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EC number: 212-742-4 | CAS number: 865-49-6
- 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
Carcinogenicity
Administrative data
- Endpoint:
- carcinogenicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- publication
- Title:
- Carcinogenicity and chronic toxicity in rats and mice exposed to chloroform by inhalation
- Author:
- Yamamoto S, Kasai T, Matsumoto M, Nishizawa T, Arito H, Nagano K, Matsushima T
- Year:
- 2 002
- Bibliographic source:
- Journal of Occupational Health 44, 283-293
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.33 (Combined Chronic Toxicity / Carcinogenicity Test)
- GLP compliance:
- no
Test material
- Reference substance name:
- Chloroform
- EC Number:
- 200-663-8
- EC Name:
- Chloroform
- Cas Number:
- 67-66-3
- Molecular formula:
- CHCl3
- IUPAC Name:
- chloroform
- Test material form:
- liquid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Fischer 344/DuCrj
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- F-344/DuCrj rats of both sexes were obtained at the age of 4 weeks from Charles River Japan Inc., Kanagawa, Japan; animals were quarantined and acclimated for 2 weeks and were housed individually in stainless steel wire hanging cages in stainless steel chambers maintained at 23 +/- 2 °C, 55 +/- 10 % relative humidity, 12 air changes per hour; fluorescent lightning gave a 12 hours light/12 hours dark cycle; animals had free access to a pellet diet (CRF-1, Oriental Yeast Co., Ltd., Tokyo) and sterilised water
Administration / exposure
- Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- Chloroform vapour-air mixture was produced by bubbling clean air through the liquid chloroform, further diluted with clean air, and supplied to the inhalation exposure chambers by the method and apparatus described by Kano et al. (2002, Journal of Occupational Health 44, 119-124).
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- not specified, but reference is given to Kano et al. (2002, Journal of Occupational Health 44, 119-124).
- Duration of treatment / exposure:
- 104 weeks
- Frequency of treatment:
- 6 hours per day, 5 days per week
Doses / concentrations
- Remarks:
- Doses / Concentrations:10, 30, 90 ppmBasis:nominal conc.
- No. of animals per sex per dose:
- 50 males and 50 females
- Control animals:
- yes, concurrent no treatment
Examinations
- Observations and examinations performed and frequency:
- Daily observations for clinical signs and mortality; animals were weighed and their food and water consumptions were measured weekly for the first 13 weeks and every 4 weeks thereafter
- Sacrifice and pathology:
- Animals found dead, in a moribund state or surviving to the end of the 2 year exposure received complete necropsy; urinary, haematological and blood biochemical parameters of all surviving animals were obtained from urine collected at the end of the 2-year exposure period and from blood samples taken at the end of the 2-year exposure period after overnight fasting; The urinary, haematological and blood biochemical parameters examined here were given in the OECD 453 guidelines. All organs were removed, weighed at necropsy and examined for macroscopically visible lesions. The histopathologically examined tissues were described in detail in Katagiri et al, 2001. The tissues for microscopic examination were fixed in 10% neutral buffered formalin, embedded in paraffin, and sections of all tissues and tumours were 5 micrometre thick, and stained with haematoxylin and eosin.
- Statistics:
- The incidence of non-neoplastic lesions and urinary data were analysed by chi-square test; the incidence of neoplastic lesions was analysed by Peto's test and Fisher's exact test; body weight, food consumption, and haematological and blood biochemical parameters were analysed by Dunnett test
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- effects observed, treatment-related
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- effects observed, treatment-related
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- effects observed, treatment-related
- Details on results:
- There was no statistical difference in the 2-year survival rate between the exposed female groups and the control group, but the survival rate of the control male group significantly decreased as compared to the exposed male groups. The growth rate of the 90 ppm group of both sexes was significantly suppressed over the controls throughout the entire exposure period.Absolute and relative kidney weights of the 90 ppm female group were statistically higher than those of the controls.No statistically increase in the incidence of kidney tumours was seen in the exposed males and females, but a case of renal cell adenoma occurring in the 90 ppm female group was very rare as compared to the historical laboratory control data. Dose-dependent increases in the occurrence of nuclear enlargement of the proximal tubule and dilatation of the tubular lumen in the kidney were observed with exposure concentrations of 30 ppm and 90 ppm. The severity of chronic progressive nephropathy significantly decreased with increasing exposure concentrations in animals of both sexes.Hepatocellular adenomas were observed in the female rats, but the incidence was not exposure-related. There was a significantly increased incidence of vacuolated cell foci in the 90 ppm female group.Nasal lesions were observed at 5 ppm and above including thickening of the bone and atrophy and respiratory metaplasia of the olfactory epithelium. Lowered incidences of pituitary gland adenoma in the 90 ppm females and myocardial fibrosis in the 90 ppm males were observed.The exposed males exhibited significantly decreased serum levels of triglyceride, phospholipids and creatinine at 30 ppm and above and total cholesterol at 90 ppm. Serum levels of BUN significantly decreased in the three exposed male groups. GOT, GPT and gamma-GTP significantly increased in the exposed males. The exposed females exhibited a significant decrease in triglyceride and an increase in gamma-GTP at 90 ppm. Positive urinary glucose was observed in the 90 ppm male group and in the 10 ppm and above exposed females.
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- 10 ppm
- Sex:
- male/female
- Basis for effect level:
- other: Histopathological changes in the kidneys
- Remarks on result:
- other: Effect type: toxicity (migrated information)
Any other information on results incl. tables
Table 1: Incidence of neoplastic lesions in the rats exposed to chloroform vapour for 104 weeks
Male |
Female |
|||||||
Group |
Control |
10 ppm |
30 ppm |
90 ppm |
Control |
10 ppm |
30 ppm |
90 ppm |
Number of animals examined |
50 |
50 |
50 |
50 |
50 |
50 |
50 |
49 |
Liver |
||||||||
Hepatocellular adenoma |
0 |
0 |
0 |
0 |
1 |
0 |
2 |
1 |
Kidneys |
||||||||
Renal cell adenoma |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
Pituitary gland |
||||||||
Adenoma |
22 |
23 |
21 |
17 |
24 |
20 |
18 |
11* |
*: significant difference at p 0.05 by Fisher exact test
Table 2: Incidence of selected non-neoplastic lesions in the liver and kidneys of rats exposed to chloroform vapour for 104 weeks
Male |
Female |
|||||||
Group |
Control |
10 ppm |
30 ppm |
90 ppm |
Control |
10 ppm |
30 ppm |
90 ppm |
Number of animals examined |
50 |
50 |
50 |
50 |
50 |
50 |
50 |
49 |
Liver |
||||||||
Total altered cell foci |
11 |
16 |
16 |
18 |
15 |
9 |
20 |
26 |
Clear cell foci |
4 |
4 |
5 |
6 |
4 |
1 |
2 |
7 |
Acidophilic cell foci |
2 |
5 |
2 |
3 |
0 |
1 |
0 |
1 |
Basophilic cell foci |
4 |
6 |
8 |
8 |
7 |
5 |
10 |
4 |
Mixed cell foci |
1 |
1 |
1 |
1 |
4 |
2 |
6 |
9 |
Vacuolated cell foci |
0 |
0 |
0 |
0 |
0 |
0 |
2 |
5* |
Kidneys |
||||||||
Nuclear enlargement: proximal tubules |
0 |
0 |
5* |
32** |
0 |
0 |
6* |
34** |
Dilatation: tubular lumen |
0 |
0 |
9* |
27** |
0 |
0 |
5* |
38** |
Chronic progressive nephropathy b) + |
3 |
11* |
10* |
17** |
8 |
19** |
27** |
15** |
2 + |
6 |
10 |
24 |
14 |
15 |
7 |
5 |
3 |
3 + |
19 |
15 |
8 |
2 |
14 |
3 |
3 |
1 |
4 + |
19 |
8 |
2 |
1 |
4 |
2 |
0 |
2 |
Significant different at p 0.05 (*) and p 0.01 (**) by Chi square test; b) the severity of chronic progressive nephropathy was classfied into four different grades according to the criteria described by Kawai (1980)
Table 3: Serum levels of blood biochemical parameters and urinalysis in rats exposed to chloroform vapour for 104 weeks
Male |
Female |
|||||||
Group |
Control |
10 ppm |
30 ppm |
90 ppm |
Control |
10 ppm |
30 ppm |
90 ppm |
Number of animals examined |
27 |
39 |
36 |
38 |
37 |
35 |
40 |
34 |
Biochemistry |
||||||||
Total protein (g/dL) |
6.7 |
7.1 |
7.0 |
6.9 |
7.0 |
7.4* |
7.3 |
7.2 |
Glucose (mg/dL) |
162 |
169 |
165 |
154 |
170 |
168 |
164 |
160 |
Total cholesterol (mg/dL) |
173 |
164 |
153 |
125** |
142 |
131 |
135 |
149 |
Triglyceride (mg/dL) |
222 |
167 |
146* |
87** |
191 |
126 |
109 |
94** |
Phospholipids (mg/dL) |
289 |
268 |
241* |
196** |
280 |
252 |
255 |
271 |
Creatinine (mg/dL) |
0.9 |
0.6 |
0.6** |
0.7** |
0.5 |
0.5 |
0.5 |
0.5 |
BUN (mg/dL) |
28.6 |
20.6** |
18.3** |
23.2** |
17.9 |
18.5 |
18.5 |
18.6 |
GOT (IU/L) |
67 |
79 |
81 |
98* |
128 |
113 |
124 |
144 |
GPT (IU/L) |
21 |
25* |
24 |
26* |
37 |
40 |
39 |
48 |
gamma-GTP (IU/L) |
4 |
8* |
10** |
7* |
4 |
4 |
5 |
6** |
LDH (IU/L) |
164 |
239 |
179 |
311 |
297 |
245 |
239* |
344 |
ALP (IU/L) |
215 |
265 |
283 |
243 |
152 |
133 |
157 |
174 |
Urinalysis |
||||||||
Glucose |
0/27 |
0/39 |
2/37 |
20/39** |
2/41 |
8/37* |
29/41** |
24/34** |
Occult blood |
3/27 |
6/39 |
4/37 |
10/39 |
2/41 |
1/37 |
4/41 |
2/34 |
Values shown are the means for each group and the urinalysis data indicate the number of animals having positive glucose or occult blood/total number of animals examined. Significant differences at p 0.05 (*) and p 0.01 (**) by Dunnett's test for biochemistry and by Chi-square test for urinalysis. BUN: blood urea nitrogen; GOT: glutamate oxaloacetate transminase; GPT: glutamate pyruvate transaminase: ALP: alkaline phosphatase; gamma-GTP: gamma-glutamyl transpeptidase; LDH: lactate dehydrogenase
Applicant's summary and conclusion
- Conclusions:
- Inhalation exposure of male and female F-344 rats to 10, 30 and 90 ppm chloroform vapour did not result in any statistically significant, exposure-related increase in the incidence of liver and kidney tumours. Exposure to chloroform at 30 and 90 ppm induced nuclear enlargement of the proximal tubules and dilatation of the tubular lumen without development of renal tumours. No significantly increased incidence of histopathological lesions in the liver was found. Slight but significant increases in the serum levels of GPT and gamma-GTP occurred in exposed male rats from 10 ppm exposure concentration. Although these two biomarkers are biologically significant, (indicative of liver cell necrosis and regeneration), they were not considered to determine a LOAEL since no dose-relationship was observed.
- Executive summary:
A combined chronic toxicity/carcinogenicity study was carried out with chloroform using female and male F-344 rats receiving inhalation exposure to chloroform vapours of 10, 30 and 90 ppm during a period of 2 years. The study was in accordance with the method B.33 suggested by the European Commission with minor restrictions.
The growth rate of female and male rats exposed to 90 ppm chloroform vapour was suppressed over the controls. Nasal lesions were observed at exposure concentrations of 10 ppm and above. The 2 -year inhalation exposure to 10, 30 or 90 ppm did not result in any significant increase in the incidence of liver and kidney tumours in both sexes. Exposure to chloroform at 30 or 90 ppm induced nuclear enlargement of the proximal tubules and dilatation of the tubular lumen without development of renal tumours. No significantly increased incidence of histopathological lesions in the liver was found. The NOAEL value for the histopathological changes in the kidneys was found to be 10 ppm.
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