Registration Dossier

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Administrative data

Description of key information

- LD50 (Males and Females combined) = 3478 (95% c.i. 3108 - 3878) mg/kg bw / LD50 (Males) = 3647 (95 % c.i. 3114 - 4567) mg/kg bw / LD50 (Females) = 3317 (95 % c.i. 2596 - 3853) mg/kg bw; OECD TG 401; RL1; GLP; read-across: Amides, C8-18 even numbered, N-[3-(dimethylamino)propyl]

- LD50 < 1740 mg/kg bw (Males and Females combined); Appraisal of the safety of chemicals in foods, drugs and cosmetics, by FDA (US), 1959; RL2; no GLP Overall LD50 considered to be in the range of 300 and 2000 mg/kg bw

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar physicochemical, toxicological and ecotoxicological properties because
- they are manufactured from similar resp. identical precursors under similar conditions
- they share structural similarities with common functional groups: tertiary amines, amides, and fatty acid chains with comparable length and degree of saturation.
- the metabolism pathway leads to comparable products: identical amine backbone and long chain fatty acids with slight differences in chain length distribution and degree of (un)saturation
As their origin is from natural sources, the used fatty acids may have a mixed and slightly varying composition with an even numbered chain length from C8 to C18. Unsaturated C18 amounts may be
included. Consequently, the target and source substance differ by their carbon chain length distribution and the degree of unsaturation in the fatty acid moiety.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Source substance
Reference substance name: Amides, C8-18 even numbered, N-[3-(dimethylamino)propyl]
Carbon chain length distribution in starting material:
C8: <= 10%
C10: 3-10%
C12: 40-65%
C14: 10-26%
C16: 6-14%
C18: 2-24%
C18 unsatd.: <= 2%
Purity: 86.8-98.6 %

Target substance
Reference substance name: Amides, C8-18, C18 unsatd, N-[3-(dimethylamino)propyl]
Carbon chain length distribution in starting material:
C8: 0-10%
C10: 2-16%
C12: 40-55%
C14: 10-22%
C16: 5-15%
C18: 0-5%
C18 unsatd.: 5-20 %
Purity: > 80 %

3. ANALOGUE APPROACH JUSTIFICATION
The read across from the source substance Amides, C8-18 even numbered, N-[3-(dimethylamino)propyl] is justified:
a) Based on the information given in section 1, it can be concluded that source and target substance are similar in structure, since they are manufactured from similar resp. identical precursors under similar conditions and all contain the same functional groups. Thus a common mode of action can be assumed.
b) The only deviation within this group of substances is a minor variety in their fatty acid moiety, which is not expected to have a relevant impact on intrinsic toxic or ecotoxic activity and environmental fate.
c) The target and source substance are all expected to undergo hydrolysis of the amide bond by amidases which would result in free fatty acids of of differing only slightly in length and degree of (unsaturation and dimethylaminopropylamine.

The read across hypothesis is based on structural similarity of target and source substance. The respecive data are summarised in the data matrix; robust study summaries are included in the Technical Dossier in the respective sections.

4. DATA MATRIX
see attached document
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
other: Appraisal of the safety of chemicals in foods, drugs and cosmetics, by FDA (US), 1959
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: gavage
Doses:
2, 2.52, 3.18, 3.98 g/kg bw
No. of animals per sex per dose:
5 males, 5 females
Control animals:
no
Statistics:
Probit analysis
Sex:
male/female
Dose descriptor:
LD50
Effect level:
< 2 000 mg/kg bw
Remarks on result:
other: 14 d LD50 based on product
Sex:
male/female
Dose descriptor:
LD50
Effect level:
< 1 740 mg/kg bw
Remarks on result:
other: 14 d LD50 based on a.i. (87%)
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 570 mg/kg bw
95% CL:
2 350 - 2 790
Remarks on result:
other: 24 h LD50 for produt with 87 % a.i. (this value corresponds to a LD50 of approx. 2236 (95 % CL 2045 - 2427) mg/kg bw for 100% a.i.).
Mortality:
2000 mg/kg bw: after 24 h: 3/10, after 14 d: 7/10
2520 mg/kg bw: after 24 h: 5/10, after 14 d: 8/10
3180 mg/kg bw: after 24 h: 6/10, after 14 d: 10/10
3980 mg/kg bw: after 24 h: 9/10, after 14 d: 10/10

For more details see "Remarks on results including tables and figures."
Clinical signs:
- The sample induced in the tested dosages obvious decreased activity, reduced pain reaction, light tremor and twitches, obvious disturbance in coordination, abnormal body posture, decreased grip- and limp tone, diarrhea and piloerection. Further on in the higher dosages from 2520 mg/kg bw upwards the animals showed emaciated flanks and ptosis.
- The described symptons were observed about 20 minutes after the application and held on partly for 24 hours. Afterwards all animals showed a normal dispositon.
Body weight:
- Normal body weight gains
Gross pathology:
- Gross necropsies performed on the animals which died generally exhibited a redness of the gastrointestinal mucous membrane.
- Necropsies performed on the surviving animals at termination exhibited no gross pathological findings.

Table 1: Number of animals dead (total number of animals: 5 males, 5 females per dose)

Dose (mg/kg bw)

Mortality after  24 h(# dead/total)

Mortality after  14 d(# dead/total)

Time range of deaths

Male

Female

Combined

Male

Female

Combined

2000

2/5

1/5

3/10

4/5

3/5

7/10

24 h – 3 d

2520

2/5

3/5

5/10

3/5

5/5

8/10

24 h – 3 d

3180

2/5

4/5

6/10

5/5

5/5

10/10

 24 h – 48 h

3980

5/5

4/5

9/10

5/5

5/5

10/10

 24 h – 48 h

Interpretation of results:
sligthly toxic
Remarks:
Migrated information Criteria used for interpretation of results: expert judgment
Conclusions:
On the basis of the results obtained after a single oral administration, the oral LD50 after 14 d of the source substance Amides, C8-18 even numbered, N-[3-(dimethylamino)propyl] was determined to be < 2000 mg/kg bw for product with 87 % a.i. (this value corresponds to a LD50 of approx. < 1740 mg/kg bw for 100% a.i.). No significant effects on body weight were observed. Decreased activity, reduced pain reaction, light tremor and twitches, obvious disturbance in coordination, abnormal body posture, decreased grip- and limp tone, diarrhea and piloerection were observed about 20 minutes after application and held on partly for 24 hours. Afterwards all animals showed a normal disposition. From doses 2520 mg/kg bw upwards the animals showed in addition emaciated flanks and ptosis.
Therefore the target substance Amides, C8-18 even numbered, C18 unsatd., N-[3-(dimethylamino)propyl] was judged to be slightly toxic based on the LD50 in males and females.
Executive summary:

In an acute oral toxicity study in accordance with the Appraisal of the safety of chemicals in foods, drugs and cosmetics, by FDA (US) 1959, groups of fasted male and female young adult Wistar rats were given a single oral dose of the source substance Amides, C8-18 even numbered, N-[3-(dimethylamino)propyl] at doses of 2000, 2520, 3180, 3980 mg/kg bw and observed for 14 days. The substance was administered as 50% suspension in arachis oil warmed at about 37 °C.

In the dose groups 2000, 2520, 3180, 3980 mg/kg bw 30, 50, 60, and 90 % of animals died after 24 hours, respectively. After 14 days 70, 80, and 100 % of animals died, respectively. In the dose group 2000 and 2520 mg/kg bw animals were found dead between 24 h and 3 days. In the two highest dose groups animals were found dead on the first 24 or 48 hours after application.

No effects on body weight were observed. Decreased activity, reduced pain reaction, light tremor and twitches, obvious disturbance in coordination, abnormal body posture, decreased grip- and limp tone, diarrhea and piloerection were observed about 20 minutes after application and held on partly for 24 hours. Afterwards all animals showed a normal disposition. At doses from 2520 mg/kg bw upwards the animals showed in addition emaciated flanks and ptosis. Gross necropsies performed on the animals which died generally exhibited a redness of the gastrointestinal mucous membrane. Necropsies performed on the surviving animals at termination exhibited no gross pathological findings.

Oral LD50(14 days) Males/Females: < 2000 mg/kg bw.

No information on content of active ingredient of the test substance in the study report. However, according to producer information the test substance has 87 % a.i., therefore the LD50 refering to 100 % a.i. is < 1740 mg/kg bw.

In addition to the 14 d LD50, a 24 h LD50 (Males/Females) of 2570 (95 % CL 2350 - 2790) mg/kg bw was calculated for the product with 87 % a.i. (this value corresponds to a LD50 of approx. 2236 (95 % CL 2045 - 2427) mg/kg bw) for 100% a.i.).

The target substance Amides, C8-18 even numbered, C18 unsatd., N-[3-(dimethylamino)propyl] was judged to be slightly toxic based on the oral LD50 (14 days) in male and female rats.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

For the assessment of the acute toxicity of Amides, C8-18, C18 unsatd, N-[3-(dimethylamino)propyl] two acute toxicity studies conducted with the closely related source substance Amides, C8-18 even numbered, N-[3-(dimethylamino)propyl] are available.

In an acute oral toxicity study (standard acute method, according to OECD 401 (February, 1987) and the EEC directive 84/449 EEC), groups of 5 male and 5 female Wistar rats were given single oral doses of Amides, C8-18 even numbered, N-[3-(dimethylamino)propyl] in arachis oil and observed for 14 days.

Oral LD50 Males and Females combined after 14 days 3478 (3108 - 3878) mg/kg of body weight

Oral LD50 Males after 14 days: 3647 (3114 - 4567) mg/kg of body weight

Oral LD50 Females after 14 days: 3317 (2596 - 3853) mg/kg of body weight

The sample induced reduced activity (apathy), disturbance of coordination, reduced reflex excitability, cyanosis/paleness, piloerection, reduced body temperature and kachexia.

Post-dosing weight gains (2 week values) of the surviving animals did not show essential differences.

The mortalities showed residues of the sample in the digestive system and redness of the mucous membrane of the digestive system.

Nothing abnormal was found in the animals necropsied on day 14.

The test substance was judged to be practically non-toxic based on the oral LD50 in male and female rats.

In an acute oral toxicity study in accordance with the Appraisal of the safety of chemicals in foods, drugs and cosmetics, by FDA (US) 1959, groups of fasted male and female young adult Wistar rats were given a single oral dose of Amides, C8-18 even numbered, N-[3-(dimethylamino)propyl] at doses of 2000, 2520, 3180, 3980 mg/kg bw and observed for 14 days. The substance was administered as 50% suspension in arachis oil warmed at about 37°C.

In the dose groups 2000, 2520, 3180, 3980 mg/kg bw 30, 50, 60, and 90 % of animals died after 24 hours, respectively. After 14 days 70, 80, and 100% of animals died, respectively. In the dose group 2000 and 2520 mg/kg bw animals were found dead between 24 h and 3 days. In the two highest dose groups animals were found dead on the first 24 or 48 hours after application.

No effects on body weight were observed. Decreased activity, reduced pain reaction, light tremor and twitches, obvious disturbance in coordination, abnormal body posture, decreased grip- and limp tone, diarrhea and piloerection were observed about 20 minutes after application and held on partly for 24 hours. Afterwards all animals showed a normal disposition. At doses from 2520 mg/kg bw upwards the animals showed in addition emaciated flanks and ptosis. Gross necropsies performed on the animals which died generally exhibited a redness of the gastrointestinal mucous membrane. Necropsies performed on the surviving animals at termination exhibited no gross pathological findings.

Oral LD50 Males/Females: < 2000 mg/kg bw.

No information on content of active ingredient of the test substance in the study report. However, according to producer information the test substance has 87% a.i., therefore the LD50 referring to 100% a.i. is < 1740 mg/kg bw.

In addition to the 14 d LD50, a 24 h LD50 (Males/Females) of 2570 (95 % CL 2350 - 2790) mg/kg bw was calculated for the product with 87 % a.i. (this value corresponds to a LD50 of approx. 2236 (95 % CL 2045 - 2427) mg/kg bw) for 100% a.i.).

The test substance Amides, C8-18 even numbered, N-[3-(dimethylamino)propyl] was judged to be slightly toxic based on the oral LD50 in male and female rats.

The overall LD50 of Amides, C8 -18, C18 unsatd., N-[3-(dimethylamino)propyl] is considered to be in the range of 300 - 2000 mg/kg bw and thus is classified as Acute Toxicity Category 4.


Justification for selection of acute toxicity – oral endpoint
no single study was selected as key study, instead all avalaible data are considered together in a weight of evidence approach

Justification for classification or non-classification

Based on relevant, reliable and adequate data Amides, C8-18, C18 unsatd, N-[3-(dimethylamino)propyl] is classified as Acute toxicity Category 4, H302: Harmful if swallowed according to the CLP Regulation (EC) No 1272/2008.

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