Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
154.7 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: substance specific (see discussion)
Overall assessment factor (AF):
11.2
Dose descriptor starting point:
NOAEC
DNEL value:
806 mg/m³
Modified dose descriptor starting point:
NOAEC
DNEL value:
1 733 mg/m³
AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEC.
AF for differences in duration of exposure:
2
Justification:
sub-chronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation route
AF for other interspecies differences:
2.5
Justification:
remaining differences
AF for intraspecies differences:
2.2
Justification:
substance specific (see discussion)
AF for the quality of the whole database:
1
Justification:
The DNEL is based on a high quality study.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
22.33 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: substance specific (see discussion)
Overall assessment factor (AF):
11.2
Dose descriptor starting point:
NOAEC
DNEL value:
806 mg/m³
Modified dose descriptor starting point:
NOAEL
DNEL value:
250.1 mg/kg bw/day
AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL.
AF for differences in duration of exposure:
2
Justification:
sub-chronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
substance specific (see discussion)
AF for other interspecies differences:
2.5
Justification:
remaining differences
AF for intraspecies differences:
2.2
Justification:
substance specific (see discussion)
AF for the quality of the whole database:
1
Justification:
The DNEL is based on a high quality study.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

There are no studies available for the registered substance (chloromethyl)triethoxysilane (CAS 15267-95-5). However, reliable data are available for the structural analogue substances (3-chloropropyl)trimethoxysilane (CAS 2530-87-2) and (3-chloropropyl)triethoxysilane (CAS 5089-70-3).

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 of the registered substance. Thus, a NOAEC of 99 ppm as actual overall mean exposure concentration will be deduced, corresponding to 806 mg/m³. The molecular weight ratio of the submission substance (CAS 15267-95-5) and the test substance (CAS 2530-87-2) is: 212 g/mol/198.72 g/mol=1.07. Therefore, the NOAEC for the submission substance is: 806 mg/m³x1.07= 862 mg/m³.

Short-term high exposures are considered unlikely given the high levels of control in place at sites producing and using the substance. DNELs for long-term exposure are therefore adequate to protect against short-term exposures and no separate short-term DNELs are calculated.

The long-term DNEL for systemic effects via the inhalation routeis determined on the basis of the 90-day inhalation NOAEC for the structural analogue substance (3-chloropropyl)trimethoxysilane (CAS 2530-87-2): 806 mg/m³; exposure duration: 6 h/d, 5 days/week. The following corrections were made:

Correction for lower human breathing rate: 4

Correction for experimental vs. occupational exposure duration: 6 h/8 h

Correction for respiratory volume (worker, light physical activity): 6.7 m³/10 m³

The molecular weight difference between target and source chemical is 212 g/mol/198.72 g/mol=1.07

Therefore the corrected NOAEC for long-term systemic effects via the inhalation route is:

806 mg/m³ x 4 x (6 h/8 h) x (6.7 m³/10 m³) x 1.07=1733 mg/m³

The following assessment factors were applied to the corrected NOAEC:

Exposure duration (sub-chronic to chronic): 2 (default)

Interspecies differences (toxicodynamics): 2.5 (default)

Interspecies differences (toxicokinetics, rat/human): 1 (substance specific, see below)

Intraspecies differences (toxicodynamics, worker): 2.24 (√5) (substance specific, see below)

Intraspecies differences (toxicokinetics, worker): 1 (substance specific, see below)

Overall Assessment Factor:11.20

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

1733 mg/m³/11.20 =154.7 mg/m³.

The long-term 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 (CAS 2530 -87 -2) (806 mg/m³) from a 90-day inhalation study in rats (exposure duration: 6 h/d, 5 d/week). The following corrections were made:

Correction for respiratory volume: 0.29 m³/kg bw/day (rat, 6 h)

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

The molecular weight difference between target and source chemical is 212 g/mol/198.72 g/mol=1.07

The corrected NOAEL (dermal) is therefore:

806 mg/m³ x 0.29 m³/kg bw/day x 1 x 1.07 = 250.1 mg/kg bw/day

The following assessment factors were applied to the corrected NOAEL:

Exposure duration (sub-chronic to chronic): 2 (default)

Interspecies differences (toxicodynamics): 2.5 (default)

Interspecies differences (toxicokinetics, rat/human): 1 (substance specific, see below)

Intraspecies differences (toxicodynamics, worker): 2.24 (√5) (substance specific, see below)

Intraspecies differences (toxicokinetics, worker): 1 (substance specific, see below)

Overall Assessment Factor: 11.20

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

250.1 mg/kg bw/day/11.20 = 22.33 mg/kg bw/day.

Allometric scaling factor (Toxicokinetics)

The allometric scaling factor accounts for metabolic differences between the test species and humans based on the caloric demand of the relevant species. The rat is thereby thought to have the ability for a faster detoxification by metabolic and excretion processes. On the other hand, any metabolism leading to more toxic molecules makes the rat more susceptible. The default allometric scaling factor is not considered to be relevant for (chloromethyl)triethoxysilane on the following grounds:

1.        The silanol hydrolysis product of the substance (and many other related substances) shows no biodegradation in a ready biodegradation test other than can be accounted for by degradation of non-silanol hydrolysis products (PFA, 2013f); this suggests that the substance and its silanol hydrolysis product are not recognised by biological systems containing all the mammalian enzymes and metabolic systems.

2.        Hydrolysis of the ethoxy groups is seen as the major, rate determining step in detoxification as the resulting silanols have an increased urinary clearance based on the decreased molecular weight and the increased water solubility and have only a low tendency to migrate into potential target cells. Subsequent enzymatic metabolism steps are unlikely and would be of limited relevance for a rapid excretion of the substance.

3.        Differences in excretion may also scale according to the allometric principle. However, for a small water soluble molecule with a strong affinity to aqueous compartments and without indications for specific organ toxicity, the role of the excretion step is seen as minimal.

4.        Toxicokinetic arguments (see also Section 5.1) show that the silanol hydrolysis product has low log Kow and hence low uptake, rapid excretion via urine, which would be true in all mammals, with minimal interspecies differences. 

Conclusion

Higher enzyme expression levels, stronger inducibility, higher substrate affinities and co-factor levels are factors that are potentially in favour of a more rapid xenobiotic metabolism, including elimination, by rodents compared to humans. Enzymes are not involved in the abiotic hydrolysis of the alkoxysilanes, and the silanols are rapidly excreted as such without prior enzymatic conjugation. This knowledge eliminates the major deal of the uncertainty on toxicokinetic interspecies differences. Since the metabolism of (chloromethyl)triethoxysilane by humans and rats does not involve enzymes, the interspecies toxicokinetic differences are reduced from 4.0 to 1.0. Likewise, there is no basis for intra-human variability of the hydrolysis step. The default intraspecies factor of 10 or 5 for consumers and workers, respectively, is reduced to 100.5and 50.5, respectively, according to the Renwick approach (Renwick et al., 2005). Only the toxicodynamic differences remain to be considered.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population