N'-[3-(dimethylamino)propyl]-N,N-dimethylpropane-1,3-diamine

Endpoint summary

Description of key information

Data generated with the related substances DMAPA and DEAPA are used for endpoint coverage. In a short-term repeated dose toxicity study, 3 -Dimethylaminopropylamin (DMAPA) caused clinical symptoms and mortality in male and female Wistar rats when administered during 28 days at the dose level of 250 mg/kg body weight, which was therefore the LOAEL for this substance. Since no adverse effects were seen at 50 mg/kg bw, this dose level was set as NOAEL. 

In a subchronic repeated dose toxicity study via oral administration, the NOAEL for DEAPA was established at 750 mg/kg bw/day in male and 250 mg/kg bw/day in female rats. 

In a maximum tolerated dose study in rabbits, there were no adverse effects up to 300 mg/kg bw/day. The MTD was considered to be within the [300;1000] mg/kg bw/day.

The same is assumed to be correct for the test substance.

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

repeated dose toxicity: oral, other

Remarks:

Maximum Tolerated Dose Study

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Data generated with the related substance DEAPA is used for endpoint coverage. Justification of this read-across approach is available in section 13.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

other: MTD

Effect level:

>= 300 - < 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

mortality

Critical effects observed:

not specified

Conclusions:

No reliable repeated dose toxicity study with the test substance is available. Data generated with the related substance DEAPA is used for endpoint coverage.
Under the experimental conditions of the study, the dose level of 1000 mg/kg bw/day given orally (gavage) was considered to have exceeded the MTD in New Zealand White female rabbits (premature euthanasia after 4 days of dosing, clinical signs of poor health in 1/3 females, body weight loss, no food consumption). There were no adverse effects up to and including 300 mg/kg bw/day based on limited to a transient body weight loss and reduction of food consumption at 300 mg/kg bw/day and no effect at 100 mg/kg bw/day. Therefore, under the experimental condition of this study, the MTD was considered to be within the [300; 1000] mg/kg bw/day interval.
The same is assumed for the target substance.

Reference 2

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

read-across from related substance

Justification for type of information:

Data from the related substance DEAPA is used to cover the endpoint. Justification for the read-accross approach is included in section 13.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

750 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

clinical signs

Key result

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

clinical signs

Key result

Critical effects observed:

no

Conclusions:

No reliable repeated dose toxicity study with the test substance is available. Data generated with the related substance DEAPA is used for endpoint coverage.
The toxicity of the test item, Diethylaminopropylamine (as pH-neutralized dose formulations), was evaluated after daily oral administration (gavage) to Sprague-Dawley rats at dose-levels of 50, 250 or 750 mg/kg/day for 13 weeks followed by a 6-week treatment-free period. Under the experimental conditions of the study, clinical signs of poor condition were observed at the dose level of 750 mg/kg/day in four females, which induced the premature sacrifice of one of them more severely affected. No other adverse effects were observed in the study. Consequently, the NOAEL (No Observed Adverse Effect Level) was established at 750 mg/kg/day in males and 250 mg/kg/day in females.
The same is assumed for the target substance.

Reference 3

Endpoint:

short-term repeated dose toxicity: oral

Type of 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:

guideline study with acceptable restrictions

Remarks:

read-across from related substance

Justification for type of information:

Data from the related substance DMAPA is used to cover this endpoint. Justification for the read-across approach is included in section 13.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no treatment-related adverse effects were seen at the mid dose level

Dose descriptor:

LOAEL

Effect level:

250 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

mortality

Key result

Critical effects observed:

no

Conclusions:

No reliable repeated dose toxicity study with the test substance is available. Data generated with the related substance DMAPA is used for endpoint coverage.
3-dimethylaminopropylamin (DMAPA) caused clinical symptoms and mortality in male and female Wistar rats when administered 28 times at the dose level of 250 mg/kg body weight, which was therefore the LOAEL for this substance. Since no adverse effects were seen at 50 mg/kg bw, this dose level was set as NOAEL .

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

250 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

GLP guideline study

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

a short-term toxicity study does not need to be conducted because a reliable sub-chronic (90 days) or chronic toxicity study is available, conducted with an appropriate species, dosage, solvent and route of administration

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

a short-term toxicity study does not need to be conducted because a reliable sub-chronic (90 days) or chronic toxicity study is available, conducted with an appropriate species, dosage, solvent and route of administration

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

a short-term toxicity study does not need to be conducted because a reliable sub-chronic (90 days) or chronic toxicity study is available, conducted with an appropriate species, dosage, solvent and route of administration

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

a short-term toxicity study does not need to be conducted because a reliable sub-chronic (90 days) or chronic toxicity study is available, conducted with an appropriate species, dosage, solvent and route of administration

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose toxicity: oral

No reliable repeated dose toxicity study with the test substance was performed. Data generated with the related substances DMAPA and DEAPA are used for endpoint coverage.

short-term study, oral

A 28-day oral toxicity study according to OECD guideline 407 (Hoechst 1996; reliability score: 2) was performed on Wistar rats exposed to DMAPA at 0, 10, 50, and 250 mg/kg/day. One of five high dose males showed impaired respiration. In contrast, 4 of 10 high dose females died during the 28-day treatment. Decreased spontaneous activity, stilted gait, swollen abdomen, and impaired respiration were observed between days 11 and 24, mainly in the females that died. All other observations were similar to controls. In the four high-dose females that died, macroscopically visible changes such as discoloration of lungs with multiple red spots on its surfaces and foamy content were observed. Histopathological examinations revealed lesions which included congestion of organs, pulmonary hemorrhage, and edema, consistent with cardiorespiratory failure as cause of death. In addition, one of the females exhibited marked loss of lymphatic follicles of the spleen with massive marginal zone and periarteriolar lymphoid sheath atrophy. The one high-dose male rat that exhibited clinical signs, had focal ballooning degeneration of the squamous epithelium of the forestomach at necropsy.

The cause of death in the high dose group is likely be related to the corrosiveness of the substance. As no other systemic toxicity and effects on organs were observed, further testing with prolonged exposure is not thought to deliver additional information.

DMAPA caused clinical symptoms and mortality in male and female Wistar rats when administered 28 times at the dose level of 250 mg/kg body weight, which was therefore the LOAEL. Since no adverse effects were seen at 50 mg/kg bw, this dose level was set as NOAEL. The female rats seem to be more sensitive. 

Subchronic study, oral

The potential toxicity of Diethylaminopropylamine (as pH-neutralized dose formulations) was evaluated following daily oral administration (gavage) to rats for 13 weeks (Papineau, 2016a). On completion of the treatment period, designated animals were held for a 6-week treatment-free period in order to evaluate the reversibility of any findings. This GLP study was carried out according to OECD test guideline No. 408 (21 September 1998). Sprague-Dawley rats were treated daily by the oral route (gavage) with the test item, Diethylaminopropylamine, for 13 weeks as follows: one group of 15 males and 15 females at the dose-level of 750 mg/kg/day (group 4) and two other groups of 10 males and 10 females at dose-levels of 50 (group 2) or 250 (group 3) mg/kg/day. One group of 15 males and 15 females received the vehicle only (drinking water treated by reverse osmosis) under the same experimental conditions, and acted as a control group (group 1). A constant dosage volume of 5 mL/kg/day was used. At the end of the treatment period, the animals were sacrificed, except for the first five group 1 and 4 animals per sex, which were kept for a 6-week treatment-free period. The actual test item concentrations in the dose formulations prepared for use in Weeks 1, 4, 8 and 13 were determined using a gas chromatography with flame ionization detection analytical method. The animals were checked daily for mortality and clinical signs. Detailed clinical examinations were performed weekly and a Functional Observation Battery (FOB) was conducted in Week 13. Body weight was recorded pre-test, on the first day of treatment and then once a week. Food consumption was recorded weekly. Ophthalmological examinations were performed on all animals before the beginning of the study and on control and test item-treated animals at the end of the treatment period (Week 13). Hematology, blood biochemistry and urinary investigations were performed at the end of the treatment and treatment-free periods (Weeks 13 and 20). Additional blood samples were collected in Weeks 13 and 20 for possible analysis of thyroid hormones levels. The estrous cycle was determined for all females over 21 or 5 consecutive days at the end of the treatment or treatment-free period, respectively. Seminology investigations (count, motility and morphology) were performed on all males at sacrifice at the end of the treatment period. On completion of the treatment or treatment-free period, the animals were sacrificed and a full macroscopic post-mortem examination was performed. Designated organs were weighed and selected tissues were preserved. A microscopic examination (including testicular staging) was performed on designated tissues from control and high-dose animals sacrificed at the end of the treatment period and from animals that died prematurely and on all macroscopic lesions from all low- and intermediate-dose animals (groups 2 and 3) sacrificed on completion of the treatment period. PAS staining in the uterus in one high-dose female and immunohistochemistry for vasopressin in the pituitary gland on one control male and two high-dose males and females were examined. The brain, forestomach, gut-associated lymphoid tissue, kidneys, mesenteric lymph nodes (males only), pituitary gland, spleen and thymus of the low- and intermediate-dose animals (groups 2 and 3) sacrificed at the end of the treatment period and of the control and high-dose animals (groups 1 and 4) sacrificed at the end of the treatment-free period were also microscopically examined as changes were revealed in these organs at the end of the treatment period.

Actual concentrations of Diethylaminopropylamine in the dose formulations administered to the animals during the study remained within an acceptable range (-6.5% to +9.2%) compared to the nominal concentrations. During the treatment period, three females given 750 mg/kg/day showed clinical signs which were considered to be adverse (i.e. hunched posture, dyspnea, abdominal, loud breathing and/or bent head). Hunched posture and piloerection were transiently noted in one female given 50 mg/kg/day. Ptyalism was observed with a dose-related incidence at 250 and 750 mg/kg/day and reflux at dosing was noted in few males and females given 750 mg/kg/day on one occasion. These signs commonly observed when a test item is administered by gavage, were considered not to be an adverse effect. One female given 750 mg/kg/day more severely affected, showed signs of poor clinical condition and therefore was sacrificed in Week 11. Microscopic findings were noted (i.e. vacuoles in the pars nervosa of the pituitary gland, in the renal tubules, in the white matter from the brain, in the choroid plexus, in the spleen and in the GALT). At Functional Observation Battery examination, slightly higher incidences of horizontal movements and rearing were recorded in males and females given 750 mg/kg/day. Body weight gain was slightly lower in males given 750 mg/kg/day during the first and the third months of the treatment period, leading to a slightly lower body weight on completion of the treatment period (-6% vs. controls). Food consumption was not affected by the test item treatment. No ophthalmology findings were observed at the end of the treatment period. Estrous cycle was not altered by the test item treatment. The epididymal sperm motility and morphology and the spermatozoa count were unaffected by the test item treatment. At hematology investigations, minimally to slightly lower hemoglobin concentration and packed cell volume were noted in males from 250 mg/kg/day as well as lower red blood cell count in males given 750 mg/kg/day. This was accompanied with slight increase in reticulocyte count at 750 mg/kg/day. There were also non-adverse lower eosinophil count and prolonged prothrombin time in males and females treated at 750 mg/kg/day. These variations were considered to be of minor toxicological importance. At blood biochemistry investigations, changes in the markers of the renal function (lower sodium and chloride levels, higher inorganic phosphorus levels and lower protein and/or albumin levels) observed in males and/or females from 250 mg/kg/day could be secondary to the electrolytes imbalance induced by the intake of chloride ions used to neutralize the test item. A minimal increase of higher aspartate aminotransferase and alanine aminotransferase activity was observed in males and females given 750 mg/kg/day. All these changes were considered to be of minor importance. At urinary investigations, hematuria in males and females given 750 mg/kg/day along with glucosuria in males were suggestive of a tubular resorption problem. Reversibility of these laboratory findings was noted at the end of the treatment-free period. At the end of the treatment period, microscopic vacuoles were seen in the kidneys (correlated with tan discoloration), brain (in choroid plexus), pars nervosa (pituitary gland), spleen, mesenteric lymph node and/or GALT in males and females treated at 750 mg/kg/day and at a lesser extent, at 250 mg/kg/day in isolated females. There was also a non-adverse orthokeratotic hyperkeratosis in the forestomach from males and females treated at 750 mg/kg/day and increased severity and incidence of lymphoid atrophy in the thymus from males and surviving females treated at 750 mg/kg/day which correlated with small thymus and lower weights and may be related in part with stress.  

Under the experimental conditions of the study, clinical signs of poor condition were observed at the dose-level of 750 mg/kg/day in four females, which induced the premature sacrifice of one of them more severely affected. No other adverse effects were observed in the study. Consequently, the NOAEL (No Observed Adverse Effect Level) was established at 750 mg/kg/day in males and 250 mg/kg/day in females.

 

Range-finding study in rat, oral

In support of the 90-day study, a dose range finding study was performed.

The potential toxicity of the test item, diethylaminopropylamine (as pH-neutralized dose formulations), was evaluated following daily oral administration (gavage) to rats for 2 weeks in order to assist the selection of dose-levels for a further OECD 408 study to be performed in the same species (Papineau, 2016b). Three groups of five male and five female Sprague-Dawley rats received the test item, by daily oral administration (gavage) for 14 days, at dose-levels of 100, 300 or 1000 mg/kg/day. The test item was administered as a solution in the vehicle (drinking water treated by reverse osmosis) at a constant dosage-volume of 5 mL/kg/day. The pH of the dosing solutions was adjusted to 8.0 (± 0.5) using a solution of hydrochloric acid. A control group of five males and five females received the vehicle alone under the same experimental conditions. Clinical signs and mortality were checked daily. Body weight was recorded once before the beginning of the treatment period, and then twice a week. Food consumption was recorded twice a week. On completion of the treatment period, the animals were euthanized and a full macroscopic post-mortem examination was performed. Designated tissues were weighed and preserved in 10% buffered formalin. A microscopic examination was performed on macroscopic lesions for all animals and on stomach with forestomach for the control and high-dose animals.

No unscheduled deaths occurred during the study. Ptyalism, not considered as an adverse sign of toxicity, was observed at 1000 mg/kg/day (1/5 males and 4/5 females). Lower body weight gain was observed at 1000 mg/kg/day in males and females over the first 3 days of the study together with slight lower food consumption. This effect was present in a lesser extent in males throughout the study and resulted in a lower final body weight. No macroscopic findings were attributed to treatment with the test item. Slight hyperplasia of squamous cells associated with minimal to slight hyperkeratosis was observed at 1000 mg/kg/day in the forestomach of 5/5 males and 4/5 females and was considered to be non-adverse. No treatment-related effects were observed at 100 and 300 mg/kg/day.

 

Maximum tolerated dose study in rabbit, oral

Under the experimental conditions of the study, the dose level of 1000 mg/kg/day given orally (gavage) was considered to have exceeded the MTD in New Zealand White female rabbits (premature euthanasia after 4 days of dosing, clinical signs of poor health in 1/3 females, body weight loss, no food consumption).

There were no adverse effects up to 300 mg/kg/day based on were limited to a transient body weight loss and reduction of food consumption at 300 mg/kg/day and no effet at 100 mg/kg/day .

Therefore and under the experimental condition of this study, the MTD was considered to be within the [300; 1000] mg/kg/day interval.

 

 

The same is assumed to be correct for the target substance. For read-across argumentation to Bis-DMAPA, see read-across document included in section 13.

 

Repeated dose toxicity: inhalation

A key study is available for the oral route of exposure. According to the REACH Regulation, only one route of exposure should be tested for repeated dose toxicity (column 2, annex VIII, section 8.6.1). Therefore, it is not necessary to perform a repeated dose toxicity study via the inhalation route of exposure.

Repeated dose toxicity: dermal

A key study is available for the oral route of exposure. According to the REACH Regulation, only one route of exposure should be tested for repeated dose toxicity (column 2, annex VIII, section 8.6.1). Therefore, it is not necessary to perform a repeated dose toxicity study via the dermal route of exposure.

Justification for classification or non-classification

According to the criteria of the CLP Regulation and based on the study results, the test substance is not to be classified.