Registration Dossier

Administrative data

Description of key information

There are no data on skin sensitisation for 3-(trimethoxysilyl)propiononitrile, so good quality data on the structurally-related source substance 3-(triethoxysilyl)propiononitrile are read-across.

In a guinea pig maximisation test, performed in accordance with OECD 406 and in compliance with GLP, 3-(triethoxysilyl)propiononitrile was found to be not sensitising (Harlan, 2010). This result is read-across to the target substance, 3-(trimethoxysilyl)propiononitrile.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 406 (Skin Sensitisation)
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
An LLNA study was not performed because there is an existing reliable study for skin sensitisation using the Guinea Pig Maximisation test method. Furthermore, the LLNA test method is not considered to be suitable for substances that contain silicon. Please refer to the attached document for further details.
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
male
Details on test animals and environmental conditions:
Animals: Albino Dunkin Hartley Guinea Pig, CRL:(HA), SPF
Breeder: Charles River Deutschland GmbH
Stolzenseeweg 32-36
88353 Kisslegg / Germany
Number of Animals for Main Study /Pretest:15 males / 3 males
Age at Pretest Start / Beginning of Acclimatization Period: 5-6 weeks
Body Weight at Pretest Start: Pretest groups: 680 -715 g
Body Weight at Beginning of Acclimatization Period: Test and control group: 604 - 748 g
Identification: By unique cage number and corresponding individual ear tag.
Randomization: Selected by hand at time of delivery. No computer generated randomization program.
Acclimatization: Twelve days for the control and test group under laboratory conditions after health examination. No acclimatization for the animals of the pretest. Only animals without any visible signs of illness were used for the study. A certificate of health was provided by the animal supplier at the animal delivery and included in the raw data.
Conditions: Standard Laboratory Conditions: Air-conditioned with ranges for room temperature 22 ± 3 °C, relative humidity 30-70% and approximately 10-15 air changes per hour. Room temperature and humidity were monitored continuously and values outside of these ranges occasionally occurred, usually following room cleaning. These transient variations are considered not to have any influence on the study and, therefore, these data are not reported but are retained at Harlan Laboratories. The animals were provided with an automatically controlled light cycle of 12 hours light and 12 hours dark. Music was played during the daytime light period.
Accommodation: Individually in Makrolon type-4 cages with standard softwood bedding (‘Lignocel’ J. Rettenmaier&Söhne GmbH&CoKG, 73494 Rosenberg / Germany, imported by Provimi Kliba AG, 4303 Kaiseraugst /Switzerland).
Diet: Pelleted standard Provimi Kliba 3418 guinea pig breeding / maintenance diet batch nos. 44/09 and 52/09, containing Vitamin C (Provimi Kliba AG, 4303 Kaiseraugst / Switzerland), ad libitum. Results of analyses for contaminants are archived at Harlan Laboratories Ltd.
Water: Community tap water from Füllinsdorf, ad libitum. Results of bacteriological, chemical and contaminant analyses are archived at Harlan Laboratories Ltd.
Route:
intradermal
Vehicle:
other: Diethylene glycol dimethyl ether
Concentration / amount:
Intradermal induction : 50% dilution of the test item
Epidermal induction 100% (undiluted)
Challenged by epidermal application of the test item at 25%
Second challenge by epidermal application of the test item at 25%
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
other: Diethylene glycol dimethyl ether
Concentration / amount:
Intradermal induction : 50% dilution of the test item
Epidermal induction 100% (undiluted)
Challenged by epidermal application of the test item at 25%
Second challenge by epidermal application of the test item at 25%
No. of animals per dose:
15 (10 test and 5 control) male albino Dunkin Hartley guinea pigs
Details on study design:
The dose levels of 3-(triethoxysilyl)propiononitrile used in the main study were based on results from intradermal and epidermal pretests.
The intradermal induction of sensitization in the test group was performed in the nuchal region with a 50% dilution of the test item in diglyme and in an emulsion of Freund's Complete Adjuvant (FCA)/physiological saline. The epidermal induction of sensitization was conducted for 48 hours under occlusion with the test item at 100% (undiluted) one week after the intradermal induction. The animals of the control group were intradermally induced with diglyme and FCA/physiological saline and epidermally induced with diglyme under occlusion. Two weeks after epidermal induction the control and test animals were challenged by epidermal application of the test item at 25% in diglyme and diglyme alone under occlusive dressing. Sixteen days after the first challenge a second challenge was performed in the same way as the previous challenge using the test group only and the test item at 25% in diglyme applied on a naive skin site.
Challenge controls:
The animals of the control group were intradermally induced with diglyme and FCA/physiological saline and epidermally induced with diglyme under occlusion.
Positive control substance(s):
yes
Remarks:
ALPHA-HEXYLCINNAMALDEHYDE at 1% (w/w) in PEG 300
Positive control results:
The sensitivity and reliability of the experimental technique employed was assessed by use of ALPHA-HEXYLCINNAMALDEHYDE which is recommended by the OECD 406 Guidelines and is known to have moderate skin sensitization properties in the guinea pig strain. The results from the most recent test run (Harlan Laboratories Study C50652, performed from 27-May-2009 to 20-Jul-2009) ) follow:
One out of 10 test animals showed skin reactions after the first challenge treatment with ALPHA-HEXYLCINNAMALDEHYDE at 1% (w/w) in PEG 300. No skin effect was observed in the control group. Eighty to ninety percent of the test animals showed discrete/patchy erythema at the 24- or 48-hour reading
after the second challenge treatment with ALPHA-HEXYLCINNAMALDEHYDE at 3% (w/v) in PEG 300. No skin effect was observed in the control group.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
0%
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
25%
No. with + reactions:
1
Total no. in group:
5
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
0%
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
25%
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
25%
No. with + reactions:
5
Total no. in group:
10
Remarks on result:
positive indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
0%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
25%
No. with + reactions:
4
Total no. in group:
10
Remarks on result:
positive indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
0%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
rechallenge
Hours after challenge:
24
Group:
test group
Dose level:
25%
No. with + reactions:
1
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
rechallenge
Hours after challenge:
24
Group:
test group
Dose level:
0%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
rechallenge
Hours after challenge:
48
Group:
test group
Dose level:
25%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
rechallenge
Hours after challenge:
48
Group:
test group
Dose level:
0%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
1% alpha-hexylcinnamaldehyde in PEG 300
No. with + reactions:
8
Total no. in group:
10
Remarks on result:
positive indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
1% alpha-hexylcinnamaldehyde in PEG 300
No. with + reactions:
9
Total no. in group:
10
Remarks on result:
positive indication of skin sensitisation
Interpretation of results:
GHS criteria not met
Conclusions:
In an in vivo skin sensitisation study in guinea pigs, conducted according to OECD TG 406 and in compliance with GLP, the test substance, 3-(triethoxysilyl)propanenitrile, was concluded to be not sensitising to skin.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

The key study for skin sensitisation (Harlan, 2010) is the only available study for this endpoint, which is read-across from the related substance 3-(triethoxysilyl)propiononitrile (CAS 919-31-3). It is a reliable guideline study, performed in accordance with OECD 406 (guinea pig maximisation test) and in compliance with GLP, and has therefore been assigned Reliability 1.

In this guinea pig maximisation study, (Harlan, 2010) albino guinea pigs were tested appropriately and in accordance with OECD test guideline 406, and in compliance with GLP. Diethylene glycol dimethyl ether was used as the vehicle. In the main study 20 guinea pigs were tested with 50% 3-(triethoxysilyl)propiononitrile in the first induction, and 100% 3-(triethoxysilyl)propiononitrile in the second induction. 25% was used in the challenge phase under occlusive conditions. Ten negative control animals received the same treatment, but without 3-(triethoxysilyl)propiononitrile. Evaluation of skin reactions were made at 24 and 48 hours after challenge and after rechallenge. Skin reactions in the control groups after the first challenge showed one animal with a moderate reaction at the 24 hour reading, and no reaction after 48 hours. Comparable local inflammation was observed in all test animals 24 hours after the first challenge; skin reactions were observed in 4/10 test animals at 48 hours. The responses were not reproduced on rechallenge, 16 days after the first challenge, and therefore under the conditions of this study, 3-(triethoxysilyl)propiononitrile was not a skin sensitiser.

Read-across justification

There are no available measured data for 3-(trimethoxysilyl)propiononitrile (CAS 2526-62-7) for skin sensitisation. Therefore, the Annex requirements are fulfilled with data on structural analogous substances. This section describes the analogue approach for fulfilling this endpoint by read-across from the source substance 3-(triethoxysilyl)propiononitrile (CAS 919-31-3), according to the Read-across Assessment Framework (RAAF)1.

Read-across is proposed in accordance with RAAF Scenario 1: “This scenario covers the analogue approach for which the read-across hypothesis is based on (bio)transformation to common compound(s). For the REACH information requirement under consideration, the property investigated in a study conducted with one source substance is used to predict the properties that would be observed in a study with the target substance if it were to be conducted. Similar properties or absence of effect are predicted. The predicted property may be similar or based on a worst-case approach.”

The read-across justification is presented (Table 1) according to RAAF scenario 1 assessment elements (AE) as outlined in Table A1 of the RAAF1:

Table 1: RAAF scenario 1 assessment elements (AE) as given in Appendix A (Table A1) of the RAAF1

AE A.1

Characterisation of source substance

AE A.2

Link of structural similarity and differences with the proposed prediction

AE A.3

Reliability and adequacy of the source study

AE 1.1

Compounds the test organism is exposed to

AE 1.2

Formation of common (identical) compound(s)

AE 1.3

Exposure of the biological target(s) to the common compound(s)

AE 1.4

The impact of parent compounds

AE 1.5

Formation and impact of non-common compounds

AE A.4

Bias that influences the prediction

1.  AE A.1 Identity and characterisation of the source substance

The source substance, 3-(triethoxysilyl)propiononitrile (CAS 919-31-3), is a triethoxysilane with a propionitrile side-chain. Its measured hydrolysis half-lives are: <0.5 h at pH 4, 6.5 h at pH 7, <0.5 h at pH 9, and 20°C (OECD 111). At physiological temperature 37.5ºC and pH 7 (relevant for genetic toxicity testing), the hydrolysis half-life is calculated as 1.6 h. The products of hydrolysis are 3-(hydroxysilyl)propiononitrile and ethanol.

The source substance has log Kow of 1.7 (QSAR), water solubility of 4000 mg/l (QSAR) and vapour pressure of 1.9 Pa at 20°C (measured).

Table 2 Summary of the structure and purity for the target 3-(trimethoxysilyl)propiononitrile (CAS 2526-62-7) and source 3-(triethoxysilyl)propiononitrile (CAS 919-31-3)

 

Target

Source

Chemical name

3-(trimethoxysilyl)propiononitrile

3-(triethoxysilyl)propiononitrile

CAS Number

2526-62-7

919-31-3

EC Number

219-764-3

213-050-5

Chemical structure

CO[Si](CCC#N)(OC)OC

CCO[Si](OCC)(OCC)CCC#N

Type

Monoconstituent

Monoconstituent

Purity (w/w)

= 95% = 100% w/w

= 90% = 100% w/w

 

Analytical data that was provided by members of the Reconsile consortium is the basis of the published Substance Identity Profiles (SIPs) and boundary compositions for these substances. The precise identity of the impurities is considered confidential because it could reveal details of the manufacturing process to other consortium members. The classification and labelling of each impurity has been checked using the ECHA CLP inventory and (for silicon containing compounds) the consortium’s own dataset. None of the impurities are considered to be potential SVHC. None of the impurities will impact the classification and labelling of the substances.

2.  AE A.2 Link of structural similarities and differences with the proposed prediction

The registration substance, 3-(trimethoxysilyl)propiononitrile, and the source substance, 3-(triethoxysilyl)propiononitrile, are both trialkoxysilanes with a propionitrile side-chain. The difference between the two substances is that the three alkoxy groups are methoxy for the target substance and ethoxy for the source substance.

Therefore, the target and source substances are structurally similar and have similar physicochemical properties (Table 3). Both have low vapour pressure (4.7 and 1.9 Pa at 25°C), moderate log Kow (0.2 and 1.7) and moderate to high water solubility (130000 and 4000 mg/l). Both hydrolyse fairly rapidly (half-life 0.4 h and 1.6 h at pH 7 and 37.5°C) to give a common hydrolysis product, 3-(hydroxysilyl)propionitrile. The non-common hydrolysis products are methanol and ethanol, which will not contribute to skin sensitisation.

Table 3 Physicochemical properties

Property

Target substance

Source substance

Substance name

3-(trimethoxysilyl)propiononitrile

3-(triethoxysilyl)propiononitrile

CAS number

2526-62-7

919-31-3

Hydrolysis half-life at pH 4 and 25°C

0.1 h (QSAR)

<0.5 h (OECD 111)

Hydrolysis half-life at pH 7 and 25°C

1.1 h (QSAR)

6.5 h (OECD 111)

Hydrolysis half-life at pH 7 and 37.5°C

0.4 h (extrapolation)

1.6 h (extrapolation)

Silanol hydrolysis product

3-(hydroxysilyl)propiononitrile

3-(hydroxysilyl)propiononitrile

Non-Si hydrolysis product

Methanol

Ethanol

Log Kowvalue

0.2 (QSAR)

1.7 (QSAR)

Vapour pressure

4.7 Pa at 25°C (QSAR)

1.9 Pa at 25°C (measured)

Water solubility

130000 mg/l (QSAR)

4000 mg/l (QSAR)

 

3.  AE A.3 Reliability and adequacy of the source study

The skin sensitisation study was read-across from 3-(triethoxysilyl)propiononitrile (CAS 919-31-3). To support the read-across there are reliable data on the source substance for most required toxicological endpoints relevant for the Annex level. Reliable data are available for acute toxicity, skin and eye irritation, skin sensitisation, genetic toxicity (in vitro), and repeated dose toxicity (oral) that can be compared with available reliable data of the target substance. Table 4 summarises the key data and their reliability (using Klimisch codes).

Of particular importance in this case is the reliability of the skin sensitisation study that is being read-across.

The study was conducted according to an appropriate OECD Test Guideline 406 and in compliance with GLP (Harlan, 2010). Under the conditions of the study, 3-(triethoxysilyl)propiononitrile was negative for skin sensitisation. The purity of the test substance used in the study was 94.5% and it was considered to represent the source substance without impurities that could influence the outcome of the study. The test is considered adequate for the purpose of classification and labelling and risk assessment.

Table 4 Summary of reliability of the key data for the target substance 3-(trimethoxysilyl)propiononitrile (CAS 2526-62-7) and source substance 3-(triethoxysilyl)propiononitrile (CAS 919-31-3)

 

Target

Source

 

3-(trimethoxysilyl)propiononitrile

3-(triethoxysilyl)propiononitrile

 

2526-62-7

919-31-3

1. Acute Toxicity

 

 

Oral

LD50 9555 mg/kg bw (male) and 10961 mg/kg bw (female)

Reliability 2 study (Bushy Run Research Center, 1981)

LD50 5600 mg/kg bw (male) (median-effect dose, calculated from the 14-day mortality data)

Reliability 2 study (Mellon Institute, 1956)

Inhalation

No reliable data

No reliable data

Dermal

LD50>15520 mg/kg bw

Reliability 1 study (Bushy Run Research Center, 1981)

LD50 5753 mg/kg bw

Reliability 2 study (Mellon Institute, 1956)

2. Irritation

 

 

Skin

Not irritating in vivo

Reliability 2 study (Bushy Run Research Center, 1981)

No data

Eye

Not irritating in vivo

Reliability 2 study (Bushy Run Research Center, 1981)

No data

3. Skin sensitisation

No data

Skin sensitization (Guinea pig maximisation method)in vivo– negative

Reliability 1 study (Arcelin, 2010,)

4. Genetic toxicity

 

 

In vitro

Bacterial mutagenicity test - negative with and without metabolic activation all strains

Reliability 2 study (Bushy Run Research Center, 1981)

Mammalian cytogenicity test – no data

Mammalian mutagenicity - negative

Reliability 1 study BSL Bioservice, 2011

Bacterial mutagenicity test - negative

Reliability 1 study (BioReliance, 2004a)

Mammalian cytogenicity test – negative

Reliability 1 study (BioReliance, 2004b)

Mammalian mutagenicity test – no data

In vivo

No data

No data

 

5. Repeated dose toxicity

 

 

Oral

90-day repeated dose oral (gavage) toxicity study – NOAEL (systemic)=100 mg/kg bw/day (male/female) (based on tubulopathy observed at doses of 1000 and 300 mg/kg bw/day)

Reliability 1 study (Eurofins, 2019)

28-day repeated dose oral (gavage) toxicity study – NOAEL (systemic)=100 mg/kg bw/day (nominal) (male/female) (based on increased organ weights and kidney effects at the 500 mg/kg bw/day (nominal) dose

Reliability 1 study (RCC, 2005)

Inhalation

No data

No data

Dermal

No data

No data

6. Reproductive toxicity

 

 

No data

28-day studyNOAEL (P): 1000 mg/kg bw/day (male/female)

NOAEL (F1): 1000 mg/kg bw/day (male/female)

Reliability 1 study (RCC, 2005)

7. Developmental toxicity

 

 

NOAEL (developmental toxicity): 1000 mg/kg bw/day

Reliability 1 study (Eurofins, 2019)

28-day study NOAEL (maternal toxicity): 1000 mg/kg bw/day

NOAEL (teratogenicity): 1000 mg/kg bw/day

Reliability 1 study (RCC, 2005)

 

4.  AE A.4 Compounds the test organism is exposed to

Under conditions relevant for in vivo skin sensitisation (pH 4.0 of skin and 20 -25°C body temperature), both the target and source substances hydrolyse rapidly (half-life 0.1 h for the target substance and <0.5 h for the source substance). Therefore, under the conditions of the in vivo skin sensitisation study the test animals may be exposed to the parent substances and their hydrolysis products, 3-(hydroxysilyl)propiononitrile and methanol or ethanol, respectively. The source and target substances and the silanol hydrolysis product have been profiled using the OECD QSAR Toolbox v. 4.1. The substances and their common silanol hydrolysis product show similar profiles for all toxicological endpoints. No alert for skin sensitisation was detected by OECD QSAR Toolbox v.4.1.

Methanol and ethanol are not expected to contribute to the skin sensitisation potential of the target and source substance.

5.  AE 1.2 and 1.3 Formation of common (identical) compound(s) and Exposure of the biological target(s) to the common compound(s)

No skin sensitisation data are available for the target substance, 3-(trimethoxysilyl)propiononitrile, therefore data are read-across from the source substance, 3-(triethoxysilyl)propiononitrile. The target and source substances are trialkoxysilanes with a propiononitrile side-chain. Both substances hydrolyse to the same silicon-containing hydrolysis product, 3-(hydroxysilyl)propiononitrile at similar rates. Their non-silanol hydrolysis products are methanol and ethanol, respectively, neither of which is considered to contribute to the skin sensitisation potential of the target or source substance.

The available key toxicity data on the source substance and target substance are summarised in Table 4. Neither of the two substances is acutely toxic via oral or dermal route, nor are they irritating to skin or eyes. Both substances have been tested for mutagenicity in bacteria and they gave negative results. The source substance also gave negative results in in vitro cytogenicity test in mammalian cells. Similarly, the target substance was concluded to be negative for mutagenicity to mammalian cells when tested in vitro. The available repeated dose toxicity data for the two substances indicate that kidney effects predominate the systemic toxic effects in rats. Therefore, based on their chemical structures and toxicity profiles, the source and target substances are likely to have the same or similar toxicokinetics and biological reactivity and can be expected to react in the same way with regard to the skin sensitisation adverse outcome pathway.

6.  AE 1.4 The impact of parent compounds

Since the registration and the source substance are both trialkoxysilanes with a propionitrile side-chain, they both have the nitrile functionality. The skin sensitisation adverse outcome pathway is heavily reliant on chemical interactions. Therefore, it is reasonable to predict that with the same functional groups, the source and target substances will react in a similar manner. In this case skin sensitisation is not triggered.

7.  AE 2.5 Occurrence of Other Effects than Covered by the Hypothesis and Justification

Not relevant.

8.  AE A.4 Bias that influences the prediction

Possible analogue substances were identified by searching the database of studies held by the Reconsile consortium and by searching in the OECD QSAR Toolbox. The databases were filtered for substances containing both an alkoxysilane and a nitrile group. The source substance was identified as the only suitable substance with reliable skin sensitisation data.


[1] European Chemicals Agency (ECHA) (2015) Read-across Assessment Framework. Appendix A, Scenario 1.


Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on the available in vivo read-across data, 3-(trimethoxysilyl)propiononitrile is not classified as a skin sensitiser according to Regulation (EC) No 1272/2008. There are no data to suggest that classification as a respiratory sensitiser is required.