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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14.8 mg/m³
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
370.3 mg/m³
Explanation for the modification of the dose descriptor starting point:

The following parameters were taken into account for the modification of the dose descriptor starting point:



  • sRVrat, 8h = 0.38 m³/kg bw

  • Absorption (ABS): oral = ½ inhalation

  • sRVhuman/wRV = 6.7 m³ (8h)/10 m³ (8h)

  • Correction factor for experimental vs. human exposure conditions (animals were exposed daily, workers work 5 days per week): 7 d (per week)/5 d (per week)


modifed NOAEC (worker, 8h inhalation) = NOAEL (oral, rat) * [1/sRV(rat, 8h)] * [ABS (oral) / ABS (inhalation)] * [sRV (human) / worker Respiratory Volume (wRV)] * [7d (per week) / 5d (per week)]


modified NOAEC (worker, 8h inhalation) = 300 mg/kg bw/d * [1/0.38 m³/kg bw/d] * [0.5 / 1] * [6.7 m³ (8h) / 10 m³ (8h)] * [7d (per week) / 5d (per week)] = 370.3 mg/m³

AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation is a NOAEL. Therefore, the default assessment factor 1 is chosen.
AF for differences in duration of exposure:
2
Justification:
The default AF for time extrapolation from subchronic exposure (OECD 443) to chronic exposure is applied.
AF for interspecies differences (allometric scaling):
1
Justification:
The AF has already been handled within the correction of the modification of the dose descriptor.
Therefore, no additional factor has to be applied.
AF for other interspecies differences:
2.5
Justification:
The default AF for other interspecies differences, i.e. toxicokinetic/-dynamic differences is used.
AF for intraspecies differences:
5
Justification:
The default factor of 5 for workers is set in line with the REACH guidance.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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:
4.2 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
420 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The following parameters were taken into account for the modification of the dose descriptor starting point:



  • Absorption (ABS): oral = dermal

  • Correction factor for experimental vs. human exposure conditions (animals were exposed daily, workers work 5 days per week): 7 d (per week)/5 d (per week)


modified NOAEL (worker, dermal) = NOAEL (oral, rat) * [ABS (oral) / ABS (dermal)] * [7d (per week) / 5d (per week)]


modified NOAEL (worker, dermal) = 300 mg/kg bw/d * [1 / 1] * [7d (per week) / 5d (per week)] = 420 mg/kg bw/d

AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation is a NOAEL. Therefore, the default assessment factor 1 is chosen.
AF for differences in duration of exposure:
2
Justification:
The default AF for time extrapolation from subchronic exposure (OECD 443) to chronic exposure is applied.
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA default factor for interspecies allometric scaling from rat to human is used.
AF for other interspecies differences:
2.5
Justification:
The default AF for other interspecies differences, i.e. toxicokinetic/-dynamic differences is used.
AF for intraspecies differences:
5
Justification:
The default factor of 5 for workers is set in line with the REACH guidance.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Long-term DNELs for systemic effects are based on the key oral extended one-generation reproductive toxicity study (according to OECD 443), in which the test item B-TEGME was administered by oral gavage to Sprague-Dawley rats at dose levels of 100, 300 and 1000 mg/kg bw/day.


Based on the results obtained in this study it was concluded that the No-Observed-Adverse-Effect-Level (NOAEL) for reproductive performance of the F0 and F1 Cohort 1B animals was 300 mg/kg/day due to the high incidences of reduced fertility in females of F1 Cohort 1B receiving 1000 mg/kg/day and the increased incidences of minimal epididymal cellular debris coupled with sperm motility and morphology changes in both F0 and F1 Cohort 1B males given 1000 mg/kg/day, accompanied with degeneration in the testes for F1 Cohort 1B males at 1000 mg/kg/day only.


Aside from the above-mentioned instances of reduced fertility and male reproductive system changes at 1000 mg/kg/day, increased incidences of basophilic tubules in the kidneys of F0 females and increased incidence of decreased lymphocytes in the cortex of the thymus in the F0 generation males were observed at 1000 mg/kg/day, therefore the NOAEL for systemic toxicity in the F0 and F1 adult animals was concluded to be 300 mg/kg/day.


The NOAEL for the F1 and F2 offspring up to weaning was concluded to be 300 mg/kg/day due to reduced early post-partum survival at 1000 mg/kg/day in both generations and low litter size in F2 litters.


There was no evidence of developmental neurotoxicity or developmental immunotoxicity on this study, therefore the NOAEL for these endpoints was concluded to be 1000 mg/kg/day.


For the derivation of DNELs, the ECHA Guidance on IR&CSA, Chapter R.8, was followed, and ECHA default assessment factors were considered to be appropriate for workers.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.6 mg/m³
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
130.4 mg/m³
Explanation for the modification of the dose descriptor starting point:

The following parameters were taken into account for the modification of the dose descriptor starting point:



  • sRVrat, 24h = 1.15 m³/kg bw

  • Absorption (ABS): oral = ½ inhalation


modifed NOAEC (general population, 24h inhalation) = NOAEL (oral, rat) * [1/sRV(rat, 24h)] * [ABS (oral) / ABS (inhalation)]


modified NOAEC (general population, 24h inhalation) = 300 mg/kg bw/d * [1/1.15 m³/kg bw/d] * [0.5 / 1] = 130.4 mg/m³

AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation is a NOAEL. Therefore, the default assessment factor 1 is chosen.
AF for differences in duration of exposure:
2
Justification:
The default AF for time extrapolation from subchronic exposure (OECD 443) to chronic exposure is applied.
AF for interspecies differences (allometric scaling):
1
Justification:
The AF has already been handled within the correction of the modification of the dose descriptor.
Therefore, no additional factor has to be applied.
AF for other interspecies differences:
2.5
Justification:
The default AF for other interspecies differences, i.e. toxicokinetic/-dynamic differences is used.
AF for intraspecies differences:
10
Justification:
The default factor of 10 for general population is set in line with the REACH guidance.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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:
1.5 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The following parameters were taken into account for the modification of the dose descriptor starting point:



  • Absorption (ABS): oral = dermal


modifed NOAEL (general population, dermal) = NOAEL (oral, rat) * [ABS (oral) / ABS (dermal)]


modified NOAEC (general population, dermal) = 300 mg/kg bw/d * [1 / 1] = 300 mg/kg bw/d

AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation is a NOAEL. Therefore, the default assessment factor 1 is chosen.
AF for differences in duration of exposure:
2
Justification:
The default AF for time extrapolation from subchronic exposure (OECD 443) to chronic exposure is applied.
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA default factor for interspecies allometric scaling from rat to human is used.
AF for other interspecies differences:
2.5
Justification:
The default AF for other interspecies differences, i.e. toxicokinetic/-dynamic differences is used.
AF for intraspecies differences:
10
Justification:
The default factor of 10 for general population is set in line with the REACH guidance.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.5 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The modification of the NOAEL is not necessary as no route-to-route extrapolation is performed.

AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation is a NOAEL. Therefore, the default assessment factor 1 is chosen.
AF for differences in duration of exposure:
2
Justification:
The default AF for time extrapolation from subchronic exposure (OECD 443) to chronic exposure is applied.
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA default factor for interspecies allometric scaling from rat to human is used.
AF for other interspecies differences:
2.5
Justification:
The default AF for other interspecies differences, i.e. toxicokinetic/-dynamic differences is used.
AF for intraspecies differences:
10
Justification:
The default factor of 10 for general population is set in line with the REACH guidance.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

The detailed information of the study and dose descriptor used as point of departure for the derivation of long-term DNELs is described in 'additional information - worker' above.


For the DNELs, the ECHA Guidance on IR&CSA, Chapter R.8, was followed, and ECHA default assessment factors were considered to be appropriate for the general population.