Absorption, Distribution and Excretion
Pregnant golden Syrian hamsters were injected with 20 uCi (4.8 mg/kg bw) of (14)C-nitrosodibutylamine (14)C-NDBA. The animals were killed after 20 min or 1 hr, and were used for whole-body autoradiography. For in vitro experiments, tissue slices from fetal (day 12 and 15 of gestation), infant (4, 10, or 20 days old) or adult (non-pregnant females) hamsters were incubated in a solution containing (14)C-NDBA (34 umol/mL; 0.12 uCi/mL) for 1 hr at 37 °C. The autoradiography showed uptake of radioactivity in the fetuses and a labeling of fetal nasal, tracheal, and bronchial mucosa exceeded the radioactivity that was present in most other fetal tissues. The metabolizing capacity of these tissues in the 15-day-old fetuses had a high capacity to form (14)C-carbon dioxide (14)CO2 and tissue-bound (14)C from the (14)C-labeled NDBA, while tissues in the 12-day-old fetuses, did not. In infant hamsters, the (14)CO2 and (14)C-tissue-binding in the respiratory tissues were in some instances higher than in the tissues of adult animals. The incubation of tissues of adult hamsters showed that the highest formation of (14)CO2 and tissue-bound (14)C was produced by the nasal olfactory mucosa.

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Metabolism / Metabolites
... After oral administration of NDBA; in guinea pigs, glucuronide of N-nitroso-n-butyl-n-(3-hydroxybutyl)amine and traces of N-nitroso-n-butyl-n-(2-hydroxy-3-carboxypropyl)amine were ... excreted.
The present investigations showed that assumed and established metabolites of dipropylnitrosamine and dibutylnitrosamine reach the Syrian hamster fetus after subcutaneous (s.c.) treatment of their mothers (at day 14 of gestation). The compounds [2-hydroxypropylpropylnitrosamine, HPPN; 2-oxopropylpropylnitrosamine, OPPN; methylpropylnitrosamine, MPN; N-nitrosobis(2-hydroxypropyl)amine, BHP; and 4-hydroxybutylbutylnitrosamine, HBBN] were still present in the examined tissue (maternal blood, placenta, fetus, amniotic fluid) 4--6 hr after s.c. injection. The overall incidence of transplacentally induced tumors was lower in the F1- than in the P-generation and comparatively longer latencies were also observed in the F1- generation. However, in some groups low incidences were found of tumors which did not occur in the mothers (i.e., nasal cavities: BHP, HBBN; trachea: HBBN; lungs: HPPN, BHP, HBBN; liver: OPN, MPN, BHP, HBBN). Compared to exposure at early gestation, the transplacental carcinogenic effect increased at day 14 of gestation. Neoplasms originating in other organs were not associated with a transplacental effect of the examined nitrosamines.
The effect of butylated hydroxyanisole (BHA) on P-450-dependent omega-hydroxylation of N,N-dibutylnitrosamine (NDBA) to N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), and the further oxidation of BBN to N-butyl-N-(3-carboxypropyl)nitrosamine (BCPN) by the alcohol/aldehyde dehydrogenase system was investigated using the post-mitochondrial supernatant of liver homogenates (S9) from acutely and chronically BHA pretreated animals or S9 fractions from untreated rats with BHA added. Acute oral BHA (50 and 250 mg.kg-1) did not change NDBA omega-oxidation, which was reduced by 35% only when the compound was administered 0.5% in the diet for 3 weeks. BCPN formation from BBN was unaffected by acute and chronic BHA pretreatment. In order to verify whether BHA or its metabolite(s) had a direct effect on NDBA and BBN oxidation, the compound was added to S9 fractions from untreated rats at various concentrations. Only when BHA concentrations were equimolar or in a 10-fold molar excess to the substrate concentration, we observed 30-50% inhibition of BBN formation and a reduced BCPN formation (60-80% of control values), from BBN. Thus, only at very high BHA concentrations could we confirm the inhibition of P-450-dependent mixed function oxidase and alcohol dehydrogenase activities involved in the metabolism of NDBA and BBN.
N-Nitrosodi-((1-14)C)butylamine (NDBA) has been shown to undergo a high first-pass metabolism in isolated perfused rat small intestinal segments. Metabolites resulting from omega-hydroxylation of NDBA, the bladder carcinogens N-nitrosobutyl-(4-hydroxybutyl)amine (NB4HBA) and N-nitrosobutyl-(3-carboxypropyl)-amine (NB3CPA), accounted for greater than 90% of the total radioactivity absorbed. In the present study using vascularly perfused rat small intestinal segments, the high first-pass metabolism of NDBA could be confirmed under near in vivo conditions despite the much higher absorption rate. At the end of the 36 min experimental period 70-80% of the dose have been absorbed via the portal blood as opposed to 1-10% of the dose after 2 h in vitro perfusion. omega-Hydroxylation was again the most important metabolic pathway. However, the relationship of NB3CPA to NB4HBA was shifted in favor of NB4HBA, indicating a concentration and absorption rate dependency in the further metabolism of NB4HBA to NB3CPA.
For more Metabolism/Metabolites (Complete) data for N,N-Dibutylnitrosoamine (16 total), please visit the HSDB record page.
N-nitrosodibutylamine has known human metabolites that include N-Butyl-N-(1-hydroxybutyl)nitrous amide.

Toxicity Summary
IDENTIFICATION AND USE: N,N-dibutylnitrosoamine (DBNA) is a pale yellow liquid. It has been used in the synthesis of di-n-butylhydrazine, although there is no indication that it has been used commercially. HUMAN STUDIES: There are no data available. ANIMAL STUDIES: DBNA caused tumors in several species of experimental animals, at several different tissue sites, and by several different routes of exposure. It was carcinogenic after a single dose, and was particularly effective as a urinary-bladder carcinogen, causing benign and/or malignant urinary-bladder tumors in mice, rats, hamsters, and guinea pigs exposed orally and in mice, rats, hamsters, and rabbits exposed by subcutaneous injection. DBNA also caused tumors of the respiratory tract following oral or prenatal exposure in hamsters, subcutaneous injection in rats, hamsters, and adult and newborn mice, and intraperitoneal injection in hamsters of both sexes. Benign or malignant liver tumors were observed in mice, rats, and guinea pigs exposed orally and in newborn mice exposed by subcutaneous injection. Tumors of the upper digestive tract occurred following oral exposure in mice, rats, and hamsters and subcutaneous injection in rats and hamsters. Intravenous injection of DBNA caused leukemia in mice of both sexes. Administration of DBNA to male rats by stomach tube caused cancer of the forestomach, in addition to cancer of the liver and urinary bladder. DBNA induced reverse mutations in Salmonella typhimurium strains TA 100, TA 1530 and TA 1535 and in Escherichia coli with metabolic activation.

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Interactions
The target organ specificity of the carcinogen dibutylnitrosamine (DBN) was examined in Syrian golden hamsters. Groups of male animals were given 8 weekly injections of the carcinogen and then were maintained on a basal diet or a diet supplemented with 1% butylated hydroxyanisole (BHA) or they were given the respective carcinogen in the drinking water until they were sacrificed at week 34. ...DBN induced lesions in the urinary bladder, forestomach, and trachea, in addition to a few preneoplastic foci in the liver and lungs. In all organs studied, preneoplastic and neoplastic populations were essentially similar to those observed in other experimental animals, with colon and tracheal lesions demonstrating alteration in polysaccharide metabolism. While inhibiting the development of hepatocellular lesions, ...and while itself inducing extensive papillomatous forestomach hyperplasia; BHA administration did not exert a significant modifying influence on tumorigenesis on other organs.
The modifying effects of concomitant antioxidant treatment on N,N-dibutylnitrosamine (DBN)-induced carcinogenesis were investigated. Male F344 rats were given 0.05% DBN in their drinking water for 16 weeks, and simultaneously administered powder diet containing 2.0% butylated hydroxyanisole (BHA) or 0.7% butylated hydroxytoluene (BHT) for 16 weeks. Control animals received drinking water containing 0.05% DBN without antioxidant treatment. The final incidences of hepatocellular carcinomas were 100, 100 and 40% in the DBN plus BHA, DBN plus BHT and DBN treated groups, respectively, the difference being significant (P less than 0.001). Lung metastases were only observed in the DBN plus BHT group and DBN plus BHA group (50%, P less than 0.001; 7%, respectively). The incidence of papillary or nodular hyperplasia of the urinary bladder in the DBN plus BHA group was significantly higher than that of the control (P less than 0.05). Furthermore, esophageal carcinomas and papillomas were observed in all DBN treated groups, with no inter-group significant variation in yield. On the other hand, combination of DBN treatment with BHA or BHT significantly reduced the resultant incidences of forestomach hyperplasia. The results clearly demonstrated that concomitant administration of antioxidants, and in particular BHT, can modify DBN carcinogenesis.
The aim of this work was to determine the effect of vitamin C, diallyl disulfide (DADS) and dipropyl disulfide (DPDS) towards N-nitrosopiperidine (NPIP) and N-nitrosodibutylamine (NDBA)-induced apoptosis in human leukemia (HL-60) and hepatoma (HepG2) cell lines using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. None of the vitamin C (5-50 microm), DADS and DPDS (1-5 um) concentrations selected induced a significant percentage of apoptosis. In simultaneous treatments, vitamin C, DADS and DPDS reduced the apoptosis induced by NPIP and NDBA in HL-60 and HepG2 cells (around 70% of reduction). We also investigated its scavenging activities towards reactive oxygen species (ROS) produced by NPIP and NDBA using 2',7'-dichlorodihydrofluorescein diacetate in both cell lines. ROS production induced by both N-nitrosamine was reduced to control levels by vitamin C (5-50 um) in a dose-dependent manner. However, DADS (5 um) increased ROS levels induced by NPIP and NDBA in HL-60 (40 and 20% increase, respectively) and HepG2 cells (18% increase), whereas DPDS was more efficient scavenger of ROS at the lowest concentration (1 microm) in both HL-60 (52 and 25% reduction, respectively) and HepG2 cells (24% reduction). The data demonstrated that the scavenging ability of vitamin C and DPDS could contribute to inhibition of the NPIP- and NDBA-induced apoptosis. However, more than one mechanism, such as inhibition of phase I and/or induction of phase II enzymes, could be implicated in the protective effect of dietary antioxidants towards NPIP- and NDBA-induced apoptosis in HL-60 and HepG2 cells.
The aim of this study was to investigate the protective effect of myricetin, quercetin, (+)-catechin and (-)-epicatechin, against N-nitrosodibutylamine (NDBA) and N-nitrosopiperidine (NPIP)-induced DNA damage in human hepatoma cells (HepG2). DNA damage (strand breaks and oxidized purines/pyrimidines) was evaluated by the alkaline single-cell gel electrophoresis or Comet assay. (+)-Catechin at the lowest concentration (10 uM) showed the maximum reduction of DNA strand breaks (23%), the formation of endonuclease III (Endo III, 19-21%) and formamidopyrimidine-DNA glycosylase (Fpg, 28-40%) sensitive sites induced by NDBA or NPIP. (-)-Epicatechin also decreased DNA strand breaks (10 uM, 20%) and the oxidized pyrimidines/purines (33-39%) induced by NDBA or NPIP, respectively. DNA strand breaks induced by NDBA or NPIP were weakly reduced by myricetin at the lowest concentration (0.1 uM, 10-19%, respectively). Myricetin also reduced the oxidized purines (0.1 uM, 17%) and pyrimidines (0.1 uM, 15%) induced by NDBA, but not the oxidized pyrimidines induced by NPIP. Quercetin did not protect against NDBA-induced DNA damage, but it reduced the formation of Endo III and Fpg sensitive sites induced by NPIP (0.1 uM, 17-20%, respectively). In conclusion, our results indicate that (+)-catechin and (-)-epicatechin at the concentrations tested protect human derived cells against oxidative DNA damage effects of NDBA and NPIP. However, myricetin at the concentrations tested only protects human cells against oxidative DNA damage induced by NDBA and quercetin against oxidative DNA damage induced by NPIP.
For more Interactions (Complete) data for N,N-Dibutylnitrosoamine (9 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Hamster sc 561 mg/kg
LD50 Hamster ip 1200 mg/kg
LD50 Hamster oral 2150 mg/kg
LD50 Rat sc 1200 mg/kg
For more Non-Human Toxicity Values (Complete) data for N,N-Dibutylnitrosoamine (6 total), please visit the HSDB record page.

[1]. Chao Zhao, et al. Distribution of N-nitrosamines in Drinking Water and Human Urinary Excretions in High Incidence Area of Esophageal Cancer in Huai'an, China. Chemosphere. 2019 Nov;235:288-296.

N-Nitrosodi-n-Butylamine can cause cancer according to an independent committee of scientific and health experts.
N-nitrosodi-n-butylamine is a pale yellow liquid.
N-Nitrosodi-n-butylamine is a nitroso compound.
N-Nitrosodi-n-butylamine is a yellow, viscous, oily nitrosamine that is highly unstable in the presence of light. N-Nitrosodiethanolamine is ubiquitously found in the environment and is a contaminant formed by the reaction of nitrites with ethanolamines in a wide range of products including tobacco, pesticides, antifreeze and personal care products. This substance is only used for research purposes to induce tumors in experimental animals. N-Nitrosodiethanolamine is reasonably anticipated to be a human carcinogen. (NCI05)

C8H18N2O

158.24

158.142

924-16-3

N-Nitrosodibutylamine-d18;1219798-82-9;N-Nitrosodibutylamine-d9

13542

Pale yellow liquid
Yellow oil

0.91 g/cm3

250.6ºC at 760 mmHg

<25℃

105.3ºC

1.456

2.57

0

3

6

11

88.1

0

O=NN(CCCC)CCCC

YGJHZCLPZAZIHH-UHFFFAOYSA-N

InChI=1S/C8H18N2O/c1-3-5-7-10(9-11)8-6-4-2/h3-8H2,1-2H3

N,N-dibutylnitrous amide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 100 mg/mL (631.95 mM)

Solubility in Formulation 1: ≥ 6.25 mg/mL (39.50 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 62.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 6.25 mg/mL (39.50 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 62.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 6.25 mg/mL (39.50 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 62.5 mg/mL clear DMSO stock solution to 900 μL corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)