1,1,1-trichloroethane

Carcinogenicity

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 for cross-reference:

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

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

Test material information

Constituent 1

Reference substance name:

Automatically generated during migration to IUCLID 6, no data available

IUPAC Name:

Automatically generated during migration to IUCLID 6, no data available

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 or test system 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 / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0 ppm
Basis:
nominal conc.

Doses / concentrations 2

Remarks:

Doses / Concentrations:
150 ppm, 0.82 mg/L
Basis:
nominal conc.

Doses / concentrations 3

Remarks:

Doses / Concentrations:
500 ppm, 2.73 mg/L
Basis:
nominal conc.

Doses / concentrations 4

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

1

Dose descriptor:

NOEL

Effect level:

> 1 500 ppm

Sex:

male/female

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

2

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.