Tumor models can be created in animals by using N-nitrosomomorpholine.

Absorption, Distribution and Excretion
After ip injection of 400 mg/kg body weight 3- (14)C-NMOR to rats, 3.3% of the label was excreted as (14)CO2 and 81% in the urine over 24 hours; 24% of the radioactivity was recovered as unchanged NMOR and 15% as N-nitrosodiethanolamine.
Male CD-1 mice were exposed to a nominal concentration of 20 ppm of 15N-nitrogen dioxide ((15)NO2) for 6 hr/day for 4 days and for 2 hr on the day 5, and to 1 g morpholine/kg body wt by gavage daily for five consecutive days. N-Nitrosomorpholine (NMOR) was found in whole mice, stomachs, skins with hair, and remains. ... The average whole mouse weighed 27.6 g and contained a total of 3903 ng of N-nitrosomorpholine. The concentration of N-nitrosomorpholine was highest in the skin, next highest in the stomach, and lowest in the remains. ... GC-MS analysis served to distinguish between the N-nitrosomorpholine of (15)N-nitrogen dioxide origin and that of other origin. ... In the stomach 73% was identified as (14) N-nitrosomorpholine, representing 1.6% of the total N-nitrosomorpholine in the mouse, and 27% as (15) N-nitrosomorpholine, representing 0.6% of the total N-nitrosomorpholine in the mouse. ...

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Metabolism / Metabolites
Acid hydrolysis of liver RNA and DNA isolated from rats /given ip injection of 400 mg/kg body wt (3-(14)c)-NMOR/...gave 6 distinct radioactive products, one of which was probably 7-(2-hydroxyethyl)guanine.
N-nitrosomorpholine is converted into N-nitroso-2-hydroxymorpholine by rat liver microsomes. The only urinary metabolite definitely identified was N-nitrosodiethanolamine.
After ip injection of 400 mg/kg body wt (3-(14)C)-NMOR to rats, 3.3% of label was excreted as (14)CO2 and 81% in urine over 24 hr; 24% of radioactivity was recovered as unchanged NMOR and 15% as N-nitrosodiethanolamine.
It has been shown in vitro with human acidic gastric juice, the nitrosomorpholine (NMOR) formation from small doses of precursors (sodium nitrite and morpholine) with a significant difference relative to the control. The presented data suggest the possibility of the nitrosation reaction in the human gastric juice under hypo- and anacidic conditions. ...
The metabolism of Nitrosomorpholine by rat liver microsomes gave acetaldehyde, formaldehyde, glyoxal and N-nitroso-2-hydroxymorpholine. Oxidation of N-nitrosomorpholine by Fenton's reagent gave acetaldehyde, glycolaldehyde, glyoxal, (2-hydroxyethoxy)acetaldehyde and N-nitroso-2-hydroxymorpholine. N-Nitroso-3-hydroxymorpholine, in water, gave mainly acetaldehyde, with glycolaldehyde, (2-hydroxyethoxy)acetaldehyde and glyoxal. These observations indicated the probability of 3-hydroxylation in the biological and chemical oxidations.

Toxicity Data
LCLo (mice) = 1,000 mg/m3/10min

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Interactions
Female Sprague-Dawley rats were randomly divided into four groups (Group 1: Control, Group 2: Sham-operated, Group 3: Ovariectomy, Group 4: ovariectomy+estrogen) with treatment of a single i.p. injection of diethylnitrosamine (100mg/ kg body weight) followed by N-nitrosomorpholine (100ppm) in drinking water for 20 weeks for the established rat HCC model. Physiological estrogen was administered by 17alpha-Ethynylestradiol at a dose of 30ug/ kg body weight while rats in the sham-operated group were treated with saline after initiation of liver carcinogenesis. Treatment of ovariectomized animals with 17alpha-Ethynylestradiol (30ug/kg body weight/ day) resulted in a significant decrease in the initiation, development and metastasis of HCC and an increase in the survival time of animals dead before the termination of experiment as compared with rats treated with ovariectomy only (p<0.05); whereas this difference disappeared when compared with the other three groups.
The effect of cysteamine (2-aminoethanethiol hydrochloride) on hepatocarcinogenesis induced by N-nitrosomorpholine was investigated in male Sprague-Dawley rats. 20 rats received alternate day sc injections of cysteamine, and beginning in exptl wk 3 were given drinking water containing 250 mg/l NMOR for 8 wk. Controls (n= 20) received saline sc. By wk 18, all rats that had received cysteamine had body and liver wt that were slightly increased over those of sodium chloride treated rats. Pre-neoplastic and neoplastic lesions staining positive for gamma-glutamyl transpeptidase or glucose-6-phosphate dehydrogenase were examined by histochemical techniques. In wk 18, quantitative histological analysis showed that prolonged administration /of/ cysteamine resulted in a significant reduction in the number of gamma-glutamyl transpeptidase-positive and glucose-6-phosphate dehydrog enase-positive hepatic lesions (from 31.4/sq cm for saline controls to 3 to 15.9/sq cm, respectively). Histologically, hepatocellular carcinomas were significantly fewer and smaller in gamma-glutamyl transpeptidase-positive and glucose-6-phosphate dehydrogenase-positive lesions in rats treated with cysteamine than in untreated rats. Admin of cysteamine also caused a significant decr in the liver norepinephrine concn and in the labeling indices of pre-neoplastic lesions and the surrounding liver.
Effects of 3,4,3',4'-tetrachlorobiphenyl on glucose-6-phosphatase (G6Pase)-altered hepatic foci of N-nitrosomorpholine treated B6C3F1 mice were investigated. 3,4,3',4'-Tetrachlorobiphenyl was chosen as a selective 3-methylcholanthrene-type inducer and tumor promoter. To initiate hepatocarcinogenesis, mice were treated with N-nitrosomorpholine (160 mg/L, in drinking water for 7 weeks), as in previous studies with the rat model. After a treatment-free interval of 22 weeks, 3,4,3'-4'-tetrachlorobiphenyl was administered (5 x 50 mg/kg, every 3 days), and liver foci were analysed 10 weeks after the start of 3,4,3',4'-tetrachlorobiphenyl treatment. The number of G6Pase-negative and -positive foci per liver was markedly diminished following 3,4,3',4'-tetrachlorobiphenyl treatment (to 32% and 57%, respectively). On the other hand, the mean volume of the remaining G6Pase-altered foci was enhanced, owing to an increase in the percentage of foci of large size (greater than 0.5 sq mm). Throughout the experimental period of 39 weeks prolonged liver injury due to N-nitrosomorpholine and 3,4,3',4'-tetrachlorobiphenyl treatment was demonstrated by histology and by elevated serum levels of glutamate-oxaloacetate transaminase. In contrast to the rat system, 3,4,3',4'-tetrachlorobiphenyl exhibited opposing effects on liver foci in the mouse model: (a) moderate tumor-promoting effects and (b) cytotoxic effects in N-nitrosomorpholine injured liver, leading to decreased numbers of liver foci.
The effects of oral fructose on hepatocarcinogenesis were investigated. Carcinogenesis was induced in male Sprague-Dawley rats by application of N-nitrosomorpholine for 7 weeks. Afterwards, the animals received fructose in the drinking water (120 g/L) and food ad libitum (group I) or tap water and food ad libitum (group II). The incidence of hepatocellular carcinoma in rats treated with N-nitrosomorpholine plus fructose was 46% as compared to 24% in animals receiving N-nitrosomorpholine alone (P < 0.05). There was no difference in the incidences of other malignancies between the groups (group I: 32.1%, group II: 32.0%). Morphometric evaluation of preneoplastic liver lesions indicated the enhancing effect of the fructose treatment several months before malignant tumors appeared. As early as 6 weeks after treatment the hepatic parenchyma occupied by focal lesions was increased from 6.7% in the animals which had received N-nitrosomorpholine alone to 8.5% (P < 0.05) in animals having received N-nitrosomorpholine plus fructose. This increase was predominantly caused by an increase in glycogen storing foci (P < 0.0005). In addition, the fructose treatment caused a histochemically detectable increase in the activity of glucose-6-phosphatase and glucose-6-phosphate dehydrogenase in both the hepatocytes of the focal lesions and the surrounding parenchyma. In the N-nitrosomorpholine plus fructose group the activity of the glucose-6-phosphatase in the foci was frequently approximately equal to the activity in the parenchyma of untreated controls.
For more Interactions (Complete) data for N-NITROSOMORPHOLINE (15 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat (route not specified) 320 mg/kg
LD50 Rat intravenous 98 mg/kg
LD50 Rat subcutaneous 170 mg/kg
LD50 Rat intraperitoneal 282 mg/kg
For more Non-Human Toxicity Values (Complete) data for N-NITROSOMORPHOLINE (8 total), please visit the HSDB record page.

[1]. K D Brunnemann, et al. N-Nitrosomorpholine and Other Volatile N-nitrosamines in Snuff Tobacco. Carcinogenesis. 1982;3(6):693-6.

n-Nitrosomorpholine can cause cancer according to an independent committee of scientific and health experts.
N-nitrosomorpholine appears as yellow crystals. Golden liquid with many crystals at 68 °F. (NTP, 1992)
N-nitrosomorpholine is a nitrosamine that is morpholine in which the hydrogen attached to the nitrogen is replaced by a nitroso group. A carcinogen and mutagen, it is found in snuff tobacco. It has a role as a carcinogenic agent and a mutagen.
N-Nitrosomorpholine is not used commercially in the United States. Limited information is available on the health effects of N-nitrosomorpholine. No information is available on the acute (short-term), chronic (long-term), reproductive, developmental, or carcinogenic effects of N-nitrosomorpholine in humans. Animal studies have reported effects on the liver from chronic exposure as well as tumors of the liver, nasal cavity, lung, and kidneys from oral exposure to N-nitrosomorpholine. EPA has not classified N- nitrosomorpholine for carcinogenicity. The International Agency for Research on Cancer (IARC) has classified N-nitrosomorpholine as a Group 2B, possible human carcinogen.
N-Nitrosomorpholine has been reported in Nicotiana tabacum with data available.
N-Nitrosomorpholine is a yellow, crystalline nitrosamine that is sensitive to light. N-Nitrosomorpholine is not used or produced commercially in the US. This substance has been found as a contaminant in rubber products, including rubber nipples for baby bottles, and is also found in several vegetables, cheeses, alcoholic beverages and fruits. N-Nitrosomorpholine is reasonably anticipated to be a human carcinogen. (NCI05)

C4H8N2O2

116.12

116.058

59-89-2

N-Nitrosomorpholine-d4;61578-30-1;N-Nitrosomorpholine-d8;1219805-76-1

6046

Yellow crystals

1.3±0.1 g/cm3

226.1±15.0 °C at 760 mmHg

29ºC

90.5±20.4 °C

0.1±0.4 mmHg at 25°C

1.547

-0.55

0

4

0

8

80.1

0

O1C([H])([H])C([H])([H])N(C([H])([H])C1([H])[H])N=O

ZKXDGKXYMTYWTB-UHFFFAOYSA-N

InChI=1S/C4H8N2O2/c7-5-6-1-3-8-4-2-6/h1-4H2

4-nitrosomorpholine

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 (861.18 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (21.53 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 25.0 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: ≥ 2.5 mg/mL (21.53 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 25.0 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: ≥ 2.5 mg/mL (21.53 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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