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Toxicological information

Carcinogenicity

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Administrative data

Endpoint:
carcinogenicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: 2c: Comparable to guidline study with acceptable restrictions. Study well documented.
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
1,1,1-trichloroethane formulation: a chronic inhalation toxicity and oncogenicity study in fischer 344 rats and B6C3f1 mice
Author:
QUAST-JF; CALHOUN-LL; FRAUSON-LE
Year:
1988
Bibliographic source:
FUNDAM-APPL-TOXICOL 11 611-625

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Principles of method if other than guideline:
Same as 451, with the following exceptions. Body weights only recorded monthly and food consumption not recorded. No individual data presented. Limited statistical analysis of results; only actual tumour incidence considered, not time of appearance.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Production grade, purity 94% (v/v).
5% stabilizers (butylenes oxide, t-amyl alcohol. Methyl butynol, nitroethane and ntitromethane)
< 1% minor impurities
Identity confirmed by gas-liquid chromatography

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals and environmental conditions:
Experiment conducted in walk in 14 .5 m2 chambers with stainless-steel ceilings and epoxy resin-coated walls and floors. Operated under dynamic airflow conditions with slight negative pressure. 12-hour photo cycle, temperature approx. 79 0F and relative humidity approximately 50 %.

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
6 hours a day, 5 days/week for 24 months (total of 516 exposures). Whole body exposure, maintained in inhalation chambers throughout the study. Experiment conducted in walk in 14 .5 m2 chambers with stainless-steel ceilings and epoxy resin-coated walls and floors. Operated under dynamic airflow conditions with slight negative pressure. Vapor generated by metering the liquid at a calculated rate in to a glass J-tube vaporization apparatus. Supplied air was heated to the minimum required to ensure the complete vaporization of the test material (approximately 90-100 0C) and mixed with air to the required concentration. Total airflow through the chambers was maintained at approximately 2000 liters/min.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analytical concentration in the chamber was determined by infrared spectrophotometry at a wavelength of 9.2 μm. Each exposure chamber was analyzed at least once per hour during the 6-hour exposure period, the time-weighed average (TWA) was calculated. TWA analytical values were 151 + 2, 502 + 5 and 1505 + 11 ppm for the 516 exposure days. Prior to initiating the study distribution in the chamber would confirmed to be uniform (+ 10 % of chamber TWA)
Duration of treatment / exposure:
24 months (total of 516 exposures)
Frequency of treatment:
6 hours a day, 5 days/week
Post exposure period:
none
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
150 ppm, 0.82 mg/L
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
500 ppm, 2.73 mg/L
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
1500 ppm, 8.19 mg/L
Basis:
nominal conc.
No. of animals per sex per dose:
50 males and 50 females
Control animals:
yes, sham-exposed

Examinations

Observations and examinations performed and frequency:
CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

PALPATION FOR MASSES: Yes
Monthly for months 12 - 24

BODY WEIGHT: Yes
- Time schedule for examinations: once every 4 weeks

FOOD CONSUMPTION (FC): no data

WATER CONSUMPTION: no data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at 6, 12, 18 and 24 months (10 rats/sex/group)
- Anaesthetic used for blood collection: no data (presumed yes as route orbital sinus)
- Parameters below were examined:

* Red blood cells:
Erythrocyte count (RBC)
Hemoglobin (Hb)
Packed cell volume (PCV)

* White blood cells:
Platelets (PLAT)
Leucocytes (WBC)
Total leukocyte count
Neutrophils (differential)
Eosinophils (differential)
Basophils (differential)
Monocytes (differential)
Lymphocytes (differential)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at 6, 12, 18 and 24 months (10 rats/sex/group)
- Anaesthetic used for blood collection: no data(presumed yes as route orbital sinus)
- Parameters below were examined:

* Metabolites and Proteins:
Albumin
A/G ratio
Cholesterol (total)
Glucose
Protein (total)
Triglycerides
Urea

* Enzymes:
Alkaline phosphatase (ALP)
g-glutamyl transpeptidase (g-GT)

Sacrifice and pathology:
ORGAN WEIGHTS: Yes -Brain-Heart -Kidneys-Liver -Testes

GROSS PATHOLOGY / HISTOPATHOLOGY: Yes.-Adrenals-Aorta-Brain -Caecum-Coagulating glands- Colon-Duodenum-Epididymes-Eyes with Harderian glands-Lacrimal gland-Heart-Ileum-Jejunum-Kidneys-Larynx-Liver (with gall bladder)-Lungs -Lymph nodes mesenteric-Mammary glands-Nasal tissue – Oral tissue- Oesophagus-Ovaries-Oviduct- Pancreas-Pituitary gland-Prostate-Rectum-Salivary glands-Sciatic nerve-Seminal vesicles-Skeletal muscle-Skin and subcutaneous tissue-Spinal cord -Spleen-Bone with bone marrow-Stomach-Testes-Thymus-Thyroids with parathyroids-Tongue-Trachea-Urinary bladder-Uterus (incl.cervix)-Vagina
For the 6, 12 and 18month sacrifice only control and high dose examined. After 24 months all tissues from the control and all treated groups were examined.
Other examinations:
Blood plasma determinations (separate report by Schumann et al, 1982)
Statistics:
Cumulative mortality was analysed for overall difference by the Gehan-Wilcoxon test. Body weight data was evaluated by Dunnett’s test; statistical outliers were identified by the sequential procedure of Grubbs (1969) and excluded from further calculations.

Results and discussion

Results of examinations

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):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not examined
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
There was no treatment-related effect on mortality or survival; although there was a greater incidence of mortality in males exposed to 500 ppm during the last few months of the study. There were no effects on body weight, clinical observations, haematology, clinical chemistry, organ weights or gross pathology.
In all groups of male mice (including controls) the most common finding was inflammation in the penile and preputial region; this is not considered to be an effect of treatment, but is a common background finding in male mice.
There were not statistically or biologically significant findings after 6, 12 or 18 months. None of the statistically identified differences at 2 years were considered to be of toxicological significance due to a lack of dose-response or their incidence was within the background range.
There were no tumors of statistical significance when comparing the control to each treated group. However, when taking into account trend there was an increased incidence of benign Harderian gland tumors in the females. Previous studies conducted at the laboratory found the background range to be 4 – 12 % ; the observations in this study fall within this range and the finding was therefore considered to be without biological significance.

Effect levels

open allclose all
Dose descriptor:
NOEL
Effect level:
> 1 500 ppm
Sex:
male/female
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Dose descriptor:
NOEL
Effect level:
> 1 500 ppm
Sex:
male/female
Remarks on result:
other: Effect type: toxicity (migrated information)

Any other information on results incl. tables

Table 1 Incidence of selected pathologies

Parameter

N = 50/sex

Exposure (ppm)

0

150

500

1500

Lacrimal/Hardarian glands

Adenoma, benign, primary

M

0

0

0

0

F

0

0

0

1

Cystadenoma, acini, benign, primary

M

8

7

5

4

F

3

1

2

6

Cystadenoma, acini, benign, primary (two)

M

0

1

0

0

F

0

0

0

0

Total (adenoma or cystadenoma

M

8

8

5

4

F

3

1

2

7

*Linear trend by Cochran-Armitage Test, α = 0.05(one-sided)

Applicant's summary and conclusion

Conclusions:
Under these experimental conditions, 1,1,1-trichloroethane has to be considered as non-carcinogenic.
Executive summary:

The potential carcinogenicity of 1,1,1-trichloroethane was evaluated following inhalation exposure for 2 years in the mouse.  The study was not GLP, but the method followed the principles of OECD Guideline 451. B 6C3F1 mice (50 Males and 50 Females/group) were exposed to 1,1,1-trichloroethane for 6 hours/day, for 5 days/week, by whole body exposure, at the dose-levels of 0, 150, 500 or 1500 ppm (0, 0.82, 2.73 of 8.19 mg/L in air) during 102 weeks.  

Body weights were recorded monthly.  Animals were observed daily for toxicity and pharmacological effects. Whole blood, serum and plasma were sampled on month 6, 12, 18 and just prior necropsy and analysed for related haematological and clinical chemistry parameters.

All animals were examined for gross pathology, and organs were weighted and submitted to histopathology.

There were no effects on body weight, haematology, clinical pathology, organ weights, gross pathology or histopathology that were considered to be due to exposure to 1,1,1-trichloroethane. 

Consequently, under the experimental conditions, the No Observed Adverse Effect Level (NOAEL) for carcinogenicity and toxicity is 1500 ppm.