Tab.2. Effects of N,N-dimethyl-p-toluidine after repeated oral administration.
| Species, strain, number per group |
Dose | Findings | References |
|---|---|---|---|
|
rat, F344, 5 ♂ |
5 days, 0, 1, 6, 20, 60, 120 mg/kg body weight and day, gavage, in corn oil |
20 mg/kg body weight and above: body weights ↓, liver: incidence of apoptosis ↑; 60 mg/kg body weight and above: liver: mitosis rate ↑, nose: transitional epithelium: hyperplasia (4/5); 120 mg/kg body weight: liver: relative weights ↑*, nose: olfactory epithelium: necrosis (4/5), degeneration (1/5) |
Dunnick et al. 2016, 2017 |
|
rat, F344, 10 ♂, 10 ♀ |
25 days, 0, 62.5, 125, 250, 500, 1000 mg/kg body weight and day, 5 days/week, gavage, in corn oil, haematological examination only |
0 mg/kg body weight: MetHb ♂: 2.4%, ♀: 2.7%; 62.5 mg/kg body weight: MetHb ♂: 6.7%, ♀: 6.4%; 62.5 mg/kg body weight and above: body weights ↓*,anaemia, methaemoglobinaemia, haematocrit values ↓**, haemoglobin ↓**, erythrocytes ↓**, reticulocytes ↑**, ALT ↑*, SDH ↑*; 125 mg/kg body weight: MetHb ♂: 12.44%, ♀: 12.8%; 125 mg/kg body weight and above: Heinz bodies ↑**; 250 mg/kg body weight: MetHb ♂: 16.6%, ♀: 16.0%; 500 mg/kg body weight: MetHb ♂: 14.75%, ♀: 15.5%; 1000 mg/kg body weight: mortality ♂ and ♀: 10/10 (after 3 days) |
Dunnick et al. 2014; NTP 2012 |
|
rat, F344, 10 ♂, 10 ♀ |
14 weeks, MetHb determined after 88 days; 0, 62.5, 125, 250, 500, 1000 mg/kg body weight and day, 5 days/week, gavage, in corn oil |
0 mg/kg body weight: blood: MetHb ♂: 2.44%, ♀: 2.88%; 62.5 mg/kg body weight: blood: MetHb ♂: 10.1%, ♀: 11.2%; 62.5 mg/kg body weight and above: body weights ↓*, blood: anaemia, methaemoglobinaemia, haematocrit values ↓**, Heinz bodies ↑**, erythrocytes ↓**, reticulocytes ↑**, spleen: haematopoiesis ↑, haemosiderin deposition ↑, ♂: congestion ↑, bone marrow: hyperplasia*, haematopoiesis ↑, nose: olfactory epithelium: degeneration*, ♂: respiratory epithelium: metaplasia**, liver: relative weights ↑** (♂: 30%, ♀: 45%), kidneys: pigmentation*, relative weights ↑**, testis: relative weights ↑**, heart: relative weights ↑**; 125 mg/kg body weight: MetHb ♂: 15.5%, ♀: 17.22%; 125 mg/kg body weight and above: blood: serum: ♂: bile acid ↑*, spleen: congestion and capsular fibrosis**, ♂: hypertrophy**, nose: olfactory epithelium: degeneration**, respiratory epithelium: hyperplasia**, ♀: respiratory epithelium: metaplasia**, liver: weights ↑** (♂: 44%, ♀: about 64%), hypertrophy**, kidneys: ♂: necrosis and mineralization**, ♀: nephropathy**; 250 mg/kg body weight: MetHb ♂: 18.2%, ♀: 19.7%; 250 mg/kg body weight and above: blood: serum: ♂: bile acid ↑**, spleen: congestion and capsular fibrosis, hypertrophy**, nose: respiratory epithelium: hyperplasia**, olfactory epithelium: metaplasia**, liver: weights ↑** (♂: 57%, ♀: 89%), ♀: necrosis, kidneys: necrosis; 500 mg/kg body weight: mortality ♂: 1/10 blood: MetHb ♂: 17.7%, ♀: 16.0%, serum: ♀: bile acid ↑**, liver: weights ↑** (♂: about 70%, ♀: about 123%), hypertrophy; 1000 mg/kg body weight: mortality ♂ and ♀: 10/10 (after 3 days) |
Dunnick et al. 2014; NTP 2012 |
|
rat, F344, 10 ♂, 10 ♀ |
86 days, 0, 6, 20, 60 mg/kg body weight and day, 5 days/week, gavage, in corn oil, haematological examination only |
0 mg/kg body weight: MetHb ♂: 4.7%, ♀: 5.1%; 6 mg/kg body weight: LOAEL MetHb ♂: 5.6%*, ♀: 5.6%, ♀: Heinz bodies ↑* (0.3%); 20 mg/kg body weight: MetHb ♂: 7.9%**, ♀: 8.4%**, Heinz bodies ↑** (♂: 0.7%, ♀: 0.9%); 20 mg/kg body weight and above: haematocrit values ↑**, erythrocytes ↓**, reticulocytes ↑**; 60 mg/kg body weight: MetHb ♂: 17.4%**, ♀: 17.1%**, Heinz bodies ↑** (♂: 3.7%, ♀: 3.8%) |
Dunnick et al. 2014; NTP 2012 |
|
rat, F344, 50 ♂, 50 ♀ |
104 weeks, 0, 6, 20, 60 mg/kg body weight and day, 5 days/week, gavage, in corn oil, no haematological examination |
6 mg/kg body weight and above: LOAEL spleen: haematopoiesis ↑*, ♀: congestion and hypertrophy, ♂: atrophy*, liver: ♀: bile duct hyperplasia*, ♂: eosinophilic foci ↑*, kidneys: ♀: nephropathy*, ♂: pigmentation*, nose: glands, respiratory epithelium: metaplasia*, ♂: hyperplasia**, respiratory epithelium: ♂: hyperplasia**; 20 mg/kg body weight and above: ♀: hyperactivity, liver: hypertrophy* (6/50), bile duct fibrosis**, ♀: eosinophilic foci ↑*, forestomach: ♂: hyperplasia and ulcer, bone marrow: ♂: hyperplasia*, lymph nodes: ♂: histiocytic infiltrates*, nose: glands, transitional epithelium: hyperplasia*, ♂: dilation*, respiratory epithelium: ♀: dilation**, hyperplasia**; 60 mg/kg body weight: body weights ↓, mortality ↑ (caused by tumours), hyperactivity, ♀: pallor of the skin, spleen: congestion**, hypertrophy**, capsular fibrosis**, atrophy**, liver: hypertrophy ↑** (♂: 31/50, ♀: 22/49), cystic degeneration**, ♀: necrosis*, nose: lesions in the olfactory and respiratory epithelium*, kidneys: ♀: pigmentation*, forestomach: ♂: inflammation*, bone marrow: hyperplasia** |
Dunnick et al. 2014; NTP 2012 |
|
mouse, B6C3F1, 10 ♂, 10 ♀ |
14 weeks,0, 15, 30, 60, 125, 250 mg/kg body weight and day, 5 days/week, gavage, in corn oil |
0 mg/kg body weight: blood: MetHb ♂: 2.0%, ♀: 2.1%; 15 mg/kg body weight and above: liver: weights ↑** (♂: 25.6%, ♀: 15.4%), vacuolation*; 30 mg/kg body weight and above: blood: MetHb ↑ (♂: 2.8%**, ♀: 2.6%**); 60 mg/kg body weight and above: blood: ♀: Heinz bodies ↑** (0.2%), nose: ♀: olfactory epithelium: degeneration*; 125 mg/kg body weight: blood: Heinz bodies ↑ (♂: 0.5%**, ♀: 0.5%**), reticulocytes ♂: ↑*, nose: hyperplasia**, olfactory epithelium: degeneration**, metaplasia**, lungs: bronchial epithelium: degeneration* and regeneration*, peribronchial epithelium: chronic inflammation*, relative weights ↑**, ♀: histiocytic infiltrates*, thymus: necrosis*; 250 mg/kg body weight: mortality ♂: 9/10, ♀: 10/10 (within 10 days) |
Dunnick et al. 2014; NTP 2012 |
|
mouse, B6C3F1, 50 ♂, 50 ♀ |
104 weeks, 0, 6, 20, 60 mg/kg body weight and day, 5 days/week, gavage, in corn oil, no haematological examination |
6 mg/kg body weight and above: liver: hypertrophy**, necrosis*, spleen: ♂: atrophy (11/50) not dose-dependent, bone marrow: ♀: hyperplasia* not dose-dependent, nose: ♀: hyperplasia in the olfactory epithelium**, metaplasia*; 20 mg/kg body weight and above: spleen: ♂: atrophy* (11/49), liver: eosinophilic foci ↑*, lungs: ♀: hyperplasia, alveolar epithelium*, forestomach: ♀: hyperplasia**, nose: ♀: lesions in the olfactory and respiratory epithelium*; 60 mg/kg body weight: ♀: body weights ↓ (> 10%), mortality ↑*, liver: ♀: fatty changes**, necrosis**, lungs: alveolar infiltrates (histiocytes)*, ♀: regeneration* (bronchial epithelium and bronchi), forestomach: ♀: inflammation and squamous cell papillomas**, nose: ♂: lesions in the olfactory and respiratory epithelium, spleen: ♀: atrophy of the red pulp*, lymph nodes: atrophy** |
Dunnick et al. 2014; NTP 2012 |
*
p < 0.05
** < 0.01
ALT: alanine aminotransferase; LOAEL: lowest observed adverse effect level; MetHb: methaemoglobin; SDH: sorbitol dehydrogenase