(3-chloropropyl)diethoxymethylsilane

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

17.14 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Modified dose descriptor starting point:

NOAEC

Value:

428.57 mg/m³

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

Justification:

based on a subchronic study

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

5

Justification:

for workers

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.43 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Value:

243.07 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No data are available for the dermal route. However, reliable data are available for the inhalation route.

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

Justification:

based on a subchronic study

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA default

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

5

Justification:

for workers

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

DNEL related information

Additional information - workers

There are no measured data available to assess the systemic toxicity potential of (3‑chloropropyl)diethoxymethylsilane, however, data is available for the structural analogue substances (3-chloropropyl)trimethoxysilane (CAS 2530-87-2) and(3-chloropropyl) triethoxysilane (CAS 5089-70-3). (3‑chloropropyl)diethoxy-methylsilane hydrolyses in contact with water, generating ethanol and (3-chloropropyl)methylsilanediol, whereas(3-chloropropyl) triethoxysilane and (3-chloropropyl)trimethoxysilane hydrolyse to produce (3-chloropropyl)silanetriol and ethanol or methanol, respectively. All of these substances hydrolyse to produce structurally similar silanol hydrolysis products and therefore are deemed to be sufficient for read-across.

Effects on prenatal developmental toxicity after repeated oral administration of the analogue substance (3-chloropropyl)triethoxysilane (CAS 5089-70-3) was investigated in the available key study (BSL, 2014) conducted according to OECD 414, and in compliance with GLP.

Groups of 24 pregnant female Crl: WI(Han) rats per dose were administered doses of 100, 300 and 1000 mg/kg bw/day via oral gavage. Animals treated with the vehicle (corn oil) served as controls. Treatment was carried out once daily during the gestation period between day 5 to day 19. Animals were observed for mortalities and clinical signs, and detailed clinical observations were performed twice daily (except weekends). Body weights and food consumption was recorded. Upon sacrifice on gestation day 20 macroscopic examination for structural abnormalities or pathological changes were performed. Fetuses were subjected to external and either, soft tissue or, skeletal and head examination.  In summary, administration of (3-chloropropyl)triethoxysilane (CAS 5089-70-3) at doses of 0, 100, 300 or 1000 mg/kg bw/day by oral gavage to pregnant female Wistar rats from gestation days 5 to 19 resulted in lower body weight, body weight gain and food consumption at 1000 mg/kg bw/day. Lower terminal body weight, uterus weight and mean total litter weight were also noted at this dose. Increased incidences of skeletal findings such as delayed ossification and lower litter weight recorded at 1000 mg/kg bw/day were considered to be attributable to the maternal effects and not adverse. An increased incidence of wavy ribs and bent scapula was also noted at this dose and these findings are recognized as part of chondrodystrophy syndrome in rats and have been demonstrated to be post-natally reversible and therefore also not adverse. Therefore the maternal and fetal No-Observed-Adverse-Effect-Levels (NOAEL) were both considered to be 300 mg/kg bw/day.

In the available key repeated-dose inhalation study (Dow Corning Corporation, 1993), conducted according to OECD 413 and in compliance with GLP, groups of 10 Sprague-Dawley rats per sex were exposed to the test item (3-chloropropyl)trimethoxysilane (CAS 2530-87-2) in a whole-body inhalation system at target concentrations of 0.5, 5, and 100 ppm for 6 hours/day, 5 days/week. After 13 weeks of exposure, rats were sacrificed and examined for changes in blood, serum chemistry, urine, organ weights and gross and histopathology. Microscopic examinations at study termination did not reveal any adverse relevant findings of toxicological concern in any dose group. Therefore, the NOAEC was set at 100 ppm (nominal concentration, corresponding to an actual overall mean exposure concentration of 99 ppm).

A supporting study is available for the structural analogue substance (3-chloropropyl)trimethoxysilane (CAS 2530-87-2). The study was conducted according to OECD 422, and in compliance with GLP (RCC, 2005). Groups of 10 Sprague-Dawley rats per sex per dose were exposed to the vapour in a whole body inhalation system at doses of 5, 25 and 100 ppm. Untreated animals served as controls. Treatment was carried out for 6 hours daily to male rats for 28 days and to female rats throughout the 14-day pre-pairing, pairing and gestation period until the individual day 19 post coitum. During the pairing period, rats were housed overnight with one male and one female in Makrolon pairing cages. The female was placed with the same male until mating occurred or two weeks elapsed. Animals were observed for mortalities and clinical signs, and detailed clinical observations were performed once per week. A functional observational battery (modified Irwin screen test) was performed once during the test (males: shortly before sacrifice; females: on day 3 post-partum). Body weights and food consumption was recorded. Parental generation males were sacrificed after they had been treated for 28 days, parental generation females were sacrificed on day 4 post-partum. A complete gross necropsy was performed on all adult animals. The litters were examined for litter size, live birth, stillbirth and any gross anomalies. The sex ratio of the pups was recorded. Pups were weighed individually on day 0, 1 and 4 post-partum. The pups were observed daily for survival and behavioural abnormalities in nesting and nursing. Dead pups and pups killed on day 4 post-partum were examined macroscopically. No test item-related effects were observed in the parental animals, including no alteration of mating behaviour and fertility. Additionally, no treatment-related effects on the litters were observed. Based on the absence of any findings the NOAEC for repeated dose toxicity, fertility, and developmental toxicity/teratogenicity was set at 100 ppm (nominal concentration, corresponding to 99.7 ppm mean analytical concentration).

Both available studies via the inhalation route resulted in a NOAEC of 100 ppm nominal vapour concentration (highest dose tested). In the pre-natal developmental study via the oral route with (3-chloropropyl)triethoxysilane (CAS 5089-70-3) maternal toxicity was observed as reduced food consumption, which consequently lead to reduced body weight gains. Furthermore, the skeletal variations observed in the fetuses plus the reduced fetal body weights gains are considered to be attributable to the material toxicity observed. Hence, the result of the inhalation study according to OECD 413 with the longest study duration will be used for the hazard assessment of the registered substance. Thus, a NOAEC of 99 ppm as actual overall mean exposure concentration will be deduced, corresponding to 804.6 mg/m³. The molecular weight ratio of the submission substance (CAS 13501-76-3) and the test substance (CAS 2530-87-2) is: 210.77 g/mol/198.72 g/mol=1.06. Therefore, the NOAEC for the submission substance is: 804.6 mg/m³x1.07= 861 mg/m³.

Repeated-dose toxicity – systemic effects – dermal route - worker:

The DNEL for systemic effects via the dermal route is determined on the basis of route-to-route extrapolation from the NOAEC for the structural analogue substance (3-chloropropyl)trimethoxysilane (804.6 mg/m³) from a 90-day inhalation study in rats (Dow Corning Corporation, 1993). The following corrections were made:

 

Exposure duration: 6 h/8 h (full shift)

Respiratory volume: 0.38 m³/kg bw (rat, 8 hour)

Route to route extrapolation (relative absorption inhalation vs. dermal): 1

Molecular weight difference between target and source chemical is 210.77/198.72 = 1.06

 

The corrected NOAEL is therefore:

804.6 mg/m³ × (6 h/8 h) × 0.38 m³/kg bw × 1 × 1.06 = 243.07 mg/kg bw/day.

 

The following assessment factors were applied to the corrected NOAEL:

Exposure duration (sub-chronic to chronic): 2

Interspecies differences (systemic): 2.5

Interspecies differences (rat/human): 4

Intraspecies differences (systemic): 5

 

 

 

The overall DNEL (repeated-dose – systemic – dermal - worker) is therefore:

243.07 mg/kg bw/day / (2×2.5×4×5) =2.43 mg/kg bw/day.

 

 

 Repeated-dose toxicity – systemic effects – inhalation route - worker:

The DNEL for systemic effects via the inhalation route is determined on the basis of the 90-day inhalation NOAEL for the structural analogue substance (3-chloropropyl)trimethoxysilane (804.6 mg/m³) (Dow Corning Corporation, 1993). The following corrections were made:

 

Exposure duration: 6 h/8 h (full shift)

Rrespiratory volume: 6.7 m³/10 m³ (worker, light physical activity)

The molecular weight difference between target and source chemical is 210.77/198.72 = 1.06.

 

The corrected NOAEC is therefore:

804.6 mg/m³ × (6 h/8 h) × (6.7 m³/10 m³) × 1.06 = 428.57 mg/m³.

 

The following assessment factors were applied to the corrected NOAEC:

Exposure duration (sub-chronic to chronic): 2

Interspecies differences (systemic): 2.5

Intraspecies differences (systemic): 5

 

The overall DNEL (repeated-dose – systemic – inhalation - worker) is therefore:

428.57 mg/m³ / (2×2.5×5) =17.14 mg/m³.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.05 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEC

Value:

152.3 mg/m³

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

Justification:

based on a subchronic study

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

10

Justification:

for general population

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.88 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Modified dose descriptor starting point:

NOAEL

Value:

175.14 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No data are available for the dermal route. However, reliable data are available for the inhalation route.

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

Justification:

based on a subchronic study

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA default

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

10

Justification:

for general population

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.33 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Value:

333.33 mg/kg bw/day

AF for dose response relationship:

1

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA default

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

10

Justification:

for general population

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.88 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Modified dose descriptor starting point:

NOAEL

Value:

175.14 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No data are available for the dermal route. However, reliable data are available for the inhalation route.

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

Justification:

based on a subchronic study

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA default

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

10

Justification:

for general population

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

DNEL related information

Additional information - General Population

There are no measured data available to assess the systemic toxicity potential of (3‑chloropropyl)diethoxymethylsilane, however, data is available for the structural analogue substances (3-chloropropyl)trimethoxysilane (CAS 2530-87-2) and(3-chloropropyl) triethoxysilane (CAS 5089-70-3). (3‑chloropropyl)diethoxy-methylsilane hydrolyses in contact with water, generating ethanol and (3-chloropropyl)methylsilanediol, whereas(3-chloropropyl) triethoxysilane and (3-chloropropyl)trimethoxysilane hydrolyse to produce (3-chloropropyl)silanetriol and ethanol or methanol, respectively. All of these substances hydrolyse to produce structurally similar silanol hydrolysis products and therefore are deemed to be sufficient for read-across.

Effects on prenatal developmental toxicity after repeated oral administration of the analogue substance (3-chloropropyl)triethoxysilane (CAS 5089-70-3) was investigated in the available key study (BSL, 2014) conducted according to OECD 414, and in compliance with GLP.

Groups of 24 pregnant female Crl: WI(Han) rats per dose were administered doses of 100, 300 and 1000 mg/kg bw/day via oral gavage. Animals treated with the vehicle (corn oil) served as controls. Treatment was carried out once daily during the gestation period between day 5 to day 19. Animals were observed for mortalities and clinical signs, and detailed clinical observations were performed twice daily (except weekends). Body weights and food consumption was recorded. Upon sacrifice on gestation day 20 macroscopic examination for structural abnormalities or pathological changes were performed. Fetuses were subjected to external and either, soft tissue or, skeletal and head examination.  In summary, administration of (3-chloropropyl)triethoxysilane (CAS 5089-70-3) at doses of 0, 100, 300 or 1000 mg/kg bw/day by oral gavage to pregnant female Wistar rats from gestation days 5 to 19 resulted in lower body weight, body weight gain and food consumption at 1000 mg/kg bw/day. Lower terminal body weight, uterus weight and mean total litter weight were also noted at this dose. Increased incidences of skeletal findings such as delayed ossification and lower litter weight recorded at 1000 mg/kg bw/day were considered to be attributable to the maternal effects and not adverse. An increased incidence of wavy ribs and bent scapula was also noted at this dose and these findings are recognized as part of chondrodystrophy syndrome in rats and have been demonstrated to be post-natally reversible and therefore also not adverse. Therefore the maternal and fetal No-Observed-Adverse-Effect-Levels (NOAEL) were both considered to be 300 mg/kg bw/day.

In the available key repeated-dose inhalation study (Dow Corning Corporation, 1993), conducted according to OECD 413 and in compliance with GLP, groups of 10 Sprague-Dawley rats per sex were exposed to the test item (3-chloropropyl)trimethoxysilane (CAS 2530-87-2) in a whole-body inhalation system at target concentrations of 0.5, 5, and 100 ppm for 6 hours/day, 5 days/week. After 13 weeks of exposure, rats were sacrificed and examined for changes in blood, serum chemistry, urine, organ weights and gross and histopathology. Microscopic examinations at study termination did not reveal any adverse relevant findings of toxicological concern in any dose group. Therefore, the NOAEC was set at 100 ppm (nominal concentration, corresponding to an actual overall mean exposure concentration of 99 ppm).

A supporting study is available for the structural analogue substance (3-chloropropyl)trimethoxysilane (CAS 2530-87-2). The study was conducted according to OECD 422, and in compliance with GLP (RCC, 2005). Groups of 10 Sprague-Dawley rats per sex per dose were exposed to the vapour in a whole body inhalation system at doses of 5, 25 and 100 ppm. Untreated animals served as controls. Treatment was carried out for 6 hours daily to male rats for 28 days and to female rats throughout the 14-day pre-pairing, pairing and gestation period until the individual day 19 post coitum. During the pairing period, rats were housed overnight with one male and one female in Makrolon pairing cages. The female was placed with the same male until mating occurred or two weeks elapsed. Animals were observed for mortalities and clinical signs, and detailed clinical observations were performed once per week. A functional observational battery (modified Irwin screen test) was performed once during the test (males: shortly before sacrifice; females: on day 3 post-partum). Body weights and food consumption was recorded. Parental generation males were sacrificed after they had been treated for 28 days, parental generation females were sacrificed on day 4 post-partum. A complete gross necropsy was performed on all adult animals. The litters were examined for litter size, live birth, stillbirth and any gross anomalies. The sex ratio of the pups was recorded. Pups were weighed individually on day 0, 1 and 4 post-partum. The pups were observed daily for survival and behavioural abnormalities in nesting and nursing. Dead pups and pups killed on day 4 post-partum were examined macroscopically. No test item-related effects were observed in the parental animals, including no alteration of mating behaviour and fertility. Additionally, no treatment-related effects on the litters were observed. Based on the absence of any findings the NOAEC for repeated dose toxicity, fertility, and developmental toxicity/teratogenicity was set at 100 ppm (nominal concentration, corresponding to 99.7 ppm mean analytical concentration).

Both available studies via the inhalation route resulted in a NOAEC of 100 ppm nominal vapour concentration (highest dose tested). In the pre-natal developmental study via the oral route with (3-chloropropyl)triethoxysilane (CAS 5089-70-3) maternal toxicity was observed as reduced food consumption, which consequently lead to reduced body weight gains. Furthermore, the skeletal variations observed in the fetuses plus the reduced fetal body weights gains are considered to be attributable to the material toxicity observed. An increased incidence of wavy ribs and bent scapula was also noted at the top dose of 1000 mg/kg bw but these findings are recognized as part of chondrodystrophy syndrome in rats and have been demonstrated to be post-natally reversible and therefore also not adverse. Hence, the result of the inhalation study according to OECD 413 with the longest study duration will be used for the hazard assessment. Thus, a NOAEC of 99 ppm as actual overall mean exposure concentration will be deduced, corresponding to 804.6 mg/m³. The molecular weight ratio of the submission substance (CAS 13501-76-3) and the test substance (CAS 2530-87-2) is: 210.77 g/mol/198.72 g/mol=1.06. Therefore, the NOAEC for the submission substance is: 804.6 mg/m³x1.07= 861 mg/m³.

Acute-dose toxicity – systemic effects – dermal route - consumer:

The DNEL for systemic effects following single exposures via the dermal route is determined based on results from a key acute dermal study in rats (Hüls AG, 1997b). In this study, the LD50 was >2000 mg/kg bw the only dose tested.

Following acute dermal exposure no mortality or systemic toxicity were seen, therefore 2000 mg/kg bw is a NOAEL, which is chosen as point of departure for an acute DNEL. The following corrections were made:

 

Modification for experimental exposure duration (4 h in study to 24 h in consumers): 1/6

 

The corrected NOAEL is therefore:

2000 mg/kg bw × 1/6 = 333.33 mg/kg bw.

 

 The following assessment factors were applied to the corrected NOAEL:

Interspecies differences (systemic): 2.5

Interspecies differences (rat/human): 4

Intraspecies differences (systemic, gen. pop.): 10

 

The overall DNEL (acute – systemic –dermal- consumer) is therefore: 333.33 mg/kg bw / (2.5×4×10) = 3.33 mg/kg bw.

 

 

Repeated-dose toxicity – systemic effects – dermal route - consumer:

The DNEL for systemic effects via the dermal route is determined on the basis of route-to-route extrapolation from the NOAEC for the structural analogue substance (3-chloropropyl)trimethoxysilane (804.6 mg/m³) from a 90-day inhalation study in rats (Dow Corning Corporation, 1993). The following corrections were made:

Exposure duration: 6 h/24 h

Number of exposures per week: 5/7 (study data)

Respiratory volume: 1.15 m³/kg (rat, 24 h)

Route to route extrapolation (relative absorption inhalation vs. dermal): 1

Molecular weight difference between target and source chemical is 210.77/198.72= 1.06

 

The corrected NOAEL is therefore:

804.6 mg/m³ × 6 h/24 h × 5/7 × 1.15 m³/kg bw × 1 × 1.06 = 175.14 mg/kg bw/day

 

The following assessment factors were applied to the corrected NOAEL:

Exposure duration (sub-chronic to chronic): 2

Interspecies differences (systemic): 2.5

Interspecies differences (rat/human): 4

Intraspecies differences (systemic, gen. pop.): 10

 

The overall DNEL (repeated-dose – systemic – dermal - consumer) is therefore:

175.14 mg/kg bw/day / (2×2.5×4×10) = 0.88 mg/kg bw/day.

 

Repeated-dose toxicity – systemic effects – inhalation route - consumer:

The DNEL for systemic effects via the inhalation route is determined on the basis of the 90-day inhalation NOAEL for structural analogue substance (3-chloropropyl)trimethoxysilane (804.6 mg/m³). The following corrections were made:

 

Exposure duration: 6 h/24 h

Number of exposures per week: 5/7

Molecular weight difference between target and source chemical is 210.77/198.72 = 1.06

 

The corrected NOAEC is therefore:

804.6 mg/m³ × 6/24 × 5/7 × 1.06 = 152.30 mg/m³

 

The following assessment factors were applied to the corrected NOAEC:

Exposure duration (sub-chronic to chronic): 2

Interspecies differences (systemic): 2.5

Intraspecies differences (systemic, gen. pop.): 10

 

The overallDNEL (repeated-dose – systemic – inhalation - consumer)is therefore:

152.30 mg/m³ / (2×2.5×10) = 3.05 mg/m³.

 

Repeated-dose toxicity – systemic effects – oral route – consumer:

The DNEL for systemic effects via the oral route is determined on the basis of the 90-day inhalation NOAEL for structural analogue substance (3-chloropropyl)trimethoxysilane (804.6 mg/m³) (Dow Corning Corporation, 1993). The following corrections were made:

 

Exposure duration: 6 h/24 h

Number of exposures per week: 5/7 (study data)                              

Respiratory volume: 1.15 m³/kg bw (rat, 24 h)

Route to route extrapolation (relative absorption inhalation vs. oral: 1

Molecular weight difference between target and source chemical is 210.77/198.72= 1.06

 

The corrected NOAEL is therefore:

804.6 mg/m³ × 6 h/24 h × 5/7 × 1.15 m³/kg bw × 1 × 1.06 = 175.14 mg/kg bw/day

 

The following assessment factors were applied to the corrected NOAEL:

Exposure duration (sub-chronic to chronic): 2

Interspecies differences (systemic): 2.5

Interspecies differences (rat/human): 4

Intraspecies differences (systemic, gen. pop.): 10

The overall DNEL (repeated-dose – systemic – oral – consumer) is therefore:

175.14 mg/kg bw/day / (2×2.5×4×10) =0.88 mg/kg bw/day.