Registration Dossier

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No data were available for the registered substance, and data are therefore read across from the structurally analogous substance [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8). In a good quality one-generation reproductive toxicity study (SEHCS, 2004) conducted to OECD 415 and GLP, the parental and reproductive NOAELs for [3-(2,3-epoxypropoxy)propyl]trimethoxysilane were 500 and ≥1000 (the highest dose tested) mg/kg bw/day, in rats. Treatment with the test substance resulted in signs of discomfort after dosing (noted for P females from early /mid gestation onwards), decreased body weight gain of males, and increased absolute and relative liver and kidney weights in P males and females. Histopathology revealed effects on livers and kidneys of males.

Link to relevant study records
Reference
Endpoint:
one-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
13.10.2003 to 30.04.2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: RCC Ltd., Laboratory Animal Services, Switzerland
- Age at study initiation: (P) x 6-8 wks
- Weight at study initiation: (P) Males: 144-184 g; Females: 162-190 g
- Fasting period before study: None
- Housing: During the pre-pairing period, males and females were housed individually. During the pairing period, the rats were housed two females/one male in Makrolon pairing cages. After positive mating or at the end of the pairing period, the males and females were housed individually again; males until necropsy and the females for the birth and rearing of young. On the day of weaning, the dam was separated from its litter.
- Use of restrainers for preventing ingestion (if dermal): yes/no
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: Seven days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22± 3
- Humidity (%): 30-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 20.10.2003 To: 30.04.2004
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The test substance was administered in dried corn oil. Mixtures of the test substance in the vehicle (weight:volume) at the appropriate concentrations were freshly prepared once per week using a magnetic stirrer.
Details on mating procedure:
- M/F ratio per cage: 1:2
- Length of cohabitation: 21 days maximum
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
- After 21 days of unsuccessful pairing replacement of first male by another male
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): individually
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Verification analyses of the actual test substance concentrations, stability during administration (2 hours) and over seven days, and homogeneity in the prepared mixtures were performed on the prepared mixtures on three days (one during pre-pairing, one during gestation and one during the lactation period). On the day of preparation, samples of each dose concentration were taken before dosing. Samples from before dosing were taken from the top, middle and bottom of the container. Later, samples were taken from the middle of the container for verification of stability at room temperature for two hours and for seven days. Analysis was performed using gas chromatography.
Duration of treatment / exposure:
Exposure period: Males: Exposed for a 70-day pre-pairing period, during pairing and until the last litter reached day 7 post-partum. Females: Exposed during pairing and until the last litter reached day 7 post-partum. Premating exposure period (males): 70 days. Premating exposure period (females): 14 days . Duration of test: until the last litter reached day 7 post-partum.
Frequency of treatment:
once daily
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
12 male and 24 female
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose levels were selected in conjunction with the sponsor, based on the results of preceding prenatal developmental and repeated dose toxicity studies.
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were examined at least twice daily for mortality and signs of a reaction to treatment and/or symptoms of ill health.

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: Daily from start of treatment until necropsy. Organs weighed were: pituitary gland, liver, kidneys, testes, prostate, seminal vesicles with coagulating glands, epididymides, ovaries and uterus with cervix and oviducts.

FOOD CONSUMPTION:
- Food consumption for females was recorded weekly from start of treatment to delivery (except mating period). During lactation, food consumption was recorded on days 1, 7 and 14 post-partum. Since pups begin to consume material feed on or about lactation day 14, food consumption was not recorded after this day. For males, food consumption was recorded weekly from treatment start until necropsy, except during mating.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
Oestrous cyclicity (parental animals):
Daily determination of the estrous cycle cycle stage beginning at pairing start until evidence of positive mating.
Sperm parameters (parental animals):
Parameters examined in P male parental generations: testes weight, epididymis weight, prostate weight, epididymides weight, histopathology of testes, prostate, seminal vesicles and epididymides.
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 8 pups/litter (4/sex/litter as nearly as possible); excess pups were killed and examined macroscopically.

PARAMETERS EXAMINED
The following parameters were examined in offspring on day 21 post-partum: number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross external and internal abnormalities, weight gain, physical or behavioural abnormalities.

GROSS EXAMINATION OF DEAD PUPS: yes, they were autopsied and/or preserved in fixative for possible further examination.
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals when the last litter was at least seven days old.
- Maternal animals: All surviving animals after the last litter of each generation was weaned.

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera. Special attention was directed to the reproductive organs. Implantation sites were counted for all dams (uteri placed in solution of ammonium sulfide).

HISTOPATHOLOGY / ORGAN WEIGHTS
- All adults, including those that died before scheduled sacrifice, or were killed in a moribund condition. The tissues histopathologically examined in all animals of the control and high dose groups were as follows: pituitary glands, liver, kidneys, testes, prostate, seminal vesicles, epididymides, ovaries, uterus, cervix and vagina. In addition, the following organs were histopathologically examined in all groups: ovaries, uterus, cervix and vagina in non-pregnant positively mated females (with day 0 post coitum); tested, epididymides, seminal vesicles with coagulating glands and prostate in males that failed to mate.
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring not selected at standardisation were killed and examined macroscopically.
- After weaning at post-partum day 21, all pups were sacrificed and examined internally and externally for abnormalities.
Statistics:
The following statistical methods were used to analyse body weights, food consumption, reproduction and pup data:
- means and standard deviations.
- if the variables could be assumed to follow a normal distribution, the Dunnett t-test, based on a pooled variance estimate, was used for intergroup comparisons (i.e. single treatment groups against the control group).
- The Steel test (rank test) was applied when the data could not be assumed to follow a normal distribution.
- Fisher's Exact test for 2x2 tables was applied if the variables could be dichotomized without loss of information.

For pup data, the litter was the appropriate unit for statistical comparison.
Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Other effects:
not examined
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS):All males survived until scheduled necropsy and no clinical signs that were attributable to treatment with the test item were noted. All females survived until scheduled necropsy. At 1000 mg/kg bw/d, starting during early/mid gestation, all females displayed signs of discomfort after dosing (pushing head through bedding). This behavior was noted as long as the females were dosed (i.e., one day prior to scheduled necropsy).

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): Mean food consumption of males and females was not affected by treatment with the test substance. At 1000 mg/kg bw/d, mean body weight gain of males during the prepairing period was slightly decreased, resulting in a slightly lower mean body weight at the end of the prepairing period (375 g compared with 409 g in the vehicle control).  Although statistical significance was only reached on single days, this reduction was considered to be test item related.  During the pairing and after pairing period, lower absolute body weights at 1000 mg/kg bw/d persisted, while body weight gain was similar to that of the vehicle control. Body weight development of females was not affected by treatment with the test item.


REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): For both generations, the fertility rate was high resulting in at least 23 litters per group for evaluation of reproduction data.  At all dosages, there were no treatment related effects on mean or median precoital time, fertility indices, mean duration of gestation and number of implantations, post-implantation loss, pup survival or litter size from birth through to weaning.


ORGAN WEIGHTS (PARENTAL ANIMALS): At 1000 mg/kg bw/d, statistically significant increased mean relative liver and kidney weights were noted for males and females.


GROSS PATHOLOGY (PARENTAL ANIMALS): No test-item related findings were noted at macroscopic examination of parental males or females.


HISTOPATHOLOGY (PARENTAL ANIMALS): In the liver of males, the severity of glycogen deposition was slightly increased at 1000 mg/kg bw/d. This finding was considered in relation with the nutritional state of the animals and of no adverse character. Kidneys A slightly increased severity of tubular hyaline change occurred in males of Group 4 (1000 mg/kg bw/d) mainly in the outer cortex.The grade was 2.5 versus 2.0 in the controls.  Probably this change reflects an increased accumulation of alpha-2-microglobulin which is male rat specific phenomenon of no toxicological relevance for humans. 
Key result
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
organ weights and organ / body weight ratios
histopathology: non-neoplastic
other: Signs of discomfort after dosing, decreased body weight gain of males, and increased absolute and relative liver and kidney weights in P males and females. Histopathology revealed effects on livers and kidneys of males.
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
VIABILITY (OFFSPRING): No effect on pup survival.


CLINICAL SIGNS (OFFSPRING): No test-item related findings or clinical signs were noted at first litter check on day 0 post-partum or during the lactation period. 

BODY WEIGHT (OFFSPRING): Pup weights at birth and during lactation were unaffected by treatment with the test item.  


GROSS PATHOLOGY (OFFSPRING): No test-item related findings were noted at macroscopic examination of pups.


OTHER FINDINGS: No treatment-related effects on sex ratios were noted.
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed.
Reproductive effects observed:
not specified

In a good quality one-generation reproductive toxicity study (reliability score 1) conducted to OECD 415 and GLP, the parental and reproductive NOAELs for [3-(2,3-epoxypropoxy)propyl]trimethoxysilane were 500 and ≥ 1000 mg/kg bw/d, in rats. Treatment with the test substance resulted in signs of discomfort after dosing (noted for P females from early /mid gestation onwards), decreased body weight gain of males, and increased absolute and relative liver and kidney weights in P males and females. Histopathology revealed effects on livers and kidneys of males.

Conclusions:
In a good quality one-generation reproductive toxicity study (reliability score 1) conducted to OECD 415 and GLP, the parental and reproductive NOAELs for [3-(2,3-epoxypropoxy)propyl]trimethoxysilane were 500 and ≥ 1000 mg/kg bw/d, in rats. Treatment with the test substance resulted in signs of discomfort after dosing (noted for P females from early /mid gestation onwards), decreased body weight gain of males, and increased absolute and relative liver and kidney weights in P males and females. Histopathology revealed effects on livers and kidneys of males. Based on these data a NOAEL for parental animals was established at 500 mg/kg bw/d. A NOAEL for reproductive effects was established at 1000 mg/kg bw/d.
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

In a reliable study conducted according to current guideline and GLP, the parental and reproductive NOAELs for [3-(2,3-epoxypropoxy)propyl]trimethoxysilane were 500 and ≥1000 mg/kg bw/d, in rats (SEHSC, 2004). Treatment with the test substance resulted in signs of discomfort after dosing (noted for P females from early /mid gestation onwards), decreased body weight gain of males, and increased absolute and relative liver and kidney weights in P males and females. Histopathology revealed effects on livers and kidneys of males. Based on these data a NOAEL for parental animals was established at 500 mg/kg bw/d. A NOAEL for reproductive effects was established at 1000 mg/kg bw/day.

Justification of read-across: please refer to justification under Effects on developmental toxicity, Additional information, below.

Effects on developmental toxicity

Description of key information

No data were available for the registered substance, and data are therefore read across from the structural analogue substance [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8).  In a good quality developmental toxicity study (reliability score 1), similar to OECD 414 and in compliance with GLP, [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8) exhibited no adverse effects on the maternal animals or the offspring (DCC, 1982). The NOAEL for maternal and developmental toxicity was at least 1000 mg/kg bw/day.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
28.10.1981 to 18.02.1982
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
Limited details on test substance, dosing during organogenesis only.
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:2
- Length of cohabitation: No data
- Further matings after two unsuccessful attempts: No data
- Verification of same strain and source of both sexes: No data
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
Test substance exposure occurred during the primary period of organogenesis, i.e., gestation days 6-15.
Frequency of treatment:
Once per day on gestation days 6-15
Duration of test:
15 days (dams killed on gestation day 20)
No. of animals per sex per dose:
20 females
Control animals:
other: yes, with water only.
Details on study design:
Sex: female
Duration of test: 3 weeks
Statistics:
Fetal body weights and body measurements, maternal body weights, weights of the maternal livers and uteri and food consumption data were analyzed statistically by a one-way analysis of variance and Dunnett's test (Steel and Torrie, 1960).  The Wilcoxon test as modified by Haseman and Hoel (1974) was used to evaluate incidences of fetal resorptions and alterations.  Other incidence data were analyzed statistically by the Fischer exact test (Seigel, 1956).  The level of significance chosen for all cases was p < 0.05.
Historical control data:
The incidence of malformations and variations in the historical controls is not available. These data were not collected by the laboratory that conducted this study.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: No adverse effects observed.
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed.
Abnormalities:
not specified
Developmental effects observed:
no

There were no test substance-related mortalities.  One rat (subsequently replaced) in the 50 mg/kg/day group died as
the result of dosing trauma.  There were no test substance-related effects on clinical condition, behaviour,
body weight, body weight gain or food consumption.  No effects on liver or gravid uterine weight were observed.  No
effects on the number of implantation sites or corpora lutea per dam were observed.  The incidence of pregnancy was not
affected by treatment with the test substance; all rats were confirmed to be pregnant at the gestation day 20
(laparo hysterectomies).  No adverse effects on the number of live fetuses per litter, mean litter size, sex ratio, fetal
body weight or crown-rump length were observed.  The incidence of fetal resorptions was not altered by test
substance administration.  No external, visceral or skeletal alterations were observed among test substance-treated rats
at an incidence that was statistically different from the control group.  When considered collectively, the incidence
of total major malformations observed in the external, soft tissue or skeletal examinations was not significantly
different among the treated groups as compared to the control group.  No major malformations were observed among
litters of rats that received either 500 or 1000 mg/kg/day of the test substance.  The sporadic variations and
malformations seen occurred at an incidence comparable to a historical control incidence for Sprague-Dawley rats
reported in the literature.

Conclusions:
In a good quality developmental toxicity study (reliability score 1), similar to OECD 414 and GLP, 3-glycidoxypropyltrimethoxysilane exhibited no adverse effects on the maternal animals or the offspring. The NOAEL for maternal and developmental toxicity was at least 1000 mg/kg bw/day.
Executive summary:

In a good quality developmental toxicity study (reliability score 1), similar to OECD 414 and GLP, 3-glycidoxypropyltrimethoxysilane exhibited no adverse effects on the maternal animals or the offspring. The NOAEL for maternal and developmental toxicity was at least 1000 mg/kg bw/day.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

No data are available for developmental toxicity with the registered substance. Data are therefore read across from [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8).

In a reliable study similar to the current guideline and in compliance with GLP, the read across substance [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83 -8) exhibited no adverse effects on the maternal animals or the offspring (DCC, 1982). The NOAEL for maternal and developmental toxicity was at least 1000 mg/kg bw/day.

There were no test substance-related mortalities or effects on clinical condition, behaviour, body weight, body weight gain or food consumption.  No effects on liver or gravid uterine weight were observed.  No effects on the number of implantation sites or corpora lutea per dam were observed.  The incidence of pregnancy was not affected by treatment with the test substance; all rats were confirmed to be pregnant at the gestation day 20 (laparo hysterectomies). No adverse effects on the number of live fetuses per litter, mean litter size, sex ratio, fetal body weight or crown-rump length were observed. The incidence of fetal resorptions was not altered by test substance administration. No external, visceral or skeletal alterations were observed among test substance-treated rats at an incidence that was statistically different from the control group. When considered collectively, the incidence of total major malformations observed in the external, soft tissue or skeletal examinations was not significantly different among the treated groups as compared to the control group.  No major malformations were observed among litters of rats that received either 500 or 1000 mg/kg/day of the test substance.  The sporadic variations and malformations seen occurred at an incidence comparable to a historical control incidence for Sprague-Dawley rats reported in the literature.

Read-across justification

There are no available measured data for [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1) for reproductive and developmental toxicity. This section describes the analogue approach for fulfilling these endpoints by read-across from the source substance, [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8), according to the ECHA Read-across Assessment Framework (RAAF)[1]. The RAAF states that “Registrants are obligated to consider and, where they can, use appropriate alternative approaches to fulfil applicable REACH information requirements concerning vertebrate animal studies. If read-across which meets the information requirements is applied, unnecessary animal testing may be avoided as there will be no need to carry out one-by-one testing of all their substances to fulfil the information requirements.”

Read-across is proposed in accordance with RAAF Scenario 2: “This scenario covers the analogue approach for which the read-across hypothesis is based on different compounds which have the same type of effect(s). For the REACH information requirement under consideration, the effects obtained in a study conducted with one source substance are used to predict the effects that would be observed in a study with the target substance if it were to be conducted. The same type of effect(s) or absence of effect is predicted. The predicted strength of the effects may be similar or based on a worst case.”

The read-across justification is presented (Table 1) according to RAAF scenario 2 assessment elements (AE) as outlined in Table B1 of the RAAF1:

Table 1: RAAF scenario 2 assessment elements (AE) as given in Appendix B (Table B1) 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 2.1

Compounds the test organism is exposed to

AE 2.2

Common underlying mechanism, qualitative aspects

AE 2.3

Common underlying mechanism, quantitative aspects

AE 2.4

Exposure to other compounds than to those linked to the prediction

AE 2.5

Occurrence of other effects than covered by the hypothesis and Justification

AE A.4

Bias that influences the prediction

 

1.  AE A.1 Characterisation of the source substance

The source substance, [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8) is a member of an alkoxysilane analogue group. It has a silicon atom bound to 3-(2,3-epoxypropoxy)propyl side-chain. The source substance is a trialkoxysilane with three methoxy groups bound to silicon. It hydrolyses rapidly to produce [3-(2,3-epoxypropoxy)propyl]silanetriol and methanol. Its measured hydrolysis half-lives are 0.15 h at pH 5, 6.5 hours at pH 7 and 0.13 h at pH 9. The pH values estimated for physiologically relevant conditions are 3.3 h at pH 7 (the known pH of lungs) and 37°C and 5 seconds at pH 2 (the known pH of the stomach) and 37°C. These values are relevant for inhalation and oral routes of exposure.

The source substance has log Kow of 0.5 at 20°C (QSAR), water solubility of 1.1E+05 mg/L mg/l at 20°C (QSAR) and vapour pressure of 1.1 Pa at 25°C (QSAR).

Table 2 Summary of the structure and purity for the target [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1) and source[3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8)

 

Target

Source

Chemical name

[3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane

[3-(2,3-epoxypropoxy)propyl]trimethoxysilane

CAS Number

2897-60-1

2530-83-8

EC Number

220-780-8

219-784-2

Chemical structure

 

 

Type

Monoconstituent

Monoconstituent

Purity (w/w)

>95%

>98%

 

Table 3 below presents a summary of the impurities that may be present in [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1) and [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8). This is based on analytical data that was provided by members of the Reconsile Consortium and 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.

Chemical structures are known for all identified impurities. CAS and EC numbers have been obtained where these exist. 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.

Table 3 Impurity profile information for the target [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1) and source [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8)

Impurity type

[3-(2,3-epoxypropoxy)propyl] diethoxy(methyl)silane (CAS 2897-60-1)

[3-(2,3-epoxypropoxy)propyl] trimethoxysilane (CAS 2530-83-8)

Comments

Total

Individual impurity

Total

Maximum individual impurity

Epoxy-functional alkoxysilanes

<5%

<1%

<2%

<2%

These are ethoxy or methoxy silanes with one alkyl-epoxy side-chain. They are close structural analogues of the source and target substance.

 

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

The target and source substances, [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1) and [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8), are structurally similar and are members of an analogue group of alkoxysilanes with epoxy-functional side-chains. They both contain a silicon atom attached to one 3-(2,3-epoxypropoxy)propyl side-chain. The target substance [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1) is a dialkoxysilane with two ethoxy groups and one methyl group bound to silicon while the source substance [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8) is a trialkoxysilane with three methoxy groups bound to silicon. Therefore, the similarities between the two structures are that both are alkoxysilanes with one 3-(2,3-epoxypropoxy)propyl side-chain. The difference between the two structures is that the three methoxy groups in the source substance are replaced by two ethoxy groups and one methyl group in the target substance.

Table 4 Physicochemical properties

Property

Target substance

Source substance

Substance name

[3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane

[3-(2,3-epoxypropoxy)propyl]trimethoxysilane

CAS number

2897-60-1

2530-83-8

Molecular weight (g/mol)

248.391

236.338

Hydrolysis half-life at 25°C

0.5 h at pH 5

11.7 h at pH 7

0.2 h at pH 9

(QSAR)

0.15 h at pH 5

6.5 h at pH 7

0.13 h at pH 9

(measured)

Hydrolysis half-life under physiological conditions

(predicted)

5 seconds at pH 2 and 37.5°C

4.4 hours at pH 7 and 37.5°C

5 seconds at pH 2 and 37.5°C

3.3 hours at pH 7 and 37.5°C

Silanol hydrolysis product

[3-(2,3-epoxypropoxy)propyl]methylsilanediol

[3-(2,3-epoxypropoxy)propyl]silanetriol

Non-Si hydrolysis product

ethanol

methanol

Log Kow value(parent)

2.7 at 20°C (QSAR)

0.5 at 20°C (QSAR)

log Kow (silicon-containing hydrolysis product)

-0.7 at 20°C (QSAR)

-2.6 at 20°C (QSAR)

Vapour pressure (parent)

0.42 Pa at 25°C (OECD 104)

1.1 Pa at 25°C (QSAR)

Vapour pressure (silicon-containing hydrolysis product)

2.8E-04 Pa at 25°C (QSAR)

1.7E-05 Pa at 25°C (QSAR)

Water solubility (parent)

1200 mg/L at 20-25°C (QSAR)

1.1E+05 mg/L at 20°C (QSAR)

Water solubility (silicon-containing hydrolysis product)

1.0E+06 mg/l at 20-25°C (limited to approximately 1000 mg/l by condensation reactions) (QSAR)

1.0E+06 mg/l at 20°C (limited to approximately 1000 mg/l by condensation reactions) (QSAR)

 

The difference in structure does not lead to a significant difference in physicochemical properties. From the table above the largest difference is for log Kowvalue, with the source substance being lower than that of the target substance. However, both of the log Kowvalues for the parent substances are greater than 0 which indicates that there is a possibility for them to reach the reproductive organs and foetuses. 

Predicted hydrolysis half-lives of the target and source substance at pH 2 (relevant for oral exposure) and 37.5°C are approximately 5 seconds. This indicates that the test organisms would mainly be expected to be exposed to the hydrolysis products of the parent and source substances after oral exposure. Both substances hydrolyse rapidly to produce similar silicon-containing hydrolysis products, [3-(2,3-epoxypropoxy)propyl]methylsilanediol and [3-(2,3-epoxypropoxy)propyl]silanetriol. The non-silicon hydrolysis products are ethanol and methanol for the target substance and the source substance, respectively.

The log Kowvalues for the silanol hydrolysis products are lower than 0 which indicates that it is unlikely that they would reach reproductive organ tissues and/or foetuses.

The parent target and source substance have molecular weights lower than 300 g/mol and high predicted water solubility which indicates that they would be expected to be quickly eliminated in the urine. The silanol hydrolysis products also have very high predicted water solubility (although limited to approximately 1000 mg/l by condensation reactions), therefore rapid elimination in urine is also likely for these.

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

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 in vivo), and repeated dose toxicity (oral and inhalation) that can be compared with available reliable data of the target substance. Table 5 summarises the key data and their reliability (using Klimisch codes).

Of particular importance in this case is the reliability of the studies that are being read-across.

For the reproductive toxicity (fertility) endpoint, a one-generation reproductive toxicity study (RCC, 2004) on [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8) is read across to [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1). This study was conducted according to OECD TG 415 and covers the key parameters specified by the method; it was conducted in compliance with GLP (Reliability 1 study; reliable without restriction). The test substance [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8) used in this study was 98.4% pure and therefore represents the source substance without impurities that could influence the outcome of the study. The highest dose (1000 mg/kg bw/day) used in the study was equal to the limit dose (1000 mg/kg bw/day) recommended for this type of study, and therefore the NOAEL derived is adequate for the purpose of classification and labelling and risk assessment.

For the developmental toxicity endpoint, a prenatal developmental toxicity study (BRRC, 1993) on [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8) is read across to [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1). This study was conducted according to OECD TG 414 and covers the key parameters specified by the method; it was conducted in compliance with GLP (Reliability 1 study; reliable without restriction). The test substance [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8) used in this study was 98% pure and therefore represents the source substance without impurities that could influence the outcome of the study. The highest dose used in the study was the limit dose, 1000 mg/kg bw/day, recommended for this type of study.

 

Table 5 Summary of reliability of the key data for the target substance [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1) and source substance [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8)

 

Target

Source

 

[3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane

[3-(2,3-epoxypropoxy)propyl]trimethoxysilane

 

2897-60-1

2530-83-8

1. Acute Toxicity

 

 

Oral

LD50> 2000 mg/kg bw/day

Reliability 1 study (DCC, 2008)

LD50> 8025 mg/kg bw/day

Reliability 2 study (Dow Corning Corporation, 1976)

Inhalation

No data

LC50≥ 5.3 mg/L air

Reliability 1 study (Allied Corporation, 1982)

Dermal

LD50> 2000 mg/kg bw/day

Reliability 1 study (WIL, 1999)

LD50> 4250 mg/kg bw/day

Reliability 1 study (Mellon, 1962)

2. Irritation

 

 

Skin

Not irritating in vivo

Reliability 1 study (WIL, 2000)

Not irritating in vivo

Reliability 1 study (Allied Corporation, 1982)

Eye

Not irritating in vivo

Reliability 1 study (WIL, 2000)

Corrosive in vivo

Reliability 1 study (IFREB, 1982)

3. Skin sensitisation

Skin sensitization (Local Lymph Node Assay) – positive

Reliability 1 study (Safepharm, 2004)

Skin sensitization (Buhler method)in vivo– negative

Reliability 1 study (Huls, 1993)

4. Genetic toxicity

 

 

In vitro

Bacterial mutagenicity test - positive

Reliability 1 study (Momentive, 2000)

 

Mammalian cytogenicity test - positive

Reliability 1 study (Momentive, 2004)

Bacterial mutagenicity test - positive

Reliability 2 study (Microtest Research, 1988)

 

 

Mammalian mutagenicity test - positive

Reliability 2 study (Litton Bionetics, 1983)

In vivo

Micronucleus test – negative

Reliability 1 study (Shin-Etsu, 2009)

 

In vivo mammalian alkaline comet assay – ambiguous

Reliability 1 study (BSL Bioservice, 2018, in draft, study on-going)

Micronucleus test – positive

Reliability 1 study (Bioreliance, 1999)

 

Micronucleus test – negative

Reliability 2 study (Hüls, 1994)

 

Micronucleus test – negative

Reliability 2 study (DCC, 1982)

 

In vivo mammalian alkaline comet assay – study planned

5. Repeated dose toxicity

 

 

Oral

28-day oral repeated dose toxicity study – NOAEL ≥ 1000 mg/kg bw/day. No adverse or adaptive findings reported.

Reliability 1 study (DCC, 1981)

28-day oral repeated dose toxicity study – NOAEL ≥ 1000 mg/kg bw/day. No adverse or adaptive findings reported.

Reliability 1 study (DCC, 1981)

 

One-generation reproductive toxicity study – NOAEL for general toxicity in parent animals = 500 mg/kg bw/day. Based on effects on liver and kidney of uncertain toxicological relevance.

Reliability 2 study (RCC, 2004)

Inhalation

No data

14-day inhalation (aerosol) repeated dose toxicity study – NOAEC = 225 mg/m3. Decreased feeding and body weights.

Reliability 2 study (DCC, 1982)

Dermal

No data

No data

6. Reproductive toxicity

 

 

No data

One-generation reproductive toxicity study – NOAEL (general systemic toxicity) = 500 mg/kg bw/day; NOAEL (reproductive toxicity) ≥ 1000 mg/kg bw/day (highest dose tested)

Reliability 1 study (RCC, 2004)

7. Developmental toxicity

 

 

No data

Prenatal developmental toxicity study – NOAEL (maternal effects) >=1000 mg/kg bw/day; NOAEL (developmental effects) >=1000 mg/kg bw/day.

Reliability 1 study (Dow Corning Corporation 1982)


 

4.  AE A.2.1 Compounds the test organism is exposed to

The source substances as well as the target substance have been predicted to hydrolyse rapidly in contact with water under conditions relevant for oral or inhalation exposure. Their estimated hydrolysis half-lives at pH 2 (relevant for oral exposure) and37.5°C are approximately 5 seconds. Therefore, the test organism is expected to be mainly exposed to their hydrolysis products, [3-(2,3-epoxypropoxy)propyl]methylsilanediol and ethanol or [3-(2,3-epoxypropoxy)propyl] silanetriol and methanol.

The hydrolysis products of the target and source substances are structurally similar. [3-(2,3-Epoxypropoxy)propyl]methylsilanediol is a silanediol with two hydroxy (silanol) groups, one methyl group and one 3-(2,3-epoxypropoxy)propyl group bound to silicon. [3-(2,3-Epoxypropoxy)propyl] silanetriol is a silanetriol with three hydroxy (silanol) groups and one 3-(2,3-epoxypropoxy)propyl group bound to silicon. Therefore, the similarities are that both hydrolysis products are silanols with one 3-(2,3-epoxypropoxy)propyl side-chain. The difference is that the methyl group in the target substance is replaced by an additional hydroxy (silanol) group in the source substance.

The source and target substances have been profiled using the OECD QSAR Toolbox v. 4.1. Parent substances and their silanol hydrolysis products show similar profiles for all toxicological endpoints. No alert for reproductive toxicity was detected by OECD QSAR Toolbox v.4.1. The only detected alert for genetic toxicity was the epoxide group present at both chemical structures. The available long-term toxicity data support the findings of the OECD QSAR Toolbox. No adverse toxic effects were observed in any of the reliable repeated dose toxicity studies for the target or source substance. Both substances have mixed results for genotoxicity from reliable in vitro andin vivodata, with conflicting results (positive and negative) fromin vivomicronucleus assays available for the source substance, and ambiguous results from an on-goingin vivomammalian alkaline comet assay on the target substance (see Section 5 below). Anin vivomammalian alkaline comet assay has been proposed for the source substance but has not yet been approved.

Ethanol is reported to have an effect on male fertility in some rat studies but not others and where noted generally involve sperm parameters(OECD, 2004a). However, where effects are noted they occur only at high doses.

Rats and mice maintained on liquid diets containing 5 – 10% ethanol for 5 weeks or longer showed some adverse physical and functional effects on the testes. Some indications of toxicity to the foetus, including deaths, growth retardation and increased malformations have been noted in rats and mice given diets in which 15-35% of the calories were derived from ethanol. However, in other studies, no effect on the foetuses were seen in mice and rabbits given drinking water containing up to 15% ethanol, or inhaling up to 20000 ppm ethanol, during pregnancy (OECD, 2004a)

Information about the effects of methanol on fertility is limited (OECD, 2004b). Slight increases in sperm abnormalities were noted in a study in mice although the effect on fertility was not investigated. In a rat 2-generation study there were no effects on fertility. In a cynomolgus monkey study no effects were noted.

In rats, foetal NOAELs have been defined up to 5000 ppm after inhaled exposure. A corresponding figure of 1000 ppm has been defined for mice, which are considered to be more sensitive. At higher concentrations litter resorptions and increased incidences of foetal variations, and in some cases, malformations e. g. exencephaly and encephalocoele have been noted at 20000 ppm in rats and 5000 ppm in mice (OECD, 2004b).

5.  AE A.2.2 and A.2.3 Common underlying mechanism, qualitative and quantitative aspects

No reproductive or developmental toxicity data are available for the target substance[3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1), therefore data were read-across from the source substance, [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8). Both substances hydrolyse at similar rate to a disilanol (1 mole) or a trisilanol (1 mole) and ethanol or methanol. Moreover, they have similar physico-chemical properties. Thus, both substances are expected to have similar toxicity profiles. The non-silanol hydrolysis products, ethanol and methanol,are not expected to be relevant for this endpoint.

The available key toxicity data on the source substance and target substances as summarised in Table 5, show that the two substances are not acutely toxic via the oral and dermal routes, they are not skin irritants, the target substance is not an eye irritant while the source substance causes irreversible eye damage, the target substance is a skin sensitiser while the source substance is not, both substances have mixed genetic toxicity results (in vitroandin vivo), with conflicting results (positive and negative) from micronucleus assays available for the source substance. There is an on-goingin vivomammalian alkaline comet assay on the target substance in which the tissues tested were liver, glandular stomach and duodenum (OECD 489, GLP). Increased comet formation was detected in duodenal cells only after application of the highest tested limit-dose of 2000 mg/kg bw. Neither a dose-response relationship nor any significant signal outside the historical control interval at the lower doses was detected. In this study, duodenum samples were preserved for histopathological analysis, which will be started in the near future for examining the possible involvement of cytotoxicity. Anin vivomammalian alkaline comet assay has been proposed for the source substance but has not yet been approved.

The results from the available higher tier test for the target substance show no adverse effects in any of the tested doses, while the results from the one-generation reproductive toxicity for the source substance showed decreased body weight gain, increased absolute and relative liver and kidney weights and histopathological findings in livers and kidneys. No adverse effects were reported in a 28-day repeated dose oral toxicity study in rats for the source substance.

6.  AE 2.4 Exposure to other compounds than to those linked to the prediction

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 vitroandin vivo), and repeated dose toxicity (oral and inhalation) that can be compared with available reliable data of the target substance. Table summarises the key data and their reliability (using Klimisch codes).

Of particular importance in this case is the reliability of the studies that are being read-across.

For the reproductive toxicity (fertility) endpoint, a one-generation reproductive toxicity study (RCC, 2004) on [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8) is read across to [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1). This study was conducted according to OECD TG 415 and covers the key parameters specified by the method; it was conducted in compliance with GLP (Reliability 1 study; reliable without restriction). The test substance [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8) used in this study was 98.4% pure and therefore represents the source substance without impurities that could influence the outcome of the study. The highest dose (1000 mg/kg bw/day) used in the study was equal to the limit dose (1000 mg/kg bw/day) recommended for this type of study, and therefore the NOAEL derived is adequate for the purpose of classification and labelling and risk assessment.

For the developmental toxicity endpoint, a prenatal developmental toxicity study (BRRC, 1993) on [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8) is read across to [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1). This study was conducted according to OECD TG 414 and covers the key parameters specified by the method; it was conducted in compliance with GLP (Reliability 1 study; reliable without restriction). The test substance [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8) used in this study was 98% pure and therefore represents the source substance without impurities that could influence the outcome of the study. The highest dose used in the study was the limit dose, 1000 mg/kg bw/day, recommended for this type of study.

Table 5 Summary of reliability of the key data for the target substance [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1) and source substance [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8)

 

Target

Source

 

[3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane

[3-(2,3-epoxypropoxy)propyl]trimethoxysilane

 

2897-60-1

2530-83-8

1. Acute Toxicity

 

 

Oral

LD50> 2000 mg/kg bw/day

Reliability 1 study (DCC, 2008)

LD50> 8025 mg/kg bw/day

Reliability 2 study (Dow Corning Corporation, 1976)

Inhalation

No data

LC50≥ 5.3 mg/L air

Reliability 1 study (Allied Corporation, 1982)

Dermal

LD50> 2000 mg/kg bw/day

Reliability 1 study (WIL, 1999)

LD50> 4250 mg/kg bw/day

Reliability 1 study (Mellon, 1962)

2. Irritation

 

 

Skin

Not irritatingin vivo

Reliability 1 study (WIL, 2000)

Not irritatingin vivo

Reliability 1 study (Allied Corporation, 1982)

Eye

Not irritatingin vivo

Reliability 1 study (WIL, 2000)

Corrosivein vivo

Reliability 1 study (IFREB, 1982)

3. Skin sensitisation

Skin sensitization (Local Lymph Node Assay) – positive

Reliability 1 study (Safepharm, 2004)

Skin sensitization (Buhler method)in vivo– negative

Reliability 1 study (Huls, 1993)

4. Genetic toxicity

 

 

In vitro

Bacterial mutagenicity test - positive

Reliability 1 study (Momentive, 2000)

 

Mammalian cytogenicity test - positive

Reliability 1 study (Momentive, 2004)

Bacterial mutagenicity test - positive

Reliability 2 study (Microtest Research, 1988)

 

 

Mammalian mutagenicity test - positive

Reliability 2 study (Litton Bionetics, 1983)

In vivo

Micronucleus test – negative

Reliability 1 study (Shin-Etsu, 2009)

 

In vivomammalian alkaline comet assay – ambiguous

Reliability 1 study (Eurofins/BSL 2018, in draft, study on-going)

Micronucleus test – positive

Reliability 1 study (Bioreliance, 1999)

 

Micronucleus test – negative

Reliability 2 study (Hüls, 1994)

 

Micronucleus test – negative

Reliability 2 study (DCC, 1982)

 

In vivomammalian alkaline comet assay – study planned

5. Repeated dose toxicity

 

 

Oral

28-day oral repeated dose toxicity study – NOAEL ≥ 1000 mg/kg bw/day. No adverse or adaptive findings reported.

Reliability 1 study (DCC, 1981)

28-day oral repeated dose toxicity study – NOAEL ≥ 1000 mg/kg bw/day. No adverse or adaptive findings reported.

Reliability 1 study (DCC, 1981)

 

One-generation reproductive toxicity study – NOAEL for general toxicity in parent animals = 500 mg/kg bw/day. Based on effects on liver and kidney of uncertain toxicological relevance.

Reliability 2 study (RCC, 2004)

Inhalation

No data

14-day inhalation (aerosol) repeated dose toxicity study – NOAEC = 225 mg/m3. Decreased feeding and body weights.

Reliability 2 study (DCC, 1982)

Dermal

No data

No data

6. Reproductive toxicity

 

 

No data

One-generation reproductive toxicity study – NOAEL (general systemic toxicity) = 500 mg/kg bw/day; NOAEL (reproductive toxicity) ≥ 1000 mg/kg bw/day (highest dose tested)

Reliability 1 study (RCC, 2004)

7. Developmental toxicity

 

 

No data

Prenatal developmental toxicity study – NOAEL (maternal effects) = 200 mg/kg bw/day based on one death in the highest dose group; NOAEL (developmental effects) ≥400 mg/kg bw/day.

Reliability 1 study (BRRC, 1993)

 

Neither the target substance,[3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1), nor the source substance, [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8), have impurities of toxicological concern.

Purity of test substance in the study with the source substance, [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8), was reported to be 98.4%.

The target substance,[3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1), has a purity of >95% and <= 100%, and no impurities are present at >1%.

Table 3 summarises the impurities that may be present in[3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1)and [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8). This is based on analytical data that were provided by members of the Reconsile Consortium. The precise identity of the impurities is considered confidential because it could reveal details of the manufacturing process to other Consortium members.

Structures are known for all identified impurities. CAS and EC numbers have been obtained where these exist. 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 source and target substances.

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

Other substances that have been considered for read-across and the reasons for rejecting them are summarised in Table 6. These have been identified by searching the database of studies held by the Reconsile Consortium and by searching in the OECD QSAR Toolbox. Substances containing both an alkoxysilane and an epoxy group were considered. Only one substance has any reproductive/developmental toxicity data: CAS 3388-04-3, 2-(3,4-epoxycyclohexyl)ethyltrimethoxysilane. For this substance, two OECD 414 studies (in rat and rabbit) are available in which no developmental toxicity is evident at any of the dose levels tested. This substance is not such a close structural analogue to the target substance as the selected source substance. Both this substance and the source substance are trimethoxysilanes (so the differences from the target substance are the same), but the selected source substance has the same side-chain as the target substance, whereas this substance does not. Therefore, it is confirmed that the source substance has been selected without bias as the source substance for read across.

Table 6 Other substance considered as source substance

CAS Number

Chemical Name

Reason for rejection as a source substance

065799-47-5

[3-(2,3-epoxypropoxy)propyl]dimethoxymethylsilane

No reproductive/developmental toxicity data

003388-04-3

2-(3,4-epoxycyclohexyl)ethyltrimethoxysilane

Different side-chain (cyclic alkane with an epoxy group rather than linear alkane with an epoxypropoxy group).

002602-34-8

[3-(2,3-epoxypropoxy)propyl]triethoxysilane

No reproductive/developmental toxicity data

010217-34-2

triethoxy-[2-(7-oxabicyclo[4.1.0]hept-3-yl)ethyl]silane

No reproductive/developmental toxicity data


[1]European Chemicals Agency (ECHA) (2015) Read-across Assessment Framework. Appendix B, Scenario 2.


Toxicity to reproduction: other studies

Additional information

Read-across justification

There are no available measured data for[3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1)for reproductive and developmental toxicity. This section describes the analogue approach for fulfilling these endpoints by read-across from the source substance,[3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8),according to the ECHA Read-across Assessment Framework (RAAF)[1]. The RAAF states that “Registrants are obligated to consider and, where they can, use appropriate alternative approaches to fulfil applicable REACH information requirements concerning vertebrate animal studies. If read-across which meets the information requirements is applied, unnecessary animal testing may be avoided as there will be no need to carry out one-by-one testing of all their substances to fulfil the information requirements.”

Read-across is proposed in accordance with RAAF Scenario 2: “This scenario covers the analogue approach for which the read-across hypothesis is based on different compounds which have the same type of effect(s). For the REACH information requirement under consideration, the effects obtained in a study conducted with one source substance are used to predict the effects that would be observed in a study with the target substance if it were to be conducted. The same type of effect(s) or absence of effect is predicted. The predicted strength of the effects may be similar or based on a worst case.”

The read-across justification is presented (Table 1) according to RAAF scenario 2 assessment elements (AE) as outlined in Table B1 of the RAAF1:

Table 1: RAAF scenario 2 assessment elements (AE) as given in Appendix B (Table B1) 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 2.1

Compounds the test organism is exposed to

AE 2.2

Common underlying mechanism, qualitative aspects

AE 2.3

Common underlying mechanism, quantitative aspects

AE 2.4

Exposure to other compounds than to those linked to the prediction

AE 2.5

Occurrence of other effects than covered by the hypothesis and Justification

AE A.4

Bias that influences the prediction

 

1.  AE A.1 Characterisation of the source substance

The source substance,[3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8) is a member of an alkoxysilane analogue group. Ithas a silicon atom bound to 3-(2,3-epoxypropoxy)propyl side-chain. The source substance is a trialkoxysilane with three methoxy groups bound to silicon. It hydrolyses rapidly to produce [3-(2,3-epoxypropoxy)propyl]silanetriol and methanol. Its measured hydrolysis half-lives are 0.15 h at pH 5, 6.5 hours at pH 7 and 0.13 h at pH 9. The pH values estimated for physiologically relevant conditions are 3.3 h at pH 7 (the known pH of lungs) and 37°C and 5 seconds at pH 2 (the known pH of the stomach) and 37°C. These values are relevant for inhalation and oral routes of exposure.

The source substance has log Kow of 0.5 at 20°C (QSAR), water solubility of 1.1E+05 mg/L mg/l at 20°C (QSAR) and vapour pressure of 1.1 Pa at 25°C (QSAR).

Table 2 Summary of the structure and purity for the target [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1) and source[3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8)

 

Target

Source

Chemical name

[3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane

[3-(2,3-epoxypropoxy)propyl]trimethoxysilane

CAS Number

2897-60-1

2530-83-8

EC Number

220-780-8

219-784-2

Chemical structure

 

 

Type

Monoconstituent

Monoconstituent

Purity (w/w)

>95%

>98%

 

Table 3 below presents a summary of the impurities that may be present in [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1) and [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8). This is based on analytical data that was provided by members of the Reconsile Consortium and 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.

Chemical structures are known for all identified impurities. CAS and EC numbers have been obtained where these exist. 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.

Table 3 Impurity profile information forthe target [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1) and source [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8)

Impurity type

[3-(2,3-epoxypropoxy)propyl] diethoxy(methyl)silane (CAS 2897-60-1)

[3-(2,3-epoxypropoxy)propyl] trimethoxysilane (CAS 2530-83-8)

Comments

Total

Individual impurity

Total

Maximum individual impurity

Epoxy-functional alkoxysilanes

<5%

<1%

<2%

<2%

These are ethoxy or methoxy silanes with one alkyl-epoxy side-chain. They are close structural analogues of the source and target substance.

 

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

The target and source substances, [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1) and [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8), are structurally similar and are members of an analogue group of alkoxysilanes with epoxy-functional side-chains. They both contain a silicon atom attached to one 3-(2,3-epoxypropoxy)propyl side-chain. The target substance [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1) is a dialkoxysilane with two ethoxy groups and one methyl group bound to silicon while the source substance [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8) is a trialkoxysilane with three methoxy groups bound to silicon. Therefore, the similarities between the two structures are that both are alkoxysilanes with one 3-(2,3-epoxypropoxy)propyl side-chain. The difference between the two structures is that the three methoxy groups in the source substance are replaced by two ethoxy groups and one methyl group in the target substance.

Table 4 Physicochemical properties

Property

Target substance

Source substance

Substance name

[3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane

[3-(2,3-epoxypropoxy)propyl]trimethoxysilane

CAS number

2897-60-1

2530-83-8

Molecular weight (g/mol)

248.391

236.338

Hydrolysis half-life at 25°C

0.5 h at pH 5

11.7 h at pH 7

0.2 h at pH 9

(QSAR)

0.15 h at pH 5

6.5 h at pH 7

0.13 h at pH 9

(measured)

Hydrolysis half-life under physiological conditions

(predicted)

5 seconds at pH 2 and 37.5°C

4.4 hours at pH 7 and 37.5°C

5 seconds at pH 2 and 37.5°C

3.3 hours at pH 7 and 37.5°C

Silanol hydrolysis product

[3-(2,3-epoxypropoxy)propyl]methylsilanediol

[3-(2,3-epoxypropoxy)propyl]silanetriol

Non-Si hydrolysis product

ethanol

methanol

Log Kow value(parent)

2.7 at 20°C (QSAR)

0.5 at 20°C (QSAR)

log Kow (silicon-containing hydrolysis product)

-0.7 at 20°C (QSAR)

-2.6 at 20°C (QSAR)

Vapour pressure (parent)

0.42 Pa at 25°C (OECD 104)

1.1 Pa at 25°C (QSAR)

Vapour pressure (silicon-containing hydrolysis product)

2.8E-04 Pa at 25°C (QSAR)

1.7E-05 Pa at 25°C (QSAR)

Water solubility (parent)

1200 mg/L at 20-25°C (QSAR)

1.1E+05 mg/L at 20°C (QSAR)

Water solubility (silicon-containing hydrolysis product)

1.0E+06 mg/l at 20-25°C (limited to approximately 1000 mg/l by condensation reactions) (QSAR)

1.0E+06 mg/l at 20°C (limited to approximately 1000 mg/l by condensation reactions) (QSAR)

 

The difference in structure does not lead to a significant difference in physicochemical properties. From the table above the largest difference is for log Kowvalue, with the source substance being lower than that of the target substance. However, both of the log Kowvalues for the parent substances are greater than 0 which indicates that there is a possibility for them to reach the reproductive organs and foetuses. 

Predicted hydrolysis half-lives of the target and source substance at pH 2 (relevant for oral exposure) and 37.5°C are approximately 5 seconds. This indicates that the test organisms would mainly be expected to be exposed to the hydrolysis products of the parent and source substances after oral exposure.Both substances hydrolyse rapidly to produce similar silicon-containing hydrolysis products, [3-(2,3-epoxypropoxy)propyl]methylsilanediol and [3-(2,3-epoxypropoxy)propyl]silanetriol. The non-silicon hydrolysis products are ethanol and methanol for the target substance and the source substance, respectively.

The log Kowvalues for the silanol hydrolysis products are lower than 0 which indicates that it is unlikely that they would reach reproductive organ tissues and/or foetuses.

The parent target and source substance have molecular weights lower than 300 g/mol and high predicted water solubility which indicates that they would be expected to be quickly eliminated in the urine. The silanol hydrolysis products also have very high predicted water solubility (although limited to approximately 1000 mg/l by condensation reactions), therefore rapid elimination in urine is also likely for these.

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

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 vitroandin vivo), and repeated dose toxicity (oral and inhalation) that can be compared with available reliable data of the target substance. Table 5 summarises the key data and their reliability (using Klimisch codes).

Of particular importance in this case is the reliability of the studies that are being read-across.

For the reproductive toxicity (fertility) endpoint, a one-generation reproductive toxicity study (RCC, 2004) on [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8) is read across to [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1). This study was conducted according to OECD TG 415 and covers the key parameters specified by the method; it was conducted in compliance with GLP (Reliability 1 study; reliable without restriction). The test substance [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8) used in this study was 98.4% pure and therefore represents the source substance without impurities that could influence the outcome of the study. The highest dose (1000 mg/kg bw/day) used in the study was equal to the limit dose (1000 mg/kg bw/day) recommended for this type of study, and therefore the NOAEL derived is adequate for the purpose of classification and labelling and risk assessment.

For the developmental toxicity endpoint, a prenatal developmental toxicity study (BRRC, 1993) on [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8) is read across to [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1). This study was conducted according to OECD TG 414 and covers the key parameters specified by the method; it was conducted in compliance with GLP (Reliability 1 study; reliable without restriction). The test substance [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8) used in this study was 98% pure and therefore represents the source substance without impurities that could influence the outcome of the study. The highest dose used in the study was the limit dose, 1000 mg/kg bw/day, recommended for this type of study.

 

Table 5 Summary of reliability of the key data for the target substance [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1) and source substance [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8)

 

Target

Source

 

[3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane

[3-(2,3-epoxypropoxy)propyl]trimethoxysilane

 

2897-60-1

2530-83-8

1. Acute Toxicity

 

 

Oral

LD50> 2000 mg/kg bw/day

Reliability 1 study (DCC, 2008)

LD50> 8025 mg/kg bw/day

Reliability 2 study (Dow Corning Corporation, 1976)

Inhalation

No data

LC50≥ 5.3 mg/L air

Reliability 1 study (Allied Corporation, 1982)

Dermal

LD50> 2000 mg/kg bw/day

Reliability 1 study (WIL, 1999)

LD50> 4250 mg/kg bw/day

Reliability 1 study (Mellon, 1962)

2. Irritation

 

 

Skin

Not irritatingin vivo

Reliability 1 study (WIL, 2000)

Not irritatingin vivo

Reliability 1 study (Allied Corporation, 1982)

Eye

Not irritatingin vivo

Reliability 1 study (WIL, 2000)

Corrosivein vivo

Reliability 1 study (IFREB, 1982)

3. Skin sensitisation

Skin sensitization (Local Lymph Node Assay) – positive

Reliability 1 study (Safepharm, 2004)

Skin sensitization (Buhler method)in vivo– negative

Reliability 1 study (Huls, 1993)

4. Genetic toxicity

 

 

In vitro

Bacterial mutagenicity test - positive

Reliability 1 study (Momentive, 2000)

 

Mammalian cytogenicity test - positive

Reliability 1 study (Momentive, 2004)

Bacterial mutagenicity test - positive

Reliability 2 study (Microtest Research, 1988)

 

 

Mammalian mutagenicity test - positive

Reliability 2 study (Litton Bionetics, 1983)

In vivo

Micronucleus test – negative

Reliability 1 study (Shin-Etsu, 2009)

 

In vivomammalian alkaline comet assay – ambiguous

Reliability 1 study (BSL Bioservice, 2018, in draft, study on-going)

Micronucleus test – positive

Reliability 1 study (Bioreliance, 1999)

 

Micronucleus test – negative

Reliability 2 study (Hüls, 1994)

 

Micronucleus test – negative

Reliability 2 study (DCC, 1982)

 

In vivomammalian alkaline comet assay – study planned

5. Repeated dose toxicity

 

 

Oral

28-day oral repeated dose toxicity study – NOAEL ≥ 1000 mg/kg bw/day. No adverse or adaptive findings reported.

Reliability 1 study (DCC, 1981)

28-day oral repeated dose toxicity study – NOAEL ≥ 1000 mg/kg bw/day. No adverse or adaptive findings reported.

Reliability 1 study (DCC, 1981)

 

One-generation reproductive toxicity study – NOAEL for general toxicity in parent animals = 500 mg/kg bw/day. Based on effects on liver and kidney of uncertain toxicological relevance.

Reliability 2 study (RCC, 2004)

Inhalation

No data

14-day inhalation (aerosol) repeated dose toxicity study – NOAEC = 225 mg/m3. Decreased feeding and body weights.

Reliability 2 study (DCC, 1982)

Dermal

No data

No data

6. Reproductive toxicity

 

 

No data

One-generation reproductive toxicity study – NOAEL (general systemic toxicity) = 500 mg/kg bw/day; NOAEL (reproductive toxicity) ≥ 1000 mg/kg bw/day (highest dose tested)

Reliability 1 study (RCC, 2004)

7. Developmental toxicity

 

 

No data

Prenatal developmental toxicity study – NOAEL (maternal effects) >=1000 mg/kg bw/day; NOAEL (developmental effects) >=1000 mg/kg bw/day.

Reliability 1 study ( Dow Corning Corporation 1982 )


 

4.  AE A.2.1 Compounds the test organism is exposed to

The source substances as well as the target substance have been predicted to hydrolyse rapidly in contact with water under conditions relevant for oral or inhalation exposure. Their estimated hydrolysis half-lives at pH 2 (relevant for oral exposure) and37.5°C are approximately 5 seconds. Therefore, the test organism is expected to be mainly exposed to their hydrolysis products, [3-(2,3-epoxypropoxy)propyl]methylsilanediol and ethanol or [3-(2,3-epoxypropoxy)propyl] silanetriol and methanol.

The hydrolysis products of the target and source substances are structurally similar. [3-(2,3-Epoxypropoxy)propyl]methylsilanediol is a silanediol with two hydroxy (silanol) groups, one methyl group and one 3-(2,3-epoxypropoxy)propyl group bound to silicon. [3-(2,3-Epoxypropoxy)propyl] silanetriol is a silanetriol with three hydroxy (silanol) groups and one 3-(2,3-epoxypropoxy)propyl group bound to silicon. Therefore, the similarities are that both hydrolysis products are silanols with one 3-(2,3-epoxypropoxy)propyl side-chain. The difference is that the methyl group in the target substance is replaced by an additional hydroxy (silanol) group in the source substance.

The source and target substances have been profiled using the OECD QSAR Toolbox v. 4.1. Parent substances and their silanol hydrolysis products show similar profiles for all toxicological endpoints. No alert for reproductive toxicity was detected by OECD QSAR Toolbox v.4.1. The only detected alert for genetic toxicity was the epoxide group present at both chemical structures. The available long-term toxicity data support the findings of the OECD QSAR Toolbox. No adverse toxic effects were observed in any of the reliable repeated dose toxicity studies for the target or source substance. Both substances have mixed results for genotoxicity from reliablein vitro and in vivo data, with conflicting results (positive and negative) from in vivo micronucleus assays available for the source substance, and ambiguous results from an on-going in vivo mammalian alkaline comet assay on the target substance (see Section 5 below). An in vivo mammalian alkaline comet assay has been proposed for the source substance but has not yet been approved.

Ethanol is reported to have an effect on male fertility in some rat studies but not others and where noted generally involve sperm parameters(OECD, 2004a). However, where effects are noted they occur only at high doses.

Rats and mice maintained on liquid diets containing 5 – 10% ethanol for 5 weeks or longer showed some adverse physical and functional effects on the testes. Some indications of toxicity to the foetus, including deaths, growth retardation and increased malformations have been noted in rats and mice given diets in which 15-35% of the calories were derived from ethanol. However, in other studies, no effect on the foetuses were seen in mice and rabbits given drinking water containing up to 15% ethanol, or inhaling up to 20000 ppm ethanol, during pregnancy (OECD, 2004a)

Information about the effects of methanol on fertility is limited (OECD, 2004b). Slight increases in sperm abnormalities were noted in a study in mice although the effect on fertility was not investigated. In a rat 2-generation study there were no effects on fertility. In a cynomolgus monkey study no effects were noted.

In rats, foetal NOAELs have been defined up to 5000 ppm after inhaled exposure. A corresponding figure of 1000 ppm has been defined for mice, which are considered to be more sensitive. At higher concentrations litter resorptions and increased incidences of foetal variations, and in some cases, malformations e. g. exencephaly and encephalocoele have been noted at 20000 ppm in rats and 5000 ppm in mice (OECD, 2004b).

5.  AE A.2.2 and A.2.3 Common underlying mechanism, qualitative and quantitative aspects

No reproductive or developmental toxicity data are available for the target substance[3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1), therefore data were read-across from the source substance, [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8). Both substances hydrolyse at similar rate to a disilanol (1 mole) or a trisilanol (1 mole) and ethanol or methanol. Moreover, they have similar physico-chemical properties. Thus, both substances are expected to have similar toxicity profiles. The non-silanol hydrolysis products, ethanol and methanol,are not expected to be relevant for this endpoint.

The available key toxicity data on the source substance and target substances as summarised in Table 5, show that the two substances are not acutely toxic via the oral and dermal routes, they are not skin irritants, the target substance is not an eye irritant while the source substance causes irreversible eye damage, the target substance is a skin sensitiser while the source substance is not, both substances have mixed genetic toxicity results (in vitroandin vivo), with conflicting results (positive and negative) from micronucleus assays available for the source substance. There is an on-goingin vivomammalian alkaline comet assay on the target substance in which the tissues tested were liver, glandular stomach and duodenum (OECD 489, GLP). Increased comet formation was detected in duodenal cells only after application of the highest tested limit-dose of 2000 mg/kg bw. Neither a dose-response relationship nor any significant signal outside the historical control interval at the lower doses was detected. In this study, duodenum samples were preserved for histopathological analysis, which will be started in the near future for examining the possible involvement of cytotoxicity. Anin vivomammalian alkaline comet assay has been proposed for the source substance but has not yet been approved.

The results from the available higher tier test for the target substance show no adverse effects in any of the tested doses, while the results from the one-generation reproductive toxicity for the source substance showed decreased body weight gain, increased absolute and relative liver and kidney weights and histopathological findings in livers and kidneys. No adverse effects were reported in a 28-day repeated dose oral toxicity study in rats for the source substance.

6.  AE 2.4 Exposure to other compounds than to those linked to the prediction

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 vitroandin vivo), and repeated dose toxicity (oral and inhalation) that can be compared with available reliable data of the target substance. Table summarises the key data and their reliability (using Klimisch codes).

Of particular importance in this case is the reliability of the studies that are being read-across.

For the reproductive toxicity (fertility) endpoint, a one-generation reproductive toxicity study (RCC, 2004) on [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8) is read across to [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1). This study was conducted according to OECD TG 415 and covers the key parameters specified by the method; it was conducted in compliance with GLP (Reliability 1 study; reliable without restriction). The test substance [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8) used in this study was 98.4% pure and therefore represents the source substance without impurities that could influence the outcome of the study. The highest dose (1000 mg/kg bw/day) used in the study was equal to the limit dose (1000 mg/kg bw/day) recommended for this type of study, and therefore the NOAEL derived is adequate for the purpose of classification and labelling and risk assessment.

For the developmental toxicity endpoint, a prenatal developmental toxicity study (BRRC, 1993) on [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8) is read across to [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1). This study was conducted according to OECD TG 414 and covers the key parameters specified by the method; it was conducted in compliance with GLP (Reliability 1 study; reliable without restriction). The test substance [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8) used in this study was 98% pure and therefore represents the source substance without impurities that could influence the outcome of the study. The highest dose used in the study was the limit dose, 1000 mg/kg bw/day, recommended for this type of study.

Table 5 Summary of reliability of the key data for the target substance [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1) and source substance [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8)

 

Target

Source

 

[3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane

[3-(2,3-epoxypropoxy)propyl]trimethoxysilane

 

2897-60-1

2530-83-8

1. Acute Toxicity

 

 

Oral

LD50> 2000 mg/kg bw/day

Reliability 1 study (DCC, 2008)

LD50> 8025 mg/kg bw/day

Reliability 2 study (Dow Corning Corporation, 1976)

Inhalation

No data

LC50≥ 5.3 mg/L air

Reliability 1 study (Allied Corporation, 1982)

Dermal

LD50> 2000 mg/kg bw/day

Reliability 1 study (WIL, 1999)

LD50> 4250 mg/kg bw/day

Reliability 1 study (Mellon, 1962)

2. Irritation

 

 

Skin

Not irritatingin vivo

Reliability 1 study (WIL, 2000)

Not irritatingin vivo

Reliability 1 study (Allied Corporation, 1982)

Eye

Not irritatingin vivo

Reliability 1 study (WIL, 2000)

Corrosivein vivo

Reliability 1 study (IFREB, 1982)

3. Skin sensitisation

Skin sensitization (Local Lymph Node Assay) – positive

Reliability 1 study (Safepharm, 2004)

Skin sensitization (Buhler method)in vivo– negative

Reliability 1 study (Huls, 1993)

4. Genetic toxicity

 

 

In vitro

Bacterial mutagenicity test - positive

Reliability 1 study (Momentive, 2000)

 

Mammalian cytogenicity test - positive

Reliability 1 study (Momentive, 2004)

Bacterial mutagenicity test - positive

Reliability 2 study (Microtest Research, 1988)

 

 

Mammalian mutagenicity test - positive

Reliability 2 study (Litton Bionetics, 1983)

In vivo

Micronucleus test – negative

Reliability 1 study (Shin-Etsu, 2009)

 

In vivomammalian alkaline comet assay – ambiguous

Reliability 1 study (Eurofins/BSL 2018, in draft, study on-going)

Micronucleus test – positive

Reliability 1 study (Bioreliance, 1999)

 

Micronucleus test – negative

Reliability 2 study (Hüls, 1994)

 

Micronucleus test – negative

Reliability 2 study (DCC, 1982)

 

In vivomammalian alkaline comet assay – study planned

5. Repeated dose toxicity

 

 

Oral

28-day oral repeated dose toxicity study – NOAEL ≥ 1000 mg/kg bw/day. No adverse or adaptive findings reported.

Reliability 1 study (DCC, 1981)

28-day oral repeated dose toxicity study – NOAEL ≥ 1000 mg/kg bw/day. No adverse or adaptive findings reported.

Reliability 1 study (DCC, 1981)

 

One-generation reproductive toxicity study – NOAEL for general toxicity in parent animals = 500 mg/kg bw/day. Based on effects on liver and kidney of uncertain toxicological relevance.

Reliability 2 study (RCC, 2004)

Inhalation

No data

14-day inhalation (aerosol) repeated dose toxicity study – NOAEC = 225 mg/m3. Decreased feeding and body weights.

Reliability 2 study (DCC, 1982)

Dermal

No data

No data

6. Reproductive toxicity

 

 

No data

One-generation reproductive toxicity study – NOAEL (general systemic toxicity) = 500 mg/kg bw/day; NOAEL (reproductive toxicity) ≥ 1000 mg/kg bw/day (highest dose tested)

Reliability 1 study (RCC, 2004)

7. Developmental toxicity

 

 

No data

Prenatal developmental toxicity study – NOAEL (maternal effects) = 200 mg/kg bw/day based on one death in the highest dose group; NOAEL (developmental effects) ≥400 mg/kg bw/day.

Reliability 1 study (BRRC, 1993)

 

Neither the target substance,[3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1), nor the source substance, [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8), have impurities of toxicological concern.

Purity of test substance in the study with the source substance, [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8), was reported to be 98.4%.

The target substance,[3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1), has a purity of >95% and <= 100%, and no impurities are present at >1%.

Table 3 summarises the impurities that may be present in[3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1)and [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8). This is based on analytical data that were provided by members of the Reconsile Consortium. The precise identity of the impurities is considered confidential because it could reveal details of the manufacturing process to other Consortium members.

Structures are known for all identified impurities. CAS and EC numbers have been obtained where these exist. 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 source and target substances.

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

Other substances that have been considered for read-across and the reasons for rejecting them are summarised in Table 6. These have been identified by searching the database of studies held by the Reconsile Consortium and by searching in the OECD QSAR Toolbox. Substances containing both an alkoxysilane and an epoxy group were considered. Only one substance has any reproductive/developmental toxicity data: CAS 3388-04-3, 2-(3,4-epoxycyclohexyl)ethyltrimethoxysilane. For this substance, two OECD 414 studies (in rat and rabbit) are available in which no developmental toxicity is evident at any of the dose levels tested. This substance is not such a close structural analogue to the target substance as the selected source substance. Both this substance and the source substance are trimethoxysilanes (so the differences from the target substance are the same), but the selected source substance has the same side-chain as the target substance, whereas this substance does not. Therefore, it is confirmed that the source substance has been selected without bias as the source substance for read across.

Table 6 Other substance considered as source substance

CAS Number

Chemical Name

Reason for rejection as a source substance

065799-47-5

[3-(2,3-epoxypropoxy)propyl]dimethoxymethylsilane

No reproductive/developmental toxicity data

003388-04-3

2-(3,4-epoxycyclohexyl)ethyltrimethoxysilane

Different side-chain (cyclic alkane with an epoxy group rather than linear alkane with an epoxypropoxy group).

002602-34-8

[3-(2,3-epoxypropoxy)propyl]triethoxysilane

No reproductive/developmental toxicity data

010217-34-2

triethoxy-[2-(7-oxabicyclo[4.1.0]hept-3-yl)ethyl]silane

No reproductive/developmental toxicity data


[1]European Chemicals Agency (ECHA) (2015) Read-across Assessment Framework. Appendix B, Scenario 2.

Justification for classification or non-classification

Based on the available data, no classification is required for reproductive toxicity in accordance with Regulation (EC) No. 1272/2008.

Additional information

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