Registration Dossier

Administrative data

Description of key information

The key acute oral toxicity study, conducted according to OECD test guideline 423 and in compliance with GLP, was selected as the most recent study available out of three reliable tests in rats (two reliability 1 and one reliability 2). The LD50was concluded to be >2000 mg/kg (Dow Corning Corporation, 2001).

The key acute inhalation study, conducted according to OECD test guideline 403 but not in compliance with GLP, was the only study available for this endpoint and was therefore assigned reliability 2. The concluded LC50 was determined to be >2.28 mg/L (>2280 mg/m3) (BRCC, 1983).

The key acute dermal toxicity study was selected as the most recent, highest reliability study (reliability 1) was conducted according to OECD test guideline 402 and in compliance with GLP. An LD50was determined to be >2000 mg/kg (WIL, 2001).

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
Study period:
2001/03/13 - 2001/11/29
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Principles of method if other than guideline:
There were no deviations from protocol that were considered to have affected the validity of the study. However, the following deviation occurred: Air exchange was maintained at a minimum of 15 air changes per hour, not a minimum of 12-15 air changes per hour as stated in the protocol.
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS

- Source: Not stated.

- Age at study initiation: 8 to 11 weeks old

- Weight at study initiation: 206 to 237 g

- Housing: Individually housed in cages with wire mesh floors (39x39x20cm)

- Diet: Standard laboratory diet (RM1(E) SQC, ad libitum

- Water: ad libitum

- Acclimation period: minimum of 7 days



ENVIRONMENTAL CONDITIONS

- Temperature (°C): 20.5 to 22°C

- Humidity (%): 35-48%

- Air changes (per hr): minimum of 15

- Photoperiod (hrs dark / hrs light): 12/12 (0600-1800h)

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 1.92 ml/kgbw to achieve a total dosage of approximately 2000 mg/kg bw

CLASS METHOD
- Rationale for the selection of the starting dose: The dose level for the study was chosen in compliance with the study guidelines.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
3M, 3F
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: Animals were observed on at least two occasions during the first hour following dosing (ca. thirty minutes apart) and thereafter at approximately hourly intervals for the remainder of Day 1 (final observation at 16.00 or 16.20). On subsequent days animals were once in the morning and again at the end of the experimental day (with the exception of Day 15 - morning only). The nature and severity of the clinical signs and time were recorded at each observation. Observations included potential changes in the skin, fur, eyes and mucous membranes, changes in respiratory, circulatory, autonomic, central nervous system, somatomotor activity and behaviour pattern. Particular attention was directed toward the observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma. The body weight of each rat was recorded on days 1 (prior to dosing), 8 and 15. Individual body weights were recorded and body weight changes and group means calculated.

- Necropsy of survivors performed: yes

- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: All animals were subjected to a macroscopic examination, which consisted of examination of the cranial, thoracic and abdominal cavities. The macroscopic appearance of all examined organs was recorded.
Statistics:
Group mean body weights were calculated using appropriate means (STRAND version 1.0). No other statistical analyses were carried out.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no treatment related deaths during the study.
Clinical signs:
Salivation was seen in all females, immediately after dosing but no clinical signs were seen in males throughout the study. Recovery of the rats as judged by external appearance and behaviour, was complete within approximately one hour of dosing.
Body weight:
Low body weight gain was recorded for one female on Day 15. All other rats were considered to have achieved satisfactory body weight gains during the study.
Gross pathology:
There were no abnormalities observed among animals sacrificed at study termination.
Other findings:
No other findings were reported.

Under the conditions of this study, the acute LD50 of Dow Corning Z-6030 Silane was determined to be greater than 2000 mg/kg bw.

Interpretation of results:
GHS criteria not met
Conclusions:
The acute lethal oral dose, conducted according to OECD 423 and in compliance with GLP, the test substance was determined to be >2000 mg/kg bw in a reliable study.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1983
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
Detail missing on animals and environmental conditions.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS

- Source: Charles River Breeding Laboratories (Kingston, NY)

- Age at study initiation: ca. 6 weeks

- Housing: Stainless steel cages, with wire floors

- Diet: Agway certified rodent chow

- Water: provided by an automatic water system

- Acclimation period: 2 weeks

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: distilled water adjusted to pH4 with acetic acid
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION

- Exposure chamber volume: 120 liters

- System of generating particulates/aerosols: Four solo-sphere nebulizers containing a 15% (w/w) solution of 3-(trimethoxysilyl)propyl methacrylate (in distilled water, adjusted to pH 4 with acetic acid) were connected to 2 large triple-necked flasks (to trap large liquid droplets) which were, in turn, connected to the exposure chamber. Dried air was passed into each nebulizer, operating at a pressure of 20 p.s.i, and the resulting aerosol conducted into the animal chamber.

- Method of particle size determination: One sample of chamber atmosphere was analysed for particle size. A 3 minute flow of air at 10 l/min was conducted through a Sierra Cascade Inspector. Particles were collected on 3 stages of glass fibre filters. Several chamber air samples were subjected to gas chromatographic analysis to determine methanol concentration.

TEST ATMOSPHERE

- Brief description of analytical method used: Every 30 minutes during exposure, a sample of chamber atmosphere was drawn through a tared fiberglass filter at the rate of 2.2 l/min. After 2 min the filter was removed, dried in a drying overn to a constant weight and the final weight recorded. The change in weight represented the amount of hydrolysed silane collected. According to the sponsor, this represents ca. 72.17% of the test substance. This factor, along with the volume of air sampled, was used to calculate the concentration of test substance in the chamber air.

- Samples taken from breathing zone: yes

VEHICLE

- Composition of vehicle (if applicable): distilled water

- Concentration of test material in vehicle (if applicable): Distilled water was adjusted to pH 4 with acetic acid and used to make a 15% solution of test substance.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
GC
Duration of exposure:
4 h
Concentrations:
2.28 mg/L
No. of animals per sex per dose:
5 males, 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: The animals were weighed just before exposure and at 7 and 14 days after exposure. All rats were observed frequently on the day of the test and daily during the subsequent observation period.

- Necropsy of survivors performed: yes
Statistics:
No statistical analysis was included in the report.
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 2.28 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Mortality:
There were no deaths.
Clinical signs:
other:
Body weight:
All animals gained weight.
Gross pathology:
No remarkable gross pathologic findings were seen.
Other findings:
None reported.
Interpretation of results:
GHS criteria not met
Conclusions:
In an acute inhalation toxicity study, conducted in a similar manner to OECD 403 but pre-GLP, an LC50 value of >2.28 mg/l (aerosol exposure) was determined.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
2 280 mg/m³

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:
2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
The drinking water for the animals was meant to be treated by reverse osmosis, but was not. This incident did not affect the quality or integrity of the study.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Crl:CD(R)(SD)IGS BR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS

- Source: Charles River Laboratories, Raleigh, NC

- Age at study initiation: 11 weeks old (males) and 12 weeks old (females) at initiation of dosing

- Weight at study initiation: 325 to 339 grams (males) and 219 to 263 grams (females) at initiation of dosing.

- Housing: Individual suspended wire-mesh cages. The animals were maintained by the animal husbandry staff of WIL Research Laboratories Inc., in accordance with standard operating procedures.

- Diet: Certified Rodent LabDiet 5002, ad libitum (PMI Nutrition International, Inc.)

- Water: Municipal water, ad libitum.

ENVIRONMENTAL CONDITIONS

- Temperature (°F): 68-74 (20-23.3°C)

- Humidity (%): 33-60 %

- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light


Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE

- Area of exposure: dorsal skin

- % coverage: 16-20% body surface

- Type of wrap if used: Gauze binders, secured with non-irritating tape.


REMOVAL OF TEST SUBSTANCE

- Washing: The bandages were removed and the sites were wiped with disposable paper towels moistened with tap water.

- Time after start of exposure: 24 hours

TEST MATERIAL

- Amount(s) applied (volume or weight with unit): 2000 mg/kg

- Concentration (if solution): undiluted

- Constant volume or concentration used: Individual doses were calculated based on body weights taken just prior to dosing and the dose volume of 1.9 ml/kg.



Duration of exposure:
24 hours
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 males and 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: Animals were observed for overt signs of toxicity at 1, 3, and 4 hours and once daily, thereafter, for a total of 14 days. Animals were observed twice daily for mortality.  The degree of erythema and eschar formation and edema at the application site was assessed 30-60 minutes after exposure and at daily intervals. Thereafter, using a 0-to-4-severity scale for each criterion. Body weights were recorded on days 0, 7, and 14. 

- Necropsy of survivors performed: yes

- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other:  On day 14, animals were sacrificed and subjected to gross necropsy and examination of the cranial, thoracic and abdominal cavities.
Statistics:
No statistical analysis was included in the report.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths during the study.
Clinical signs:
Five animals were noted with wet and/or dried red, yellow and/or brown material around the nose, eye(s), base of tail and/or urogenital areas on study days 0 and/or 1. These findings are typically noted in association with the bandage application procedures and were not considered to be related to the test article. Additionally, a single animal was noted with an isolated occurrence of soft feces on study day 1. There were no other clinical findings.
Body weight:
All females lost from 2-16 grams (1-7%) of initial (study day 0) body weigh during the first week of the study. All animals gained weight during the second week and with the exception of one female, which was within 8 grams (3%) of its initial body weight, had surpassed their initial body weight. These losses were slight and, with the absence of other signs of systemic toxicity, were not considered to be a result of the test article. There were no other remarkable body weight changes noted during the study.
Gross pathology:
There were no gross necropsy findings for any examined tissues.
Other findings:
- Other observations: Very slight erythema and very slight edema were noted for seven and four animals, respectively, which completely subsided by study day 5. Desquamation was observed sporadically for five animals during study days 2-7. There were no other dermal findings noted during the study.

The LD50 was determined to be greater than 2000 mg/kg bw. These findings indicate that 3-(trimethoxysilyl)propyl methacrylate has a very low order of acute percutaneous toxicity.

Interpretation of results:
GHS criteria not met
Conclusions:
The acute dermal toxicity study, conducted according to OECD 402 and in compliance with GLP, an LD50 value of >2000 mg/kg was determined in a reliable study.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

In the key acute oral study, conducted according to OECD test guideline 423 and in compliance with GLP, an LD50of >2000 mg/kg was determined for male and female rats. Salivation was observed in all females immediately after dosing and noted for up to 1 hour. There were no clinical signs in males. Low bodyweight gain was recorded for one female on Day 15. No abnormalities were detected at necropsy (Dow Corning Corporation, 2001).

In a supporting acute oral toxicity study, conducted according to the now deleted OECD test guideline 401 and in compliance with GLP, an LD50 value of >2000mg/kg was determined (WIL, 2001).

In another supporting acute oral toxicity study, conducted according to OECD test guideline 401 but pre-GLP, an LD50 value of >5.0 ml/kg bw was determined (Consultox Labs, 1976).

In an acute oral toxicity study, not conducted according to any OECD test guideline and pre-GLP, a LD50 value of 22.6 ml/kg was reported in a summary report (RTECS, 1967).

 

In the key acute inhalation study, conducted according to OECD test guideline 403 but not in compliance with GLP, an LC50 >2280 mg/m3 (aerosol exposure) was determined. Slow righting reflex and laboured breathing were observed immediately after exposure. No abnormalities were detected at necropsy (BRRC, 1983).

 

In the key acute dermal toxicity study, conducted according to OECD test guideline 402 and in compliance with GLP, an LD50 >2000 was determined. There were no clinical signs of toxicity and no abnormalities at necropsy. Minor local skin irritation effects were observed (WIL, 2001).

In an acute dermal toxicity study, not according to any guideline and pre-GLP, the dose of 20 ml/kg of the test substance resulted in no mortalities or adverse skin reactions (Mellon, 1964).

Justification for classification or non-classification

Based on the available data 3-trimethoxysilylpropyl methacrylate does not require classification for acute toxicity according to Regulation (EC) No 1272/2008.