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Administrative data

Link to relevant study record(s)

Description of key information

No studies are available, the discussion below on the toxicokinetics and mechanisms of action of nitrogen trifluoride has primarily been drawn from the open literature.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - inhalation (%):
100

Additional information

Absorption:

Pulmonary uptake of nitrogen trifluoride (NF3) occurs at the respiratory bronchioles, alveolar ducts and sacs. The exchange of NF3 between the air and the body depends on a number of physical (e.g. mass transfer and diffusion), as well as physiological factors (e.g. alveolar ventilation and cardiac output) which are controlled by environmental conditions, physical exertion and other processes. The diffusion of NF3 across the alveolar capillary membrane is an entirely passive process of gas diffusion.

 

Distribution and mode of action:

NF3 oxidises erythrocyte haemoglobin (Hb) to methaemoglobin (MetHb), which is unable to carry oxygen, with death ensuing from the resulting anoxia (Ruff, 1931; Torkelsonet al., 1962; Dostet al.,1970a). The valence change in Hb changes from 2+ to 3+ through the loss of an electron, however the exact mechanism for the reaction is poorly understood. Reaction of NF3 with Hb bothin vitroandin vivowith anaesthetised dogs indicates that one mole of NF3 oxidises three haem equivalents (Dostet al., 1971), suggesting that inhaled NF3 reacts only with circulating Hb. The authors speculated that the capillary bed of the lung constituted the sole site of the reaction due to the very low solubility and reactivity of NF3. Death in monkeys, dogs, rats and mice following acute exposures was attributed to MetHb formation or conversely, the amount of oxyhaemoglobin remaining in the blood as measured immediately after exposure. A decrease in oxyhaemoglobin to less than 4g/100 mL (i.e. a >75% MetHb) invariably resulted in death of these animals. 

 

MetHb is normally accounts for <1% of the total blood Hb (Bloom and Brandt, 2008). Clinically MetHb is diagnosed when the %MetHb is greater than 1.5%. Most individuals tolerate levels less than 10% MetHb, but cyanosis may be obvious when MetHb concentration exceeds 5-10%. Levels above 20% are considered clinically significant. Signs and symptoms associated with MetHb concentrations in humans are summarized in Table 7.1-01. The ACGIH biological exposure index (BEI) for NF3 is measured by the level of MetHb in the blood. the BEI is set at level of 1.5% MetHb in blood after the end of the shift (NLM, 2000).

 

Table 7.1-01: Signs and symptoms associated with MetHb concentrations in humans

MetHb concentration (%)

Signs and symptoms

1.1

Normal level

1 – 15

No adverse effects

15 – 20

Clinical cyanosis (chocolate brown blood; no hypoxic symptoms

30

Fatigue; recovery without treatment

20 – 45

Anxiety, exertional dyspnea, weakness, fatigue, dizziness, lethargy, headache, syncope, tachycardia

45 – 55

Decreased level of consciousness

55 – 70

Hypoxic symptoms: semi-stupor, lethargy, seizures, coma, bradycardia, cardiac arrhythmias

>70

Heart failure from hypoxia; high incidence of mortality

>85

Lethal

Source: Kiese (1974) & Seger (1992)

 

MetHb reduces NADH-dependent cytochrome b5 reductase (also called MetHb reductase or NADH-diaphorase) which is present in the erythrocyte (Bloom and Brandt 2008). This enzyme accounts for 60-95% of the MetHb reduction. Two other less important reducing systems are present. The combined MetHb reduction pathways can reduce the ferric (Fe+3) iron of MetHb at a rate of approximately 15%/h. Rats in which 50% or more of Hb was oxidized required about 2 h to reduce the MetHb levels to less than 10% (Dostet al. 1970a). MetHb levels remained elevated at 2-5% for several days.

 

In addition to reducing the capacity of the blood to transport oxygen, NF3 causes the oxyhaemoglobin dissociation curve to shift to the left, reducing the amount of oxygen unloaded at the tissues. A reduction in unloading of oxygen is particularly serious in tissues such as myocardium where 60-70% of the oxygen in arterial blood is usually extracted (compared to 25% in many other tissues).

 

Fluoride ion distribution in several tissues were examined following an acute exposure of rats to NF3 (5000 ppm for 50 mins). Over the entire sampling period (0 – 48 h post exposure) the fluoride content in tissue was comparable to data presented by the authors for normal tissues. The exception to this was blood rich tissues (i.e., kidney, liver, spleen) along with RBC. The high content observed in the spleen was most likely due to the high concentration of erythrocytes present. One of the functions of the spleen is to remove erythrocytes containing Heinz bodies, as NF3 selectively targets RBC, oxidising Hb, forming Heinz bodies; the high concentration of fluoride ions within the spleen is therefore not surprising (Dostet al., 1970a).

 

Table 7.1-02: Fluroide ion content of tissues (μg F/g tissue wet wt) of normal rats

Tissue

Mean

Range

n

Bone

308

230 - 403

6

Blood plasma

-

-

-

Lung

2.0

0.8 - 2.8

8

Kidney

1.3

0.2 – 1.4

9

Liver

0.9

0.2 - 1.4

7

Spleen

2.0

0.5 - 4.0

8

Heart

1.8

0.5 - 3.8

10

Muscle (skeletal)

1.7

0.3 - 3.3

9

Stomach

1.8

0.4 - 3.1

9

Small intestine

1.6

0 - 2.6

8

Caecum

2.2

1.2 - 4.4

9

Large intestine

3.1

0.7 - 5.7

9

Brain

2.4

0 - 3.0

9

Fat

1.7

0.5 - 3.0

8

Testes

1.3

0 – 3.7

10

 

Table 7.1-03: distribution of fluoride ion in rat tissues (μg F/g tissue wet wt) following exposure to 5000 ppm for 50 minutes

Tissue

0

2

6

Mean

Range

n

Mean

Range

n

Mean

Range

n

Plasma

8.1

6.1 – 11.3

4

 

 

 

1.6

1.4 – 2.1

3

RBC

28

18.5 – 30.0

3

15.1

14.9 – 15.4

2

24.9

18.2 – 33.0

3

Bone

198

178 – 227

3

17

140 – 239

3

250

185 - 294

3

Lung

3.0

2.5 – 3.5

3

2.0

0.1 – 3.5

3

2.4

1.2 – 3.9

3

Kidney

6.9

5.7 – 8.5

3

3.5

2.3 -5.7

3

4.5

1.2 – 9.8

3

Liver

2.6

1.6 – 3.3

3

0.9

0.6 – 1.3

3

0.9

0.7 – 1.3

3

Spleen

5.7

1.0 – 11.2

3

10.1

2.8 – 23.4

3

12.3

3.7 -28.6

3

Heart

5.4

3.7 – 7.5

3

3.5

1.5 -6.5

3

3.8

1.8 – 5.9

3

Muscle (skeletal)

2.2

1.6 – 3.0

3

2.0

0.7 – 4.1

3

2.8

0.3 – 4.8

3

Stomach

2.1

0.8 – 2.6

2

1.7

1.3 – 2.3

3

3.2

1.2 – 6.5

3

Small intestine

1.4

1.0 – 1.8

3

2.2

1.7 – 2.9

3

1.1

0.1 – 2.3

3

Caecum

4.9

3.3 – 8.0

3

3.6

2.0 6.7

3

3.5

2.5 – 5.6

3

Large intestine

2.9

1.9 – 4.3

2

3.0

2.2 – 5.0

3

1.7

1.1 – 2.3

2

Brain

2.9

3.2 – 3.7

3

1.5

0.1 – 1.9

3

1.6

0.4 – 3.6

3

Fat

2.4

1.2 – 4.1

3

2.3

1.3 – 3.2

3

2.3

1.7 – 2.4

3

Testes

4.3

2.6 – 5.5

3

3.6

1.9 -6.6

3

2.2

0.2 – 5.5

3

 

 Tissue

12

24

48

Mean

Range

n

Mean

Range

n

Mean

Range

n

RBC

18.8

18.4 – 19.3

2

23.6

17.7 – 31.7

3

16.4

14 – 18.8

3

Bone

324

251 – 318

3

253

251 – 318

3

243

207 -263

3

Lung

1.8

1.6 -2.0

3

2.5

2.2 – 3.0

3

1.5

1.5 – 1.5

2

Kidney

2.2

1.9 -2.5

3

1.8

1.7 - 2.0

3

1.2

1.1 – 1.4

2

Liver

3.1

2.9 – 3.5

3

1.1

0.5 – 2.0

3

0.7

0.7 -0.8

2

Spleen

4.4

1.7 – 6.0

3

4.3

1.5 – 5.8

3

6.1

5.8 -6.5

2

Heart

3.4

2.0 – 5.1

3

2.2

2.2 – 2.3

3

4.1

2.7 – 5.6

2

Muscle (skeletal)

0.7

0.7 – 0.8

3

0.7

0.5 – 0.8

3

0.7

0.5 -1.0

2

Stomach

1.9

1.6 – 2.5

3

1.6

1.2 – 2.2

3

1.3

0.8 -1.8

2

Small intestine

1.6

0.7 – 2.9

3

1.2

1.1 – 1.3

3

0.6

0.4 -0.9

2

Caecum

3.6

2.3 – 5.0

3

3.4

2.3 – 5.5

3

1.0

0.9 – 1.2

2

Large intestine

1.9

1.2 -2.7

3

3.2

2.2 – 3.7

3

1.6

1.1 – 2.2

2

Brain

1.0

0.8 – 1.2

3

0.8

0.7 – 0.9

3

0.8

0.8 – 0.8

2

Fat

1.2

1.1 – 1.2

3

1.4

1.2 – 1.8

3

1.1

1.1 – 1.2

2

Testes

1.3

1.0 – 1.5

3

1.4

0.9 – 2.1

3

1.2

1.2 – 3.1

2

Taken from Dostet al(1970a).

Where mean values are outside the normal controls (Table 7.1-02) the values have been italicised

 

Although fluoride accumulation in the adrenal or thyroid were not measured in this study, despite the concerns raised by Lee and Jacobs (1968) that some nitrogen fluorides may selectively deposit in the thyroid following observations that rats intoxicated with trifluoramine oxide (NF3O) do concentrate fluoride in some form in the endocrine organ, no adverse effects in either the adrenal glands or thyroid were observed in the 90 d study.

 

MetHb is usually accompanied by the presence of Heinz bodies. Heinz bodies are precipitates of protein in erythrocytes that develop after oxidation of Hb. Erythrocytes with Heinz bodies are removed by the spleen, however in the case of NF3 intoxication, as the spleen is the target organ the ability of the spleen to remove these is greatly affected.

 

It is conceivable that other non-hypoxic mechanisms of action underlying the biological effects of NF3 may involve alteration in other signalling pathways. Due to the propensity of NF3 to oxidise haem containing proteins it is also conceivable that NF3 may also inhibit cytochrome c oxidase (terminal enzyme in the mitochondrial electron transport chain), haem loss from proteins, disruption in iron homeostasis, alteration in cellular redox status (leading to an increase in cellular oxidative stress) and ion channel activity (in particular Ca2+activated K+channels), and modulation of protein kinase pathways.

 

Metabolism

NF3 is a direct acting chemical and metabolism is not involved in formation of MetHb. Studies conducted by Dost (1970a, b, 1971) using inorganic fluoride do not suggest the existence of any fluoride-bearing degradation products which behave differently from fluoride ions. Rats exposed to 5000 ppm of NF3 for 50 mins exhibited a moderate increase in tissue fluoride, which disappeared in one day. However, a high concentration of fluoride persisted in erythrocytes and in some animals in spleens for up to 48 h post-exposure. Dost and colleagues also noted that some NF3 may selectively deposit in the thyroid.

 

Excretion

Data regarding excretion of fluoride ions is limited. From the GLP repeat dose studies conducted the main principal route of excretion is through the kidneys and into the urine.

 

Susceptible populations

There are individuals who are sensitive to chemicals that oxidise Hb to MetHb (Eaton & Gilbert, 2008). Individuals with an inherited deficiency of NADH-methaemoglobin reductase have 10-15% of their circulating blood pigment in the form of MetHb. This condition is inherited as an autosomal recessive trait and is characterised by a deficiency in NADH-cytochrome b5 reductase activity. The effect is primarily cosmetic as these individuals have a compensatory polycythemia, although symptoms may occur during exercise. Other individuals may have a deficiency of erythrocyte NADPH-glucose-6-phosphate dehydrogenase, an enzyme responsible (viathe pentose phosphate shunt), for generating an alternate source of energy for the cell; these individuals do not have elevated levels of MetHb as this is a minor MetHb reducing system (Kiese, 1974; Seger 1992). The Hb of individuals with defective Hb M or H is more susceptible to auto-oxidation of the ferric iron (Seger, 1992; Smith, 1996). Individuals with Hb M maintain MetHb levels of 25-30% and are clinically cyanotic. Individuals with Hb H suffer from chronic haemolytic anaemia (thalassemia). Individuals with anaemia may be more sensitive to MetHb-forming chemicals than healthy individuals.

 

NADH-methaemoglobin reductase is deficient in neonates making them especially sensitive to chemicals that cause methaemoglobinaemia (Gregus & Klassen, 2001). NADH lacks full activity until infants are 4 months of age.

 

Results from animal studies indicate that inhaled NF3 can increase haemoglobin concentration and haematocrit ratio, which probably represents a compensation for the reduction in oxygen transport caused by NF3. At high NF3 concentrations, excessive increases in haemoglobin and haematocrit may impose an additional workload on the heart and compromise blood flow to the tissues.

 

References:

Bloom, J.C. & J.T. Brandt. (2008). Chapter 11: Toxic Responses of the Blood. pp. 455-484 in Casarett & Doull’s Toxicology: The Basic Science of Poisons. New York: McGraw Hill Companies, Inc.

 

Dost, F.N., Reed, D.J. & Wang, C.H. (1970a). Toxicology of nitrogen trifluoride.Toxicol. Appl. Pharmacol.17, pp 585-596

 

Dost, F.N., Reed, D.J. & Wang, C.H. (1970b). Fluoride distribution following acute intoxication with nitrogen and halogen fluorides and with sodium fluoride.Toxicol. Appl. Pharmacol.17, pp 575-584.

 

Dost, F.N., Reed, D.J., Johnson, D.E. & Wang, C.H. (1971). Stoichiometry of the reaction of haemoglobin with nitrogen trifluoridein vitroandin vivo.J. Pharmacol. Exp. Therap.176, pp 448-454.

 

Eaton, D.L. & Gilbert, S.G. (2008). Chapter 2: Principles of toxicology. pp 16 in Casarett & Doull’s Toxicology: The basic science of poisons. New York: McGraw Hill Companies, inc.

 

Gregus, Z & Klassen, C.D. (2001). Chapter 3: Mechanisms of toxicity. In Casarett and Doull’s Toxicology: The basic science of poisons. New York: McGraw Hill Companies, inc.

 

Kiese, M. 1974. Methemoglobinemia: A Comprehensive Treatise. Cleveland, OH: CRC Press

 

NLM (2012). HSDB (Hazardous Substances Data Bank)., Bethedsa, MD, National Laboratory of Medicine [http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+7783-54-2]

 

Ruff, O. (1931). Zur Kenntnis des Stickstoff-3-fluroids.Z. Anorg. Allgem. Chem.197, pp 273-286

Seger, D.L. 1992. Methemoglobin-Forming Chemicals. pp. 800-806 in: J.B. Sullivan and G.R. Krieger, Eds., Hazardous Materials Toxicology: Clinical Principles of Environmental Health. Baltimore, MD: Williams & Wilkins Co.

 

Seger, D.L. (1992). Methemoglobin-forming chemicals. pp 800-806 in: J.B. Sullivan & G.R. Krieger, eds., Hazardous materials toxicology: clinical principles of environmental health. Baltimore, MD: Williams & Wilkins Co.

 

Smith, R.P. (1996). Toxic responses of the blood. pp 335-354 in Casarett and Doull’s Toxicology: The basic science of poisons. New York: McGraw Hill Companies, inc.