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Toxicological information

Carcinogenicity

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Description of key information

Not carcinogenic; NOAEC = 47106 mg/m3 (highest dose tested)

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study was selected as the key study because the information provided for the hazard endpoint is sufficient for the purpose of classification and labelling and/or risk assessment.
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
GLP compliance:
yes
Species:
rat
Strain:
other: Crl:CD(R)(SD)BR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Labs, Kingston, New York
- Age at study initiation: weanling rats
- Weight at study initiation: not reported
- Fasting period before study: none
- Housing: stainless steel, wire-mesh cages. Housed 3/cage upon arrival
- Diet (e.g. ad libitum): Purina Laboratory Chow Checkers #5001 (PLCC) available ad libitum except during exposures
- Water (e.g. ad libitum): ad libitum except during exposures
- Acclimation period: 12 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24±2°C
- Humidity (%): 50%±10%
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): not reported
Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
other: air
Details on exposure:
Test substance vapors were generated by warming cylinders containing liquefied test substance in a 21-27°C water bath. The vapors were metered into the intake manifold at the top of the chamber. Filtered, conditioned air also entered the top of the chamber, swept the test material into the respective exposure chambers and was exhausted out the bottom of the chambers. Chamber concentrations of the test substance were regulated by controlling the flow rate of test substance vapors into each exposure chamber. Filtered air, alone, was metered in a similar manner into the control chamber. Total flow of air in the control and test substance chambers was maintained at approximately 800 L/min.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Chamber atmospheres were analyzed by a GC every half hour during the 6 hour daily exposure period.
Duration of treatment / exposure:
2 years
Frequency of treatment:
6 hours/day, 5 days/week (excluding holidays)
Remarks:
Doses / Concentrations:
0, 0.2, 1.0, and 2.5%
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
0, 0.21, 1.02, and 2.47%
Basis:
analytical conc.
No. of animals per sex per dose:
100
Control animals:
yes, concurrent vehicle
Details on study design:
The study was designed to evaluate the potential chronic toxicity and oncogenicity of the test substance in male and female rats when exposed by inhalation. This route was chosen because it most appropriately simulates potential human exposure.
Observations and examinations performed and frequency:
See section 7.5.3 for details on clinical observations, body weight, clinical chemistry, hematology, and urinalysis.
Sacrifice and pathology:
See section 7.5.3 for details on pathology methods. See table 1 for listing of organs examined.
Statistics:
The incidences of histopathological lesions were compared to control group incidences by the Fisher's Exact test. See section 7.5.3 for additional information on other parameters.
Histopathological findings: neoplastic:
no effects observed
Details on results:
See Section 7.5.3 for results on clinical observations, body weight, hematology, clinical chemistry, urinalysis, organ weight and non-neoplastic histopathologic effects.

Neo-plastic Histopathologic Effects:
An increase in the incidence of mammary tumors was observed in female rats. The increased incidence of benign tumors in the low- and high-exposure groups were considered not to be biologically significant because of the lack of correlation with exposure concentration and because of inherent difficulties in correctly diagnosing tumors as benign or malignant. Thus, instead of considering specific tumor type, the total number of rats with at least one benign or malignant tumor was used for comparison of the incidence of mammary tumors in female rats. This comparison revealed a statistically significant increase in the incidence in the high-exposure group. Whereas this incidence was statistically greater, the biological significance of this difference was questioned after comparison with historical control data. In five long-term studies conducted at the test facility between 1980 and 1985, the overall incidence of control group female rats with at least one benign or one malignant tumor was 53%. Thus the incidence of mammary tumors for female rats exposed to test substance vapors (37%) was not significantly different from the mammary tumor incidence reported in long-term inhalation studies conducted at the test facility. The statistically significant increase in mammary tumors was considered not to be compound related. Rather, the control group incidence was uncharacteristically low in comparison with the historical control group incidence.
Dose descriptor:
NOAEL
Effect level:
2.5 other: %
Sex:
male/female
Basis for effect level:
other: No neoplastic lesions were observed that could be attributable to test substance exposure.
Remarks on result:
other: Effect type: carcinogenicity (migrated information)

Exposure Group:

 

0 ppm

 

2000 ppm

 

10000 ppm

 

25000 ppm

 

No. Rats/Group

 

78

 

79

 

77

 

75

 

No. Rats histologically examined:

 

75

 

77

 

74

 

70

 

No. Rats with at least one benign mammary tumor:

 

16

 

30*

 

24

 

29*

 

No. Rats with at least one malignant mammary tumor:

 

14

 

16

 

16

 

20

 

No. Rats with at least one benign or malignant mammary tumor:

 

27

 

34

 

35

 

37*

 

% Rats with at least one benign or malignant mammary tumor:a

 

 

36.0

 

44.2

 

47.3

 

52.9

 

* = Statistically different from the control group (p<0.05) by the Fisher’s Exact test.

 

Conclusions:
The test substance was not carcinogenic.

The study and the conclusions which are drawn from it fulfil the quality criteria (validity, reliability, repeatability).
Executive summary:

A 2-year inhalation study was conducted in male and female rats (see Section 7.5.3 for details on the study design). Ten rats/sex/group were sacrificed and necropsied at 6, 12, and 18 months and all rats alive at the 2-year time point. All rats underwent both gross and microscopic examinations.  No neoplastic lesions were observed that could be attributable to test substance exposure. An increase in the incidence of mammary tumors (benign or malignant) was observed in female rats in the 2.5% exposure group. The incidence of mammary tumors was considered not to be compound related because the incidences of tumors in the control group were uncharacteristically low in comparison with the control groups incidence in studies previously conducted at Haskell Laboratory.

The test substance was not carcinogenic in this test.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
47 106 mg/m³
Study duration:
chronic
Species:
rat
Quality of whole database:
High quality study according to guideline and under GLP

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Male and female rats were exposed to either 0, 0.2, 1 or 2.5% (v/v) DME via inhalation for 24 months. Carcinogenic effects were not observed at any concentration tested. Based on this information, the NOAEL for carcinogenicity was 2.5% (47106 mg/m3).


Justification for selection of carcinogenicity via oral route endpoint:
Study is technically not feasible.

Justification for selection of carcinogenicity via inhalation route endpoint:
Only relevant study available.

Justification for selection of carcinogenicity via dermal route endpoint:
Study is technically not feasible.

Justification for classification or non-classification

Based on results of repeated inhalation studies, the substance does not need to be classified for carcinogenicity according the EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.