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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.65 mg/m³
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Value:
116.35 mg/m³
AF for dose response relationship:
1
Justification:
Default value (ECHA)
AF for differences in duration of exposure:
2
Justification:
Default value (ECHA) from subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
rat vesus human According to table R.8-4 in chapter R.8 of the ECHA guidance document the AF of 4 is already included in the route to route extrapolation.
AF for other interspecies differences:
2.5
Justification:
Default value (ECHA)
AF for intraspecies differences:
5
Justification:
Default value (ECHA)
AF for the quality of the whole database:
1
Justification:
A GLP guideline study is used
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
23.2 mg/m³
DNEL related information
DNEL extrapolated from long term DNEL

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:
1.32 mg/kg bw/day
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Value:
132 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Penetration oral compared to dermal assumed similar; default.

AF for dose response relationship:
1
Justification:
Default value (ECHA)
AF for differences in duration of exposure:
2
Justification:
Default value (ECHA) from subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Default value (ECHA)
AF for other interspecies differences:
2.5
Justification:
Default value (ECHA)
AF for intraspecies differences:
5
Justification:
Default value (ECHA)
AF for the quality of the whole database:
1
Justification:
A GLP guideline study is used
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.6 mg/kg bw/day
Route of original study:
Oral
DNEL related information
DNEL extrapolated from long term DNEL

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

Ditolylether (CAS 28299-41-4)

DNELs

Repeated dose toxicity

Basis for delineation of the DNEL:

Study

Repeated dose study

Rat, male, female,

subchronic oral feed study over 90 days

rat: 0 (control), 550, 1650 or 5000 ppm

(ca. 0, 45, 132 or 425 mg/kg bw/d - male rats;

ca. 0, 56, 174 or 604 mg/kg bw/d - female rats) via diet.

Effects, NOAEL

NOAEL = 132 mg/kg bw/day (male rats), NOAEL = 174 mg/kg bw/day (female rats)

5000 ppm : in the males body weight gain reduced by ca. 10 %;

in both sexes liver weights increased, but histopathological changes did not occur and cytochrome P-450 and N- or O-Demethylases were not induced

Reference

Kroetlinger F, Schilde B (1988)

Baylectrol 4900 – Subchronische toxikologische Untersuchungen an Ratten (Fütterungsversuch über 3 Monate)

Bericht-Nr.: 16353

Bayer AG

Fachbereich Toxikologie

1.) Long-term toxixity – systemic effects (workers)

Long-term oral or dermal route-systemic effects (worker) using default extrapolation factors (penetration oral compared to dermal both assumed similar; default):

NOAEL(rat) from a subchronic toxicity study: 132 mg/kg bw/day

Penetration oral compared to dermal (both assumed 100%) 1

For interspecies differences rat vs. human: 4

For remaining interspecies differences: 2.5

For intraspecies differences in workers: 5

For extrapolation of exposure duration subchronic to chronic: 2

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 100

Worker DNEL long-term for oral or dermal route-systemic: 1.32 mg/kg bw/day

Long-term inhalation route-systemic effects (worker):

NOAEL(rat) from a subchronic toxicity study: 132 mg/kg bw/day

Correction of the starting point according to REACH Guidance R8 (Version 2.1, November 2012, Figure R.8-3):

Corrected inhalatory NOAEC = Oral NOAEL (132 mg/kg) x 1/0.38 m³/kg x 6.7 m³/10m³ x 0.5

=> NOAEC worker = 116.36 mg/m³

For interspecies differences rat vs. human: 1 (according TGD Table

R.8-4. already covered by correction of starting point)

For remaining interspecies differences: 2.5

For intraspecies differences in workers: 5

For extrapolation of exposure duration subchronic to chronic: 2

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 25

Worker DNEL long-term for inhalation exposure: 4.65 mg/m³

2.) Short-term toxicity – systemic effects (workers)

In an inhalation hazard test a discriminating concentration > 521 mg/m³ was found. In this study no mortality, no signs of toxicity and no delayed effects were observed. Concerning the systemic effects an exceeding factor of 5 based on the DNEL for long term exposure seems justified.

In an acute dermal study a discriminating dose > 2.5 ml/kg bw (2587 mg/kg bw), (rats, male + female) was found; no deaths and no symptoms of poisoning were observed. Concerning the systemic effects an exceeding factor of 5 based on the DNEL for long term exposure seems justified.

Worker DNEL short-term for dermal route-systemic: 6.6 mg/kg bw

Worker DNEL short-term for inhalation exposure: 23.2 mg/m³

3.) Reproductive Toxicity – systemic effects (workers)

A 2-generation toxicity study (OECD TG 416) is not available. However, no effects on reproductive organs were observed in an oral feed study for 90 days in rats. The pathologic evaluation consisted of gross and microscopic examination of reproductive organs, in male rats, prostate, seminal vesicle, testis and epididymis; in the female rats, mammary gland, uterus, and ovary.

No treatment-related changes were observed for any reproductive organ investigated during macroscopic and microscopic examination of all major organs (NOAEL = 425 mg/kg bw/day (rats, male) and NOAEL = 604 mg/kg bw/day (rats, female).

Ditolylether was investigated in a developmental toxicity oral gavage study in rats and gave no evidence of embryotoxicity, or fetotoxicty at non-maternally toxic dose levels (up to and including 300 mg/kg bw/day = NOAEL for maternal toxicity). 1000 mg/kg bw/d: signs of maternal toxicity: body weight gain reduced during the whole gestation, treatment-related deaths (mortality: 4/25); signs of embryotoxicity: reduced number and decreased weights of the fetuses

The NOAEL for reproductive toxicity in rats is therefore 300 mg/kg bw/day.

Additional or higher assessment factors than those used for the delineation of the DNEL from the repeated dose toxicity study are not necessary. As the NOAEL for reproductive toxicity (300 mg/kg bw/day) is higher than the NOAEL for repeated dose toxicity (132 mg/kg bw/day), the derivation of a separate DNEL for reproductive toxicity is not necessary, because the DNEL for repeated dose toxicity covers both endpoints.

Conclusion (systemic effects):

Worker DNEL long-term for oral or dermal route-systemic: 1.32 mg/kg bw/day

Worker DNEL long-term for inhalation exposure: 4.65 mg/m³

Worker DNEL short-term for oral or dermal route-systemic: 6.6 mg/kg bw/day

Worker DNEL short-term for inhalation exposure: 23.2 mg/m³

4. Long-term and short-term dermal or inhalation route - local effects (worker)

Ditolylether was slightly irritating to the skin (OECD TG 404), and not irritating to the eyes (OECD TG 405) in animal experiments. A classification for skin sensitization is not necessary. Although a weak skin sensitization potential of undiluted ditolyl ether cannot be fully excluded based on guinea pig skin sensitization tests the available experimental data point out a very weak skin sensitizing potential and/or skin irritation potential of the pure, undiluted compound. Diluted compound (50%) showed no skin effect.

Overall, no hazard is identified for local effects.

Conclusion (local effects):

Worker DNEL long-term for oral or dermal route-local: no hazard identified

Worker DNEL long-term for inhalation exposure: no hazard identified

Worker DNEL short-term for oral or dermal route-local: no hazard identified

Worker DNEL short-term for inhalation exposure: no hazard identified

References:

• Kroetlinger F, Schilde B, Baylectrol 4900 – Subchronische toxikologische Untersuchungen an Ratten (Fuetterungsversuch ueber 3 Monate), Bericht no. 16353, Bayer AG (1988)

• Ditolylether, BUA-Stoffbericht 18 (1988), and BUA-Stoffbericht 193 (Ergänzungsberichte III)

• ECHA – Guidance on information requirements and chemical safety assessment, Part E: Risk Characterisation, November 2012

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.14 mg/m³
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEC
Value:
57.39 mg/m³
AF for dose response relationship:
1
Justification:
Default value (ECHA)
AF for differences in duration of exposure:
2
Justification:
Default value (ECHA) from subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
rat vesus humanAccording to table R.8-4 in chapter R.8 of the ECHA guidance document the AF of 4 is already included in the route to route extrapolation
AF for other interspecies differences:
2.5
Justification:
Default value (ECHA)
AF for intraspecies differences:
10
Justification:
Default value (ECHA)
AF for the quality of the whole database:
1
Justification:
A GLP guideline study is used
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.7 mg/m³
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

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:
0.66 mg/kg bw/day
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Value:
132 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Penetration oral compared to dermal assumed similar; default.

AF for dose response relationship:
1
Justification:
Default value (ECHA)
AF for differences in duration of exposure:
2
Justification:
Default value (ECHA) from subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
rat vesus humanAccording to table R.8-4 in chapter R.8 of the ECHA guidance document the AF of 4 is already included in the route to route extrapolation
AF for other interspecies differences:
2.5
Justification:
Default value (ECHA)
AF for intraspecies differences:
10
Justification:
Default value (ECHA)
AF for the quality of the whole database:
1
Justification:
A GLP guideline study is used
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.3 mg/kg bw/day
Route of original study:
Oral
DNEL related information
DNEL extrapolated from long term DNEL

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:
0.66 mg/kg bw/day
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Value:
132 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Default value (ECHA)
AF for differences in duration of exposure:
2
Justification:
Default value (ECHA) from subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
rat vesus humanAccording to table R.8-4 in chapter R.8 of the ECHA guidance document the AF of 4 is already included in the route to route extrapolation
AF for other interspecies differences:
2.5
Justification:
Default value (ECHA)
AF for intraspecies differences:
10
Justification:
Default value (ECHA)
AF for the quality of the whole database:
1
Justification:
A GLP guideline study is used
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.3 mg/kg bw/day
Route of original study:
Oral
DNEL related information
DNEL extrapolated from long term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Ditolylether (CAS 28299-41-4)

DNELs

Repeated dose toxicity

Basis for delineation of the DNEL:

Study

Repeated dose study

Rat, male, female,

subacute oral feed study over 90 days

rat: 0 (control), 550, 1650 or 5000 ppm

(ca. 0, 45, 132 or 425 mg/kg bw/d - male rats;

ca. 0, 56, 174 or 604 mg/kg bw/d - female rats) via diet.

Effects, NOAEL

NOAEL = 132 mg/kg bw/day (male rats), NOAEL = 174 mg/kg bw/day (female rats)

5000 ppm : in the males body weight gain reduced by ca. 10 %;

in both sexes liver weights increased, but histopathological changes did not occur and cytochrome P-450 and N- or O-Demethylases were not induced

Reference

Kroetlinger F, Schilde B (1988)

Baylectrol 4900 – Subchronische toxikologische Untersuchungen an Ratten (Fütterungsversuch über 3 Monate)

Bericht-Nr.: 16353

Bayer AG

Fachbereich Toxikologie

1.) Long-term toxixity – systemic effects (general population)

Long-term oral or dermal route-systemic effects (general population) using default extrapolation factors (penetration oral compared to dermal both assumed similar; default):

NOAEL(rat) from a subchronic toxicity study: 132 mg/kg bw/day

Penetration oral compared to dermal (both assumed 100%) 1

For interspecies differences rat vs. human: 4

For remaining interspecies differences: 2.5

For intraspecies differences in general population: 10

For extrapolation of exposure duration subchronic to chronic: 2

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 200

General population DNEL long-term for oral or dermal route-systemic: 0.66 mg/kg bw/day

Long-term inhalation route-systemic effects (general population):

NOAEL(rat) from a subchronic toxicity study: 132 mg/kg bw/day

Correction of the starting point according to REACH guidance R8 (Version 2.1, November 2012, Figure R.8-3):

Corrected inhalatory NOAEC = Oral NOAEL (132 mg/kg) x 1/1.15 m³/kg x 0.5

=> NOAEC general population = 57.39 mg/m³

For interspecies differences rat vs. human: 1 (according TGD Table

R.8-4. already covered by correction of starting point)

For remaining interspecies differences: 2.5

For intraspecies differences in general population: 10

For extrapolation of exposure duration subchronic to chronic: 2

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 50

General population DNEL long-term for inhalation exposure: 1.14 mg/m³

2.) Short-term toxicity – systemic effects (general population)

Ditolylethyl is proposed to be classified as Xn, R22 (GHS: Acute Tox.4, H 302). This proposed classification belongs to no hazard band according ECHA guidance on information requirements and chemical safety assessment Part E: Risk characterization November 2012.

Concerning the systemic effects an exceeding factor of 5 based on the DNEL for long term exposure seems justified.

In an inhalation hazard test a discriminating concentration > 521 mg/m³ was found. In this study no mortality, no signs of toxicity and no delayed effects were observed. Concerning the systemic effects an exceeding factor of 5 based on the DNEL for long term exposure seems justified.

In an acute dermal study a LD50 > 2.5 ml/kg bw (discriminating dose 2587 mg/kg bw), (rats, male + female) was found; no deaths and no symptoms of poisoning were observed. Concerning the systemic effects an exceeding factor of 5 based on the DNEL for long term exposure seems justified.

Therefore

General population DNEL short-term for oral or dermal route-systemic: 3.3 mg/kg bw

General population DNEL short-term for inhalation exposure: 5.7 mg/m³

3.) Reproductive Toxicity – systemic effects (general population)

A 2-generation toxicity study (OECD TG 416) is not available. However, no effects on reproductive organs were observed in an oral feed study for 90 days in rats. The pathologic evaluation consisted of gross and microscopic examination of reproductive organs, in male rats, prostate, seminal vesicle, testis and epididymis; in the female rats, mammary gland, uterus, and ovary.

No treatment-related changes were observed for any reproductive organ investigated during macroscopic and microscopic examination of all major organs (NOAEL = 425 mg/kg bw/day (rats, male) and NOAEL = 604 mg/kg bw/day (rats, female).

Ditolylether was investigated in a developmental toxicity oral gavage study in rats and gave no evidence of embryotoxicity, or fetotoxicity at non-maternally toxic dose levels (up to and including 300 mg/kg bw/day = NOAEL for maternal toxicity). 1000 mg/kg bw/d: signs of maternal toxicity: body weight gain reduced during the whole gestation treatment-related deaths (mortality: 4/25); signs of embryotoxicity: reduced number and decreased weights of the fetuses

The NOAEL for reproductive toxicity in rats is therefore 300 mg/kg bw/day.

Additional or higher assessment factors than those used for the delineation of the DNEL from the repeated dose toxicity study are not necessary. As the NOAEL for reproductive toxicity (300 mg/kg bw/day) is higher than the NOAEL for repeated dose toxicity (132 mg/kg bw/day), the derivation of a separate DNEL for reproductive toxicity is not necessary, because the DNEL for repeated dose toxicity covers both endpoints.

Conclusion (systemic effects):

General population DNEL long-term for oral or dermal route-systemic: 0.66 mg/kg bw/day

General population DNEL long-term for inhalation exposure: 1.14 mg/m³

General population DNELshort-term for oral or dermal route-systemic: 3.3 mg/kg bw/day

General population DNEL short-term for inhalation exposure: 5.7 mg/m³

4. Long-term and short-term dermal or inhalation route - local effects (worker)

Ditolylether was slightly irritating to the skin (OECD TG 404), and not irritating to the eyes (OECD TG 405) in animal experiments. A classification for skin sensitization is not necessary. Although a weak skin sensitization potential of undiluted ditolyl ether cannot be fully excluded based on guinea pig skin sensitization tests the available experimental data point out a very weak skin sensitizing potential and/or skin irritation potential of the pure, undiluted compound. Diluted compound (50%) showed no skin effect.

Overall, no hazard is identified for local effects.

Conclusion (local effects):

General population DNEL long-term for oral or dermal route-local: no hazard identified

General population DNEL long-term for inhalation exposure: no hazard identified

General population DNEL short-term for oral or dermal route-local: no hazard identified

General population DNEL short-term for inhalation exposure: no hazard identified

References:

• Kroetlinger F, Schilde B, Baylectrol 4900 – Subchronische toxikologische Untersuchungen an Ratten (Fuetterungsversuch ueber 3 Monate), Bericht no. 16353, Bayer AG (1988)

• Ditolylether, BUA-Stoffbericht 18 (1988), and BUA-Stoffbericht 193 (Ergänzungsberichte III)

• ECHA – Guidance on information requirements and chemical safety assessment, Part E: Risk Characterisation, November 2012