N'-(ethylcarbonimidoyl)-N,N-dimethylpropane-1,3-diamine monohydrochloride

Endpoint summary

Description of key information

A reliable, guideline study according to OECD 423 is available and providing an LD50 cut-off value of 500 mg/kg bw to rats.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Wistar

Remarks:

Crl: WI(Han)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, 97633 Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: 8 to 11 weeks old
- Weight at study initiation: 162 to 189 g for all animals
- Fasting period before study: No
- Housing: Full barrier in an air-conditioned room. Housed individually in IVC cages including saw fibre bedding.
- Diet (e.g. ad libitum): Free access to Altromin maintenance diet.
- Water (e.g. ad libitum): Free access to tap water.
- Acclimation period: At least 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3°C
- Humidity (%): 55 +/- 10%
- Air changes (per hr): 10 per hour
- Photoperiod (hrs dark / hrs light): Artificial lighting (12 hours light/dark cycles)

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

Aqua ad injectionem

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 0.2 g/mL or 0.03 g/mL
- Amount of vehicle (if gavage): 10 mL/Kg
- Justification for choice of vehicle: Standard vehicle for test type and chosen based on its non-toxic characteristics.

MAXIMUM DOSE VOLUME APPLIED: 10 mL/Kg

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: No toxicity data available and accordingly limit dose chosen.

Doses:

The starting dose was selected to be 2000 mg/kg bw. This was then followed by two further doses of 300 mg/kg bw.

No. of animals per sex per dose:

3 females per step (3 at 2000 mg/kg bw and 6 at 300 mg/kg bw)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were weighed on Day 1 (prior to dosing) and days 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: Clinical signs were noted on the day of dosing and then once daily during the observation period.

Statistics:

Not applicable to study type

Sex:

female

Dose descriptor:

LD50 cut-off

Effect level:

500 mg/kg bw

Based on:

test mat.

Mortality:

All animals that received 2000 mg/kg bw were found dead within 3 hours post dose (3/3). During step two (300 mg/kg bw), one animal was found dead 1 day post dose (1/6).

Clinical signs:

other: 2000 mg/kg bw: Signs observed in two animals included recumbency, apathy, ataxia and half-eyelid closure. 300 mg/kg bw: The most relevant signs at this dose (observed in the majority of animals) were piloerection, reduced spontaneous activity, recumbency

Gross pathology:

2000 mg/kg bw: No significant necropsy findings were noted.
300 mg/kg bw: In the animal found dead a bloated stomach, duodenum, jejunum, ileum with Peyer’s patches, mesenteric lymph node, caecum and colon were noted along with a red discolouration of the lung. Red spots in the lung were also observed in another surviving animal and no other significant findings were observed in the groups

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

A reliable, guideline study is available providing an LD50 cut-off value of 500 mg/kg bw to rats.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

500 mg/kg bw

Quality of whole database:

1

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

September 2017 to Dec 2017

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

1987

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Version / remarks:

August 1998

Qualifier:

according to guideline

Guideline:

other: EC No. 440/2008 Part B

Version / remarks:

Acute Toxicity (Dermal), May 2008

Qualifier:

according to guideline

Guideline:

other: Appendix to Director General Notification, No. 12-Nousan-8147

Version / remarks:

Agricultural Production Bureau, Ministry of Agriculture, Forestry and Fisheries of Japan (JMAFF), November 2000, including the most recent revisions.

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

Batch no: AAN0680
Purity: 99.9%
Expiry: 30 August 2018

Species:

rat

Strain:

other: Crl: WI(Han)

Sex:

male/female

Details on test animals or test system and environmental conditions:

5 males and 5 females per dose group (females will be nulliparous and non-pregnant).
Target age at the initiation of dosing: Between 10 and 12 weeks old. Animals to be used within the study will be of approximately the same age.
Target weight at the initiation of dosing: 230 to 380 g (males) and 130 to 280 (females).
Environmental conditions:
Temperature: 18 to 24°C
Humidity: 40 to 70%
Light Cycle: 12-hours light and 12-hours dark (except during designated procedures)
Ventilation: At least 10 air changes per hour

Type of coverage:

occlusive

Vehicle:

propylene glycol

Details on dermal exposure:

A single dose of test item was administered to the appropriate animals by dermal application on Day 1. One day before dosing, an area of approximately 5x7 cm on the back of the animals was clipped. The test item was applied in an area of approximately 10% of the total body surface, i.e. approximately 25 cm² for males and 18 cm² for females. The test item was held in contact with the skin with a dressing, consisting of a surgical gauze patch (Surgy 1D), successively covered with aluminum foil and Coban elastic bandage. A piece of Micropore tape was additionally used for fixation of the bandages in females only. The application period was 24 hours, after which the dressing was removed and the skin cleaned of residual test item using water.

Duration of exposure:

24 hours

Doses:

The starting dose level was 2000 mg/kg body weight. Based on mortality animals were dosed at the lower doses of 200 and 1000 mg/kg following a stepwise approach. First three females were dosed at 200 mg/kg, based on the absence of mortality in this group three females were dosed at 1000 mg/kg. Finally, two females and five males were dosed at 200 mg/kg in order to achieve guideline requirements. The dose volume for each animal was based on the body weight measurement prior to dosing.A dose volume of 10 mL/kg body weight was used for each dose. The dosing formulations were stirred continuously during dose administration.

No. of animals per sex per dose:

3 females - 200mg/kg
3 females - 1000mg/kg
2 x females, 5 x males - 200mg/kg

Control animals:

no

Details on study design:

A single dose of test item was administered to the appropriate animals by dermal application on Day 1. One day before dosing, an area of approximately 5x7 cm on the back of the animals was clipped. The test item wias applied in an area of approximately 10% of the total body surface, i.e. approximately 25 cm² for males and 18 cm² for females. The test item was held in contact with the skin with a dressing, consisting of a surgical gauze patch (Surgy 1D), successively covered with aluminum foil and Coban elastic bandage. A piece of Micropore tape was additionally be used for fixation of the bandages in females only. The application period wias 24 hours, after which the dressing was removed and the skin cleaned of residual test item using water or an appropriate vehicle. The dose level was 2000 mg/kg body weight. The dose volume for each animal was based on the body weight measurement prior to dosing. A dose volume of 10 mL/kg body weight was used for each dose. The dosing formulations was stirred continuously during dose administration.

Preliminary study:

At 2000 mg/kg, all males and four females were found dead on Day 2 prior to the removal of the test item and the remaining female was killed in extremis on Day 2 prior to the removal of the test item.
At 1000 mg/kg, all three females were found dead on Day 3. At 200 mg/kg, no mortality occurred.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 200 - <= 1 000 mg/kg bw

Based on:

test mat.

Mortality:

At 2000 mg/kg, all males and four females were found dead on Day 2 prior to the removal of the test item and the remaining female was killed in extremis on Day 2 prior to the removal of the test item.
At 1000 mg/kg, all three females were found dead on Day 3. At 200 mg/kg, no mortality occurred.

Clinical signs:

other: At 2000 mg/kg, no clinical signs were noted on the day of dosing. At 1000 mg/kg, lethargy, hunched posture, uncoordinated movements, piloerection, general erythema of the treated skin, alopecia of the left cheek, chromodacryorrhoea of the snout and/or hyp

Gross pathology:

At 2000 mg/kg, isolated reddish foci on the thymus and/or many dark red foci of the ileum were noted. Gelatinous subcutis of the treated skin and/or forelegs were noted for all animals, this finding was most likely caused by to the treatment method. At 1000 mg/kg, several black foci or dark red discoloration of the glandular mucosa of the stomach were noted. Advanced autolysis was noted for all animals, this finding was considered not toxicologically relevant. At 200 mg/kg, a diaphragmatic hernia of the right medial lobe of the liver was noted for one male, this finding is occasionally seen in rats of this age and strain and was therefore considered not related to treatment.

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

The dermal LD50 value of 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in Wistar rats was established to be within the range of 200-1000 mg/kg body weight.

Based on these results:
• According to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2015) (including all amendments), 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride should be classified as: toxic in contact with skin (Category 3) for acute toxicity by the dermal route.
• According to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride should be classified as Category 3 and should be labeled as H311: Toxic in contact with skin.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Quality of whole database:

1

Additional information

The dermal LD50 value of 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in Wistar rats was established to be within the range of 200-1000 mg/kg body weight.

Based on these results:

• According to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2015) (including all amendments), 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride should be classified as: toxic in contact with skin (Category 3) for acute toxicity by the dermal route.

• According to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride should be classified as Category 3 and should be labeled as H311: Toxic in contact with skin.