Dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride

Endpoint summary

Description of key information

Skin Irritation :

The dermal irritation potential of target chemical was assessedin various in- vitro and in-vivo experimental studies.Based on the available studies,it can be concluded that the testchemical is able to cause skin irritation and considered as irritating. Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Category 2 (irritant)''. 

Eye Irritation:

The ocular irritation potential of target chemical was assessedin various in- vitro and in-vivo experimental studies.Based on the available studies,it can be concluded that the test chemical is unable to cause eye irritation and considered as irritating. Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Category 2".

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

data is from authoritative database

Qualifier:

equivalent or similar to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

To evaluate the dermal irritation potential of the test chemical in rabbits

GLP compliance:

not specified

Specific details on test material used for the study:

Name of test material (as cited in study report): 1-Octadecanaminium, N,N-dimethyl-N-[3-(trimethoxysilyl)propyl]-, chloride
- Molecular formula : C26H58Cl1N1O3Si1
- Molecular weight : 496.30g/mol
- Smiles notation : c1ccc(cc1)CCOC(=O)c2cccc[Si](OC)(OC)(OC)CCCN(C)(C)(CL)CCCCCCCCCCCCCCCCCCc2O
- InChl: 1S/C26H58NO3Si.ClH/c1-7-8-9-10-11-12-13-14-15-16-17-18-19-20-21-22-24-27(2,3)25-23-26-31(28-4,29-5)30-6;/h7-26H2,1-6H3;1H/q+1;/p-1
- Substance type: Organic
- Physical state: Liquid

Species:

rabbit

Strain:

not specified

Details on test animals or test system and environmental conditions:

no data

Type of coverage:

not specified

Preparation of test site:

not specified

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

no data

Duration of treatment / exposure:

no data

Observation period:

no data

Number of animals:

no data

Details on study design:

no data

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: no data

Remarks on result:

other: severe irritation observed

Irritant / corrosive response data:

Severe irritation observed

Interpretation of results:

Category 2 (irritant) based on GHS criteria

Conclusions:

An acute study was designed to evaluate the dermal irritation potential of Dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride in rabbits. Dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride was considered to be an irritant to rabbit skin.

Executive summary:

An acute study was designed to evaluate the dermal irritation potential of Dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chlorideinrabbits.

Test chemical was applied into the rabbit skin (dose and duration not specified) and the effects were observed.

 Dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride was considered to be an irritant to rabbit skin.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Justification for type of information:

The supporting QMRF report has been attached

Qualifier:

equivalent or similar to guideline

Guideline:

other: Prediction was done using OECD QSAR toolbox v3.4

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.4

GLP compliance:

not specified

Specific details on test material used for the study:

Name of test material (as cited in study report): 1-Octadecanaminium, N,N-dimethyl-N-[3-(trimethoxysilyl)propyl]-, chloride
- Molecular formula : C26H58Cl1N1O3Si1
- Molecular weight : 496.30g/mol
- Smiles notation : c1ccc(cc1)CCOC(=O)c2cccc[Si](OC)(OC)(OC)CCCN(C)(C)(CL)CCCCCCCCCCCCCCCCCCc2O
- InChl: 1S/C26H58NO3Si.ClH/c1-7-8-9-10-11-12-13-14-15-16-17-18-19-20-21-22-24-27(2,3)25-23-26-31(28-4,29-5)30-6;/h7-26H2,1-6H3;1H/q+1;/p-1
- Substance type: Organic
- Physical state: Liquid

Species:

rat

Strain:

other: SPF-Russian strain

Details on test animals or tissues and environmental conditions:

no data

Vehicle:

water

Controls:

not specified

Amount / concentration applied:

0.1 mL

Duration of treatment / exposure:

24 hours

Observation period (in vivo):

6 days

Number of animals or in vitro replicates:

3

Details on study design:

no data

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: 6d

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritant / corrosive response data:

Severe irritation was observed

Estimation method: Takes mode value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

((((((("a" or "b" or "c" or "d" or "e") and("f" and(not "g")) ) and("h" and(not "i")) ) and("j" and(not "k")) ) and("l" and(not "m")) ) and("n" and(not "o")) ) and("p" and "q") )

Domain logical expression index: "a"

Referential boundary:The target chemical should be classified as Alkoxysilanes AND Cationic (quaternary ammonium) surfactants by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary:The target chemical should be classified as AlkoxySilane AND Ammonium salt AND Silane AND Surfactants - Cationic by Organic Functional groups

Domain logical expression index: "c"

Referential boundary:The target chemical should be classified as AlkoxySilane AND Overlapping groups AND Surfactants - Cationic by Organic Functional groups (nested)

Domain logical expression index: "d"

Referential boundary:The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Nitrogen, single bonds  [N{v+5}] AND Silicon, aromatic or oxygen attach [-Si-] by Organic functional groups (US EPA)

Domain logical expression index: "e"

Referential boundary:The target chemical should be classified as Anion AND Cation AND Quaternary ammonium salt by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "f"

Referential boundary:The target chemical should be classified as No alert found by DNA binding by OASIS v.1.4

Domain logical expression index: "g"

Referential boundary:The target chemical should be classified as Radical OR Radical >> ROS formation after GSH depletion (indirect) OR Radical >> ROS formation after GSH depletion (indirect) >> Haloalcohols OR SN2 OR SN2 >> Alkylation OR SN2 >> Alkylation >> Alkylphosphates, Alkylthiophosphates and Alkylphosphonates OR SN2 >> Alkylation by epoxide metabolically formed after E2 reaction OR SN2 >> Alkylation by epoxide metabolically formed after E2 reaction >> Haloalcohols OR SN2 >> Alkylation, direct acting epoxides and related OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines by DNA binding by OASIS v.1.4

Domain logical expression index: "h"

Referential boundary:The target chemical should be classified as No alert found by DNA binding by OECD

Domain logical expression index: "i"

Referential boundary:The target chemical should be classified as Michael addition OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes OR Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated amides OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated esters by DNA binding by OECD

Domain logical expression index: "j"

Referential boundary:The target chemical should be classified as Non binder, non cyclic structure by Estrogen Receptor Binding

Domain logical expression index: "k"

Referential boundary:The target chemical should be classified as Non binder, MW>500 by Estrogen Receptor Binding

Domain logical expression index: "l"

Referential boundary:The target chemical should be classified as No alert found by Protein binding by OASIS v1.4

Domain logical expression index: "m"

Referential boundary:The target chemical should be classified as Ionic interaction OR Ionic interaction >> Electrostatic interaction of tetraalkylamonium ion with protein carboxylates OR Ionic interaction >> Electrostatic interaction of tetraalkylamonium ion with protein carboxylates >> Tetraalkylammonium ions by Protein binding by OASIS v1.4

Domain logical expression index: "n"

Referential boundary:The target chemical should be classified as AlkoxySilane AND Overlapping groups AND Surfactants - Cationic by Organic Functional groups (nested)

Domain logical expression index: "o"

Referential boundary:The target chemical should be classified as Alcohol OR Allyl OR Ammonium salt OR Ether OR Organic amide and thioamide by Organic Functional groups (nested)

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is >= 2.19

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is <= 8.6

Interpretation of results:

Category 2 (irritating to eyes) based on GHS criteria

Conclusions:

1-Octadecanaminium, N,N-dimethyl-N-[3-(trimethoxysilyl)propyl]-, chloride was estimated to be irritating to rabbit eyes.

Executive summary:

The ocular irritation potential of 1-Octadecanaminium, N,N-dimethyl-N-[3-(trimethoxysilyl)propyl]-, chloride was estimated using OECD QSAR toolbox v3.4

1-Octadecanaminium, N,N-dimethyl-N-[3-(trimethoxysilyl)propyl]-, chloride was estimated to be irritating to rabbit eyes.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin Irritation:

In different studies, the test chemical has been investigated for potential for dermal irritation to a greater or lesser extent. The studies are based on in- vitro and in-vivo experimental conducted in human and rabbits which have been summarized as below:

An acute study was designed (HSDB)test chemical (last updated Oct 2016) to evaluate the dermal irritation potential of test chemical in rabbits. Test chemical was applied into the rabbit skin (dose and duration not specified) and the effects were observed. Test chemical was an irritant to the skin of rabbits.

Various studies were summarized in OT50546181, DUPONT CHEM CO, 1992 to evaluate the dermal irritation potential of test chemical in rabbits and humans.

An acute study was designed to evaluate the skin irritation potential of test chemical in New Zealand white rabbits. The procedure followed fulfills the requirements outlined in the O.E.C.D. Short-Term and Long-Term Toxicology Groups Final Report." published in December, 1979. A single semi-occlusive contact of 0.5ml of Dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride with the intact skin of six male albino rabbits for four hours resulted in moderate redness with slight swelling at one hour after washing. Slight to moderate redness with slight to moderate swelling was observed when examined at 24, 48 and 72 hours. Based on these observations, it can be considered that exposure to test chemical may result in moderate to severe dermal irritation.

 

An acute study was designed to evaluate the skin irritation potential of test chemical in albino rabbits. A single exposure of test chemical to intact and abraded skin for several hours may cause slight erythema and edema. Repeated, prolonged contact over a period of several days may cause blisters and superficial burns. Based on these observations, it can be considered that exposure to test chemical may result in slight to moderate dermal irritation.

Skin irritation test was performed using Human repeated insult patch test (HRIPT) using 2% concentration. The test solution was freshly prepared daily.The results showed that overall incidence of skin irritating reactions were observed in only 2 volunteers of 450 volunteers. The percentage of positive reactions observed was 0.4%.Very slight erythema with very slight edema in 2/450 volunteers.Therefore, based on the above observation Dow Corning 5700 (27668-52-6) was determined to be not irritating.

Another Skin irritation test was observed in human by using various sock materials like wool, cotton, nylon, orlon and-spandex treated with test chemical was used in 23 male volunteers for 32 days. 32 days exposure to 1-Octadecanaminium, N,N-dimethyl-N-[3-(trimethoxysilyl)propyl]-, chloride did not show any evidence of dermal irritation in the human volunteers.Hence, test chemical can be considered as not irritating to human skin.

Similar Skin irritation test was performed in human by using various sock materials like wool, cotton, nylon, orlon and-spandex treated with test chemical was used in 44 male volunteers for 90 days. After exposure it was observed that there was not skin irritation was observed. 90 days of continuous exposure to test chemical didnot show any evidence of dermal reactions or irritation in 44 male volunteers. Hence, test chemical can be considered as not irritating to human skin.

The primary dermal irritation potential of the similar test substance was evaluated according to Draize method. Adult rabbits were used for the study. 0.5 ml of 25%, 2.5%, and 1.25% solutions of the Stearalkonium Chloride was applied to clipped areas of intact and abraded rabbit skin. The treated areas were covered with gauze and wrapped to keep the test material in contact with the skin and to decrease the rate of vaporization. The wrapping and test material were removed 24 hours following application. The sites were examined and scored separately for erythema and edema at 24 and 72 hours. Primary dermal irritation indices were calculated according to the Draize procedure for 25%, 2.5%, and 1.25% concentrations of the material. The mean scores for 24- and 72-hour readings were averaged to determine the irritation index. Primary irritation indices were calculated to be 6.0, 2.4, and 1.0 for the 25%, 1.25%, and 2.5% solutions, respectively. Based on the primary irritation indices, test chemical can be considered as mild irritant to skin.

The dermal irritation potential of test article was determined according to the OECD 439 test guideline for this study. The MatTek EpiDerm™ model was used to assess the potential dermal irritation of the test article by determining the viability of the tissues following exposure to the test article via MTT. Tissues were exposed to the test article and controls for ~one hour, followed by a 42 hour post-exposure recovery period. The viability of each tissue was determined by MTT assay. The MTT data show the assay quality controls were met and passed the acceptance of criteria. The mean of OD  for test chemical was determined to be 2.054.The standard deviation of viabilities for test chemical were calculated to be 9.30.The Mean % tissue viability compared to negative control (n=3) of the test chemical was determined to be 94.6%.Hence, under the current experimental test conditions it was concluded that test chemical was considered to be non-irritating to human skin and can thus be classified as “not classified'' as per CLP Regulation.

All these studies lead to a conclusion that Test chemical is indeed not irritating to skin. Hence, comparing the above annotations with the criteria of CLP regulation, Test chemical can be classified under the category “category 2 -irritant”.

 

Eye Irritation:

In different studies, the test chemical has been investigated for potential for ocular irritation to a greater or lesser extent. The studies are based on in- vitro and in-vivo experimental conducted in rabbits conducted which have been summarized as below:

The ocular irritation potential of test cemical was estimated using OECD QSAR toolbox v3.4 .Test chemical was estimated to be irritating to rabbit eyes.

An acute study was designed (HSDB- test chemical, last updated Oct 2016) to evaluate the eye irritation potential of test chemical in rats. Test chemical was instilled into the rat’s eyes (dose and duration not specified) and the effects were observed. Test chemical was an irritant to the eyes of rats.

Various studies were summarized in OT50546181, DUPONT CHEM CO, 1992 to evaluate the dermal irritation potential of test chemical in rabbits.

An acute study was designed to evaluate the eye irritation potential of test chemical in New'Zealand white rabbits. The procedure followed fulfills the requirements outlined in the O.E.C.D. Short-Term and Long-Term Toxicology Groups Final Report." published in December, 1979. A single instillation of 0.1 ml of undiluted test chemical was instilled into the eyes of rabbits. The test chemical instillation was followed by washing resulted in marked conjunctival redness and swelling, iritis and corneal necrosis persisting for several days. Examination of eyes after 14 and 21 days showed reduced conjunctival inflammation but corneas of all rabbits appeared severely scarred. According to OECD definition, test chemical was an irritant to the eyes of rabbits. Direct eye contact with test chemical may result in permanent loss of vision.

Another acute study was designed to evaluate the skin irritation potential of test chemical in albino rabbits. Exposure to undiluted test chemical in albino rabbits may cause severe irritation.Direct contact will result in tissue destruction leading to permanent impairment of vision. Based on these observations, it can be considered that exposure to test chemical may result in severe ocular irritation.

In vivo and in vitro studies were conducted by P. GAUTHERON et.al, 1994 to evaluate the ocular irritation potential of the similar substance 57-09-0 (Hexadecyltrimethylammonium bromide).

A multinational interlaboratory study to investigate the bovine corneal opacity and permeability (BCOP) assay was conducted. The assays were carried out in 12 European laboratories with different types of activity. In each of these laboratories 52 substances, with a wide range of structure, physical form and irritant properties, were tested and in vitro scores were compared.

The Bovine Corneal Opacity and Permeability (BCOP) assay, which is based on the method of Muir, is an in vitro test which has been developed recently. Originally, it was devoted to predicting the irritant potential of process intermediates compounds in development. The assay uses corneas, one of the target tissues of ocular irritancy, from freshly collected bovine eyes, and two endpoints are investigated, namely corneal opacity and the disruption of the corneal barrier as assessed by the passage of a fluorescent dye.

Preparation of the corneas: Bovine eyes were collected from a commercial abattoir in a plastic jar containing 1 litre HBSS for approximately 25 eyes. Buffer storage and eyes transportation to the laboratories were performed at ambient temperature, and the eyes were used within 2 hr of the killing of the animals. During dissection great care was taken to avoid damage of corneal surfaces (epithelial and endothelial). Each cornea was carefully examined, and those presenting defects, such as neovascularization, pigmentation, opacity or scratches were discarded. Globes were first dissected free of surrounding tissues and placed in a jar containing fresh HBSS. Selected corneas were dissected with a 2-3-mm rim of sclera for easier handling, and stored in a petri dish containing HBSS until use. Corneas were then mounted in holders filled with MEM, and incubated for 1 hr in a water-bath at 32°C.

 Treatment: At the end of the incubation period, the medium was removed from both compartments of the holders, using a needle attached to a vacuum pump or a syringe. The posterior compartment was then refilled with MEM, whereas the anterior compartment was filled with the test compound or its vehicle. Two treatment protocols were used depending on the physical state (liquid or solid) of the product evaluated.

Solids were prepared as an approximate 20% solution or suspension (200mg + 1 ml) in MEM using a mortar and pestle for homogeneous preparations, and a volume of 0.75 ml was applied on the epithelium with an appropriate syringe and needle. Corneas were placed in a horizontal position for 4 hr at 32°C. The compound was then removed and the epithelium was washed at least three times (until the cornea was free of particles; gentle swirling movements of the holders were sometimes necessary) with approximately 4ml medium. Both compartments were refilled with medium, and opacity measurement was performed immediately without any further incubation. The number of corneas per experiment was 15, including a control group of three corneas treated with MEM, and two groups of six corneas treated with test compounds. Thus, two compounds were tested per day, and since there are two treatment regimens, chemicals were grouped by pairs: 15 pairs of liquids and surfactants, and 11 pairs of solids.

Opacity measurement: The opacitometer (Electro- Design, Riom, France) determines the difference in light transmission between a treated and a control cornea, and displays a numerical opacity value (arbitrary units). The apparatus was previously calibrated with standardized opaque sheets of polyester, and values obtained with test substances generally ranged between 0 and 150.

 Permeability: This second step of the assay was performed immediately after the measurement of opacity. The medium was again removed from both chambers of holders, and replaced by fresh medium in the posterior compartment, and by 1 ml fluorescein solution (0.4% for liquids and surfactants, 0.5% for solids) in contact with the epithelium. Corneas were then incubated in a horizontal position for 90 min at 32°C. Medium from the posterior chamber was then removed, and its optical density (O.D.) determined with a spectrophotometer at 490 nm.

 SCORING SYSTEM:

 In vitro score = opacity value + 15 times O.D. value

O.D = Optical density

The following classification system was established for in vitro scores:

0-25 = mild irritant, 25.1-55 = moderate irritant,  >/55.1 = severe irritant.

The Mean In vitro score for Hexadecyltrimethylammonium bromide was 66.4

Based on the classification scheme for BCOP assay, Hexadecyltrimethylammonium bromide was evaluated as a severe irritant.

Hexadecyltrimethylammonium bromide was evaluated for eye irritation in vivo. The tests were performed according to EEC (1984 and 1991) and French (1984 and 1991) directives with few modifications.

Three rabbits were used per test compound, and maximal average score (MAS) as well as score at day 1 were calculated. At the request of the participants, any mass of material present in the conjunctival sac was removed after the 1-hr observation. Also, a fluorescein solution was used for observation of corneal lesions. Only ocular lesions (cornea, iris and conjunctiva) were scored (Draize et al., 1944) at 1 hr, then at 1, 2, 3, 4, 7 and 14 days. In the case of positive score, eyes were also examined at 21 days. Raw data were also used to classify chemicals according to the rating system described by Kay and Calandra (1962), and the EC criteria. The MAS score for Hexadecyltrimethylammonium bromide was determined to be 69.0 and score measured at day 1 was 49.7.Hexadecyltrimethylammonium bromide was evaluated as R36 (irritant) according to EEC(1984) directives and Extreme Irritant according to Kay and Calandra (1962).

Hence based on the scores and evaluation criteria, Hexadecyltrimethylammonium bromide can be considered as an eye irritant.

Draize tests were conducted (Toxicology in Vitro 13 (1999) 73 – 98) according to the OECD guidelines for the similar substance 112-03-6 (Stearyltrimethylammonium chloride).

In the first validation, 100 ml aqueous solution or a suspension of Stearyltrimethylammonium chloride(10%) was applied to the right eyes of male New Zealand white rabbits (2.30±2.98 kg, 13 wk of age). Left eyes remained untreated as a control. Eyes were observed at 1 hr, 4 hr, and every 24 hr thereafter for 7 days. Three rabbits were used for test. MAS [Maximum average scores] and scores at 24 hr after application calculated for cornea, iris, conjunctivae and the sum of these scores (total average score) were used for comparison with in vitro data. According to the classification by Kay and Calandra (1962), chemicals can be classified as follows based on their MAS scores: non-irritants = (0≤MAS <0.5),  slight irritants = (0.5≤MAS< 15), mild irritants = (15≤MAS< 25), moderate irritants = (25≤MAS <50) and severe irritants  = (50≤MAS)

The Maximum Average Score[MAS] obtained for 10% Stearyltrimethylammonium chloride was 91.3 after 7 days and the average scores after 24 hours was 56.3. According to the classification based on the MAS scores Stearyltrimethylammonium chloride can be considered to be an eye irritant.

The ocular irritation potential of test article was determined according to the OECD 492 test guideline for this study. The MatTek EpiOcular™ model was used to assess the potential ocular irritation of the test articles by determining the viability of the tissues following exposure to the test article via MTT. Tissues were exposed to liquid test articles and controls for ~30 minutes, followed by a ~12 minute post-soak and approximately 2 hour recovery after the post-soak. The viability of each tissue was determined by MTT assay. The MTT data show the assay quality controls were met, passing the acceptance criteria. The mean of OD for test chemical was determined to be 1.889.The mean % tissue viability of test chemical was determined to be 86.4%. Hence, under the experimental test conditions it was concluded that test chemical was considered to be non-irritating to the human eyes and and can thus be classified as “Not classified’’ as per CLP Regulation.

Based on the available data for the target as well its various substances and applying the weight of evidence approach, test chemical can be considered as an eye irritant.

Justification for classification or non-classification

The skin and eye irritation potential of test chemical was observed in various studies. The results obtained from these studies indicate that the chemical is likely to cause skin and eye irritation. Hence the test chemical can be classified under the category “Category 2” for skin and eye as per CLP.