TITLE PAGE

STUDY TITLE

Report

Cobalt 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 IDENTIFICATION

SPONSOR

PART 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 used 

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 limits of their administrative authority.

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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
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CONTRIBUTORS TO THE STUDY / SUPERVISORY LABORATORY 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:

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GLP CERTIFICATE (FROM THE COMPETENT AUTHORITY)

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CONTENTS

TITLE PAGE

STATEMENT OF NO DATA CONFIDENTIALITY CLAIMS

GLP COMPLIANCE STATEMENT

FLAGGING CRITERIA

SIGNATURE PAGE

CONTRIBUTORS TO THE STUDY / SUPERVISORY LABORATORY PERSONNEL

STATEMENT OF THE QUALITY 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 METHODS

3.1. TEST ITEM

3.2. TEST SYSTEM

3.3. HOUSING AND DIET

3.4. TEST GROUPS AND TARGET CONCENTRATIONS

3.5. GENERATION OF THE INHALATION 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 monitoring 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

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3.7. EXPERIMENTAL PROCEDURE

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 EXAMINATIONS

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 EXAMINATIONS

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

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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 ABBREVIATIONS

8.1. CLINICAL EXAMINATIONS

8.2. ANALYTICAL DATA AND EXPOSURE PARAMETERS

8.3. CLINICAL PATHOLOGY

8.4. PATHOLOGY

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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 observations 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 Weights

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

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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 Parameters ID-1 

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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 observations report

Male animals IIA-58 - IIA-59

Female animals IIA-60 - IIA-61

Individual Body Weights

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 IIB 1 – IIB 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

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MEASUREMENTS OF EXPOSURE PARAMETERS

Exposure parameters (Daily Means) IID-1 - IID-4 

Particle size analysis (Individual measurements) IID-5 - IID-48

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PART III: SUPPLEMENT

Analysis of the test substance 

Historical control data of clinical pathology testing

Functional Observational Battery (FOB)

Detailed description of examinations, ranking and documentation procedures

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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 consecutive 

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/m3. 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, recovery 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 

Mean SD (μm)

1 0.2 0.25 0.17 2.0 to 3.9

2 1 1.42 0.42 2.5 to 5.7

3 5 5.10 1.24 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.

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The following substance-related adverse effects were observed in the lungs: 

Test group 3 (5 mg/m3, main 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 animals graded minimal to slight in both 

sexes

• 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 minimal to slight

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

Test group 3 (5 mg/m3, recovery Group)

• Increased absolute and relative lung weights in males and females

• Cellular debris, alveolar in all male and female animals graded 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 moderate 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 

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• 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 

males 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/m3 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.

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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 

Concentration (NOAEC) after 3 months exposure to dusts. 

2.2. SELECTION OF CONCENTRATIONS

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 epithelium. 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 

significantly 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 some effect

0.2 mg/m3: as the low concentration and the expected no adverse effect concentration

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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 effects: Sub-chronic 

inhalation toxicity 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 initiation 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

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The study was performed according to the following time table: 

Table 2: Study 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).

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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 examination 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 

. 

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3. MATERIALS AND METHODS 

3.1. TEST ITEM

The technical material provided by the sponsor was coarse. No dust aerosol could be 

generated. Therefore, the technical material was 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 substance: 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 facility.

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

data.

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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 

respective 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.

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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 cm2

). 

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 humidity 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 from these ranges did not occur.

The room was completely disinfected using a disinfector ("AUTEX", fully automatic, formalinammonia-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.

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3.4. TEST GROUPS AND TARGET CONCENTRATIONS

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/m3) 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/m3) 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 animals were observed for 4 weeks after the 

exposure period.

Table 5: Recovery groups (males)

Test group Concentration

(mg/m3) 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/m3) 1 No. of animals Animal No.

0 0 5 91-95

3 5 5 96-100

 

1

 test substance concentration

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3.5. GENERATION OF THE INHALATION ATMOSPHERES

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 

compressed 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. Compressed 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 

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Figure 1: Generator system

Test group 1:

Test Group 2 – 3:

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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 reflect 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. Determination 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 concentrations and 

standard deviations for the entire study were derived.

In these groups, the constancy of concentrations in the inhalation systems were 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 (Sartorius AG, Göttingen, Germany) 

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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 filter was placed into the filter holder. By means of a vacuum compressed air 

pump a defined volume 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, with reference to the sample 

volume of the inhalation atmosphere.

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.

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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) 

• Sampling probe internal diameter 7 mm 

Balance Sartorius M3P-000V001 and LC 1201S-00MS (Sartorius AG, Göttingen, 

Germany)

Sampling for particle size analyses: 

Preweighed metal collecting discs and a backup particle filter were placed into the cascade 

impactor: One 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:

Gravimetrical 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 66161: 

Partikelgrößenanalyse, Beuth-Vertrieb GmbH, Berlin und Köln, Germany).

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

Particle size 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. Drinking 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 contract 

laboratory.

3.6.6. Bedding and enrichment analyses

The bedding and enrichment are regularly assayed for contaminants (chlorinated

hydrocarbons and heavy metals).

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3.7. EXPERIMENTAL PROCEDURE

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 substance 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: t99 (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.

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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 period 

suitable to reach 65 exposures.

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

Figure 2: Exposure system

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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.

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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 protocols 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 records 

are considered as raw data. Relevant disturbances are reported under “Results”.

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3.8. CLINICAL EXAMINATIONS 

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 times 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. activity/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

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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 consumption 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 media with an 

ophthalmoscope (HEINE Optotechnik, Herrsching, Germany) after administration of a 

mydriatic (Mydrum, Chauvin ankerpharm GmbH, Rudolstadt, Germany).

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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 cm2). 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 (touching 

the cage or rack, noise) were avoided during these examinations in order not to influence the 

behavior 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 minutes. 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

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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 measurement was performed in the dark using the TSE Labmaster System

(TSE Systems GmbH, Bad Homburg, Germany) with 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 cm2

) 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.

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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 

of 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-K3 as anticoagulant using a 

particle counter (Advia 120 model; Bayer, Fernwald, Germany):

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Table 10: Hematology parameters 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, 6th 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)

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3.9.2. Clinical chemistry

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

clinicochemical parameters 

Table 12: Clinical chemistry parameters and methods

Enzyme (systematic name and 

system number)

Unit Method, wavelength 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-γglutamyl-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

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Blood 

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 dehydrogenase method

Neumann, U. and Ziegenhorn, J.: XVI, 

Nordiska kongressen for klinisk kemi och 

klinisk fysiologi 1977, Oulu, Finland; Roche 

working instructions

Creatinine

(CREA)

μmol/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/ glycerol3-phosphate oxidase/4-aminophenazone

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

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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 pathology.

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

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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

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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).

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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.

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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 pathologist.

 

* One level does include the base of the epiglottis.

† One level includes nasopharyngeal duct; the 4 levels allow adequate examination of the squamous, 

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.

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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 comparison 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, footsplay test, motor 

activity

Blood parameters 

(with bidirectional 

changes)

Non-parametric one-way 

analysis using KRUSKALWALLIS 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 WILCOXONtest (one-sided) with 

Bonferroni-Holm adjustment 

for the hypothesis of equal 

medians

* for p < 0.05

** for p < 0.01

Holm (1971): 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 KRUSKALWALLIS 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

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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 

Mean SD (mg/m3)

0 -

1 0.2 0.25 0.17 -

2 1 1.42 0.42 12.4

3 5 5.10 1.24 14.7

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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 are 

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 66

Measured concentrations [mg/m3]

Exposure numbers

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

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Figure 4: Examples of concentration real time records

Test group 1

Test group 2 

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Test group 3 

Figure 5: Examples of concentration real time records showing variations

Test group 2 

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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).

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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 about

67 times per hour can be calculated by dividing the supply air flow through the volume of 

each inhalation system. 

Daily means of relative humidities in the inhalation systems ranged between 34.0 and 

63.7 %. Daily means 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 

aerodynamic 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 the 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/m3) 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

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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 chemical 

contaminants. The number of microorganisms did not exceed 1*105/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 tolerable contaminants. Individual results are to be found in 

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4.2. CLINICAL EXAMINATIONS 

Summary Tables of the results can be found in Part I (Tables IA-1 - IA-49); individual values 

are to be found in Part II (Tables IIA-1 - IIA-125).

4.2.1. Mortality

No deaths were recorded throughout the study.

4.2.2. Clinical observations

(Summary tables 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 tables 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. 

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

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

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

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

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Body weight change 

The body weight changes of all exposed female 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 substancerelated, 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 significant 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 (maximum -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 - IIA83 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 - IIA89 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 

concentration-response relationship. 

The individual ophthalmologic findings are archived with the raw data.

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4.2.7. Functional observational battery

(Summary tables IA-30 - IA-45 in Part I and individual value tables IIA-90 - IIA-117 

in Part II)

On the day of the performance of the Functional Observation Battery, the animals were not 

exposed to the test substances. 

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.

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Figure 10: Motor activity of male animals

Figure 11: Motor activity of female animals

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4.3. CLINICAL PATHOLOGY

Summary tables of the results are given in the Appendix of PART I; individual values 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/m3), 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/m3

), 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 parameters were observed.

After the recovery period in males of test group 3 (5 mg/m3

), 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 liver 

enzymes was altered. Therefore, these higher liver enzyme activities after the recovery 

period were regarded as treatment-related, but not adverse.

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After the recovery period in males of test group 3 (5 mg/m3

), 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.

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4.4. PATHOLOGY 

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 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 147%** 186%** 205%** 148%** 160%** 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.

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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 slight 

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

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Lung 

There were numerous treatment – related findings in alveoli and bronchi, diagnostic terms 

are explained below.

Alveoli

Cellular debris: thin (2 μm) strands of eosinophilic tissue interpreted as necrotic alveolar 

septae, sometimes coiled, admixed with polygonal eosinophilic 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 pneumocyte activation characterized by cuboidal 

to flattened cells with granular to foamy basophilic cytoplasm

Emphysema: Tearing of alveolar septae 

Bronchi

Reduced number of clara cells: reduction of number of dome shaped Clara cells 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 material, 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

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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

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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.

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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.

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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

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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 aerosols 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 

inflammation/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 animals 

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 animals were 

regarded as adverse. All other findings recorded were considered to be incidental in nature 

and not related to treatment. 

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6. CONCLUSION

Inhalation exposure of 0.2, 1 and 5 mg/m3 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.

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. 1st 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.

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8. LIST OF ABBREVIATIONS 

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 EXAMINATIONS 

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.

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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 = Head-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/m3 = 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

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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

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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 = α2-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

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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 = 1012/liter

giga/L = giga/liter = 109 /liter

μkat/L = microkatal/liter

nkat/L = nanokatal/liter

PPM = parts per million

mg/kg = mg/kilogram

μL = microliter

ML = mL(milliliter)

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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).

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IA- 1

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary - Clinical Observation 

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

day -2 [06:00 - 18:00] -> day 121 [06:00 - 18:00]

Animals examined N 15 10 10 15dead sacrificed scheduled

N 15 10 10 15

% 100.0 100.0 100.0 100.0

normal NAD

N 15 10 10 15

% 100.0 100.0 100.0 100.0

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IA- 2

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary - Clinical Observation 

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

day -2 [06:00 - 18:00] -> day 120 [06:00 - 18:00]

Animals examined N 15 10 10 15Animals with signs N0 0 2 3 % 0.0 0.0 20.0 20.0dead sacrificed scheduled

N 15 10 10 15% 100.0 100.0 100.0 100.0

fur reduced fur care

N0 0 2 3% 0.0 0.0 20.0 20.0

normal NAD

N 15 10 10 15% 100.0 100.0 100.0 100.0

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IA- 3

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary - Clinical Observation 

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

day 0 [DCO] -> [DCO]

Animals examined N 15 10 10 15

normal NAD

N 15 10 10 15

% 100.0 100.0 100.0 100.0

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IA- 4

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary - Clinical Observation 

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

day 43 [DCO] -> [DCO]

Animals examined N 15 10 10 15

normal NAD

N 15 10 10 15

% 100.0 100.0 100.0 100.0

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IA- 5

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary - Clinical Observation 

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

day 85 [DCO] -> [DCO]

Animals examined N 15 10 10 15

normal NAD

N 15 10 10 15

% 100.0 100.0 100.0 100.0

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IA- 6

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary - Clinical Observation 

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

day 0 [DCO] -> [DCO]

Animals examined N 15 10 10 15

normal NAD

N 15 10 10 15

% 100.0 100.0 100.0 100.0

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IA- 7

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary - Clinical Observation 

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

day 43 [DCO] -> [DCO]

Animals examined N 15 10 10 15

normal NAD

N 15 10 10 15

% 100.0 100.0 100.0 100.0

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IA- 8

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary - Clinical Observation 

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

day 85 [DCO] -> [DCO]

Animals examined N 15 10 10 15

normal NAD

N 15 10 10 15

% 100.0 100.0 100.0 100.0

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Statistic Profile = Dunnett test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics 

n=DUNNETT 

IA- 9

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary Body Weights - BW / Body Weights [g] 

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

day -2 Mean 

S.d. N 

266.0

10.5

15

n 269.1 

12.2 

10 

267.1

8.9

10

266.0

9.7

15

day 0 Mean 

S.d. N 

258.9

10.4

15

n 265.2 

11.5 

10 

264.8

12.8

10

261.7

9.2

15

day 2 Mean 

S.d. N 

259.8

12.1

15

n 261.0 

12.6 

10 

260.4

13.9

10

256.7

12.6

15

day 5 Mean 

S.d. N 

272.4

13.1

15

n 274.0 

14.2 

10 

271.4

15.4

10

261.9

14.0

15

day 9 Mean 

S.d. N 

271.0

13.3

15

n 273.2 

14.6 

10 

270.6

18.5

10

261.6

16.1

15

day 12 Mean 

S.d. N 

277.9

14.1

15

n 283.7 

17.2 

10 

281.9

20.8

10

270.5

16.5

15

day 16 Mean 

S.d. N 

280.7

15.9

15

n 285.2 

20.0 

10 

281.5

24.3

10

267.7

17.2

15

day 19 Mean 

S.d. N 

290.8

16.1

15

n 297.4 

21.1 

10 

292.1

23.7

10

280.1

18.7

15

day 23 Mean 

S.d. N 

292.3

18.2

15

n 300.5 

22.0 

10 

291.7

27.8

10

279.1

19.3

15

day 26 Mean 

S.d. N 

303.1

17.3

15

n 310.3 

23.0 

10 

302.9

27.3

10

290.3

19.9

15

day 30 Mean 

S.d. N 

303.2

17.9

15

n 308.9 

24.4 

10 

301.6

31.1

10

287.9

21.9

15

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Statistic Profile = Dunnett test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics 

n=DUNNETT 

IA- 10

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary Body Weights - BW / Body Weights [g] 

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

day 33 Mean 

S.d. N 

310.0

16.9

15

n 317.2 

25.2 

10 

310.9

29.4

10

298.7

21.2

15

day 37 Mean 

S.d. N 

311.0

17.3

15

n 317.3 

25.8 

10 

311.7

32.0

10

297.3

22.5

15

day 40 Mean 

S.d. N 

320.8

16.9

15

n 327.6 

25.4 

10 

321.9

31.8

10

307.8

22.6

15

day 44 Mean 

S.d. N 

321.5

16.9

15

n 326.9 

25.2 

10 

322.0

34.7

10

308.1

23.1

15

day 47 Mean 

S.d. N 

328.2

17.9

15

n 334.5 

26.5 

10 

329.5

34.1

10

317.0

23.1

15

day 51 Mean 

S.d. N 

327.8

22.0

15

n 334.0 

25.4 

10 

327.3

35.9

10

316.1

24.7

15

day 54 Mean 

S.d. N 

336.9

21.5

15

n 343.6 

25.7 

10 

337.5

36.2

10

326.3

25.4

15

day 58 Mean 

S.d. N 

336.9

21.8

15

n 343.5 

26.7 

10 

333.8

38.0

10

324.0

26.9

15

day 61 Mean 

S.d. N 

344.5

22.3

15

n 352.5 

28.0 

10 

342.7

38.4

10

333.7

26.4

15

day 65 Mean 

S.d. N 

342.0

23.4

15

n 351.2 

27.7 

10 

334.9

37.3

10

328.6

27.9

15

day 68 Mean 

S.d. N 

348.2

22.8

15

n 358.8 

30.0 

10 

346.5

39.1

10

338.2

27.5

15

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Statistic Profile = Dunnett test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics 

n=DUNNETT

IA- 11

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary Body Weights - BW / Body Weights [g] 

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

day 72 Mean 

S.d. N 

347.7

23.2

15

n 359.1 

30.9 

10 

346.3

41.4

10

336.1

28.6

15

day 75 Mean 

S.d. N 

354.0

24.3

15

n 366.9 

31.5 

10 

353.6

41.0

10

344.1

28.2

15

day 79 Mean 

S.d. N 

350.1

21.4

15

n 361.7 

34.8 

10 

350.8

45.6

10

339.1

29.4

15

day 82 Mean 

S.d. N 

356.8

24.5

15

n 370.1 

32.7 

10 

359.1

43.6

10

347.3

29.3

15

day 86 Mean 

S.d. N 

356.4

25.0

15

n 367.6 

31.7 

10 

353.9

45.1

10

342.3

30.0

15

day 89 Mean 

S.d. N 

362.1

25.7

15

n 373.2 

31.9 

10 

362.1

45.5

10

350.4

29.8

15

day 92 Mean 

S.d. N 

345.3

31.7

15

n 347.8 

30.3 

10 

337.1

44.5

10

334.1

33.3

15

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Statistic Profile = Dunnett test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics 

n=DUNNETT 

IA- 12

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary Body Weights - BW / Body Weights [g] 

Sex: Male - Phase: In-life 

G 0 / M

Test group 0

G 3 / M

Test group 3

day 93 Mean 

S.d. N 

372.9

33.9

5

n 360.9

21.1

5

day 96 Mean 

S.d. N 

376.8

34.0

5

n 362.1

20.1

5

day 100 Mean 

S.d. N 

389.1

36.2

5

n 376.2

21.4

5

day 103 Mean 

S.d. N 

394.8

37.4

5

n 385.4

20.5

5

day 107 Mean 

S.d. N 

399.5

39.6

5

n 390.1

19.0

5

day 110 Mean 

S.d. N 

404.8

40.7

5

n 395.1

20.8

5

day 114 Mean 

S.d. N 

412.0

44.1

5

n 402.3

22.2

5

day 117 Mean 

S.d. N 

414.9

44.4

5

n 407.8

21.9

5

day 121 Mean 

S.d. N 

401.5

42.0

5

n 391.3

22.0

5

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Statistic Profile = Dunnett test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics 

n=DUNNETT 

IA- 13

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary Body Weights - BW / Body Weights [g] 

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

day -2 Mean 

S.d. N 

179.3

5.8

15

n 181.0 

5.5 

10 

179.7

8.0

10

180.3

8.3

15

day 0 Mean 

S.d. N 

177.2

6.9

15

n 180.1 

7.8 

10 

177.6

6.2

10

178.7

7.2

15

day 1 Mean 

S.d. N 

174.2

7.4

15

n 175.6 

10.8 

10 

171.6

8.0

10

177.6

8.4

15

day 4 Mean 

S.d. N 

181.5

8.6

15

n 182.9 

8.0 

10 

181.0

5.6

10

181.0

7.6

15

day 8 Mean 

S.d. N 

180.5

7.9

15

n 183.6 

8.0 

10 

180.7

6.6

10

180.3

8.3

15

day 11 Mean 

S.d. N 

184.4

6.5

15

n 189.1 

7.0 

10 

184.1

9.9

10

186.1

9.8

15

day 15 Mean 

S.d. N 

185.6

7.0

15

n 190.2 

7.9 

10 

183.4

10.1

10

184.9

11.0

15

day 18 Mean 

S.d. N 

190.4

6.4

15

n 194.0 

7.5 

10 

190.4

8.7

10

191.5

10.9

15

day 22 Mean 

S.d. N 

189.9

6.5

15

n 194.4 

8.7 

10 

190.1

8.2

10

192.3

11.3

15

day 25 Mean 

S.d. N 

195.4

8.4

15

n 199.9 

10.1 

10 

195.3

8.0

10

198.2

9.8

15

day 29 Mean 

S.d. N 

194.4

8.5

15

n 199.1 

11.0 

10 

194.2

7.2

10

197.1

10.7

15

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n=DUNNETT 

IA- 14

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary Body Weights - BW / Body Weights [g] 

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

day 32 Mean 

S.d. N 

197.6

9.0

15

n 202.5 

8.6 

10 

199.4

7.9

10

201.8

9.7

15

day 36 Mean 

S.d. N 

198.4

9.8

15

n 202.9 

9.6 

10 

200.0

7.9

10

201.6

9.8

15

day 39 Mean 

S.d. N 

205.0

10.1

15

n 208.1 

8.4 

10 

202.4

10.5

10

206.8

10.9

15

day 43 Mean 

S.d. N 

204.3

10.5

15

n 207.2 

9.2 

10 

201.8

11.3

10

204.8

11.1

15

day 46 Mean 

S.d. N 

207.8

8.7

15

n 211.0 

8.2 

10 

208.6

10.4

10

209.3

10.2

15

day 50 Mean 

S.d. N 

205.9

9.5

15

n 209.3 

8.4 

10 

205.8

10.8

10

205.5

10.4

14

day 53 Mean 

S.d. N 

209.1

11.7

15

n 214.1 

10.3 

10 

211.4

9.5

10

212.3

10.2

15

day 57 Mean 

S.d. N 

208.2

11.2

15

n 212.1 

11.6 

10 

208.7

8.5

10

210.4

10.5

15

day 60 Mean 

S.d. N 

210.6

11.4

15

n 214.1 

10.3 

10 

212.5

9.2

10

214.2

9.8

15

day 64 Mean 

S.d. N 

208.3

11.8

15

n 213.9 

10.0 

10 

209.6

9.4

10

211.1

10.0

15

day 67 Mean 

S.d. N 

213.4

11.9

15

n 219.0 

8.9 

10 

211.6

12.2

10

216.1

11.3

15

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n=DUNNETT

IA- 15

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary Body Weights - BW / Body Weights [g] 

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

day 71 Mean 

S.d. N 

212.7

11.6

15

n 217.1 

10.4 

10 

210.2

11.1

10

214.2

12.2

15

day 74 Mean 

S.d. N 

216.6

10.0

15

n 220.7 

10.4 

10 

215.9

10.0

10

218.0

12.5

15

day 78 Mean 

S.d. N 

215.3

10.7

15

n 220.7 

10.2 

10 

213.4

9.3

10

216.0

13.4

15

day 81 Mean 

S.d. N 

217.5

12.1

15

n 224.1 

11.7 

10 

218.2

9.3

10

220.2

10.1

15

day 85 Mean 

S.d. N 

213.9

10.6

15

n 217.5 

14.3 

10 

211.5

9.8

10

213.5

12.6

15

day 88 Mean 

S.d. N 

216.8

11.7

15

n 224.2 

10.7 

10 

217.5

8.6

10

219.6

11.9

15

day 92 Mean 

S.d. N 

204.5

12.2

15

n 204.6 

10.2 

10 

196.8

8.7

10

206.7

15.8

15

Page 96 of 513

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n=DUNNETT 

IA- 16

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary Body Weights - BW / Body Weights [g] 

Sex: Female - Phase: In-life 

G 0 / F

Test group 0

G 3 / F

Test group 3

day 95 Mean 

S.d. N 

216.2

11.3

5

n 224.0

10.4

5

day 99 Mean 

S.d. N 

225.9

11.3

5

n 233.1

11.8

5

day 102 Mean 

S.d. N 

228.7

11.9

5

n 236.1

10.1

5

day 106 Mean 

S.d. N 

231.8

11.3

5

n 237.3

10.2

5

day 109 Mean 

S.d. N 

233.5

14.8

5

n 239.9

12.4

5

day 113 Mean 

S.d. N 

233.4

15.2

5

n 239.1

13.4

5

day 116 Mean 

S.d. N 

235.3

13.5

5

n 242.0

13.7

5

day 120 Mean 

S.d. N 

222.3

10.8

5

n 227.7

10.6

5

Page 97 of 513

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d = day; n=DUNNETT 

IA- 17

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary Changes Body Weights - BW / Body Weights [g] 

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

d -2 -> 0 Mean 

S.d. N 

-7.1

3.4

15

n -3.9 

5.2 

10 

-2.3

5.8

10

* -4.3

3.6

15

d 0 -> 2 Mean 

S.d. N 

1.05.3

15

n -4.2 

4.6 

10 

* -4.4

1.9

10

* -5.0

5.2

15

** 

d 5 -> 9 Mean 

S.d. N 

-1.4

4.4

15

n -0.7 

2.2 

10 

-0.8

4.0

10

-0.4

5.7

15

d 12 -> 16 Mean 

S.d. N 

2.84.9

15

n 1.5 

4.1 

10 

-0.5

5.6

10

-2.7

3.8

15

** 

d 19 -> 23 Mean 

S.d. N 

1.53.8

15

n 3.1 

3.1 

10 

-0.4

6.2

10

-1.1

4.2

15

d 26 -> 30 Mean 

S.d. N 

0.03.7

15

n -1.4 

3.0 

10 

-1.4

5.7

10

-2.4

3.7

15

d 33 -> 37 Mean 

S.d. N 

1.03.5

15

n 0.1 

3.3 

10 

0.83.3

10

-1.4

3.6

15

d 40 -> 44 Mean 

S.d. N 

0.75.7

15

n -0.7 

2.3 

10 

0.13.9

10

0.21.9

15

d 47 -> 51 Mean 

S.d. N 

-0.4

6.1

15

n -0.5 

2.4 

10 

-2.2

3.8

10

-0.9

3.0

15

d 54 -> 58 Mean 

S.d. N 

0.04.0

15

n 0.0 

4.2 

10 

-3.7

3.4

10

* -2.3

3.0

15

d 61 -> 65 Mean 

S.d. N 

-2.5

2.4

15

n -1.3 

2.9 

10 

-7.9

7.3

10

** -5.1

3.0

15

Page 98 of 513

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n=DUNNETT; d = day 

IA- 18

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary Changes Body Weights - BW / Body Weights [g] 

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

d 68 -> 72 Mean 

S.d. N 

-0.5

2.5

15

n 0.3 

2.0 

10 

-0.2

3.6

10

-2.1

3.2

15

d 75 -> 79 Mean 

S.d. N 

-3.9

6.0

15

n -5.2 

6.3 

10 

-2.8

6.2

10

-4.9

4.3

15

d 82 -> 86 Mean 

S.d. N 

-0.4

4.2

15

n -2.5 

3.2 

10 

-5.3

3.9

10

** -5.0

2.5

15

** 

Page 99 of 513

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d = day; n=DUNNETT 

IA- 19

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary Changes Body Weights - BW / Body Weights [g] 

Sex: Male - Phase: In-life 

G 0 / M

Test group 0

G 3 / M

Test group 3

d 89 -> 93 Mean 

S.d. N 

2.22.6

5

n 2.6

3.8

5

d 96 -> 100 Mean 

S.d. N 

12.3

3.4

5

n 14.1

3.5

5

d 103 -> 107 Mean 

S.d. N 

4.72.9

5

n 4.7

3.5

5

d 110 -> 114 Mean 

S.d. N 

7.23.4

5

n 7.2

2.9

5

Page 100 of 513

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Statistic Profile = Dunnett test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics 

d = day; n=DUNNETT 

IA- 20

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary Changes Body Weights - BW / Body Weights [g] 

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

d -2 -> 0 Mean 

S.d. N 

-2.1

3.4

15

n -0.9 

5.0 

10 

-2.2

3.1

10

-1.6

5.0

15

d 0 -> 1 Mean 

S.d. N 

-3.0

4.8

15

n -4.5 

5.9 

10 

-5.9

5.6

10

-1.1

5.3

15

d 4 -> 8 Mean 

S.d. N 

-1.0

2.3

15

n 0.7 

2.1 

10 

-0.3

1.8

10

-0.7

2.9

15

d 11 -> 15 Mean 

S.d. N 

1.23.5

15

n 1.1 

3.0 

10 

-0.7

1.7

10

-1.1

2.3

15

d 18 -> 22 Mean 

S.d. N 

-0.5

1.8

15

n 0.4 

2.0 

10 

-0.2

1.0

10

0.82.1

15

d 25 -> 29 Mean 

S.d. N 

-1.1

1.7

15

n -0.8 

1.5 

10 

-1.1

2.4

10

-1.1

2.2

15

d 32 -> 36 Mean 

S.d. N 

0.82.0

15

n 0.4 

2.4 

10 

0.57.0

10

-0.3

1.8

15

d 39 -> 43 Mean 

S.d. N 

-0.7

3.0

15

n -0.9 

2.7 

10 

-0.6

2.3

10

-2.0

4.0

15

d 46 -> 50 Mean 

S.d. N 

-1.9

2.1

15

n -1.7 

2.1 

10 

-2.7

2.0

10

-2.8

2.9

14

d 53 -> 57 Mean 

S.d. N 

-1.0

2.9

15

n -2.0 

3.1 

10 

-2.7

2.0

10

-1.9

2.4

15

d 60 -> 64 Mean 

S.d. N 

-2.3

1.8

15

n -0.2 

3.1 

10 

-2.9

2.0

10

-3.2

2.6

15

Page 101 of 513

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Statistic Profile = Dunnett test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics 

n=DUNNETT; d = day 

IA- 21

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary Changes Body Weights - BW / Body Weights [g] 

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

d 67 -> 71 Mean 

S.d. N 

-0.7

2.2

15

n -1.9 

2.6 

10 

-1.4

2.7

10

-1.9

2.2

15

d 74 -> 78 Mean 

S.d. N 

-1.3

1.9

15

n 0.0 

2.2 

10 

-2.5

2.2

10

-2.0

2.7

15

d 81 -> 85 Mean 

S.d. N 

-3.6

3.4

15

n -6.7 

6.5 

10 

-6.7

7.2

10

-6.7

6.2

15

Page 102 of 513

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Statistic Profile = Dunnett test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics 

d = day; n=DUNNETT 

IA- 22

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary Changes Body Weights - BW / Body Weights [g] 

Sex: Female - Phase: In-life 

G 0 / F

Test group 0

G 3 / F

Test group 3

d 88 -> 92 Mean 

S.d. N 

-1.4

0.8

5

n 1.0

2.7

5

d 95 -> 99 Mean 

S.d. N 

9.77.4

5

n 9.0

3.2

5

d 102 -> 106 Mean 

S.d. N 

3.11.5

5

n 1.2

1.6

5

d 109 -> 113 Mean 

S.d. N 

-0.1

1.9

5

n -0.8

4.0

5

Page 103 of 513

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Statistic Profile = Dunnett test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics 

d = day; n=DUNNETT 

IA- 23

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary Food Consumption Per Animal Per Day [g/d] 

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 

d 5 -> 9 Mean [g] 

S.d. N 

23.0

1.1

3

n 22.1 

0.6 

2 

X 24.0

1.1

2

X 22.6

2.6

3

d 12 -> 16 Mean [g] 

S.d. N 

23.2

0.7

3

n 22.4 

0.0 

2 

X 23.5

0.7

2

X 21.8

1.4

3

d 19 -> 23 Mean [g] 

S.d. N 

23.2

0.6

3

n 22.8 

1.2 

2 

X 22.6

0.6

2

X 22.3

2.0

3

d 26 -> 30 Mean [g] 

S.d. N 

24.2

0.2

3

n 23.0 

0.3 

2 

X 23.6

1.1

2

X 22.9

2.4

3

d 33 -> 37 Mean [g] 

S.d. N 

23.1

0.3

3

n 22.4 

0.4 

2 

X 23.1

0.0

2

X 21.6

2.8

3

d 40 -> 44 Mean [g] 

S.d. N 

22.0

0.9

3

n 21.4 

0.4 

2 

X 21.6

0.6

2

X 21.2

2.3

3

d 47 -> 51 Mean [g] 

S.d. N 

20.7

2.2

3

n 20.1 

2.9 

2 

X 20.2

3.0

2

X 20.4

4.9

3

d 54 -> 58 Mean [g] 

S.d. N 

22.4

1.1

3

n 22.7 

1.0 

2 

X 22.3

0.4

2

X 21.6

2.3

3

d 61 -> 65 Mean [g] 

S.d. N 

22.3

0.9

3

n 23.2 

0.3 

2 

X 21.8

0.3

2

X 21.3

1.9

3

d 68 -> 72 Mean [g] 

S.d. N 

21.4

1.3

3

n 23.1 

0.6 

2 

X 22.4

0.3

2

X 22.0

1.6

3

Page 104 of 513

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Statistic Profile = Dunnett test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics 

n=DUNNETT; d = day 

IA- 24

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary Food Consumption Per Animal Per Day [g/d] 

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

d 75 -> 79 Mean [g] 

S.d. N 

21.3

1.2

3

n 22.1 

0.4 

2 

X 21.8

0.3

2

X 20.7

1.8

3

d 82 -> 86 Mean [g] 

S.d. N 

19.4

1.7

3

n 19.1 

2.5 

2 

X 17.6

2.5

2

X 18.4

3.1

3

d 89 -> 91 Mean [g] 

S.d. N 

21.2

0.8

2

X 21.2 

0.4 

2 

X 20.9

0.2

2

X 20.4

0.6

2

X 

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d = day

IA- 25

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary Food Consumption Per Animal Per Day [g/d] 

Sex: Male - Phase: In-life 

G 0 / M

Test group 0

G 3 / M

Test group 3

d 89 -> 93 Mean [g] 

N 

22.3

1

21.7

1

d 96 -> 100 Mean [g] 

N 

22.4

1

22.3

1

d 103 -> 107 Mean [g] 

N 

22.1

1

22.0

1

d 110 -> 114 Mean [g] 

N 

23.3

1

23.2

1

d 117 -> 120 Mean [g] 

N 

23.6

1

23.1

1

Page 106 of 513

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d = day; n=DUNNETT 

IA- 26

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study n Wistar rats i

dust exposure Summary Food Consumption Per Animal Per Day [g/d] 

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

d 4 -> 8 Mean [g] 

S.d. N 

15.4

1.5

3

n 16.2 

0.3 

2 

X 15.7

0.5

2

X 14.6

1.1

3

d 11 -> 15 Mean [g] 

S.d. N 

15.5

0.3

3

n 15.9 

0.1 

2 

X 15.4

0.8

2

X 15.2

1.5

3

d 18 -> 22 Mean [g] 

S.d. N 

16.1

1.0

3

n 16.4 

0.3 

2 

X 15.8

0.6

2

X 16.3

1.5

3

d 25 -> 29 Mean [g] 

S.d. N 

16.1

0.8

3

n 16.4 

0.1 

2 

X 16.4

1.1

2

X 16.3

1.6

3

d 32 -> 36 Mean [g] 

S.d. N 

16.1

1.1

3

n 16.1 

0.1 

2 

X 16.0

1.2

2

X 16.0

1.2

3

d 39 -> 43 Mean [g] 

S.d. N 

15.7

0.9

3

n 15.8 

0.1 

2 

X 16.2

1.8

2

X 15.5

1.3

3

d 46 -> 50 Mean [g] 

S.d. N 

13.6

2.4

3

n 13.8 

2.8 

2 

X 14.2

3.5

2

X 14.2

2.8

3

d 53 -> 57 Mean [g] 

S.d. N 

15.2

0.7

3

n 15.8 

0.4 

2 

X 17.0

0.1

2

X 15.8

1.6

3

d 60 -> 64 Mean [g] 

S.d. N 

15.4

0.7

3

n 16.1 

0.2 

2 

X 16.2

0.6

2

X 15.6

1.3

3

d 67 -> 71 Mean [g] 

S.d. N 

15.2

0.7

3

n 15.6 

0.7 

2 

X 15.9

0.6

2

X 15.4

1.3

3

d 74 -> 78 Mean [g] 

S.d. N 

14.8

1.2

3

n 15.6 

0.4 

2 

X 15.3

1.3

2

X 15.4

1.3

3

d 81 -> 85 Mean [g] 

S.d. N 

11.3

3.3

3

n 13.0 

3.4 

2 

X 13.1

4.2

2

X 11.3

4.1

3

d 88 -> 91 Mean [g] 

S.d. N 

14.9

1.3

2

X 15.1 

1.1 

2 

X 14.7

0.8

2

X 15.1

0.9

2

X 

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d = day

IA- 27

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary Food Consumption Per Animal Per Day [g/d] 

Sex: Female - Phase: In-life 

G 0 / F

Test group 0

G 3 / F

Test group 3

d 88 -> 92 Mean [g] 

N 

14.8

1

17.3

1

d 95 -> 99 Mean [g] 

N 

15.6

1

17.2

1

d 102 -> 106 Mean [g] 

N 

15.2

1

16.4

1

d 109 -> 113 Mean [g] 

N 

14.8

1

16.3

1

d 116 -> 119 Mean [g] 

N 

15.0

1

16.5

1

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Table IA - 28

INCIDENCE OF OPHTHALMOLOGICAL FINDINGSmale animals day -2 day 83

group 0 group 1 group 2 group 3 group 0 group 3

0 mg/m3 0.2 mg/m3 1 mg/m3 5 mg/m3 0 mg/m3 5 mg/m3

Number of animals examined 10 10 10 10 10 10Without ophthalmological findings 0100 00remainder of the pupillary membrane 2230 00corneal stippling 10 9 10 10 10 10

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Table IA - 29

INCIDENCE OF OPHTHALMOLOGICAL FINDINGSfemale animals day -2 day 83

group 0 group 1 group 2 group 3 group 0 group 3

0 mg/m3 0.2 mg/m3 1 mg/m3 5 mg/m3 0 mg/m3 5 mg/m3

Number of animals examined 10 10 10 10 10 10Without ophthalmological findings 1021 01remainder of the pupillary membrane 2423 22corneal stippling 9 8 7 8 10 9

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Project No.: Table IA - 30

Mean values day 90

male animals

test group 0 test group 1 test group 2 test group 3

HOME CAGE OBSERVATION Rank N=10 N=10 N=10 N=10

posture- animal is sitting or laying 05578- animal is standing or moving 15532- squatting posture 20000- abdominal position 30000- abdominal position with splayed limbs 40000- lateral position 50000- oblique head posture 60000- opisthotonus 70000tremors- no tremors 0 10 10 10 10

- slight tremors 10000- moderate tremors 20000- severe tremors 30000convulsions- no convulsions 0 10 10 10 10

- slight convulsions 10000- moderate convulsions 20000- severe convulsions 30000abnormal movements- no abnormalities 0 10 10 10 10

- manege movements 10000- head shaking 20000- excessive cleaning 30000- frequent chewing 40000impairment of gait- animal is not walking during observation 05578- no impairment of gait 15532- stiff gait 20000- slight impairment of coordination, unsteady gait 30000- moderate impairment of coordination, shuffling gait 40000- severe impairment of coordination, dragging of the hindlimbs 50000- severe impairment of coordination, with splayed limbs 60000- animal is unable to walk (abdominal or lateral position) 70000other findings 0 10 10 10 10

FUNCTIONAL OBSERVATIONAL BATTERY

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Project No.: Table IA - 31

Mean values day 90

male animals

test group 0 test group 1 test group 2 test group 3

OPEN FIELD OBSERVATIONS Rank N=10 N=10 N=10 N=10

behavior 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 handling 10000- animal shows no resistance against the handling but appears indifferent 20000- animal is difficult to handle, it shows aggressiveness 30000- animal is very difficult to handle, it shows severe aggressiveness 40000fur- nothing abnormal detected 0 10 10 10 10

- discolored fur 10000- urine staining of anogenital region 20000- piloerection 30000- alopecia 40000- reduced care on fur 50000skin- nothing abnormal detected 0 10 10 10 10

- discolored skin 10000- reddening 20000- paleness 30000- 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 discharge 10000- reddish discharge 20000

FUNCTIONAL OBSERVATIONAL BATTERY

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Project No.: Table IA - 32

Mean values day 90

male animals

test group 0 test group 1 test group 2 test group 3

OPEN FIELD OBSERVATIONS Rank N=10 N=10 N=10 N=10

lacrimation- no lacrimation 0 10 10 10 10

- slight lacrimation 10000- moderate lacrimation 20000- severe lacrimation 30000eyes/pupil size- nothing abnormal detected, pupils contracted at room light 0 10 10 10 10

- chromodacryorrhea 10000- exophthalmos 20000- pupils dilated 30000- abnormal shape of pupils 40000- oblique eye posture 50000- opacity 60000- cataract 70000posture- animal is sitting or laying 00000- animal is standing or moving 1 10 10 10 10

- squatting posture 20000- abdominal position 30000- abdominal position with splayed limbs 40000- lateral position 50000- oblique head posture 60000- opisthotonus 70000palpebral closure- nothing abnormal detected 0 10 10 10 10

- eyelid(s) slight closure 10000- eyelid(s) half closure 20000- eyelid(s) permanent closure 30000

FUNCTIONAL OBSERVATIONAL BATTERY

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Project No.: Table IA - 33

Mean values day 90

male animals

test group 0 test group 1 test group 2 test group 3

OPEN FIELD OBSERVATIONS Rank N=10 N=10 N=10 N=10

respiration- nothing abnormal detected 0 10 10 10 10

- respiration labored 10000- gasping/respiratory sounds 20000- respiration accelerated 30000- respiration irregular 40000tremors- no tremors 0 10 10 10 10

- slight tremors 10000- moderate tremors 20000- severe tremors 30000convulsions- no convulsions 0 10 10 10 10

- slight convulsions 10000- moderate convulsions 20000- severe convulsions 30000abnormal movements/stereotypics- no abnormalities 0 10 10 10 10

- manege movements 10000- head shaking 20000- excessive cleaning 30000- frequent chewing 40000impairment of gait- animal is not walking during observation 00000- no impairment of gait 1 10 10 10 10

- stiff gait 20000- slight impairment of coordination, unsteady gait 30000- moderate impairment of coordination, shuffling gait 40000- severe impairment of coordination, dragging of the hindlimbs 50000- severe impairment of coordination, with splayed limbs 60000- animal is unable to walk (abdominal or lateral position) 70000

FUNCTIONAL OBSERVATIONAL BATTERY

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Project No.: Table IA - 34

Mean values day 90

male animals

test group 0 test group 1 test group 2 test group 3

OPEN FIELD OBSERVATIONS Rank N=10 N=10 N=10 N=10

activity/arousal level- normal exploration of the area 0 10 10 10 10

- reduced exploration of the area 10000- severe reduced exploration of the area, animal apathetic 20000- increased exploration of the area, sudden or jerky movements 30000- hyperactivity 40000feces- no defecation during observation period 0 10 9 10 10

- feces without abnormalities 10100- discolored feces 20000- crumbly feces 30000- soft feces 40000- muicid feces 50000- diarrhea 60000urine- no urination during observation period 09788- urine without abnormalities (some wet areas on the filter paper) 11322

- discoloration of urine 20000- polyuria (great wet areas on the filter paper) 30000

FUNCTIONAL OBSERVATIONAL BATTERY

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Project No.: Table IA - 35

Mean values day 90

male animals

test group 0 test group 1 test group 2 test group 3

SENSORIMOTOR TESTS/REFLEXES Rank N=10 N=10 N=10 N=10

approach response- no reaction 0 10 10 10 10

- approaching to object 10000- escape reaction 20000- aggressive reaction and attacking of object 30000touch response- no reaction 0 10 10 10 10

- orientation to the stimulus 10000- escape after touch 20000- aggressive reaction and attacking of object 30000- reaction to the stimulus but no ability to localize (e.g. turning to wrong side) 40000

vision- nothing abnormal detected (grasping with forelimbs) 0 10 10 10 10

- no grasping 10000pupillary reflex- nothing abnormal detected, physiological adaptation of the pupil to light 0 10 10 10 10

- retarded adaptation of the pupil to light 10000- no adaptation of the pupil to light, pupils permanently contracted 20000- no adaptation of the pupil to light, pupils permanently dilated 30000pinna reflex- immediate response to the stimulus 0 10 10 10 10

- no response to the stimulus 10000audition- nothing abnormal detected, immediate normal response to the stimulus 0 10 10 10 10- no response 10000- increased response 20000- hyperreaction 30000coordination of movements- nothing abnormal detected, immediate righting response 0 10 10 10 10- retarded righting response 10000- fails to turn into upright position, animal stays in lateral position 20000- no righting response, animal stays in dorsal position 30000

FUNCTIONAL OBSERVATIONAL BATTERY

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Project No.: Table IA - 36

Mean values day 90

male animals

test group 0 test group 1 test group 2 test group 3

SENSORIMOTOR TESTS/REFLEXES Rank N=10 N=10 N=10 N=10

behavior during handling- normal behavior, easy to handle, animal is tense, but it shows no resistance 0 10 10 10 10- very easy to handle, animal is limply hanging in the hand 10000- slightly difficult to handle, animal shows a slight resistance against handling 20000- difficult to handle, animal shows a severe resistance against handling 30000vocalization- no or only sporadic vocalizations when touched 0 10 10 10 10- very frequent vocalizations when touched 10000- vocalizations always when touched 20000- vocalization without touching 30000pain perception- nothing abnormal detected, immediate response to the stimulus 0 10 10 10 10

- weak or retarded reaction to the stimulus 10000- no response to the stimulus 20000- hyperreaction to the stimulus 30000other findings 0 10 10 10 10

FUNCTIONAL OBSERVATIONAL BATTERY

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Project No.: Table IA - 37

Mean values day 90

female animals

test group 0 test group 1 test group 2 test group 3

HOME CAGE OBSERVATION Rank N=10 N=10 N=10 N=10posture- animal is sitting or laying 06344- animal is standing or moving 14766- squatting posture 20000- abdominal position 30000- abdominal position with splayed limbs 40000- lateral position 50000- oblique head posture 60000- opisthotonus 70000tremors- no tremors 0 10 10 10 10- slight tremors 10000- moderate tremors 20000- severe tremors 30000convulsions- no convulsions 0 10 10 10 10- slight convulsions 10000- moderate convulsions 20000- severe convulsions 30000abnormal movements- no abnormalities 0 10 10 10 10- manege movements 10000- head shaking 20000- excessive cleaning 30000- frequent chewing 40000impairment of gait

- animal is not walking during observation 06344- no impairment of gait 14766

- stiff gait 20000- slight impairment of coordination, unsteady gait 30000- moderate impairment of coordination, shuffling gait 40000- severe impairment of coordination, dragging of the hindlimbs 50000- severe impairment of coordination, with splayed limbs 60000- animal is unable to walk (abdominal or lateral position) 70000other findings 0 10 10 10 10

FUNCTIONAL OBSERVATIONAL BATTER

Y

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Project No.: Table IA - 38

Mean values day 90

female animals

test group 0 test group 1 test group 2 test group 3

OPEN FIELD OBSERVATIONS Rank 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 handling 10000- animal shows no resistance against the handling but appears indifferent 20000

- animal is difficult to handle, it shows aggressiveness 30000- animal is very difficult to handle, it shows severe aggressiveness 40000fur

- nothing abnormal detected 0 10 10 8 7

- discolored fur 10000

- urine staining of anogenital region 20000- piloerection 30000- alopecia 40000- reduced care on fur 50023skin- nothing abnormal detected 0 10 10 10 10- discolored skin 10000- reddening 20000- paleness 30000- 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 discharge 10000- reddish discharge 20000

FUNCTIONAL OBSERVATIONAL BATTER

Y

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Project No.: Table IA - 39

Mean values day 90

female animals

test group 0 test group 1 test group 2 test group 3

OPEN FIELD OBSERVATIONS Rank N=10 N=10 N=10 N=10lacrimation- no lacrimation 0 10 10 10 10- slight lacrimation 10000- moderate lacrimation 20000- severe lacrimation 30000eyes/pupil size- nothing abnormal detected, pupils contracted at room light 0 10 10 10 10- chromodacryorrhea 10000- exophthalmos 20000- pupils dilated 30000- abnormal shape of pupils 40000- oblique eye posture 50000- opacity 60000

- cataract 70000posture- animal is sitting or laying 00000- animal is standing or moving 1 10 10 10 10- squatting posture 20000- abdominal position 30000- abdominal position with splayed limbs 40000- lateral position 50000- oblique head posture 60000- opisthotonus 70000palpebral closure- nothing abnormal detected 0 10 10 10 10- eyelid(s) slight closure 10000- eyelid(s) half closure 20000- eyelid(s) permanent closure 30000

FUNCTIONAL OBSERVATIONAL BATTER

Y

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Project No.: Table IA - 40

Mean values day 90

female animals

test group 0 test group 1 test group 2 test group 3

OPEN FIELD OBSERVATIONS Rank N=10 N=10 N=10 N=10respiration- nothing abnormal detected 0 10 10 10 10- respiration labored 10000- gasping/respiratory sounds 20000- respiration accelerated 30000- respiration irregular 40000tremors- no tremors 0 10 10 10 10- slight tremors 10000- moderate tremors 20000- severe tremors 30000convulsions- no convulsions 0 10 10 10 10- slight convulsions 10000- moderate convulsions 20000- severe convulsions 30000abnormal movements/stereotypics- no abnormalities 0 10 10 10 10- manege movements 10000- head shaking 20000- excessive cleaning 30000- frequent chewing 40000impairment of gait

- animal is not walking during observation 00000- no impairment of gait 1 10 10 10 10

- stiff gait 20000

- slight impairment of coordination, unsteady gait 30000- moderate impairment of coordination, shuffling gait 40000- severe impairment of coordination, dragging of the hindlimbs 50000- severe impairment of coordination, with splayed limbs 60000- animal is unable to walk (abdominal or lateral position) 70000

FUNCTIONAL OBSERVATIONAL BATTER

Y

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Project No.: Table IA - 41

Mean values day 90

female animals

test group 0 test group 1 test group 2 test group 3

OPEN FIELD OBSERVATIONS Rank N=10 N=10 N=10 N=10activity/arousal level

- normal exploration of the area 0 10 10 10 10

- reduced exploration of the area 10000- severe reduced exploration of the area, animal apathetic 20000

- increased exploration of the area, sudden or jerky movements 30000- hyperactivity 40000feces- no defecation during observation period 0 10 10 10 10- feces without abnormalities 10000- discolored feces 20000- crumbly feces 30000- soft feces 40000- muicid feces 50000- diarrhea 60000urine- no urination during observation period 08896- urine without abnormalities (some wet areas on the filter paper) 12214- discoloration of urine 20000- polyuria (great wet areas on the filter paper) 30000

FUNCTIONAL OBSERVATIONAL BATTER

Y

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Project No.: Table IA - 42

Mean values day 90

female animals

test group 0 test group 1 test group 2 test group 3

SENSORIMOTOR TESTS/REFLEXES Rank N=10 N=10 N=10 N=10approach response- no reaction 0 10 10 10 10- approaching to object 10000

- escape reaction 20000- aggressive reaction and attacking of object 30000touch response- no reaction 0 10 10 10 10- orientation to the stimulus 10000- escape after touch 20000- aggressive reaction and attacking of object 30000- 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 grasping 10000pupillary reflex

- nothing abnormal detected, physiological adaptation of the pupil to light 0 10 10 10 10

- retarded adaptation of the pupil to light 10000

- no adaptation of the pupil to light, pupils permanently contracted 20000- no adaptation of the pupil to light, pupils permanently dilated 30000pinna reflex- immediate response to the stimulus 0 10 10 10 10- no response to the stimulus 10000audition- nothing abnormal detected, immediate normal response to the stimulus 0 10 10 10 10

- no response 10000- increased response 20000- hyperreaction 30000coordination of movements- nothing abnormal detected, immediate righting response 0 10 10 10 10

- retarded righting response 10000- fails to turn into upright position, animal stays in lateral position 20000- no righting response, animal stays in dorsal position 30000

FUNCTIONAL OBSERVATIONAL BATTER

Y

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Project No.: Table IA - 43

Mean values day 90

female animals

test group 0 test group 1 test group 2 test group 3

SENSORIMOTOR TESTS/REFLEXES Rank N=10 N=10 N=10 N=10behavior during handling- normal behavior, easy to handle, animal is tense, but it shows no resistance 0 10 10 10 10

- very easy to handle, animal is limply hanging in the hand 10000- slightly difficult to handle, animal shows a slight resistance against handling 20000- difficult to handle, animal shows a severe resistance against handling 30000vocalization- no or only sporadic vocalizations when touched 0 10 10 10 10

- very frequent vocalizations when touched 10000- vocalizations always when touched 20000- vocalization without touching 30000pain perception- nothing abnormal detected, immediate response to the stimulus 0 10 10 10 10

- weak or retarded reaction to the stimulus 10000

- no response to the stimulus 20000- hyperreaction to the stimulus 30000other findings 0 10 10 10 10

FUNCTIONAL OBSERVATIONAL BATTER

Y

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Statistic Profile = Kruskal-Wallis + Wilcoxon test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics 

k=KRUSKAL-WALLIS 

IA- 44

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary Functional Observation Battery 

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

Feces [N] day 90

Mean S.d. N 

00

10

k 0 

1 

10 

00

10

00

10

Rearing [N] day 90

Mean S.d. N 

84

10

k 7 

4 

10 

84

10

93

10

GS F [Newton] day 90

Mean S.d. N 

4.30.7

10

k 4.1 

0.5 

10 

4.20.7

10

3.80.7

10

GS H [Newton] day 90

Mean S.d. N 

3.50.6

10

k 3.5 

0.4 

10 

3.90.4

10

3.30.6

10

FST [cm] day 90

Mean S.d. N 

9.80.9

10

k 9.5 

1.6 

10 

9.11.3

10

9.71.0

10

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Statistic Profile = Kruskal-Wallis + Wilcoxon test (two-sided), * p<=0.05, ** p <=0.01, X = Group excluded from statistics 

k=KRUSKAL-WALLIS 

IA- 45

Study 

ToxData© System 3.0

Subchronic 90-day inhalation study in Wistar rats dust exposure Summary Functional Observation Battery 

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

Feces [N] day 90

Mean S.d. N 

00

10

k 0 

0 

10 

00

10

00

10

Rearing [N] day 90

Mean S.d. N 

17

5

10

k 15 

5 

10 

12

6

10

15

5

10

GS F [Newton] day 90

Mean S.d. N 

3.80.7

10

k 3.7 

0.8 

10 

4.20.8

10

4.00.5

10

GS H [Newton] day 90

Mean S.d. N 

3.30.6

10

k 2.9 

0.4 

10 

2.90.4

10

2.90.4

10

FST [cm] day 90

Mean S.d. N 

8.50.9

10

k 8.2 

0.9 

10 

8.41.3

10

8.70.6

10

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 TABLE IA - 46 

 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) 

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 TABLE IA - 47 

 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) 

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 TABLE IA - 48 

 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) 

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 TABLE IA - 49 

 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

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Statistic 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

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Statistic 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

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Statistic 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

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Statistic 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

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Statistic 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 sponsors
Statistic 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 sponsors
Statistic 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

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Statistic 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

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Statistic 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 sponsors
Statistic 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 sponsors
Statistic 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 sponsors
Statistic 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 sponsors
Statistic 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 

[μmol/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 sponsors
Statistic 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 

[μmol/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

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Statistic 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 sponsors
Statistic 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

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Statistic 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

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Statistic 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

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Statistic 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

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Statistic 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

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Exposure Parameters

Inhalation Laboratory · Proj. No.: Table ID - 1

Study Summary of Means of Chamber Parameters ± Standard Deviation (SD) Supply air SDSupply air into the dilution tube SDCompressed air SDExhaust air SDExhaust air from the dilution tube SDChamber 

temperatureSDChamber humiditySDSubstance flowConcentration of substanceSD

[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

3.3 2.5

2.3 1.9 - 2.6

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

2.3 2.2

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

30 May 2012 04 Jun 2012

2.4

38.7

 -

 -

3.4

63.7 66.4 55.5

3.8 -

49.7

2.4

 -

3.8 4.0

2.1 - 3.1

 -

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

 - 2.4 2.7

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 -

3.0 3.2

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 -

 - 3.5 3.0

 -

 -

 - 2.5 2.0

47.8 41.7 -

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STUDY TITLE

Report

Cobalt Lithium Manganese Nickel oxide

- Subchronic 90-day inhalation study in Wistar rats 

dust exposure

TEST FACILITY

TEST FACILITY PROJECT IDENTIFICATION

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 used 

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 limits of their administrative authority.

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CONTENTS OF PART II (TABLES SECTION; INDIVIDUAL VALUES)

TITLE 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 observations report

Male animals IIA-58 - IIA-59

Female animals IIA-60 - IIA-61

Individual Body Weights

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 IIB 1 – IIB 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

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MEASUREMENTS OF EXPOSURE PARAMETERS

Exposure parameters (Daily Means) IID-1 - IID-4 

Particle size analysis (Individual measurements) IID-5 - IID-48

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Exposure 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

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Exposure 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

[m3/h] [m3/h] [m3/h] [m3/h] [m3/h] [%RH] [°C] [mg/m3]

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

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Exposure 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

[m3/h] [%RH] [°C]

Supply air Compressed

air

Exhaust air 

[m3/h] [m3/h]

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Exposure 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

[m3/h] [%RH] [°C]

Supply air Compressed

air

Exhaust air 

[m3/h] [m3/h]

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STUDY TITLE

Report

Cobalt Lithium Manganese Nickel oxide

- Subchronic 90-day inhalation study in Wistar rats 

dust exposure

TEST FACILITY

TEST FACILITY PROJECT IDENTIFICATION

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 used 

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 limits of their administrative authority.

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CONTENTS OF PART III (SUPPLEMENT) 

TITLE PAGE

TABLE OF CONTENTS

Analysis of the test substance 

Historical control data of clinical pathology testing

Functional Observational Battery (FOB)

Detailed description of examinations, ranking and documentation procedures

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HISTORICAL 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

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HISTORICAL 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 33

Mean 7.75

Minimum 7.28

Maximum 8.25

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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

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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 detail.

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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)

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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

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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

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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

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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)

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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

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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 contracts 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 animal 

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

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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 resistance 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

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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 animal 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 rat.

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.

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