Table 3.

Carcinogenicity test guidelines and haematological endpoints in the regulatory toxicological studies

Test guideline	Test procedure	Haematology	Histopathology Organs of interest for leukaemia
Repeated dose 28‐day oral toxicity study in rodents OECD 407 (2008)	Animals: Rat young adults 5 M & 5 F/group 3 doses tested + 1 control group Exposure: 28 days	Parameters: RBC parameters Total and differential leucocyte count, Platelet count Blood clotting time/potential Frequency: once at the end of the test period	Bone Marrow, Thymus, Spleen, LN, liver
Repeated dose 90‐day oral toxicity study in rodents OECD 408 (1998)	Animals: Rat young adults 10 M & 10 F/group 3 doses tested + 1 control group Exposure: 90 days	Parameters: RBC parameters Total and differential leucocyte count, Platelet count Blood clotting time/potential Frequency: once at the end of the test period	Bone Marrow, Thymus, Spleen, LN, liver
Repeated dose 90‐day oral toxicity study in non‐rodents OECD 409 (1998)	Animals: Dog young adults 4 M & 4 F/group 3 doses tested + 1 control group Exposure: 90 days	Parameters: RBC parameters Total and differential leucocyte count, Platelet count Blood clotting time/potential Frequency: Prior to first exposure Monthly or midway At the end of test period	Bone Marrow, Thymus, Spleen, LN, liver
Chronic Toxicity Studies OECD 452 (2009)	Animals: Rodent young adults 20 M & 20 F/group Non‐rodent young adults 4 M & 4 F/group 3 doses tested + 1 control group Exposure: 52 weeks	Parameters: RBC parameters Total and differential leucocyte count, Platelet count Blood clotting time/potential If the chemical has an effect on the haematopoietic system, reticulocyte counts and bone marrow cytology may also be performed although not routinely conducted Frequency: At 3, 6, and 12 months and at the end of test period	Bone Marrow, Thymus, Spleen, LN, liver
Carcinogenicity Studies OECD 451 (2009)	Animals: Rodent young adults 50 M & 50 F/group 3 doses tested + 1 control group Exposure: 104 weeks rat 78 weeks mouse	At the discretion of the study director: Blood samples may be taken for haematology and clinical biochemistry Blood smears may also be prepared for examination, particularly if bone marrow is the target organ Frequency: At the end of test period At the discretion of the study director	Bone Marrow, Thymus, Spleen, LN, liver Non‐neoplastic histopathological findings Neoplastic histopathological findings
Combined Chronic Toxicity/Carcinogenicity Studies OECD 453 (2009)	Rodent young adults 50 M & 50 F/group (carcinogenicity phase) 10 M & 10 F/group (chronic phase) 3 doses tested + 1 control group Exposure: 52 weeks rat (chronic phase) 104 weeks rat (carcinogenicity phase)	Parameters: RBC parameters Total and differential leucocyte count, Platelet count Blood clotting time/potential Min 10 M & 10 F/group If the chemical has an effect on the haematopoietic system, reticulocyte counts and bone marrow cytology may also be performed although not routinely conducted Frequency: At 3, 6, and 12 months and at the end of test period	Bone Marrow, Thymus, Spleen, LN, liver Non‐neoplastic histopathological findings Neoplastic histopathological findings
Extended One‐Generation Reproductive Toxicity Study OECD TG 443 (2012)	20 M & 20 F (20 litters/group targeted) 3 doses tested + 1 control group Exposure: P: 10 weeks (2 weeks premating, 2 weeks mating 6 weeks post‐mating) F: 6 weeks (in utero +preweaning) + 0–22 weeks according to cohorts F1A: 6 weeks (in utero +preweaning) + 10 week	Parameters: RBC parameters Total and differential leucocyte count Platelet count Blood clotting time/potential Parents: all Cohort F1A: 10 M & 10 F/group Frequency: Once at the end of the test period	P and F1A: spleen, liver and thymus all animals Cohort 1A: Bone marrow + lymph nodes of 10 M and 10 F: group Splenic lymphocyte subpopulation analysis (CD4+ and CD8+ T lymphocytes, B lymphocytes, and natural killer cells) Splenic lymphocyte subpopulation analysis (CD4+ and CD8+ T lymphocytes, B lymphocytes, and natural killer cells) → to evaluate if exposure impacts immunological steady state distribution

LN: Lymph Nodes.