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Diss Factsheets

Administrative data

Description of key information

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

As nitrogen trifluoride is a gas, the oral route of exposure is not relevant

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:

A NOAEL was deemed to be 5 ppm (equivalent to 14.8 mg/m3) for both males and females based on the evidence of haemolytic anaemia at the LOAEL of 20 ppm.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:

no local effects observed

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:

As nitrogen trifluoride is a gas, the dermal route of exposure is not relevant

Justification for selection of repeated dose toxicity dermal - local effects endpoint:

As nitrogen trifluoride is a gas, the dermal route of exposure is not relevant

Repeated dose toxicity: inhalation - systemic effects (target organ)cardiovascular / hematological: heart; cardiovascular / hematological: spleen; cardiovascular / hematological: other; digestive: liver

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Data waiving:
exposure considerations
Justification for data waiving:
a short-term toxicity study by the oral route does not need to be conducted because an appropriate inhalation study is available and inhalation is the most appropriate route of administration as based on the provided thorough and rigorous exposure assessment
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
As nitrogen trifluoride is a gas, the oral route of exposure is not relevant
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
n/a

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
9 December 2002 to 17 April 2003
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP, TG compliant
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3465 (90-Day Inhalation Toxicity)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Age:5 wks(males and females)
Weight at dosing:184 - 239g(males); 131 - 186g(females)
Source:Charles River Breeding Labs
Acclimation period:6 days
Diet:PMI certified rodent diet #5002ad libitum(with the exception of food held during exposure. Furthermore, animals were fasted overnight prior to blood sampling)
Water:tap water,ad libitum(with the exception of water held during exposure)
Housing:individually housed
 
Environmental conditions -
Temperature:22 – 24°C
Humidity:40 - 60%
Air changes:not stated
Photoperiod:12 hours of light/day
Route of administration:
inhalation: gas
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
Generation of test atmosphere / chamber description:
A gas atmosphere of NF3 was generated by metering the test substance in air from a high pressure cylinder located in a remote generation shed. The test substance was metered into the air stream with a Brooks model 1355 Sho-Rate Flowmeter. Filtered, high-pressure air introduced into the top of the chamber carried the resulting atmosphere into the exposure chamber.

All exposure chambers were constructed of stainless steel and glass (NYU style) with a nominal internal volume of 300 L. A baffle at the chamber inlet promoted uniform chamber distribution of the test atmosphere.

During exposure, rats were placed within wire-mesh cages and exposed whole-body inside the exposure chamber. The chamber volume was chosen so that the total body volume of the test animals did not exceed 5% of the chamber volume.

Chamber airflow was set at the beginning of each exposure to achieve at least 10 air changes/h. Chamber temperature was targeted at 22 ± 2°C. Chamber relative humidity was targeted at 50 ± 10%. Airflow, temperature, and relative humidity were monitored continually. Chamber oxygen concentration was targeted to at least 19%, with oxygen concentration measured 1 – 2 times during each exposure.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Chamber concentrations of NF3 were controlled by varying the test substance feed rate to the air stream.
Duration of treatment / exposure:
90 d
Frequency of treatment:
6h/d, 5/d/wk for a total of 65 exposures
Dose / conc.:
5 ppm (nominal)
Dose / conc.:
20 ppm (nominal)
Dose / conc.:
50 ppm (nominal)
Dose / conc.:
100 ppm (nominal)
No. of animals per sex per dose:
15/sex/gp
Control animals:
yes, concurrent vehicle
Details on study design:
Animals were assigned to dose groups randomly, based on weight. In total there were 5 dose groups, 4 treatment and 1 control group all consisting of 15 animals/dose/sex. Animals were exposed (whole-body) to NF3 in air 6 h/d for a total of 65 exposures at concentrations of 0, 5, 20, 50 or 100 ppm. At the end of the treatment period 10 rats/sex were sacrificed and subject to full histopathological examination. The remaining animals (5/sex/gp) were allowed to recover for 1 month. At the end of the recovery period, blood and urine samples were collected for clinical analyses, and all surviving rats were sacrificed for anatomic pathology examination.
Observations and examinations performed and frequency:
Daily during exposure. Post exposure each rat was individually handled and examined for abnormal behaviour and appearance.
Sacrifice and pathology:
Sacrifice and Gross Pathology:
Gross pathological examination was performed on all animals, grossly observable organ or tissue changes were recorded, with any tissue of abnormal appearance preserved in 10% NBF. All gross lesions, adrenals, aorta, bone (with marrow), brain (cerebellum, cerebrum, medulla/pons, midbrain), caecum, eyes (+ optic nerve), femur/knee joint, heart, intestine (small: duodenum, ileum, jejunum; large: colon), kidneys, larynx, liver, lung, lymph nodes (mandibular, mesenteric), mammary area, nose (4 sections), oesophagus, pancreas, pharynx, prostate, rectum, salivary glands, sciatic nerve, seminal vesicles, skeletal muscle, spinal cord (cervical, lumbar, thoracic), spleen stomach, sternum, testes (+epididymis), thyroid (+parathyroids), trachea, uterus (+ovaries and cervix), urinary bladder, vagina

Histopathology:
All collected tissues, detailed above were processed and received a full histological examination for all control and high dose groups. Target organs and gross observations from rats in the 5, 20, and 50 ppm exposure groups were also examined. Target organs and gross observations were examined in all of the rats sacrificed after the one month recovery in order to assess the reversibility of test substance-related microscopic effects.

Organ weights:
Adrenal glands, brain, epididymides, heart, kidneys, liver, lungs, ovaries, spleen, testes, thymus, uterus.
Other examinations:
Food consumption:
Mean daily food consumption was determined.

Opthalmoscopic examination:
Not determined

Recovery period
At the conclusion of the 90-day exposure period, 5 rats/sex/gp were allowed to recover for ~1 month. During the recovery period, exposures were not conducted; however, in-life observations and measurements (clinical observations, body weights, and individual food consumption) were continued. Prior to the end of the recovery period, all surviving rats underwent a clinical pathology evaluation. At the conclusion of the recovery period, surviving rats were sacrificed and appropriate tissues collected for microscopic evaluation.

Haematology & clinical chemistry:
Collected from main study animals just prior to necropsy. For recovery animals, blood sampled at the end of the recovery period.
The following haematology and serum clinical chemistry parameters were measured:
Haematology: erythrocyte count, neutrophills, leukocytes, band neutrophils, platelets, lymphocytes, atypical ;lymphocytes, haemocrit, haemoglobin concentration, monocytes, mean corpuscular volume, mean corpuscular haemoglobin, eosinophils, basophils, mean corpuscular haemoglobin concentration, MetHb concentration, Heinz bodies, microscopic blood smear examination, absolute reticulocyte count, red cell distribution width, prothrombin time, activated thromboplastin time, absolute reticulocyte count
Clinical chemistry: alanine aminotransferase, albumin, alkaline phosphatase, aspartate aminotransferase, calcium, cholesterol, chloride, creatinine, fluoride, globulin, glucose, phosphorus, potassium, sodium, sorbitol dehydrogenase, total bilirubin, total protein, triglycerides, urea nitrogen

Urinalysis:
Urine collected the night prior to the last exposure. The following urinary parameters were measured:
Volume, colour, clarity, quality, osmolality, urobilinogen, pH, hemoglobin or occult blood, fluoride concentration, glucose, protein, bilirubin, ketone (acetoacetic acid), microscopic urine sediment
Statistics:
Appropriate statistical analyses (Levene’s test for homogeneity, Shapiro-Wilk test for normality, ANOVA F-test, Kruskal-Wallis test, Jonckheere-Terpstra trend test, Dunnett's test, Dunn's test, Cochran-Armitage test for trend) were undertaken
Clinical signs:
no effects observed
Description (incidence and severity):
All animals survived to the scheduled necropsy. No test material related clinical signs of toxicity were observed.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No test material related effects were observed.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Since Heinz bodies cause positive interference in the determination of haemoglobin concentration the RBC was considered to be the most reliable indicator of circulating erythrocyte mass. Decrements in red cell mass were accompanied by appropriately increased reticulocytes in M and F rats exposed to 20, 50, or 100 ppm, indicating appropriately accelerated red cell production. Because reticulocytes are larger than mature red cells, these groups tended to have increased mean cell volume. M rats exposed to 100 ppm and F rats exposed to 50 or 100 ppm had increased red cell distribution width, indicating a variably sized population of red cells, which was also consistent with accelerated red cell production.

Microscopically, there was an increase in the number of blood smears with greater than trace polychromatophilic erythrocytes (PCE) in M rats exposed to 100 ppm and in F rats exposed to 50 or 100 ppm. The presence of PCE in the systemic circiulation indicates immaturity in the red cell population. Due to increased MetHb formation, reducing the bloods ability to carry oxygen, the compensatory response is to increase cell turn over. As a result developing erythrocytes are unable to mature fully, resulting in immature cells released into the systemic circulation, Further support comes from the increase in the number of animals with Howell-Jolly bodies (or micronuclei) observed/blood smear. Howell-Jolly bodies are remnants of nuclear DNA that are normally observed in conjunction with accelerated red cell production. These changes resulted from the appropriate acceleration of red cell production described above. In addition, the incidence and degree of acanthocytes observed on smears was increased in male and female rats exposed to 100 ppm.

Increases in the incidence of red cells containing Heinz bodies (marker of denatured Hb – indicating oxidative damage) were observed in animals exposed to 50 or 100 ppm. The % of MetHb tended to be minimally higher in rats exposed at dose level of 20 ppm and greater. The difference however in % MetHb concentration in individual animals was small. MetHb is produced normally in the body, and is continually reduced to functional haemoglobin. The presence of Heinz bodies and the increased %MetHb are both indicators of oxidant damage to red blood cells. Although neither indicator of oxidative damage was of significant magnitude to alter oxygen distribution to tissues, the measurements indicated that oxidant damage was a likely factor resulting in the decreased red cell mass.
Increases in total white cell counts were also observed, these increases were considered treatment related and were possible secondary to the haemolytic effect (data not presented). These increases observed however remained within the laboratory’s historical control range. See table Table 7.5.3/01-1: Selected haematology parameters in other any information.

After one month of recovery (test day 128), red cell mass parameters were increased compared to end of study values and compared to concurrent controls in all groups of previously exposed rats, in a concentration-related manner (variable statistical significance). This effect was exaggerated in M rats by the presence of one control rat with results suggesting intercurrent disease unrelated to treatment (decreased red cell mass, red cell morphologic changes, increased white blood cell count). The changes in rats previously exposed to NF3 were likely due to extramedullary haematopoiesis present at the time of discontinuation of administration of test material. It is likely that many red cell precursors continued to develop into mature red cells although the need for accelerated red cell production was gone. The lack of erythropoietic stimulus during this rebound phase probably resulted in generally lower reticulocyte counts and lower red cell distribution width in exposed rats compared to controls (variable statistical significance). Therefore, these changes after recovery were expected sequelae of the regenerative process, and confirm the reversibility of the haemolytic effects. All other red cell parameters, including instrument-generated and microscopic data, were similar to control values after one month of recovery.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Bilirubin concentration was mildly increased in M rats exposed to 100 ppm and in female rats exposed to 50 and 100 ppm at test day 94. This was considered to be secondary to increased haemoglobin turnover resulting from the red cell toxicity described above. Increased bilirubin was therefore secondary to the hematologic effects.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Mean urine fluoride concentrations were increased in the all treated groups. This would indicate that NF3 was metabolised, with fluoride ions released.

At the end of dosing the incidence of positive tests for urinary bilirubin was increased. This change was expected in light of the aforementioned increases in serum bilirubin concentration in these groups and are considered to be a secondary process resulting from oxidant injury of red cells and haemolysis. After one month of recovery (test day 128), urine bilirubin concentrations were similar across all groups. See Table 7.5.3/01-2: Selected urinary parameters in other any information.
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
Mean absolute spleen weights were increased 7%, 20%, 45%, and 110% in male rats and 18%, 15%, 76%, and 127% in female rats in the 5, 20, 50, and 100 ppm exposure groups, respectively, as compared to controls. Since there was no treatment-related effect on body weights, mean spleen weight/body weight and spleen weight/brain weight ratios were similarly increased. The increase in spleen weight parameters correlated with the gross observation of dark and/or large spleens (see Gross Observations) and the microscopic finding of congestion at these exposure levels.

Following the one-month recovery period, mean organ weight parameters were considered increased only in the spleen at the highest exposure level (100 ppm) in both sexes. Mean absolute spleen weights were increased 17% and 13% in the 100 ppm male and female rats, respectively, as compared to controls. The increased mean weights were not statistically significant since the increases were small and the individual animal variability (i.e., standard deviations) was high. Although spleens were no longer grossly enlarged or microscopically congested in the recovery rats, there was still an exposure-related increase in microscopic pigment accumulation. The small increase in mean splenic weight parameters in the 100 ppm exposed rats was probably the result of this persistence of accumulated pigment.
Description (incidence and severity):
Test material related enlarged and/or dark spleen and dark liver were observed in all test material treated animals sacrificed on day 94. In the recovery animals no test material related gross observations were noted. See table 7.5.3/01-3: Selected gross pathology spleen findings parameters in main study animals in other many information.
Description (incidence and severity):
Microscopic changes that typically occur are secondary to increased red blood cell turnover were observed in the liver, kidneys, spleen and bone marrow of treated rats, increasing with incidence with increasing dose. See table 7.5.3/01-3: Selected histopathology findings in main study animals in any other information.

Following the one-month recovery period, the only remaining test-substance related microscopic finding was the persistence of haemosiderin pigment in the spleen, liver, and kidneys (F only). Both the incidence and severity of the pigment was slightly less in the recovery rats, as compared to the 90-day sacrifice rats, indicating that the deposition of pigment had ceased and the slow removal of pigment was in process.

The treatment-related increase in medullary (bone marrow) and extramedullary (spleen and liver) haematopoiesis, observed in the 90-day sacrifice rats, and associated splenic congestion, was not apparent in the one-month recovery rats. Increased haematopoiesis and splenic congestion were therefore considered to be completely reversible effects. See table 7.5.3/01-4: Selected histopathology findings in recovery animals in any other information.
Dose descriptor:
NOAEC
Effect level:
ca. 5 ppm
Sex:
male/female
Basis for effect level:
other: evidence of haemolytic anaemia (20 ppm and greater)
Dose descriptor:
NOAEC
Remarks:
reproductive organs
Effect level:
> 100 ppm
Sex:
male/female
Basis for effect level:
other: HDT - no adverse effects
Critical effects observed:
not specified

OBSERVATIONS:

Haematology

 

Table 7.5.3/01-1: Selected haematology parameters

Parameter

Day

Males

Females

0

5

20

50

100

0

5

20

50

100

RBC (x106/uL)

94

8.92

8.76

8.33*

8.32*

7.54*

8.29

8.21

7.69*

6.80*

6.72*

128

8.40

8.89

8.85

8.79

9.20*

7.95

8.34

8.38

8.69*

8.40

Hb (g/dL)

94

15.7

15.3

15.0*

14.9*

13.9*

15.6

15.3

14.8*

13.7*

13.6*

128

14.5

15.5

15.5

15.5

16.1

14.8

15.3

15.8*

16.2*

16.1*

Ht (%)

94

49.2

48.0

47.4

47.7

44.2*

47.6

47.8

45.6

42.6*

42.8*

128

45.4

48.8

48.8

49.3

51.0*

45.7

47.2

48.3

50.2*

49.5*

MCV (fl)

94

55.3

54.7

56.9

57.3*

58.6*

57.5

58.3

59.3

62.7*

63.6*

12

54.0

54.9

55.1

56.0

55.5

57.7

56.6

57.6

57.7

59.0

%Methb

94

0.5

0.5

0.6

0.7*

0.6

0.5

0.5

0.6

0.6#

0.6#

128

0.5

0.4

0.5

0.5

0.4

0.7

0.7

0.7

0.7

0.7

Absolute ret. Count (x103/uL)

94

186.4

223.2

250.7

325.5*

451.9*

150.0

201.6

229.6*

357.4*

416.9*

128

264.3

204.5

156.6

138.6#

152.0

166.2

156.5

172.2

121.5

125.4

* p<0.05 (Dunnett’s test)

#p<0.05 (Dunn’s test)

 

Urinalysis:

 

Table 7.5.3/01-2: Selected urinary parameters

Parameter

Day

Males

Females

0

5

20

50

100

0

5

20

50

100

Bilirubin

(no. of +ve)

94

2/10

4/10

4/10

5/10

7/10

2/10

2/10

3/10

4/10

4/10

128

1/5

1/5

1/5

1/5

1/5

0/5

0/5

2/5

0/5

2/5

Fluoride (ug)

94

8.4

9.2

13.6

21.8*

47.1*

5.4

5.7

9.4*

14.2*

25.7*

128

12.1

16.5

12.7

15.6

25.4*

7.8

12.3

8.3

10.0

17.1

#p<0.05 (Mann-Whitney U test)

 

Sacrifice and Gross Pathology:

 

Table 7.5.3/01-3: Selected gross pathology spleen findings parameters in main study animals

Parameter

Males

Females

0

5

20

50

100

0

5

20

50

100

Large

0/10

1/10

3/10

8/10

10*10

0/10

0/10

0/10

4/10

10/10

Dark

0/10

2/10

5/10

9/10

9/10

0/10

1/10

4/40

10/10

10/10

Large and/or dark

0/10

2/10

5/10

9/10

10/10

0/10

1/10

4/10

10/10

10/10

(no. of affected animals / no. of animals examined)

 

Histopathology:

 

Table 7.5.3/01-3: Selected histopathology findings in main study animals

Parameter

Males

Females

0

5

20

50

100

0

5

20

50

100

Spleen

- Pigment, increased

0/10

0/10

10/10

10/10

10/10

0/10

2/10

10/10

10/10

10/10

-EMH, increased

1/10

2/10

7/10

6/10

10/10

0/10

2/10

6/10

9/10

10/10

- Congestion

0/10

2/10

10/10

10/10

10/10

0/10

4/10

10/10

10/10

10/10

 

Liver

- Pigment, increased

0/10

0/10

0/10

6/10

10/10

0/10

0/10

0/10

10/10

10/10

-EMH, increased

0/10

0/10

0/10

2/10

7/10

0/10

1/10

0/10

5/10

10/10

 

Kidney

- Pigment, increased

0/10

0/10

0/10

0/10

5/10

0/10

0/10

0/10

2/10

10/10

 

Bone marrow

- Haematopoiesis, increased

0/10

0/10

1/10

4/10

7/10

1/10

2/10

2/10

8/10

10/10

(no. of affected animals / no. of animals examined)

EMH – extramedullary haematopoiesis .

 

Table 7.5.3/01-4: Selected histopathology findings in recovery animals

Parameter

Males

Females

0

5

20

50

100

0

5

20

50

100

Spleen

- Pigment, increased

0/10

0/10

5/10

5/10

5/10

0/10

1/10

510

5/10

5/10

-EMH, increased

0/0

1/10

0/10

0/10

0/10

0/10

0/10

0/10

0/10

0/10

- Congestion

0/10

/10

0/10

0/10

0/10

0/10

0/10

0/10

0/10

0/10

 

Liver

- Pigment, increased

0/10

0/10

0/10

0/10

2/10

0/10

0/10

0/10

2/10

5/10

-EMH, increased

0/10

0/10

0/10

0/10

0/10

0/10

0/10

0/10

0/10

0/10

 

Kidney

- Pigment, increased

0/10

0/10

0/10

0/10

0/10

0/10

0/10

0/10

1/10

3/10

 

Bone marrow

- Haematopoiesis, increased

0/10

1/10

0/10

0/10

0/10

0/10

0/10

0/10

0/10

0/10

(no. of affected animals / no. of animals examined)

EMH – extramedullary haematopoiesis

 

Conclusions:
Based on the results of this study, the NOAEL was deemed to be 5 ppm for males and females based on evidence of haemolytic anaemia (20 ppm and greater). 
Executive summary:

Nitrogen trifluoride was administeredviawhole-body exposure to groups of rat (15/sex/gp) at concentrations of 0, 5, 20, 50 or 100 ppm for 6 h/d for a total of 65 exposures. At the end of the treatment period 10 rats/sex were sacrificed and subject to full histopathological examination. The remaining animals (5/sex/gp) were allowed to recover for 1 month. At the end of the recovery period, blood and urine samples were collected for clinical analyses, and all surviving rats were sacrificed for anatomic pathology examination. The maximum dose tested was based on result of a 2-week inhalation study where a dose of 100 ppm caused significant haemolysis.

 

Following exposure no effects on body weight or adverse clinical signs of toxicity attributed to the test material were observed.

Haematological analysis at the end of the 90 d exposure period confirmed that red cell mass parameters (red cell count, haemoglobin, haematocrit) were mildly to moderately decreased in M and F rats exposed to 20 ppm and above. Heinz bodies (50 ppm and above) and %MetHb (20 ppm and above) were also increased. These changes indicated that oxidative damage to red cells resulting in extravascular haemolysis was a likely cause for the decrements in red cell mass. Decrements in red cell mass were accompanied by appropriately increased reticulocytes, indicating regeneration of red blood cells. Red cell regeneration was characterized by increased mean cell volume, red cell distribution width, polychromasia, and Howell-Jolly bodies. Other changes considered secondary to the red cell effects included increased platelets, white blood cell counts, and serum and urine bilirubin in some groups of rats. There were no statistically significant or treatment related changes in plasma fluoride concentrations at the end of the exposure period. At this same time-point, the mean amounts of excreted fluoride (urine fluoride) were increased in M and F rats exposed to 20, 50, or 100 ppm. After one month of recovery, urine fluoride concentrations were still increased in M rats previously exposed to 100 ppm.

 

Test material-related increases in haematopoiesis and pigment deposition were observed in multiple organs of treated rats. Congestion was noted in the spleen of rats exposed to the test material. Increased haematopoiesis in the bone marrow, spleen, and liver, as well as splenic congestion, was present in rats sacrificed following the exposure period, but not in rats following the recovery period. In addition, increased pigment deposition in the spleen, liver, and kidney was slightly reduced in the recovery rats, as compared to the 90-day sacrifice rats.

 

Test-material-related effects on gross pathology and organ weights were only observed in the spleen where congestion and pigment deposition resulted in large dark spleens with increased organ weight parameters. In the one-month recovery rats, only a small increase in mean splenic weight parameters was still present in the high dose groups (probably as a result of persistence of increased splenic pigment).

 

All of the test-material related effects on organ weights, gross pathology, and histopathology were considered to be normal, reversible, physiological responses to increased red cell turnover (haemolysis). While the organ weight, gross pathology, and histopathology effects were, in themselves, not adverse, their incidence and severity correlated with the degree of increased red cell turnover demonstrated by the haematology parameters.

 

Based on the results of this study, the NOAEL was deemed to be 5 ppm for males and females based on evidence of haemolytic anaemia (20 ppm and greater). 

 

Of note the author concluded different a NOAEL based on the lack of adverse effects, with the NOAEL for males and females set at 50 and 20 ppm, respectively. The author’s opinion was that the effects observed were not considered adverse, but normal physiological responses to haemolysis. As haemolysis is the principle outcome following exposure to NF3, this is considered to be a toxic insult, and therefore the NOAEL needs to be established taking this into account. Therefore the NOAEL of 5 ppm is deemed a suitable NOAEL to reflect haemolysis and histopathological findings reported at the LOAEL (20 ppm).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
14.8 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
KL.1

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
n/a

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
n/a

Additional information

Repeat oral toxicity

As nitrogen trifluoride is a gas, the oral route of exposure is not relevant.

 

Repeat dermal toxicity

As nitrogen trifluoride is a gas, the dermal route of exposure is not relevant.

 

Repeat inhalationtoxicity

In this study the NOAEL of 20 ppm (equivalent to 59.2 mg/m3[1 ppm = 2.96 mg/m3, Health Council of the Netherlands, 2004]) was established for both males and females, based on the effects observed (discussed above at LOAEL of 100 ppm). 

In the sub-chronic (90 d) inhalation study (O’Neill, 2003) similar test material related changes observed in the sub-acute study were also observed in this study, with the principal toxic effect being manifest as haemolytic anaemia, with secondary responses associated with this. A secondary response to the haemolytic anaemia, increased erythropoiesis which resulted in immature erythrocytes being released into the systemic circulation. In addition to the blood, target organs of toxicity were those associated with the greatest blood flow / those that are involved in haematopoiesis, principally the spleen, liver and kidney. Splenic congestion was noted, with increased pigment deposition noted in these organs at termination. These are secondary responses to the loss of large amounts of circulating RBC in the form of erythropoiesis manifest in the spleen, liver and bone marrow. Enlarged and/or dark spleen, dark liver were observed, which was deemed characteristic of Hb pigment deposition.

In recovery animals these effects were not as severe, suggesting that following withdrawal of the toxic insult recovery was observedalbeitwith some rebound effects (i.e. generally lower reticulocyte counts and lower red cell distribution width in exposed rats compared to controls following the lack of erythropoietic stimulus. It is likely that many red cell precursors continued to develop into mature red cells although the need for accelerated red cell production was gone). Whilst MetHb concentration could not be determined in the high dose animals (due to a colour change in the plasma caused by large amounts of MetHb formation), the presence of an increased incidence of Heinz body formation (i.e. marker of oxidised Hb) confirmed an increase in the amount of MetHb in circulating RBC.

In this study the NOAEL was deemed to be 5 ppm (equivalent to 14.8 mg/m3) for both males and females based on the evidence of haemolytic anaemia at the LOAEL of 20 ppm.

Of note the author concluded different a NOAEL based on the lack of adverse effects, with the NOAEL for males and females set at 50 and 20 ppm, respectively. The author’s opinion was that the effects observed were not considered adverse, but normal physiological responses to haemolysis. As haemolysis is the principle outcome following exposure toNF3, this is considered to be a toxic insult, and therefore the NOAEL needs to be established taking this into account. Therefore the NOAEL of 5 ppm is deemed a suitable NOAEL to reflect haemolysis and histopathological findings reported at the LOAEL (20 ppm).

 

References:

Health Council of the Netherlands: Committee on updating occupational exposure limits. Nitrogen trifluoride; health-based reassessment of administrative occupational exposure limits. The Hague: Health Council of the Netherlands, 2004; 2000/15OSH/125.

Justification for classification or non-classification

Repeat oral toxicity:w aiver requested as NF3 is a gas the oral route of exposure is not relevant.

 

Repeat toxicity inhalation:The test material should be classified as “STOT – repeated exposure 2” and the hazard statement ‘H373: May causes damage to blood through prolonged or repeated exposure via inhalation exposure” should be applied according to the harmonised classification in Regulation 1272/2008.

 

Repeat toxicity dermal: waiver requested as NF3 is a gas the dermal route of exposure is not relevant