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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
repeated dose toxicity: dermal
Remarks:
other: cancerogenicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No data on guideline and GLP. Trimethylenediamine is structural very similar to the test substance ethylenediamine (difference: chain length / one CH2-group). Thus, the test result is justified for read across with respect to trimethylenediamine.

Data source

Reference
Reference Type:
publication
Title:
Dermal Oncogenicity studies on ethylenediamine in male C3H mice.
Author:
DePass, L.R., Fowler, E.H. and Yang, R.S.H
Year:
1984
Bibliographic source:
Fundam. Appl. Toxicol. 4:641-645.

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The maximum tolerated dose (for local effects) was applied to the back of 50 male mice three times weekly throughout their lifespan. Positive (3-methylcholanthrene) and negative (water) control groups (50 mice/group) were included.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Substance no 1: Purity 99,91%, 0,07% ammonia
Substance no 2: Purity 99.1%;
Impurities:
0.54 % pyrazine,
0.08 % ammonia,
0.03 % water,
0.02 % monomethylamine,
0.02 % ethylamine,
0.02 % N-methyl-piperazine,
0.02 % methylpyrazine,
trace dimethylamine,
trace ethanol,
trace N-ethylpiperazine,
trace ethylpyrazine ,

Test animals

Species:
mouse
Strain:
C3H
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: C3H/HeJ mice from Jackson Laboratories, Bar Harbor, Maine
- Age at study initiation: 74 to 79 days of age
- Housing: Housed individually in stainless steel cages with wire mesh floors. All mice were housed in the same room with
controlled lighting
- Diet (e.g. ad libitum): Ziegler Bros. NIH 07 pellets (Gardners, Pa.)
- Water (e.g. ad libitum): water from an automatic watering system

Administration / exposure

Type of coverage:
open
Vehicle:
water
Details on exposure:
Mice were treated three times weekly for their complete life span with 25 µL per application of each substance. Substances were applied with an Eppendorf pipet to the back of each mouse from which the fur was clipped once weekly.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentrations verified monthly during the study
Duration of treatment / exposure:
complete life span

Frequency of treatment:
3x/wk
Doses / concentrations
Remarks:
Doses / Concentrations:
25 μL of 1% aqueous solution/application
Basis:

No. of animals per sex per dose:
Treatment group singly housed: 50 mice
Control animals:
yes, concurrent vehicle
Details on study design:
Control group singly housed: 50 mice received distilled water. Control group housed 5/cage: 40 mice received water
Positive control:
Positive control group housed 5/cage: 40 mice received 0.1% 3-methylcholanthrene in acetone

Examinations

Observations and examinations performed and frequency:
All mice were examined daily, and the onset and progress of tumor growth were recorded monthly.

Results and discussion

Effect levels

open allclose all
Dose descriptor:
NOAEL
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Mild fibrosis suggesting irritation to skin was noted
Remarks on result:
not measured/tested
Remarks:
25 μL of 1% solution used; Effect level not specified in more detail
Dose descriptor:
NOAEL
Effect level:
8.3 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Weight of male mice 0.03 kg
Dose descriptor:
NOAEL
Effect level:
10.2 mg/kg bw/day (actual dose received)
Based on:
test mat.
Remarks:
/calculated from EDA to trimethylenediamine
Sex:
male
Basis for effect level:
other: calculated from EDA to trimethylenediamine

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Mean survival time of the exposure group for substance 2 (598 days) was shorter than that of the singly housed control group (626 days); no treatment-related macroscopic or histopathologic findings; one mouse of the exposure group had a dermal fibrosis at application site and another one had a mammary adenocarcinoma. One sebaceous adenoma of the skin of the thorax was noted in the control group individually housed.

In the exposure group for substance 1, 1 mouse had a myxosarcoma at the base of the tail, and 11 animals had mild to moderate dermal fibrosis, suggesting skin irritation. Survival time did not differ from negative control groups.

In the 3-methylcholanthrene group, 39 of 40 mice had skin tumors including 37 with confirmed squamous cell carcinomas.

In conclusion:

The dermal repeated dose NOAEL was 8.3 mg/kg bw/day EDA (actually received dose), corresponding to 10.2 mg/kg bw/day trimethylenediamine (read across).

Applicant's summary and conclusion