Common use of Study Protocols Clause in Contracts

Study Protocols. The conduct of inhalation exposures will be performed according to the following test guideline concerning repeated dose inhalation toxicity studies: - 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. In addition the study was carried out taking into account the following guidelines: - Organization for Economic Cooperation and Development (OECD), OECD Guidelines for Testing of Chemicals, Section 4: Health Effects, Method 453 "Combined Chronic Toxicity/Carcinogenicity Study in Rodents" adopted 07 Sep 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.33.: Combined Chronic Toxicity/Carcinogenicity Test - US Environmental Protection Agency (EPA), Health Effects Test Guidelines OPPTS870.4300, Combined Chronic Toxicity/Carcinogenicity, EPA 712-C-98-212, August 1998 In deviation to the guidelines, only females were exposed, because female rats are considered to be slightly more sensitive concerning carcinogenicity after inhalation exposure to dust aerosols (▇▇▇▇▇▇ et al. 2000). The chronic study was started with 100 rats per dose group. 50 animals per dose group were sacrificed after 24 months. The remaining animals are currently kept exposure-free till natural death or till month 30. The intention for this extension is to enhance study sensitivity. It is known that a relevant portion of particle induced tumours become detectable first rather late in rats. The study sensitivity to detect lung tumours will be further enhanced by an extended lung histopathology as 60 instead of 6 slices will be studied per lung. Satellite groups were sacrificed after 12 months (chronic group with 10 animals per dose for histopathology) and after 3 months, 12 months, and 24 months (for kinetic/organ burden evaluations). Results for 3 months have been reported in deliverables .4.3 and 4.4. Main exposure groups are used for histopathology examinations (carcinogenicity groups). Post-exposure animals are sacrificed and examined after 30 months or if the only 25% or less animals are still alive. Animals of each group which die during the exposure or post-exposure period are examined as well.

Study Protocols. The conduct of inhalation exposures will be performed according to the following test guideline concerning repeated dose inhalation toxicity studies: - 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. In addition the study was carried out taking into account the following guidelines: - Organization for Economic Cooperation and Development (OECD), OECD Guidelines for Testing of Chemicals, Section 4: Health Effects, Method 453 "Combined Chronic Toxicity/Carcinogenicity Study in Rodents" adopted 07 Sep 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.33.: Combined Chronic Toxicity/Carcinogenicity Test - US Environmental Protection Agency (EPA), Health Effects Test Guidelines OPPTS870.4300, Combined Chronic Toxicity/Carcinogenicity, EPA 712-C-98-212, August 1998 In deviation to the guidelines, only females were exposed, because female rats are considered to be slightly more sensitive concerning carcinogenicity after inhalation exposure to dust aerosols (▇▇▇▇▇▇ et al. 2000). The chronic study was started with 100 rats per dose group. 50 animals per dose group were sacrificed after 24 months. The remaining animals are currently kept exposure-free till natural death or till month 30. e. December 2015. The intention for this extension is was to enhance study sensitivity. It is known that a relevant portion of particle induced tumours become detectable first rather late in rats. The study sensitivity to detect lung tumours will be was further enhanced by an extended lung histopathology as 60 instead of 6 slices sliced will be studied per lung. Satellite groups were sacrificed after 12 months (chronic group with 10 animals per dose for histopathology) and after 3 months, 12 months, and 24 months (for kinetic/organ burden evaluations). Results for 3 months have been reported in deliverables .4.3 and 4.4. Main exposure groups are used for histopathology examinations (carcinogenicity groups). Post-Groups of 50 animals (of each exposure level) were sacrificed and examined after 24 months of exposure. Additional groups of 50 animals are were kept without exposure up to 30 months and animals were sacrificed and examined after 30 months or if the only 25% or less animals are were still alive. Animals of each group which die died during the exposure or post-exposure period are examined as well.