.0 5.4 0.0 35.2 1.2 22.6 0.2 162.48 3.68 1.7 Wed 18 Apr 2012 14 11 13 10 4.5 0.0 1.6 0.0 5.4 0.0 35.6 0.8 22.6 0.3 245.77 4.45 2.75 Thu 19 Apr 2012 15 12 14 11 4.5 0.0 1.6 0.0 5.4 0.0 35.4 1.2 22.8 0.4 177.5 6.70 1.16 Fri 20 Apr 2012 16 13 15 12 4.5 0.0 1.6 0.0 5.4 0.0 34.0 2.2 22.6 0.2 76.46 5.39 0.78 Sat 21 Apr 2012 17 16 Sun 22 Apr 2012 18 17 Mon 23 Apr 2012 19 14 18 13 4.5 0.0 1.6 0.0 5.4 0.0 35.5 1.1 22.7 0.3 116.46 6.48 1.03 Tue 24 Apr 2012 20 15 19 14 4.5 0.0 1.6 0.0 5.4 0.0 35.5 1.1 22.6 0.4 116.46 6.56 3.30 Wed 25 Apr 2012 21 16 20 15 4.5 0.0 1.6 0.0 5.4 0.0 35.9 1.3 22.4 0.3 46.58 4.13 1.17 Thu 26 Apr 2012 22 17 21 16 4.5 0.0 1.5 0.0 5.4 0.0 35.5 0.8 22.5 0.2 46.58 5.39 2.02 Fri 27 Apr 2012 23 18 22 17 4.5 0.0 1.5 0.0 5.4 0.0 34.9 0.7 22.7 0.3 46.58 3.67 1.13 Sat 28 Apr 2012 24 23 Sun 29 Apr 2012 25 24 Mon 30 Apr 2012 26 19 25 18 4.5 0.0 1.6 0.0 5.4 0.0 38.2 2.1 22.5 0.3 46.58 4.83 1.15 Tue 01 May 2012 27 20 26 19 4.5 0.0 1.5 0.0 5.4 0.0 35.7 1.3 22.7 0.4 69.88 4.68 1.47 Wed 02 May 2012 28 21 27 20 4.5 0.0 1.5 0.0 5.4 0.0 39.6 0.9 22.5 0.3 69.88 4.44 1.04 Thu 03 May 2012 29 22 28 21 4.5 0.0 1.5 0.0 5.4 0.0 35.4 1.0 22.7 0.4 69.88 3.86 1.63 Fri 04 May 2012 30 23 29 22 4.5 0.0 1.5 0.0 5.4 0.0 36.1 1.1 22.5 0.3 69.88 3.98 1.75 Sat 05 May 2012 31 30 Sun 06 May 2012 32 31 Mon 07 May 2012 33 24 32 23 4.5 0.0 1.5 0.0 5.4 0.0 35.8 0.9 22.6 0.3 104.82 5.22 1.38 Tue 08 May 2012 34 25 33 24 4.5 0.0 1.5 0.0 5.4 0.0 35.6 0.9 22.7 0.3 69.88 4.43 1.18 Wed 09 May 2012 35 26 34 25 4.5 0.0 1.5 0.0 5.4 0.0 39.7 0.8 22.5 0.2 69.88 4.89 0.86 Thu 10 May 2012 36 27 35 26 4.5 0.0 1.5 0.0 5.4 0.0 40.8 0.8 22.7 0.3 69.88 5.41 0.89 Fri 11 May 2012 37 28 36 27 4.5 0.0 1.5 0.0 5.4 0.0 40.9 1.0 23.0 0.3 69.88 4.89 1.67 Sat 12 May 2012 38 37 Sun 13 May 2012 39 38 Mon 14 May 2012 40 29 39 28 4.5 0.0 1.5 0.0 5.4 0.0 36.9 1.0 22.8 0.3 69.88 4.38 1.55 Tue 15 May 2012 41 30 40 29 4.5 0.0 1.5 0.0 5.4 0.0 36.9 1.5 22.8 0.3 69.88 5.65 0.96 Wed 16 May 2012 42 31 41 30 4.5 0.0 1.5 0.0 5.4 0.0 37.5 1.7 22.6 0.3 58.23 4.16 0.54 Thu 17 May 2012 43 32 42 31 4.5 0.0 1.5 0.0 5.5 0.1 37.3 1.2 22.5 0.3 46.58 4.85 0.46 Fri 18 May 2012 44 33 43 32 4.5 0.0 1.5 0.0 5.6 0.0 37.0 0.7 22.8 0.3 58.23 4.30 0.60 Sat 19 May 2012 45 44 Sun 20 May 2012 46 45 Mon 21 May 2012 47 34 46 33 4.5 0.0 1.5 0.0 5.6 0.0 40.3 2.6 23.0 0.3 58.23 4.58 0.30 Tue 22 May 2012 48 35 47 34 4.5 0.0 1.5 0.0 5.6 0.0 39.7 1.9 22.8 0.3 58.23 4.16 0.12 Wed 23 May 2012 49 36 48 35 4.5 0.0 1.5 0.0 5.6 0.0 42.3 2.7 22.8 0.3 58.23 5.23 0.64 Thu 24 May 2012 50 37 49 36 4.5 0.0 1.5 0.0 5.6 0.0 41.3 2.2 22.9 0.3 58.23 6.08 0.98 Fri 25 May 2012 51 38 50 37 4.5 0.0 1.5 0.0 5.6 0.0 36.5 1.3 23.0 0.3 58.23 3.90 0.56 Sat 26 May 2012 52 51 Sun 27 May 2012 53 52 Mon 28 May 2012 54 39 53 38 4.5 0.0 1.5 0.0 5.6 0.0 36.6 0.7 22.8 0.2 58.23 4.86 0.16 Tue 29 May 2012 55 40 54 39 4.5 0.0 1.5 0.0 5.6 0.0 36.7 0.8 22.8 0.2 58.23 4.69 0.19 Wed 30 May 2012 56 41 55 40 4.5 0.0 1.5 0.0 5.5 0.0 40.0 2.1 22.9 0.3 58.23 5.13 0.14 Thu 31 May 2012 57 42 56 41 4.5 0.0 1.5 0.0 5.6 0.0 39.5 2.1 22.8 0.3 58.23 5.29 0.14

Fri 01 Jun 2012 58 43 57 42 4.5 0.0 1.5 0.0 5.6 0.0 37.1 1.0 22.8 0.3 58.23 5.20 0.29
Sat 02 Jun 2012 59 58
Sun 03 Jun 2012 60 59

Mon 04 Jun 2012 61 44 60 43 4.5 0.0 1.6 0.0 5.6 0.0 37.8 1.2 22.8 0.3 58.23 5.19 0.35

Tue 05 Jun 2012 62 45 61 44 4.5 0.0 1.6 0.0 5.6 0.0 37.2 0.9 22.8 0.4 58.23 5.34 0.23

Wed 06 Jun 2012 63 46 62 45 4.5 0.0 1.6 0.0 5.6 0.0 36.5 1.2 22.7 0.3 58.23 5.22 0.22

Thu 07 Jun 2012 64 47 63 46 4.5 0.0 1.6 0.0 5.5 0.0 40.3 2.1 22.8 0.3 58.23 6.17 1.30

Fri 08 Jun 2012 65 48 64 47 4.5 0.0 1.6 0.0 5.6 0.0 39.0 3.3 22.8 0.2 58.23 5.18 0.13
Sat 09 Jun 2012 66 65
Sun 10 Jun 2012 67 66

Mon 11 Jun 2012 68 49 67 48 4.5 0.0 1.6 0.0 5.6 0.0 39.8 2.1 22.5 0.1 87.35 6.84 2.36

Tue 12 Jun 2012 69 50 68 49 4.5 0.0 1.6 0.0 5.6 0.0 38.6 1.5 22.6 0.3 46.58 5.27 1.47

Wed 13 Jun 2012 70 51 69 50 4.5 0.0 1.6 0.0 5.6 0.0 40.7 2.4 22.5 0.1 50.15 5.57 2.84

Thu 14 Jun 2012 71 52 70 51 4.5 0.0 1.6 0.0 5.6 0.0 38.6 1.5 22.4 0.2 94.02 5.73 0.9

Fri 15 Jun 2012 72 53 71 52 4.5 0.0 1.6 0.0 5.6 0.0 39.5 2.2 22.6 0.1 62.68 4.85 2.36
Sat 16 Jun 2012 73 72
Sun 17 Jun 2012 74 73

Mon 18 Jun 2012 75 54 74 53 4.5 0.0 1.6 0.0 5.6 0.0 42.3 1.8 22.6 0.1 62.68 4.37 0.54

Tue 19 Jun 2012 76 55 75 54 4.5 0.0 1.6 0.0 5.6 0.0 41.7 2.2 22.5 0.2 50.15 5.11 0.22

Wed 20 Jun 2012 77 56 76 55 4.5 0.0 1.6 0.0 5.6 0.0 43.5 2.2 22.7 0.4 50.15 5.16 0.43

Thu 21 Jun 2012 78 57 77 56 4.5 0.0 1.6 0.0 5.6 0.0 41.9 1.8 22.5 0.3 50.15 4.24 0.24

Fri 22 Jun 2012 79 58 78 57 4.5 0.0 1.6 0.0 5.6 0.0 36.8 0.9 22.5 0.2 50.15 4.15 1.54
Sat 23 Jun 2012 80 79
Sun 24 Jun 2012 81 80

Mon 25 Jun 2012 82 59 81 58 4.5 0.0 1.6 0.0 5.6 0.0 36.6 0.9 22.7 0.3 125.36 2.88 1.59

Tue 26 Jun 2012 83 60 82 59 4.5 0.0 1.6 0.0 5.6 0.0 37.6 0.6 22.6 0.2 100.29 4.49 2.87

Wed 27 Jun 2012 84 61 83 60 4.5 0.0 1.6 0.0 5.6 0.0 41.0 1.2 22.6 0.1 95.28 4.09 1.91

Thu 28 Jun 2012 85 62 84 61 4.5 0.0 1.6 0.0 5.6 0.0 43.2 2.0 22.7 0.3 87.76 5.35 0.63

Fri 29 Jun 2012 86 63 85 62 4.5 0.0 1.6 0.0 5.6 0.0 43.5 2.2 22.8 0.3 94.02 4.88 1.25
Sat 30 Jun 2012 87 86
Sun 01 Jul 2012 88 87

Mon 02 Jul 2012 89 64 88 63 4.5 0.0 1.6 0.0 5.6 0.0 41.9 1.4 22.5 0.2 50.15 4.81 0.25
Tue 03 Jul 2012 90 FOB 89 64 4.5 0.0 1.6 0.0 5.6 0.0 41.6 1.9 22.1 0.3 86.44 4.92 0.76
Wed 04 Jul 2012 91 65 90 FOB 4.5 0.0 1.6 0.0 5.6 0.0 42.5 1.9 22.1 0.3 50.15 4.83 0.26

Thu 05 Jul 2012 92 91 65 4.5 0.0 1.6 0.0 5.6 0.0 43.8 1.8 22.3 0.3 62.68 4.10 0.50

Study mean 68 Exposures 4.5 0.0 1.6 0.0 5.5 0.0 38.2 1.4 22.7 0.3 89.9 5.10 1.27
S.D. 0.0 0.0 0.1 2.7 0.2 87.6 1.24

Study mean - males 65 Exposures 4.5 0.0 1.6 0.0 5.5 0.0 38.0 1.4 22.7 0.3 90.4 5.12 1.29
S.D. 0.0 0.0 0.1 2.6 0.2 88.9 1.25

Study mean - females 65 Exposures 4.5 0.0 1.6 0.0 5.5 0.0 38.1 1.4 22.7 0.3 90.8 5.13 1.30

S.D. 0.0 0.0 0.1 2.7 0.2 88.8 1.23 Chamber humidity Chamber temperature

[mg/m3] Concentration of substance

[%RH] [°C] [m3/h] Supply air Compressed

air Exhaust air

[m3/h] [m3/h]



### Page 474 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 475 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 476 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 477 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 478 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 479 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 480 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 481 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 482 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 483 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 484 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 485 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 486 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 487 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 488 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 489 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 490 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 491 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 492 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 493 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 494 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 495 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 496 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Page 497 of 513

This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### STUDY TITLE

Report

Cobalt Lithium Manganese Nickel oxide

- Subchronic 90

- day inhalation study in Wistar rats dust exposure

TEST FACILITY

TEST FACILITY PROJECT IDEN TIFICATION

PART III OF III ( SUPPLEMENT )

This document contains manufacturing and trade secrets of the Sponsor(s). It is the property of the Sponsor(s) and may be use d only for that purpose for which it was intended by the Sponsor(s). Every other or additional use, exploitation, reproduction, publication or submission to other parties require the written permission of the Sponsor(s), with the exception of regulatory agencies acting within the li mits of their administrative authority.



### Page 498 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### CONTENTS OF PART I I I ( SUPPLEMENT )

TITLE PAGE

TABLE OF CONTENTS

Analysis of the test substance

H istorical cont rol data of clinical pathology testing

Functional Observational Battery (FOB) Detailed description of examinations, ranking and documentation procedures

Page 499 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsThis document is the proper~ of the sponsors (specif~ed on page 1 ), use by other parties requires v~tten permission by the sponsors 

### Page 500 of 513HISTORICAL CONTROL DATA OF CLINICAL PATHOLOGY TESTING 1)

Species: Rat
Sex: Male
Strain: Wistar Age: 18 weeks Study period: 3 months Fasting before blood sampling: 16 hours

Anaesthesia Isoflurane Data print out at 30-Jan-13 Clinical Chemistry Instrument: Hitachi 917, Roche Haematology Analyzer ADVIA 120, Bayer

Parameter: HGB HCT ALT AST K

Unit: MMOL/L L/L MYKAT/L MYKAT/L MMOL/L

Study No, Animals

examined administra

tion via Sampling

month
01170 10 diet 06/05 9.2 0.427 0.46 1.38 4.56
01143 10 diet 08/04 9.4 0.423 0.55 1.57 4.69
04076 10 diet 04/06 9.4 0.423 0.51 1.37 4.69
04066 10 diet 09/05 9.5 0.431 0.50 1.58 4.58
03078 10 diet 12/05 9.2 0.421 0.57 1.64 4.42
04072 10 diet 01/06 9.7 0.422 0.55 1.73 4.71 03085 15 gavage 08/06 9.2 0.404 0.47 1.43 4.55
05056 10 diet 09/06 9.6 0.418 0.57 1.61 4.70
05071 10 diet 05/07 9.2 0.419 0.61 1.78 4.54
06071 10 diet 07/07 9.3 0.398 0.81 1.92 4.60
07010 10 diet 08/07 9.5 0.396 0.63 1.62 4.42
01224 10 diet 09/07 9.6 0.408 0.71 1.70 4.66 05083 10 gavage 09/07 9.6 0.408 0.68 1.63 4.36 06084 10 gavage 11/07 9.2 0.402 0.67 1.66 4.38 06085 10 gavage 11/07 9.5 0.411 0.73 1.56 4.57
07091 10 diet 07/08 9.5 0.420 0.80 1.87 4.35 07097 15 gavage 09/08 9.3 0.412 0.76 2.16 4.59 07098 15 gavage 09/08 9.3 0.412 0.76 1.86 4.42
08020 10 diet 10/08 9.2 0.411 0.82 1.83 4.53
04114 10 inhalation 12/08 9.1 0.412 0.94 1.95 4.46
04117 10 diet 01/09 9.4 0.434 0.75 1.92 4.42
99178 10 diet 02/09 9.4 0.430 0.74 1.82 4.67
01233 10 diet 02/09 9.4 0.427 0.75 1.98 4.50 01236 10 drinking 07/09 9.4 0.419 0.69 1.54 4.36
07128 10 diet 09/09 9.3 0.415 0.66 1.52 4.43
05118 10 inhalation 11/09 9.4 0.425 0.91 1.75 4.64
09030 10 diet 12/09 9.5 0.430 0.81 1.99 4.75
07119 10 diet 04/09 9.7 0.441 0.67 1.63 4.53
08C004 10 diet 09/10 9.2 0.439 0.81 2.29 4.70 08S001 10 gavage 08/10 9.8 0.428 0.61 1.71 4.69
02I001 10 inhalation 07/10 9.3 0.418 0.71 2.01 4.82 06S003 10 gavage 12/10 9.2 0.448 0.62 1.63 4.68
07C018 10 diet 12/10 9.0 0.442 0.74 2.22 4.64

N 33 33 33 33 33

Mean 9.4 0.420 0.68 1.75 4.56

Minimum 9.0 0.396 0.46 1.37 4.35

Maximum 9.8 0.448 0.94 2.29 4.82

document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsorsHISTORICAL CONTROL DATA OF CLINICAL PATHOLOGY TESTING 1)

Species: Rat
Sex: Female
Strain: Wistar Age: 18 weeks Study period: 3 months Fasting before blood sampling: 16 hours

Anaesthesia Isoflurane Data print out at 30-Jan-13 Haematology Analyzer ADVIA 120, Bayer

Parameter: RBC

Unit: TERA/L

Study No, Animals

examined Administration

via Sampling

month

01170 10 diet 06/05 7.45

01143 10 diet 08/04 7.58

04076 10 diet 04/06 7.55

04066 10 diet 09/05 7.69

03078 10 diet 12/05 7.52

04072 10 diet 01/06 7.74

03085 15 gavage 08/06 7.34

05056 10 diet 09/06 7.43

05071 10 diet 05/07 7.88

06071 10 diet 07/07 7.64

07010 10 diet 08/07 7.79

01224 10 diet 09/07 7.38

05083 10 gavage 09/07 7.28

06084 10 gavage 11/07 7.31

06085 10 gavage 11/07 7.46

07091 10 diet 07/08 8.00

07097 15 gavage 09/08 7.94

07098 15 gavage 09/08 7.73

08020 10 diet 10/08 8.11

04114 10 inhalation 12/08 7.99

04117 10 diet 01/09 7.83

99178 10 diet 02/09 8.21

01233 10 diet 02/09 7.84

01236 10 drinking 07/09 8.03

07128 10 diet 09/09 7.87

05118 10 inhalation 11/09 7.54

09030 10 diet 12/09 7.81

07119 10 diet 04/09 8.04
08C004 10 diet 09/10 7.98 08S001 10 gavage 08/10 7.85

02I001 10 inhalation 07/10 7.61 06S003 10 gavage 12/10 8.25
07C018 10 diet 12/10 7.92

N 3 3

Mean 7.75
Minimum 7.28

Maximum 8.25



### Page 502 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### Functional Observational Battery (FOB): Detailed description of examinations, ranking and documentation procedures

The following describes in detail the scope of examinations and the ranking of the findings.

HOME CAGE OBSERVATIONS

1. Posture

The posture of the animals is examined for any abnormal findings.

0 animal is sitting or lying 1 animal is standing and moving 2 squatting posture 3 abdominal position 4 abdominal position with splayed limbs 5 lateral position 6 oblique head posture 7 opisthotonus

2. Tremors

Any tremors are documented.

0 no tremors 1 slight tremors 2 moderate tremors 3 severe tremors

3. Convulsions

If convulsions are seen, the severeness will be assessed. If possible, also the type of convulsions, i.e. clonic (alternate muscular contraction and relaxation in rapid succession) or tonic (characterized by continuous tension), is documented.

0 no convulsions 1 slight convulsions 2 moderate convulsions 3 severe convulsions

Page 503 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 4. Abnormal movements

Any abnormal movement or bizarre behaviour is documented.

0 no abnormalities 1 manege movements 2 head shaking 3 excessive cleaning 4 frequent chewing

5. Gait abnormalities

If any impairment of gait is observed, the type and severeness is documented. Different types of gait impairment are ataxia (irregularity of muscular action), paralysis (loss of motor function) and paresis (slight or incomplete paralysis). If possible, also the affected limbs (forelimbs, hindlimbs) are documented.

0 animal is not walking during observation 1 no impairment of gait 2 stiff gait 3 slight impairment of coordination, unsteady gait 4 moderate impairment of coordination, shuffling gait 5 severe impairment of coordination, dragging of the hindlimbs 6 severe impairment of coordination, with splayed limbs 7 animal is unable to walk (abdominal or lateral position)

6. Other findings

0 no other findings

* If findings appear which are not included in this grading system, they will be described in detai l.

Page 504 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### OPEN FIELD OBSERVATIONS

1. Behavior on removal from the cage

The animal is removal from the home cage, and the reaction is documented.

0 animal is tense, but it shows no resistance against handling 1 animal shows a slight resistance against the handling 2 animal shows no resistance against the handling but appears indifferent 3 animal is difficult to handle, it shows aggressiveness 4 animal is very difficult to handle, it shows severe aggressiveness

2. Fur

The fur of the animals is examined for any abnormal signs.

0 nothing abnormal detected 1 discolored fur 2 urine staining of anogenital region 3 piloerection 4 alopecia 5 reduced care on fur

3. Skin

The visible parts of the skin (e.g. nose) are examined for any abnormal signs.

0 nothing abnormal detected 1 discolored skin 2 reddening 3 paleness 4 dehydration (exsiccosis) 5 hypothermia (skin feels cold during handling) 6 lesion(s) 7 crust(s)

4. Salivation

The area around the mouth is examined for signs of discharge; if possible, also the color of discharge is documented.

0 no salivation 1 slight salivation (area around the mouth is moist) 2 moderate salivation (wet mouth) 3 severe salivation (mouth very wet, wet paws)

Page 505 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 5. Nasal discharge

Any discharge is documented.

0 no discharge, dry nose 1 clear discharge 2 reddish discharge

6. Lacrimation

Any lacrimation or secretion of pigmented tears is documented. If possible, the color of the tears is also assessed.

0 no lacrimation 1 slight lacrimation 2 moderate lacrimation 3 severe lacrimation

7. Eyes/Pupil size

0 nothing abnormal detected, pupils contracted at room light 1 chromodacryorrhea 2 exophthalmus 3 pupils dilated 4 abnormal shape of pupils 5 oblique eye posture 6 opacity 7 cataract

8. Posture

The posture of the animals is examined for any abnormal findings.

0 animal is sitting or lying 1 animal is standing and moving 2 squatting posture 3 abdominal position 4 abdominal position with splayed limbs 5 lateral position 6 oblique head posture 7 opisthotonus

Page 506 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 9. Palpebral closure

The level of eyelid closure is examined. Usually, the eyelids of rats are completely opened (except when blinking).

0 nothing abnormal detected 1 eyelid(s) slight closure 2 eyelid(s) half closure 3 eyelid(s) permanent closure

10. Respiration

The respiration is examined for any abnormalities.

0 nothing abnormal detected 1 respiration labored 2 gasping/respiratory sounds 3 respiration accelerated 4 respiration irregular

11. Tremors

Any tremors are documented.

0 no tremors 1 slight tremors 2 moderate tremors 3 severe tremors

12. Convulsions

If convulsions are seen, the severeness will be assessed. If possible, also the type of convulsions, i.e. clonic (alternate muscular contraction and relaxation in rapid succession) or tonic (characterized by continuous tension), is documented.

0 no convulsions 1 slight convulsions 2 moderate convulsions 3 severe convulsions

Page 507 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 13. Abnormal movements/ stereotypes

Any abnormal movements or bizarre behavior are documented

0 no abnormalities 1 manege movements 2 head shaking 3 excessive cleaning 4 frequent chewing

14. Gait abnormalities

If any impairment of gait is observed, the type and severeness will be documented. Different types of gait impairment are ataxia (irregularity of muscular action), paralysis (loss of motor function) and paresis (slight or incomplete paralysis). If possible, also the affected limbs (forelimbs, hindlimbs) are documented.

0 animal is not walking during observation 1 no impairment of gait 2 stiff gait 3 slight impairment of coordination, unsteady gait 4 moderate impairment of coordination, shuffling gait 5 severe impairment of coordination, dragging of the hindlimbs 6 severe impairment of coordination, with splayed limbs 7 animal is unable to walk (abdominal or lateral position)

15. Activity/ arousal level

The activity of the animals in the open field and the arousal level is examined for any deviation from normal.

0 normal exploration of the area 1 reduced exploration of the area 2 severe reduced exploration of the area, animal apathetic

3 increased exploration of the area

, sudden or jerky movements 4 hyperactivity

Page 508 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 16. Feces excreted within 2 minutes

The appearance and consistency of the feces are described. The number of scybala is documented separately.

0 no defecation during observation period 1 feces without abnormalities 2 discolored feces 3 crumbly feces 4 soft feces 5 muicid feces 6 diarrhea

17. Urine excreted within 2 minutes

The amount and the color of the urine are described.

0 no urination during observation period 1 urine without abnormalities (some wet areas on the filter paper) 2 discoloration of urine 3 polyuria (great wet areas on the filter paper)

18. Rearing within 2 minutes

In the open field, the animals usually rear several times in order to explore the new environment. A rear is counted, if both forelimbs are removed from the floor. The number of rearings is counted within a 2 minute observation period.

Documentation:

- ( number)

Page 509 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### SENSORY

- MOTORIC TEST/REFLEXES

1. Reaction to an object being moved towards the face (Approach response)

A stick is approached slowly to the head of the animal. Normal reaction of the animal is to approach to the object or to ignore the object.

0 no reaction 1 approaching to object 2 escape reaction 3 aggressive reaction and attacking of object

2. Touch sensitivity (Touch Response)

The animal is touched with a stick along the flank. Normal reaction is to orientate to the stimulus or to ignore the stimulus.

0 no reaction 1 orientation to the stimulus 2 escape after touch 3 aggressive reaction and attacking of object 4 reaction to the stimulus but no ability to localize (e.g. turning to wrong side)

3. Vision (Visual placing response)

The animal is held on the tail and moved slowly towards the wire cover of a cage. Normal reaction of the animal is to stretch the forelimbs in order to grasp the object.

0 nothing abnormal detected (grasping with forelimbs) 1 no grasping

Page 510 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 4. Pupillary reflex

The capacity of the pupils to adapt to darkness and to light is examined. The animals are put into a dark box for about 10 seconds and the pupils are examined using an electric torch. Normally, the pupil dilates in the dark and contrac ts immediately in the light.

0 nothing abnormal detected, physiological adaptation of the pupil to light 1 retarded adaptation of the pupil to light 2 no adaptation of the pupil to light, pupils permanently contracted 3 no adaptation of the pupil to light, pupils permanently dilated

5. Pinna reflex

The pinna of the animal is touched with a small bristle. Normally, the animal jerks the pinna or head immediately after the stimulus.

0 immediate response to the stimulus 1 no response to the stimulus

6. Audition (Auditory startle response)

The animal is exposed to a sharp, electrically produced noise and the reaction to the sound is tested. Normally the animal shows a startle response (e.g. moving the ears, jerking, jumping backwards).

0 nothing abnormal detected, immediate normal response to the stimulus 1 no response 2 increased response 3 hyperreaction

7. Coordination of movements (Righting response)

The animal is turned into dorsal position and released. Normal reaction is that the anim al immediately turns to an upright position.

0 nothing abnormal detected, immediate righting response 1 retarded righting response 2 fails to turn into upright position, animal stays in lateral position 3 no righting response, animal stays in dorsal position

Page 511 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 8. Behavior during handling

0 normal behavior, easy to handle, animal is tense, but it shows no resistance against handling 1 very easy to handle, animal hangs limply in the hand 2 slightly difficult to handle, animal shows a slight resista nce against handling 3 difficult to handle, animal shows a severe resistance against handling

9. Vocalization

0 no or only sporadic vocalizations when touched 1 very frequent vocalizations when touched 2 vocalizations always when touched 3 vocalization without touching

10. Pain perception (Tail pinch)

The tip of the tail is squeezed with a forceps. Normally the animal responds to the stimulus, e.g. it moves away.

0 nothing abnormal detected, immediate response to the stimulus 1 weak or retarded reaction to the stimulus 2 no response to the stimulus 3 hyperreaction to the stimulus

11. Other findings

0 no other findings

* If findings appear which are not included in this grading system, they will be described in detail

Page 512 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors

### 12. Grip strength of forelimbs and hindlimbs

Measurement of grip strength is performed according to the method described by Meyer et al. 1979 (Neurobehavioral Toxicology, 1, 233

- 236):

The animal is brought into a position that forelimbs/hindlimbs are able to grip the metal bar of a newtonmeter. Then the animal is pulled gently backwards until it releases the grid. The average of two measurements is taken for each hindlimbs and forelimbs.

Documentation:

- (number)

13. Landing foot

- splay test

The anim al is held about 30 cm above and dropped onto a flat area covered with putty. This results in clearly visible footprints. The distance between the fourth digits of the left and right hindlimb is measured. The average of two measurements is taken for each r at.

Documentation:

- (number)

GENERAL REMARK:

Details of localization or color, or detailed descriptions of findings (e.g. tonic or clonic convulsions) have to be described using abbreviations (letter or a combination of letters), if they are not already given in the SOP.

Page 513 of 513 This document is the property of the sponsors (specified on page 1), use by other parties requires written permission by the sponsors