Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.3 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
75
Dose descriptor starting point:
LOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
LOAEC
Value:
246.8 mg/m³
Explanation for the modification of the dose descriptor starting point:

LOAECcorr = LOAELoral*(1/0.38 m³/kg bw/day)*(ABSoral-rat/ABSinh-human)*(6.7 m³ (8h)/10 m³ (8h))*(exposure duration rat (7days)/exposure duration worker (5 days) = 100 mg/kg bw/day*(1/0.38 m³/kg bw/day)*(1/1)*0.67*1.4 = 246.8 mg/m³. In contrast to the recommendations of the ECHA Guidance, a factor of 1 (equal absorption of 100% assumed for the oral and the inhalative route for animals and humans) was included for the extrapolation from oral to inhalation absorption, as there is no valid data suggesting that inhalation leads to higher absorption than oral ingestion (recommendation of the VCI Working group "Toxicology", 2008). Molecules with a molecular weight <500 and a log Kow between 0 and 4 can be assumed to be well absorbed equivalently by the oral and inhalation route. Oral absorption may be reduced for acids and bases depending on their pKa value and their electric charge in the GI tract. More lipophilic substances may be better absorbed in the GI tract due to solubilisation with bile acids, and thus oral absorption may be higher than inhalation absorption (VCI Working group "Toxicology", 2008). Unless valid data suggest that inhalation leads to higher absorption than oral ingestion, equal absorption will be assumed when extrapolating from oral to inhalation route. ABSoral-rat=oral absorption rate in rats, ABSinh-human=inhalation absorption rate in humans .

AF for dose response relationship:
3
Justification:
The dose descriptor starting point is based on a LOAEL
AF for differences in duration of exposure:
2
Justification:
The DNEL is 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:
Default AF
AF for intraspecies differences:
5
Justification:
Default AF for workers
AF for the quality of the whole database:
1
Justification:
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:
0.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
300
Dose descriptor starting point:
LOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
LOAEL
Value:
140 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

LOAELcorr = LOAELoral*(ABSoral-rat/ABSdermal-human)*(exposure duration animal (7 days)/exposure duration worker (5 days)) = (100 mg/kg bw/day)*(1/1)*(7/5) = 140 mg/kg bw/day. It is assumed that the dermal absorption rate is 100% of that of the oral absorption according to ECHA CSA Guidance Chapter R.7c Figure R.7.12-5.

ABSoral-rat=oral absorption rate in rats, ABSdermal-human=dermal absorption rate in humans.

AF for dose response relationship:
3
Justification:
The dose descriptor starting point is based on a LOAEL.
AF for differences in duration of exposure:
2
Justification:
The DNEL is based on a subchronic study.
AF for interspecies differences (allometric scaling):
4
Justification:
Default AF
AF for other interspecies differences:
2.5
Justification:
Default AF
AF for intraspecies differences:
5
Justification:
Default AF for workers
AF for the quality of the whole database:
1
Justification:
The DNEL is absed 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:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Repeated dose toxicity

For the oral route, a reliable key OECD 408 study in compliance with GLP is available for the test substance (Eurofins, 2019). This study is a valid investigation of the toxicological effects resulting from repeated oral-gavage administration of the test item to male and female rats for at least 90 days. The test item was administered in corn oil as vehicle at dosages of 100, 300, and 1000 mg/kg body weight/day, and controls received the vehicle alone. The main induced findings in the urinary system were urothelial hyperplasia of the lower urinary tract (renal pelvis, urinary bladder, ureter and/or urethra) in males at ≥ 100 mg/kg bw/day and females at ≥ 300 mg/kg bw/day, precipitates in the urine in males at ≥ 100 mg/kg bw/day and females at ≥ 300 mg/kg bw/day, hyaline droplets in the renal cortex of males at ≥ 100 mg/kg bw/day and lipid-laden cell accumulations were detected within the renal medulla or bladder submucosa from both genders at 1000 mg/kg bw/day. The changes in urinary tract correlate to macroscopic findings at necropsy (granular sticky, yellow abnormal content in the urinary bladder). The no observed adverse effect level (NOAEL) of Methyl [3-(trimethoxysilyl)propyl]carbamate (CAS 23432-62-4) in this study is considered to be at 100 mg/kg bw/day in females; the NOAEL for males could not be established (LOAEL = 100 mg/kg bw/day).

 

Inhalation route – worker:

The following correction was made to the oral LOAEL:

Correction for relative absorption oral vs. inhalation: 1

Correction for respiratory volume (rat/worker): 0.38 m³/kg bw (8 h)

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

Correction for exposure duration (rat vs. worker): 7 days / 5 days

Therefore, the corrected LOAEC for repeated-dose systemic effects via inhalation is:

100 mg/kg bw x 1/0.38 m³/kg bw x (6.7 m³/10 m³) * 1.4 = 246.8 mg/m³

 

Dermal route – worker:

As no reliable information is available from acute dermal or dermal repeated dose toxicity tests regarding dermal absorption, a conservative approach is applied, and thus the relative dermal absorption as compared to the oral absorption was set to 1.

Correction for exposure duration (rat vs. worker): 7 days / 5 days

Therefore, the corrected LOAEL for repeated-dose systemic effects via dermal route is:

10 mg/kg bw x 1 x 1.4 = 140 mg/kg bw/day

 

Acute toxicity:

Acute dermal toxicity studies are available with the structural analogue substances methyl-N-{[dimethoxy(methyl)silyl]methyl}carbamate (CAS 23432-65-7) and Methyl-N-[(trimethoxysilyl)methyl]carbamate (CAS 23432-64-6), conducted according to OECD 402 and in compliance with GLP, revealed no mortality or any clinical signs of toxicity throughout the observation period. No changes of the skin at the application site were observed (BSL Bioservice, 2003a,b).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.6 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
150
Dose descriptor starting point:
LOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
LOAEC
Value:
87 mg/m³
Explanation for the modification of the dose descriptor starting point:

LOAECcorr = LOAELoral*(1/1.15 m³/kg bw/day (24h)) *(ABSoral-rat/ABSinh-human) = 100 mg/kg bw/day*(1/1.15 m³/kg bw /day)*(1/1) =87.0 mg/m³. In contrast to the recommendations of the ECHA Guidance, a factor of 1 (equal absorption of 100% assumed for the oral and the inhalative route for animals and humans) was included for the extrapolation from oral to inhalation absorption, as there is no valid data suggesting that inhalation leads to higher absorption than oral ingestion (recommendation of the VCI Working group "Toxicology", 2008). Molecules with a molecular weight <500 and a log Kow between 0 and 4 can be assumed to be well absorbed equivalently by the oral and inhalation route. Oral absorption may be reduced for acids and bases depending on their pKa value and their electric charge in the GI tract. More lipophilic substances may be better absorbed in the GI tract due to solubilisation with bile acids, and thus oral absorption may be higher than inhalation absorption (VCI Working group "Toxicology", 2008). Unless valid data suggest that inhalation leads to higher absorption than oral ingestion, equal absorption will be assumed when extrapolating from oral to inhalation route.ABSoral-rat=oral absorption rate in rats, ABSinh-human=inhalation absorption rate in humans.

AF for dose response relationship:
3
Justification:
The dose descriptor starting point is based on a LOAEL.
AF for differences in duration of exposure:
2
Justification:
The DNEL is 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:
Default AF
AF for intraspecies differences:
10
Justification:
Default AF for general population
AF for the quality of the whole database:
1
Justification:
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

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.25 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Dose descriptor starting point:
LOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
LOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

LOAELcorr = LOAELoral*(ABSoral-rat/ABSdermal-human) = (100 mg/kg bw/day)*(1/1) = 100 mg/kg bw/day. It is assumed that the dermal absorption rate is 100% of that of the oral absorption according to ECHA CSA Guidance Chapter R.7c Figure R.7.12-5. ABSoral-rat=oral absorption rate in rats, ABSdermal-human=dermal absorption rate in humans.

AF for dose response relationship:
3
Justification:
The dose descriptor starting point is based on a LOAEL
AF for differences in duration of exposure:
2
Justification:
The DNEL is based on a subchronic study.
AF for interspecies differences (allometric scaling):
4
Justification:
Default AF for rats
AF for other interspecies differences:
2.5
Justification:
Default AF
AF for intraspecies differences:
10
Justification:
Default AF for general population
AF for the quality of the whole database:
1
Justification:
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:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Dose descriptor starting point:
LOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
LOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
no route to route extrapolation necessary
AF for dose response relationship:
3
Justification:
The dose descriptor starting point is based on a LOAEL
AF for differences in duration of exposure:
2
Justification:
The DNEL is based on a subchronic study.
AF for interspecies differences (allometric scaling):
4
Justification:
Default AF for rats
AF for other interspecies differences:
2.5
Justification:
Default AF
AF for intraspecies differences:
10
Justification:
Default AF for general population
AF for the quality of the whole database:
1
Justification:
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:
acute toxicity
Route of original study:
Oral
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Repeated dose toxicity

For the oral route, a reliable key OECD 408 study in compliance with GLP is available for the test substance (Eurofins, 2019).

This study is a valid investigation of the toxicological effects resulting from repeated oral-gavage administration of the test item to male and female rats for at least 90 days. The main induced findings in the urinary system were urothelial hyperplasia of the lower urinary tract (renal pelvis, urinary bladder, ureter and/or urethra) in males at ≥ 100 mg/kg bw/day and females at ≥ 300 mg/kg bw/day, precipitates in the urine in males at ≥ 100 mg/kg bw/day and females at ≥ 300 mg/kg bw/day, hyaline droplets in the renal cortex of males at ≥ 100 mg/kg bw/day and lipid-laden cell accumulations were detected within the renal medulla or bladder submucosa from both genders at 1000 mg/kg bw/day. The changes in urinary tract correlate to macroscopic findings at necropsy (granular sticky, yellow abnormal content in the urinary bladder). The no observed adverse effect level (NOAEL) of Methyl [3-(trimethoxysilyl)propyl]carbamate (CAS 23432-62-4) in this study is considered to be at 100 mg/kg bw/day in females; the NOAEL for males could not be established (LOAEL = 100 mg/kg bw/day).

 

Inhalation route – general population:

The following correction was made to the oral LOAEL:

Correction for relative absorption oral vs. inhalation: 1

Correction for respiratory volume (rat/general population): 1.15 m³/kg bw (24 h)

Therefore, the corrected LOAEC for repeated-dose systemic effects via inhalation is:

100 mg/kg bw x 1/1.15 m³/kg bw = 87.0 mg/m³

 

Dermal route – general population:

As no reliable information is available from acute dermal or dermal repeated dose toxicity tests regarding dermal absorption, a conservative approach is applied, and thus the relative dermal absorption as compared to the oral absorption was set to 1.

Therefore, the corrected LOAEL for repeated-dose systemic effects via dermal route is:

100 mg/kg bw x 1 = 100 mg/kg bw/day

Oral route – general population:

No rote to route extrapolation was necessary

 

Acute toxicity:

For the oral route, a reliable key OECD 423 study in compliance with GLP is available for the registered substance. This study is a valid investigation of the toxicological effects resulting from single oral-gavage administration of the test item to male and female rats. No mortality occurred and no test material-related clinical signs of toxicity were noted up to the limit dose of 2000 mg/kg bw (BSL Bioservice, 2002).

Acute dermal toxicity studies are available with the structural analogue substances methyl-N-{[dimethoxy(methyl)silyl]methyl}carbamate (CAS 23432-65-7) and Methyl-N-[(trimethoxysilyl)methyl]carbamate (CAS 23432-64-6), conducted according to OECD 402 and in compliance with GLP, revealed no mortality or any clinical signs of toxicity throughout the observation period. No changes of the skin at the application site were observed (BSL Bioservice, 2003a,b).