N'-(3-aminopropyl)-N,N-dimethylpropane-1,3-diamine

Carcinogenicity

Description of key information

No carcinogenicity data is available on N'-(3-aminopropyl)-N,N-dimethylpropane-1,3-diamine. 
C3H/HeJ mice (50 males/group) were administered the analogue substance diethylenetriamine in water via the dermal route at 0 or 1.25 mg/animal/day (~ 0 or 56.3 mg/kg-bw/day) 3 days/week for the lifetime of the animals. No treatment-related skin tumors or increased incidence of any internal tumors were observed. The survival time and mortality rates were not markedly different between the treated and control groups.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: dermal

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: Study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

Mice were dosed dermally three times/week for a lifetime. Gross and histopathological examinations were performed on all animals.

GLP compliance:

not specified

Species:

mouse

Strain:

other: C3H/HeJ

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Jackson Laboratories (Bar Harbor, ME)
- Age at study initiation: no data
- Weight at study initiation: no data
- Housing: individually in stainless-steel cages with wire-mesh floors
- Diet: Ziegler Brothers, NIH 07 pellets (Gardners, PA) ad libitum
- Water: ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

dermal

Vehicle:

water

Details on exposure:

TEST SITE
- Area of exposure: back of each mouse
- % coverage: no data
- Type of wrap if used: none
- Time intervals for shavings or clipplings: once weekly

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 25 µl
- Concentration (if solution): 5%
- Constant volume or concentration used: yes

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Monthly analyses of the aqueous dilutions of DETA-HP administered to the animals revealed a mean ± SD concentration of 5.07 ± 0.26% DETA and other amines by weight.
The aqueous dilutions of DETA-C contained a mean ± SD concentration of 5.15 ± 0.33% DETA and other amines by weight.

Duration of treatment / exposure:

complete life span (ca. 20 months)

Frequency of treatment:

three times weekly

Post exposure period:

none

Remarks:

Doses / Concentrations:
1.25 mg/animal
Basis:
other: nominal in water 25 µl in 5% solution v/v

Remarks:

Doses / Concentrations:
56.3 mg/kg bw
Basis:
other: Estimate as calculated from data from average of initial body weights and milligrams administered.

No. of animals per sex per dose:

50

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale:
In a preliminary study to determine the chronic dosing concentration, groups of 5 C3H/HeJ mice were dosed daily for 10 days with 25 ul of solutions of 5% or 10% DETA (BRRC Sample No. 41-259) in deionized water. The preliminary test indicated that 5% DETA-HP was relatively non-irritating and non-toxic to the mice in the preliminary study and, therefore, it was the concentration used in the chronic study.

Observations and examinations performed and frequency:

Mice were observed daily for mortality and were carefully examined monthly for lesions of the skin.

Sacrifice and pathology:

Ten mice from each test group were scheduled for sacrifice at 18 months to evaluate their tissues for possible pathologic changes. All livers, kidneys, and lungs from the 18-month sacrifice were fixed for histopathologic examination.

Necropsies were performed on all mice shortly after death or after sacrifice of culled and moribund animals. Necropsy included the careful examination of the skin and body cavities, and the recording of observations. All suspect tumors and the dorsal skin of all mice, with or without tumors, were fixed in 10% neutral buffered formalin (NBF). In addition, all livers, kidneys, and lungs were fixed in NBF for possible histopathologic examination. Sections were prepared from the dorsal skin of all mice and any suspect internal tumors. Histopathologic examinations were performed and reported.

Statistics:

Mortality incidences were assessed by the product-limit method (Kaplan and Meier, 1958). The Mantel-Cox and Breslow statistics were used for testing the equality of the survival curves (Mantel, 1966; Brewlow, 1970).

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):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

In the group that received DETA-HP as a 5% (v/v) dilution in deionized water the mean survival time was not statistically different from that of the deionized water control group (587 versus 626 days, respectively). No papillomas or carcinomas were observed on the skin of any mice in either the DETA-HP-treated group or the deionized water control group. A sebaceous adenoma on the skin of the thorax was observed on a mouse in the deionized water control group.

No skin or subcutaneous tumors were found i n the DETA-HP-treated mice sacrificed following 18 months of treatment. However, one nodule was found in a negative control mouse at the end of 18 months which was histologically diagnosed as a sebaceous adenoma.

In the lifetime study no skin or subcutaneous neoplasms were found in the DETA-HP-treated mice or in the negative control mice. Other gross and microscopic findings in the 18-month interim sacrifice mice and the lifetime studies for the DETA-HP and negative control mice were consistent with the spontaneous background incidence of inflammatory and neoplastic lesions in this strain used in lifetime studies.

Relevance of carcinogenic effects / potential:

There was no evidence of an oncogenic effect

Dose descriptor:

NOAEL

Effect level:

>= 56.3 mg/kg bw/day

Sex:

male

Basis for effect level:

other: 3 times weekly

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Dose descriptor:

NOAEL

Effect level:

>= 56.3 mg/kg bw/day

Sex:

male

Basis for effect level:

other: 3 times weekly

Remarks on result:

other: Effect type: toxicity (migrated information)

Executive summary:

Diethylenetriamine (DETA) was tested in a total of 100 male C3H/HeJ mice in a study involving dermal application of two products of different degrees of purity, DETA High Purity (DETA-HP, 96.77% diethylenetriamine, 1.78% N-(2-aminoethyl)piperazine, remaining components other amines) and DETA Commercial Grade (DETA-C 90.8% diethylenetriamine, 8.9% N-(2-aminoethyl)piperazine, 0.34% ethylenediamine). The test substances were applied as a 5% aqueous solution. A 10% diethylenetriamine solution had caused open skin wounds, and so the non-irritating 5% solution was considered to be the highest possible concentration that could be used in a lifetime study. The treatment involved the application of 25 µl of the test solution (1.25 mg) to the dorsal skin of the mice (which was shaved once a week) three times a week for their entire lives. The mice were observed daily. After 18 months, the skin, liver, kidneys and lungs from 10 mice/group were fixed for histological examination. The average survival time for the mice was 587 days in the DETA-HP group and 662 days in the DETA-C group. The animals in the control group, which were treated with 25 µl water, lived for 626 days on average. 2 tumours were found in total. One mouse in the control group had a sebaceous gland adenoma of the thorax, and one in the DETA-C group had a cavernous haemangioma of the neck region. This type of haemangioma was also observed in historical controls in the institute carrying out the study. Also the effects on other organs corresponded to the spontaneous occurrence in the control groups of the strain studied. Diethylenetriamine thus had no carcinogenic activity in this study.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

53.6 mg/kg bw/day

Study duration:

chronic

Species:

mouse

Quality of whole database:

Read across to diethylenetriamine

Justification for classification or non-classification

According to REGULATION (EC) No 1272-2008 and Annex VI of Commission Directive 2001/59/EC:

Not classified, based on the data available on the analoque substance, diethylenetriamine.

Additional information

No carcinogenicity data is available on N'-(3-aminopropyl)-N,N-dimethylpropane-1,3-diamine (DMAPAPA). However an analogue substance, diethylenetriamine (DETA) was tested in a total of 100 male C3H/HeJ mice in a study involving dermal application of two products of different degrees of purity, DETA High Purity (DETA-HP, 96.77% diethylenetriamine, 1.78% N-(2-aminoethyl)piperazine, remaining components other amines) and DETA Commercial Grade (DETA-C 90.8% diethylenetriamine, 8.9% N-(2-aminoethyl)piperazine, 0.34% ethylenediamine) (de Pass et al., 1987). The test substances were applied as a 5% aqueous solution. A 10% diethylenetriamine solution had caused open skin wounds, and so the non-irritating 5% solution was considered to be the highest possible concentration that could be used in a lifetime study. The treatment involved the application of 25 µl of the test solution (1.25 mg) to the dorsal skin of the mice (which was shaved once a week) three times a week for their entire lives. The mice were observed daily. After 18 months, the skin, liver, kidneys and lungs from 10 mice/group were fixed for histological examination. The average survival time for the mice was 587 days in the DETA-HP group and 662 days in the DETA-C group. The animals in the control group, which were treated with 25 µl water, lived for 626 days on average. 2 tumours were found in total. One mouse in the control group had a sebaceous gland adenoma of the thorax, and one in the DETA-C group had a cavernous haemangioma of the neck region. This type of haemangioma was also observed in historical controls in the institute carrying out the study. Also the effects on other organs corresponded to the spontaneous occurrence in the control groups of the strain studied. Diethylenetriamine thus had no carcinogenic activity in this study.

Justification for selection of carcinogenicity via dermal route endpoint:
Key study