Registration Dossier

Diss Factsheets

Toxicological information

Toxicological Summary

Currently viewing:

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
29.1 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Dose descriptor starting point:
NOAEL
Value:
250 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
364.1 mg/m³
Explanation for the modification of the dose descriptor starting point:

According to the ECHA Guidance on IR&CSA, Chapter R.8, the standard respiratory volume (sRV) for the rabbit was calculated from the sRV for humans (per kg bw; average human bodyweight 70 kg) and applying the corresponding allometric scaling factor for the rabbit of 2.4. The modified NOAEC was then further calculated according to the guidance.

sRV(rabbit, 8h) = sRV(human, 8h) x allometric scaling factor = (6.7m³/70kg bw) x 2.4 = 0.23 m³/kg bw/d

NOAEC,modified (worker, 8h) = NOAEL,oral * [1/sRV(rabbit)] * [absorption (ABS),oral-rabbit / ABS(inh-human)] * [sRV(human) / worker Respiratory Volume (wRV)]

NOAEC,modified (worker, 8h) = 250 mg/kg bw/d * [1/0.23 m³/kg bw/d] * [0.5 / 1] * [6.7 m³ (8h) / 10 m³ (8h)]

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:
1
Justification:
No time extrapolation is required for developmental toxicity as increasing exposure duration does not increase the incidence or severity of adverse effects.
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:
8.3 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
30
Dose descriptor starting point:
NOAEL
Value:
250 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
250 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The modified NOAEL was calculated according to the guidance ECHA Guidance on IR&CSA, Chapter R.8.

Following the guideline and assuming that, in general, dermal absorption will not be higher than oral absorption, no default factor (i.e. factor 1) is used to perform oral-to-dermal extrapolation.

NOAEL,modified (worker, 8h) = NOAEL,oral * [ABS(oral-rabbit) / ABS(derm-human)]

NOAEL,modified (worker, 8h) = 250 mg/kg bw/d * [1 / 1]

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:
1
Justification:
No time extrapolation is required for developmental toxicity as increasing exposure duration does not increase the incidence or severity of adverse effects.
AF for interspecies differences (allometric scaling):
2.4
Justification:
ECHA default factor for allometric scaling of rabbit 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 are based on the key oral developmental toxicity study (according to OECD 414), in which the test item B-TEGME was administered by gavage to three groups, each of 25 pregnant female New Zealand White, Crl:KBL strain rabbits from implantation to one day prior to the expected day of parturition (GD 6-28) at dose levels of 100, 250 and 500 mg/kg bw/day. A control group was dosed with drinking water. Clinical signs, body weight change and food consumption were monitored in dams during the study. On GD 29 the animals were sacrificed and the post-mortem examinations included gravid uterus weight and number of corpora lutea, implantations, early and late resorptions. At the end of the study all fetuses were examined externally and for soft tissue and skeletal malformations and variations. For each half of a litter skeletal head examinations were performed.

There were no maternal effects and/or malformations in the fetuses observed for the treatment groups of 100 and 250 mg/kg bw/d. Dams treated with 500 mg/kg bw/d showed a lower food consumption of 7% compared to the control group. There were three death or abortions observed in this dose group, immediately before term (GD 28/29). The following necropsy indicated enteropathy in the animals. The observed fetuses of the high-dose group had an increased incidence of visceral (mainly in the urogenital tract) or skeletal (mainly at the axial skeleton) malformations. Some findings were above the historical range. The observed incidences of external, skeletal and cartilage variations were all increased and above the historical range.
The oral administration of B-TEGME to pregnant rabbits by gavage, at dose levels of 100, 250 and 500 mg/kg bw/day from implantation to one day prior to the expected day of parturition (GD 6-28), did cause evidence of maternal toxicity at the high-dose level of 500 mg/kg bw/d, such as bortions/mortality and reduced food consumption. In conclusion, the no observed adverse effect level (NOAEL) for maternal toxicity is 250 mg/kg bw/d. Since there was evidence for treatment-related adverse effects of the test substance on fetal morphology at the high-dose of 500 mg/kg bw/d, the no observed adverse effect level (NOAEL) for prenatal developmental toxicity is 250 mg/kg bw/d.

For the DNELs, the ECHA Guidance on IR&CSA, Chapter R.8, Version: 2.1 from November 2012 was followed, and ECHA 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:
7.2 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
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:
250 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
181.1 mg/m³
Explanation for the modification of the dose descriptor starting point:

According to the ECHA Guidance on IR&CSA, Chapter R.8, the standard respiratory volume (sRV) for the rabbit was calculated from the sRV for humans (per kg bw; average human bodyweight 70 kg) and applying the corresponding allometric scaling factor for the rabbit of 2.4. Themodified NOAEC was then further calculated according to the guidance.

sRV(rabbit, 24h) = sRV(human, 24h) x allometric scaling factor = (20m³/70kg bw) x 2.4 = 0.69 m³/kg bw/d

NOAEC,modified (general population, 24h) = NOAEL,oral * [1/sRV(rabbit)]* [absorption (ABS),oral-rabbit / ABS(inh-human)]

NOAEC,modified (general population, 24h) = 250 mg/kg bw/d * [1/0.69 m³/kg bw/d]* [0.5 / 1]

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:
1
Justification:
No time extrapolation is required for developmental toxicity as increasing exposure duration does not increase the incidence or severity of adverse effects.
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:
4.1 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
60
Dose descriptor starting point:
NOAEL
Value:
250 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
250 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The modified NOAEL was calculated according to the guidance ECHA Guidance on IR&CSA, Chapter R.8.

Following the guideline and assuming that, in general, dermal absorption will not be higher than oral absorption, no default factor (i.e. factor 1) is used to perform oral-to-dermal extrapolation.

NOAEL,modified (general population, 24h) = NOAEL,oral * [ABS(oral-rabbit) / ABS(derm-human)]

NOAEL,modified (general population, 24h) = 250 mg/kg bw/d * [1 / 1]

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:
1
Justification:
No time extrapolation is required for developmental toxicity as increasing exposure duration does not increase the incidence or severity of adverse effects.
AF for interspecies differences (allometric scaling):
2.4
Justification:
ECHA default factor for allometric scaling of rabbit 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:
4.1 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
60
Dose descriptor starting point:
NOAEL
Value:
250 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
250 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:
1
Justification:
No time extrapolation is required for developmental toxicity as increasing exposure duration does not increase the incidence or severity of adverse effects.
AF for interspecies differences (allometric scaling):
2.4
Justification:
ECHA default factor for allometric scaling of rabbit 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 for the derivation of a point of departure for the hazard assessments is described in additional information of the worker.

For the DNELs, the ECHA Guidance on IR&CSA, Chapter R.8, Version: 2.1 from November 2012 was followed, and ECHA assessment factors were considered to be appropriate for the genral population.

Categories Display