Registration Dossier

Administrative data

Description of key information

Acute oral toxicity: LD50 > 2000 mg/kg bw, OECD Guideline 423; RL1; GLP; read-across Stearic acid 3-(dimethylaminopropyl)amide
Acute dermal toxicity: LD50 expected to be > 2000 mg/kg bw; no testing required
Acute inhalation toxicity: not necessary due to exposure considerations

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:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar toxicological properties because
• they are manufactured from similar or identical precursors under similar conditions
• they share structural similarities with common functional groups: quaternary amines, amides, and saturated fatty acid chains with comparable length
• the metabolism pathway leads to comparable products (amine backbone and long chain fatty acids) and non-common products predicted to have no toxicological effects (long chain fatty acids).

Therefore, read-across from the existing acute toxicity studies on the source substances is considered as an appropriate adaptation to the standard information requirements of REACH regulation

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
see justification for read-across attached to IUCLID section 13

3. ANALOGUE APPROACH JUSTIFICATION
see justification for read-across attached to IUCLID section 13

4. DATA MATRIX
see justification for read-across attached to IUCLID section 13
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Species:
rat
Route of administration:
oral: gavage
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
act. ingr.
Interpretation of results:
GHS criteria not met
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The available studies were conducted according to guideline and are of high quality.

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

No experimental data on acute toxicity are available for the target substance C16 Alkylamidopropyltrimethylammonium Chloride. However, reliable data from an oral acutetoxicity study conducted with the closely related source substance Stearic acid 3-(dimethylaminopropyl)amide is available.

Supporting data are available from an acute oral toxicity study conducted with Cetrimonium chloride. A justification for read-across is given below.

 

Acute oral toxicity

In an acute oral toxicity study according to OECD guideline 423, adopted 17 December 2001 and EU method B.1 tris, May 2008, 6 female, fasted, 8-9 weeks old Wistar strain ratswere given a single oral dose of Stearic acid 3-(dimethylaminopropyl)amide in Propylene glycol by gavage at a dose of 2000 mg/kg bw and observed for 14 days.

The test substance was administered as 2 dosages of 1000 mg/kg bw within 24 hours. The first on t=0 and the second on t=3 hours. Multiple dosages given within 24 hours are regarded as a single dose.

2/6 animals died on day 2 and 3, respectively. Clinical signs shown by the animals found dead and surviving animals included lethargy, hunched posture, uncoordinated movements, piloerection, diarrhoea, chromodacryorrhoea, pallor, and/or ptosis.

The surviving animals had recovered from the symptoms between days 7 and 10.

The two animals found dead showed either slight weight gain or weight loss. 3/4 surviving females showed body weight loss between days 1 and 8. These animals again gained body weight between days 8 and 15. One surviving female showed body weight gain that was considered to be similar to that expected of normal untreated animals of the same age and strain.

One female found dead showed watery-turbid fluid in the stomach and watery-clear, yellowish fluid in the small intestines. The other female found dead showed a reduced size of the spleen. Pelvic dilation of the kidneys was noted in one surviving female. Other surviving females had no macroscopic abnormalities.

Oral LD50 (rat, females) > 2000 mg/kg bw

 

The oral LD50 of the source substance Cetrimonium Chloride was 450 mg/kg bw in female rats and 861 mg/kg bw in male rats. The effects described were mainly related to the gastrointestinal tract (bleeding in the mucous membrane of the stomach, swollen stomach, etc.) and thus, probably result from local corrosive effects.

 

As the target substance C16 Alkylamidopropyltrimethylammonium Chloride was not irritating to skin, no such effects to the gastrointestinal tract are to be expected. Thus, the result of the source substance Stearic acid 3-(dimethylaminopropyl)amide is considered to be more relevant for the target substance C16 Alkylamidopropyltrimethylammonium Chloride.

 

Acute inhalation toxicity

Given that inhalation is not a relevant route of exposure, testing by the inhalation route is not necessary according to REACH Regulation Annex VIII 8.5.2 Column 2. Inhalation is not a relevant route of exposure to C16 Alkylamidopropyltrimethylammonium Chloride. This applies to both workers and the general population and is due to the physicochemical properties of the substance and the nature of the products where it is used. C16 Alkylamidopropyltrimethylammonium Chloride is a waxy solid. Generation of inhalable particles such as dust or aerosols is therefore not to be expected. Vaporisation needs not to be considered due to the substance’s very low vapour pressure of 2.7E-07 Pa at 20°C. The generation of aerosols is excluded by technical means or product design. The substance is not used in spray applications. The most likely route of human exposure for workers and consumers is the dermal route. Results of laboratory animal studies show a low acute toxicity after oral exposure. Therefore the acute intrinsic toxic activity of C16 Alkylamidopropyltrimethylammonium Chloride is considered to be low. The occurrence of a systemic toxicity relevant to humans after inhalation is unlikely and therefore the conduct of an acute inhalation toxicity study is unjustified.

 

Acute dermal toxicity

The testing of acute dermal toxicity of C16 Alkylamidopropyltrimethylammonium Chloride amide is scientifically not justified based on retrospective data analyses undertaken by Creton et al. (2010) and Seidle et al. (2010) to ascertain the value of regulatory requirements prescribing multiroute testing for acute systemic toxicity. These analyses have examined the concordance among regulatory classifications for acute oral, dermal, and/ or inhalation toxicity for ~500 agrochemical and biocidal active substances and nearly 2000 industrial chemicals. The findings from these two independent reviews have revealed that acute dermal studies of pure substances do not add value above and beyond oral data for hazard classification of pesticides, biocides, or chemicals.

 

According to the COMMISSION REGULATION (EU) 2016/863 of 31 May 2016 amending Annexes VII and VIII to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) as regards skin corrosion/irritation, serious eye damage/eye irritation, skin sensitisation and acute toxicity, recent “scientific analysis of available data fromin vivoacute toxicity studies have shown that substances that are not toxic via the oral route may be expected with high certainty to be also non-toxic via the dermal route. Therefore, testing those substances via the dermal route does not provide essential information for their safety assessment.”

 

The oral LD50 was determined to be > 2000 mg/kg bw based on read-across from a closely related substance. Thus, no toxicity via the dermal route is to be expected.

 

References

Creton S. et al.: Acute toxicity testing of chemicals—Opportunities to avoid redundant testing and use alternative approaches, Critical Reviews in Toxicology, 2010; 40(1): 50–83

Seidle T. et al.: Cross-Sector Review of Drivers and Available 3Rs Approaches for Acute Systemic Toxicity Testing, TOXICOLOGICAL SCIENCES 116(2), 382–396 (2010).

 

 

Based on the available information, the acute toxicity of C16 Alkylamidopropyltrimethylammonium Chloride is low. There are no data gaps in acute toxicity. Even though there is no information on acute toxicity in humans, there is no reason to believe that the low acute toxicity observed in experimental animals would not be relevant for human health.

 

Justification for read-across

For details on substance identity, toxicokinetics and detailed toxicological profiles, please refer also to the general justification for read-across attached as pdf document to section 13 of the IUCLID file.

 

Structural similarity

a. Structural similarity and functional groups

The target substance C16 Alkylamidopropyltrimethylammonium Chloride is manufactured from hexadecanoic acid and N,N-dimethyl-propylenediamine. Methyl chloride is used to quaternise the dimethylamino group of the fatty acid amidoamine.

The substance is composed of mainly C16 amides (ca. 92%) of DMAPA and small amounts of the C14 (ca. 2.5%) and C18 amide (ca. 5.5%).

 

The source substance Stearic acid 3-(dimethylaminopropyl)amide is manufactured from octadecanoic acid and N,N-dimethylpropylenediamine. It is composed of mainly C18 amides (> 89.8%) of DMAPA and small amounts of the C16 amide (<7%).

 

The source substance Cetrimonium chloride is a quaternary ammonium salt manufactured from the tertiary amine N,N-dimethylhexadecanamine and quaternised with Methyl chloride.

 

b. Common breakdown products

The metabolism that is expected to occur is for the target substance C16 Alkylamidopropyltrimethylammonium Chloride and the source substance Stearic acid 3-(dimethylaminopropyl)amide the hydrolysis of the amide-bond by amidases. Metabolism would result in free fatty acids and di- or trimethylaminopropylamine. The free fatty acids enter normal metabolic pathways (e.g. degradation by the mitochondrial beta-oxidation process) and are therefore indistinguishable from fatty acids from other sources including diet.

The amine compounds are not expected to be further metabolised, but excreted via the urine mainly unchanged. 

The most likely metabolism of the second source substance Cetrimonium chloride is oxidation of the alkyl chain.

 

c. Differences

Chain length:

The slight differences in fatty acid chain length (higher percentage of C16 in the target substance vs. higher percentage C18 in the source substance Stearic acid 3-(dimethylaminopropyl)amide) are not considered to be of relevance for systemic toxicty.

 

Methylation/quaternation:

The target substance C16 Alkylamidopropyltrimethylammonium Chloride is methylated during the manufacturing process resulting in the quaternised ammonium ion.

Stearic acid 3-(dimethylaminopropyl)amide)on the other hand is not methylated during the manufacturing process. But based on physicochemical data (pKa) it is concluded that at physiological relevant pH, the substance is mostly protonated similarly resulting in a positively charged ammonium ion.

 

Amide:

In contrast to the source substance Cetrimonium chloride, the target substance C16 Alkylamidopropyltrimethylammonium Chloride as well as the source substance Stearic acid 3-(dimethylaminopropyl)amide) containa polar amide function which may be susceptible to enzymatic hydrolysis. However, the available repeated dose toxicity studies conducted with the source substances Cetrimonium chloride and C12-18 TMAC on the one hand andthe source substance Stearic acid 3-(dimethylaminopropyl)amide) on the other hand demonstrate, that this structural difference has no important effect on the outcome of the studies.

 

Comparison of acute oral toxicity data

Endpoint

Target substance

C16 Alkylamidopropyltrimethylammonium Chloride 

Source substance

Stearic acid 3-(dimethylaminopropyl)amide

Cetrimonium chloride

Acute oral toxicity

No data, read-across

LD50 (rat, females) > 2000 mg/kg bw

 

OECD 423, rat, RL 1, GLP

LD50 females = 450 mg/kg bw

Acute toxicity 4

 

OECD TG 401, RL1, GLP

 

No experimental data are available for the target substance.

The oral LD50 of the closely related source substance Stearic acid 3-(dimethylaminopropyl)amide in female rats was > 2000 mg/kg bw.

The oral LD50 of the closely related source substance Cetrimonium Chloride was450 mg/kg bw in female rats and 861 mg/kg bw in male rats. The effects described were mainly related to the gastrointestinal tract (bleeding in the mucous membrane of the stomach, swollen stomach, etc.) and thus, probably result from local corrosive effects.

 

As the target substance C16 Alkylamidopropyltrimethylammonium Chloride was not irritating to skin, no such effects to the gastrointestinal tract are to be expected. Thus, the result of the source substance Stearic acid 3-(dimethylaminopropyl)amide is considered to be more relevant for the target substance C16 Alkylamidopropyltrimethylammonium Chloride.

 

Quality of the experimental data of the analogues:

The source substance Stearic acid 3-(dimethylaminopropyl)amide has been tested in a reliable study according to OECD TG 423. The source substance Cetrimonium chloride has been tested in a reliable study according to OECD TG 401.

The tests have been conducted according to GLP criteria. Therefore these data have no uncertainties and can be used in an analogue approach. The available data from the source chemical is sufficiently reliable to justify the read-across approach.

 

Conclusion for read-across

The physico-chemical and structural similarities between of the source and the target substances as presented above support the read-across hypothesis. Adequate and reliable scientific information indicates that the source and target substances and their subsequent degradation products have similar toxicity profiles under the experimental conditions in the considered studies for the endpoint acute toxicity.

Thus, the results obtained with the source substances Stearic acid 3-(dimethylaminopropyl)amide are considered to be also relevant for the target substance C16 Alkylamidopropyltrimethylammonium Chloride.

 

Justification for classification or non-classification

Based on the available relevant and reliable data C16 Alkylamidopropyltrimethylammonium Chloride does not need to be classified and labelled according to the CLP Regulation (EC) No 1272/2008 with respect to acute toxicity.