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EC number: 216-088-0 | CAS number: 1493-27-2
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Description of key information
By analogy with 1-fluoro-4-nitrobenzene, methemoglobinemia and damages to the spleen have been observed. Oral NOAEL is 5 mg/kg and inhalation NOAEC is 13 mg/m3.
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- No data
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Study well conducted, sufficiently detailed, according to standardised guidelines but not GLP.
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- The test substance is orally administered daily in graduated doses to several groups of experimental animals, one dose level per group for a period of 5 weeks. During the period of administraion the animals are observed closely, each day for signs of toxicity.
- GLP compliance:
- no
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- No data
- Route of administration:
- oral: gavage
- Vehicle:
- olive oil
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 5 weeks
- Frequency of treatment:
- daily
- Remarks:
- Doses / Concentrations:
5, 15 and 45 mg/kg bw/day
Basis:
actual ingested - No. of animals per sex per dose:
- 10 per sex per dose
- Control animals:
- yes, concurrent vehicle
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: No
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: YES
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 2, 5, 7 and 9 weeks
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 5M/5F after 2 weeks, 5M/5F after 5 weeks, 5M/5F after 7 weeks and 5M/5F after 9 weeks
- Parameters checked in table [No.?] were examined.
CLINICAL CHEMISTRY: No
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (liver, kidneys and spleen) - Other examinations:
- No
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- PRE-TEST RESULTS:
In a pre-test, rats were orally administered the test substance at 50, 100 and 200 mg/kg bw/day. At 200 mg/kg bw/day, mortality was rapidly induced by the test substance in all animals. At 100 and 50 mg/kg bw/day, hematological effects were observed : anaemia with reticulocytosis and increasedof blood platelet (methemoglobinemia: 20 %).
At gross necropsy an enlargement of the spleen was observed. Histopatology results showed a significant effect of the test substance at 100 mg/kg bw/day at liver, spleen, kidney and testicules level. At 50 mg/kg bw/day, an effect at the spleen level was only observed.
MAIN TEST RESULTS:
CLINICAL SIGNS AND MORTALITY
No mortality was observed at any tested doses.
BODY WEIGHT AND WEIGHT GAIN
The weigth gain was similar between control and treated animals.
HAEMATOLOGY
A hemaological toxicity was observed after treatment with graduated doses of the test substance. (cf. Table 1)
Effect on percentage of Methemoglobinemia, significant at 15 and 45 mg/kg/d. This effect is reversible after 2 weeks of rest
GROSS PATHOLOGY
At 45 mg/kg bw/day, all animals showed hypertrophy of the spleen.
HISTOPATHOLOGY: NON-NEOPLASTIC
After 5 weeks, histological results showed a dose-dependant congestion of the spleen with a splenic hemosiderosis. After 9 weeks, only clusters of hemosiderin in macrophages were observed. After 4 weeks of rest, the spleen congestion disappeared, but hemosiderosis is observed and important at 45 mg/kg/d. - Key result
- Dose descriptor:
- NOEL
- Effect level:
- 5 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Methemoglobinemia
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 5 mg/kg bw/day (nominal)
- System:
- haematopoietic
- Organ:
- blood
- spleen
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
- Conclusions:
- Under the conditions of this test, the test substance induced hematological effects with a modification of the structure of the spleen.
- Executive summary:
Male and female rats (10 per sex per dose) were orally administered 5, 15 and 45 mg/kg bw/day of the test substance daily during 5 weeks. At the end of the exposure, half of the animals were sacrificed and the others were kept for 4 weeks without treatment to detect recovery from toxic effects. Animals were examined for hematological effects (haemoglobin concentraion, hematocrit, platelet count, erythrocyte count). The test substance induced mainly hematological effects with alteration of the spleen. Nevertheless, as soon as the treatment is finished all animals showed reversibility of the observed effects.
Reference
Table 1: Hematological effect of the test substance
Treatment | Erythroctes (E+03) and Methemoglobinemia (%) |
|||
2 weeks | 5 weeks | 7 weeks | 9 weeks | |
Control | 7840 | 8495 (3.32) |
8196 (2.0) |
8002 (2.2) |
45 mg/kg bw/day | 6050 | 6536 (9.30) |
7662 (3.5) |
7828 (3.0) |
15 mg/kg bw/day | 6454 | 7277 (8.76) |
/ | / |
5 mg/kg bw/day | 6516 | 7940 (5.70) |
/ | / |
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 5 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- The study is not GLP but a well conducted 5 weeks rat oral study.
Repeated dose toxicity: inhalation - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- From 06 November To 08 March 1976
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Study well conducted, sufficiently detailed, according to standardised guidelines, but not GLP.
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Male and female rats were exposed to the test substance for 4 hours per day, 6 days per week during 4 weeks. Following the exposure, a rest period of 4 weeks was performed. Hematology examinations were performed at 2, 4, 6 and 8 weeks. Clinical Biochemistry examinations were performed at the end of the exposure (4 weeks). Histology and necropsy were also performed at the end of the exposure.
- GLP compliance:
- no
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- No data
- Route of administration:
- inhalation: vapour
- Type of inhalation exposure:
- whole body
- Vehicle:
- air
- Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Glass chamber
- Exposure chamber volume: 100 L with flow rate of 500L/h
OTHER:
Each day, the product was diluted in ethanol (CAS: 64-17-5)
- Solution (3) = 130 mg/m3 (0.050 ml/heure)
Product 4 ml + ethanol 11.2 ml
- Solution (2) = 40 mg/m3 (0.015 ml/heure)
Product 1.5 ml + ethanol 17.5 ml
- Solution (1) = 130 mg/m3 (0.005 ml/heure)
Dilution 1/10 of solution 3
solution (3) 1 ml + ethanol 9 ml - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 4 hours
- Frequency of treatment:
- 6 days per week for 4 weeks
- Remarks:
- Doses / Concentrations:
13, 40 and 130 mg/m3 (0.013, 0.04 and 0.13 mg/l)
Basis:
nominal conc. - No. of animals per sex per dose:
- 8 per dose per sex
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Exposure time: 4 hours, 6 days a week and for 4 weeks, with 4 weeks of reversibility.
After 4 weeks of treatment, 5 males and 5 females per dose were sacrified in order to examine haematology (hemoglobinemia, numeration, erythrocytes and leucocytes), biochemistry (urea and bilirubin) and necropsy.
Other animals were observed during 4 weeks (reversibility).
Haematology was examined after 2 and 4 weeks for animals sacrified after 4 weeks, after 6 and 8 weeks for the others. - Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: No
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: No
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at 2, 4, 6 and 8 weeks
- Anaesthetic used for blood collection: yes
- Animals fasted: No data
- How many animals: 5 per sex at the end of exposure/ 3 per sex after a week of rest.
- Parameters checked in table [No.1] were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the exposure (4 weeks).
- Animals fasted: No data
- How many animals: 5 per sex.
- Parameters checked in table [No.1] were examined.
URINALYSIS: yes
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: YES (Histopatology of heart, lung, liver, spleen, kidneys and adrenal glands was performed) - Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- not examined
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY
No mortality related to test substance was observed and no clinical signs were reported. One female died due to an anesthesic accident.
HAEMATOLOGY
After 2 weeks of treatment, no effect was observed in all animals. At the end of the exposure (4 weeks), a slight decrease in the erythrocytes count and a significant decrease of leucocytes count at the highest tested doses were observed. In addition, the methemoglobin increased at 40 mg/m3 (3.3 %) and became anormal at the highest tested dose (4.5 %). After two weeks of rest, all parameters showed comparable values to controls. (For details see Table 1)
CLINICAL CHEMISTRY
No significant effect on clinical biochemistry parameters (sodium, potassium, urea, total protein, alkaline phosphatase and alanine aminotransferase) was observed. (For details see Table 2)
GROSS PATHOLOGY
No effect has been observed.
HISTOPATHOLOGY
An effect of the test substance on the spleen was observed. The number of foci of extramedullary hematopoiesis were increased in the red pulpe of the spleen and were accompanied by an increase of splenic hemosiderin and venous sinus congestion. After 4 weeks of rest, foci of hematopoiesis have decreased in all animals. Only clusters of hemosiderin in macrophages were persistant. - Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 0.013 mg/L air (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Effects on spleen
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 0.013 mg/L air (nominal)
- System:
- haematopoietic
- Organ:
- blood
- spleen
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
- Conclusions:
- Under the conditions of this test, the test substance showed a toxic effect at the blood cell level.
- Executive summary:
Male and female rats were exposed to the test substance for 4 hours per day, 6 days per week during 4 weeks. Following the exposure, a rest period of 4 weeks was performed. Hematology examinations were performed at 2, 4, 6 and 8 weeks. Clinical Biochemistry examinations were performed at the end of the exposure (4 weeks). Histology and necropsy were also performed at the end of the exposure. Animals were exposed at 13, 40 or 130 mg/m3 of the test substance. No mortality related to test substance was observed and no clinical signs were reported. One female died due to an anesthesic accident. After 2 weeks of treatment, no effect was observed in all animals. At the end of the exposure (4 weeks), a slight decrease in the erythrocytes count and a significant decrease of leucocytes count at the highest tested doses were observed. In addition, the methemoglobin increased at 40 mg/m3 (3.3 %) and became anormal at the highest tested dose (4.5 %). After two weeks of rest, all parameters showed comparable values to controls. No significant effect on clinical biochemistry parameters (sodium, potassium, urea, total protein, alkaline phosphatase and alanine aminotransferase) was observed. No gross pathologic effect has been observed. An effect of the test substance on the spleen was observed. The number of foci of extramedullary hematopoiesis were increased in the red pulpe of the spleen and were accompanied by an increase of splenic hemosiderin and venous sinus congestion. After 4 weeks of rest, foci of hematopoiesis have decreased in all animals. Only clusters of hemosiderin in macrophages were persistant. Under the conditions of this test, the test substance showed a toxic effect at the blood cell level.
Reference
Table 1: Hematologic results
Time | Groups | H % |
Hb g/100 ml |
Erytrocyte E+03/mm3 |
Leucocytes/mm3 | Methemoglobin |
After 2 weeks | Control | 45.2 2.17 |
15.0 0.23 |
7788 584.6 |
11880 3565.4 |
/ |
Control (ethanol) | 44.3 2.34 -0.63 |
15.0 0.55 -0.08 |
7750 245.2 -0.15 |
9466 2498.5 -1.32 |
/ | |
13 mg/m3 | 42.7 1.97 -2.03 |
14.7 0.76 -0.73 |
7113 491.5 -2.1 |
10933 4233.0 -0.39 |
/ | |
40 mg/m3 | 46.0 1.54 0.71 |
15.5 0.52 2.1 |
7503 404.7 -0.95 |
12767 2834.0 0.46 |
/ | |
130 mg/m3 | 44.1 2.40 -0.74 |
14.7 0.86 -0.65 |
7450 395.7 -1.1 |
12917 2324.0 0.53 |
/ | |
After 4 weeks | Control | 49.3 2.9 |
15.8 1.0 |
8777 886 |
19289 33250 |
2.36 0.45 |
Control (ethanol) | 48.3 1.88 -0.93 |
15.3 0.87 -1.13 |
8494 552 -0.85 |
15070 2865 -2.97 |
2.57 0.35 1.09 |
|
13 mg/m3 | 46.6 (-) 1.90 -2.44 |
15.0 0.76 -1.96 |
7940 (-) 642 -2.38 |
13930 (--) 2735 -3.85 |
2.87 (+) 0.53 2.35 |
|
40 mg/m3 | 46.9 2.38 -2.0 |
14.8 (-) 0;69 -2.4 |
8004 (-) 436 -2.46 |
12570 (---) 1865 -5.50 |
3.25 0.41 4.65 (+++) |
|
130 mg/m3 | 45.2 (--) 2.1 -3.57 |
14.4 (-) 0.99 -2.97 |
7724 (-) 676 -2.93 |
11510 (---) 1995 -6.26 |
4.54 0.91 6.76 (+++) |
|
After 6 weeks | Control | 45.3 4.3 |
15;6 0.23 |
8183 368 |
9983 1762 |
/ |
Control (ethanol) | 50.0 1.8 1.77 |
16.0 0.34 2.08 |
7866 457 -1.32 |
10516 2125 0.47 |
/ | |
13 mg/m3 | 49.0 1.8 1.94 |
15.9 0.64 0.83 |
7953 573 -0.83 |
11867 4694 0.92 |
/ | |
40 mg/m3 | 49.8 2.9 2.14 |
15.3 0.56 -1.21 |
2270 423 0.38 |
10767 1261 0.89 |
/ | |
130 mg/m3 | 49.3 2.7 1.93 |
15.5 0.27 -0.68 |
8133 242 -0.28 |
9500 1445 0.52 |
/ | |
After 8 weeks | Control | / | / | 7753 380 |
/ | 2.58 0.62 |
Control (ethanol) | / | / | 7460 535 -1.06 |
/ | / | |
13 mg/m3 | / | / | 7810 460 0.23 |
/ | / | |
40 mg/m3 | / | / | 8013 373 1.19 |
/ | / | |
130 mg/m3 | / | / | 7670 259 -0.44 |
/ | 1.97 0.30 -2.20 |
Statistically significant from control at : 95 % (+ or -), 99 % ( ++ or --), 99.9 % (+++ or ---)
Table 2: Chemical biochemistry results
Groups | Na mEq/l | K mEq/l | Urea g/l | Bilirubin mg/l | Proteins g/l | alkaline phosphatase | alanine aminotransferase |
Control | 147.0 2.2 |
6.1 0.8 |
0.44 0.10 |
0.47 0.28 |
61.7 4.0 |
331 89 |
94* 62 |
Control (ethanol) | 147.0 2.0 |
6.0 0.6 |
0.45 0.17 |
0.34 0.23 |
61.2 1.2 |
346 36 |
58 18 |
13 mg/m3 | 147.6 2.2 |
5.4 0.3 |
0.40 0.12 |
0.80 0.30 |
59.0 4.3 |
322 91 |
50 7 |
40 mg/m3 | 148.5 2.1 |
6.2 0.4 |
0.42 0.07 |
0.81 0.13 |
56.0 7.1 |
301 27 |
104* 151 |
130 mg/m3 | 149.0 4.1 |
5.6 0.4 |
0.46 0.07 |
0.97 1.34 |
56.6 4.2 |
296 31 |
70 44 |
* Elevated medium due to an outlier.
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEC
- 13 mg/m³
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- The study is not GLP but a well conducted 4 weeks rat inhalation (vapor) study.
Repeated dose toxicity: inhalation - local effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- From 06 November To 08 March 1976
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Study well conducted, sufficiently detailed, according to standardised guidelines, but not GLP.
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Male and female rats were exposed to the test substance for 4 hours per day, 6 days per week during 4 weeks. Following the exposure, a rest period of 4 weeks was performed. Hematology examinations were performed at 2, 4, 6 and 8 weeks. Clinical Biochemistry examinations were performed at the end of the exposure (4 weeks). Histology and necropsy were also performed at the end of the exposure.
- GLP compliance:
- no
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- No data
- Route of administration:
- inhalation: vapour
- Type of inhalation exposure:
- whole body
- Vehicle:
- air
- Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Glass chamber
- Exposure chamber volume: 100 L with flow rate of 500L/h
OTHER:
Each day, the product was diluted in ethanol (CAS: 64-17-5)
- Solution (3) = 130 mg/m3 (0.050 ml/heure)
Product 4 ml + ethanol 11.2 ml
- Solution (2) = 40 mg/m3 (0.015 ml/heure)
Product 1.5 ml + ethanol 17.5 ml
- Solution (1) = 130 mg/m3 (0.005 ml/heure)
Dilution 1/10 of solution 3
solution (3) 1 ml + ethanol 9 ml - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 4 hours
- Frequency of treatment:
- 6 days per week for 4 weeks
- Remarks:
- Doses / Concentrations:
13, 40 and 130 mg/m3 (0.013, 0.04 and 0.13 mg/l)
Basis:
nominal conc. - No. of animals per sex per dose:
- 8 per dose per sex
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Exposure time: 4 hours, 6 days a week and for 4 weeks, with 4 weeks of reversibility.
After 4 weeks of treatment, 5 males and 5 females per dose were sacrified in order to examine haematology (hemoglobinemia, numeration, erythrocytes and leucocytes), biochemistry (urea and bilirubin) and necropsy.
Other animals were observed during 4 weeks (reversibility).
Haematology was examined after 2 and 4 weeks for animals sacrified after 4 weeks, after 6 and 8 weeks for the others. - Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: No
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: No
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at 2, 4, 6 and 8 weeks
- Anaesthetic used for blood collection: yes
- Animals fasted: No data
- How many animals: 5 per sex at the end of exposure/ 3 per sex after a week of rest.
- Parameters checked in table [No.1] were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the exposure (4 weeks).
- Animals fasted: No data
- How many animals: 5 per sex.
- Parameters checked in table [No.1] were examined.
URINALYSIS: yes
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: YES (Histopatology of heart, lung, liver, spleen, kidneys and adrenal glands was performed) - Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- not examined
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY
No mortality related to test substance was observed and no clinical signs were reported. One female died due to an anesthesic accident.
HAEMATOLOGY
After 2 weeks of treatment, no effect was observed in all animals. At the end of the exposure (4 weeks), a slight decrease in the erythrocytes count and a significant decrease of leucocytes count at the highest tested doses were observed. In addition, the methemoglobin increased at 40 mg/m3 (3.3 %) and became anormal at the highest tested dose (4.5 %). After two weeks of rest, all parameters showed comparable values to controls. (For details see Table 1)
CLINICAL CHEMISTRY
No significant effect on clinical biochemistry parameters (sodium, potassium, urea, total protein, alkaline phosphatase and alanine aminotransferase) was observed. (For details see Table 2)
GROSS PATHOLOGY
No effect has been observed.
HISTOPATHOLOGY
An effect of the test substance on the spleen was observed. The number of foci of extramedullary hematopoiesis were increased in the red pulpe of the spleen and were accompanied by an increase of splenic hemosiderin and venous sinus congestion. After 4 weeks of rest, foci of hematopoiesis have decreased in all animals. Only clusters of hemosiderin in macrophages were persistant. - Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 0.013 mg/L air (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Effects on spleen
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 0.013 mg/L air (nominal)
- System:
- haematopoietic
- Organ:
- blood
- spleen
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
- Conclusions:
- Under the conditions of this test, the test substance showed a toxic effect at the blood cell level.
- Executive summary:
Male and female rats were exposed to the test substance for 4 hours per day, 6 days per week during 4 weeks. Following the exposure, a rest period of 4 weeks was performed. Hematology examinations were performed at 2, 4, 6 and 8 weeks. Clinical Biochemistry examinations were performed at the end of the exposure (4 weeks). Histology and necropsy were also performed at the end of the exposure. Animals were exposed at 13, 40 or 130 mg/m3 of the test substance. No mortality related to test substance was observed and no clinical signs were reported. One female died due to an anesthesic accident. After 2 weeks of treatment, no effect was observed in all animals. At the end of the exposure (4 weeks), a slight decrease in the erythrocytes count and a significant decrease of leucocytes count at the highest tested doses were observed. In addition, the methemoglobin increased at 40 mg/m3 (3.3 %) and became anormal at the highest tested dose (4.5 %). After two weeks of rest, all parameters showed comparable values to controls. No significant effect on clinical biochemistry parameters (sodium, potassium, urea, total protein, alkaline phosphatase and alanine aminotransferase) was observed. No gross pathologic effect has been observed. An effect of the test substance on the spleen was observed. The number of foci of extramedullary hematopoiesis were increased in the red pulpe of the spleen and were accompanied by an increase of splenic hemosiderin and venous sinus congestion. After 4 weeks of rest, foci of hematopoiesis have decreased in all animals. Only clusters of hemosiderin in macrophages were persistant. Under the conditions of this test, the test substance showed a toxic effect at the blood cell level.
Reference
Table 1: Hematologic results
Time | Groups | H % |
Hb g/100 ml |
Erytrocyte E+03/mm3 |
Leucocytes/mm3 | Methemoglobin |
After 2 weeks | Control | 45.2 2.17 |
15.0 0.23 |
7788 584.6 |
11880 3565.4 |
/ |
Control (ethanol) | 44.3 2.34 -0.63 |
15.0 0.55 -0.08 |
7750 245.2 -0.15 |
9466 2498.5 -1.32 |
/ | |
13 mg/m3 | 42.7 1.97 -2.03 |
14.7 0.76 -0.73 |
7113 491.5 -2.1 |
10933 4233.0 -0.39 |
/ | |
40 mg/m3 | 46.0 1.54 0.71 |
15.5 0.52 2.1 |
7503 404.7 -0.95 |
12767 2834.0 0.46 |
/ | |
130 mg/m3 | 44.1 2.40 -0.74 |
14.7 0.86 -0.65 |
7450 395.7 -1.1 |
12917 2324.0 0.53 |
/ | |
After 4 weeks | Control | 49.3 2.9 |
15.8 1.0 |
8777 886 |
19289 33250 |
2.36 0.45 |
Control (ethanol) | 48.3 1.88 -0.93 |
15.3 0.87 -1.13 |
8494 552 -0.85 |
15070 2865 -2.97 |
2.57 0.35 1.09 |
|
13 mg/m3 | 46.6 (-) 1.90 -2.44 |
15.0 0.76 -1.96 |
7940 (-) 642 -2.38 |
13930 (--) 2735 -3.85 |
2.87 (+) 0.53 2.35 |
|
40 mg/m3 | 46.9 2.38 -2.0 |
14.8 (-) 0;69 -2.4 |
8004 (-) 436 -2.46 |
12570 (---) 1865 -5.50 |
3.25 0.41 4.65 (+++) |
|
130 mg/m3 | 45.2 (--) 2.1 -3.57 |
14.4 (-) 0.99 -2.97 |
7724 (-) 676 -2.93 |
11510 (---) 1995 -6.26 |
4.54 0.91 6.76 (+++) |
|
After 6 weeks | Control | 45.3 4.3 |
15;6 0.23 |
8183 368 |
9983 1762 |
/ |
Control (ethanol) | 50.0 1.8 1.77 |
16.0 0.34 2.08 |
7866 457 -1.32 |
10516 2125 0.47 |
/ | |
13 mg/m3 | 49.0 1.8 1.94 |
15.9 0.64 0.83 |
7953 573 -0.83 |
11867 4694 0.92 |
/ | |
40 mg/m3 | 49.8 2.9 2.14 |
15.3 0.56 -1.21 |
2270 423 0.38 |
10767 1261 0.89 |
/ | |
130 mg/m3 | 49.3 2.7 1.93 |
15.5 0.27 -0.68 |
8133 242 -0.28 |
9500 1445 0.52 |
/ | |
After 8 weeks | Control | / | / | 7753 380 |
/ | 2.58 0.62 |
Control (ethanol) | / | / | 7460 535 -1.06 |
/ | / | |
13 mg/m3 | / | / | 7810 460 0.23 |
/ | / | |
40 mg/m3 | / | / | 8013 373 1.19 |
/ | / | |
130 mg/m3 | / | / | 7670 259 -0.44 |
/ | 1.97 0.30 -2.20 |
Statistically significant from control at : 95 % (+ or -), 99 % ( ++ or --), 99.9 % (+++ or ---)
Table 2: Chemical biochemistry results
Groups | Na mEq/l | K mEq/l | Urea g/l | Bilirubin mg/l | Proteins g/l | alkaline phosphatase | alanine aminotransferase |
Control | 147.0 2.2 |
6.1 0.8 |
0.44 0.10 |
0.47 0.28 |
61.7 4.0 |
331 89 |
94* 62 |
Control (ethanol) | 147.0 2.0 |
6.0 0.6 |
0.45 0.17 |
0.34 0.23 |
61.2 1.2 |
346 36 |
58 18 |
13 mg/m3 | 147.6 2.2 |
5.4 0.3 |
0.40 0.12 |
0.80 0.30 |
59.0 4.3 |
322 91 |
50 7 |
40 mg/m3 | 148.5 2.1 |
6.2 0.4 |
0.42 0.07 |
0.81 0.13 |
56.0 7.1 |
301 27 |
104* 151 |
130 mg/m3 | 149.0 4.1 |
5.6 0.4 |
0.46 0.07 |
0.97 1.34 |
56.6 4.2 |
296 31 |
70 44 |
* Elevated medium due to an outlier.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- The study is not GLP but a well conducted 4 weeks rat inhalation (vapor) study.
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Justification for classification or non-classification
Based on the classification criteria of EU Regulation 1272/2008 (CLP), with an oral NOAEL=5 mg/kg bw/day and an inhalation NOAEC of 13 mg/m3, 1-fluoro-2nitrobenzene is classified as Single Target Organ Toxicant – Repeated Exposure category 1 (STOT-RE cat.1) with blood and spleen as target organs.
Data are only available for oral and inhalation studies, however, dermal route cannot be excluded and no specific route can be specified.
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