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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.23 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
179.4 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
37.5
Dose descriptor starting point:
LOAEC
AF for dose response relationship:
3
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.6 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):
100
Modified dose descriptor starting point:
NOAEL
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
AF for interspecies differences (allometric scaling):
4
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
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

1-WORKERS

During unloading, unpacking and charging, dermal and/or inhalation contact is possible with:

-Liquid substance

-Evaporated substance 

That is the reason why we consider theinhalation and dermal routeas relevant exposure, and corresponding long term DNELs will therefore be derived:

 

1-1 DNEL short term, local effects, inhalation

Provided the R20 "harmful by inhalation" classification of the test substance, the derivation of a DNEL (acute, inhalation route) is relevant. The acute inhalation rat toxicity study (TNO, 1999) was used for DNEL derivation, considering that the LC50 was equal to 3670 mg/m3 (over a 4‑hour exposure).

Irregular breathing was observed in all rats exposed to 2670 mg/m3 (group B) and 4540 mg/m3 (group C) during the third hour of exposure, and in all rats exposed to 3720 mg/m3 (group D) during the second and third hour of exposure.

Shallow breathing was seen in all rats exposed to 2670 mg/m3 (group B ) during the last hour of exposure and in all (surviving) rats exposed to 3720 or 4540 mg/m3 during the third and fourth hour of exposure. Wet fur (head, breast and/or nose) was observed after exposure in all surviving rats exposed to 2670, 3720 or 4540 mg/m3.

Animals that died during or shortly after exposure showed numerous abnormalities. Stiffly closed eyes were seen in several rats. Two male rats of each group exposed to 3720, 4540 or 5480 mg/m3 showed presence of white substance in the eye chamber of both eyes; one male and one female exposed to 5480 mg/m3 showed the same finding but in one eye chamber only. Upon autopsy, almost all rats showed dark and swollen livers and dark discoloured, occasionally blood-containing, lungs. In addition, upon removal of the organs (such as liver) in animals exposed to the highest concentration, much oedema was observed as confirmed by the presence of large amounts of fluid. Occasional findings consisted of swollen blood vessels in various organs such as stomach, caecum, intestines, testes and/or seminal vesicles. At terminal sacrifice of the surviving rats 14 days after exposure, no abnormalities were observed.

·        Step 1: Selection of the relevant dose descriptor:

LOAEC (4 hours) = 2670 mg/m3 based on irregular and shallow breathing.

·        Step 2: Modification of the starting point:

-Time extrapolation to the reference period of 15 minutes for acute effects, using the modified Haber's law (Cnx t = k) with a coefficient of 3 for extrapolation from a longer to a shorter exposure duration:

LOAEC (15 minutes) = 6728 mg/m3

-Correction of the respiratory volume for relevant duration is not appropriate because the target effet concerned local repiratory effects.

LOAEC (15 min) = 6728 mg/m3

·        Step 3: Assessment factors:

- Interspecies differences: as massive exposure by inhalation is considered, no toxicokinetic assessment factor is applied. However, a factor of2.5to correct for differences other than differences in metabolic rate is applied.

- Intraspecies differences: the default assessment factor of5is applied.

- Exposure duration:1(it’s an acute DNEL extrapoled to 15 minutes)

- Dose response:3(LOAEC)

- Quality of whole database:1

Total assessment factor = 37.5

·        Step 4: DNEL derivation:

Worker DNEL (acute inhalation, local effects) = 6728 / 37.5 = 179.4 mg/m3

 

1-2 DNEL Long term, systemic toxicity, inhalation

For the selection of the starting point and the leading effects we used the same repeated dose toxicity study used for undecylenic acid DNEL derivation. We used a read across approach for evaluation of the long term toxicity endpoints with using data obtained on undecylenic acid for evaluation of methyl undecenoate.The justification for read across is that we demonstrated in vitro that methyl undecenoate undergo rapid hydrolysis to undecylenic acid under simulated gastric conditions (pH hydrolysis study report, see section 5.1.2 of IUCLID), this major result should therefore indicate that the read-across for the repeated dose toxicity endpoint is relevant. It should also be noted that only some relatively minor toxic effects were being observed, not exceeding category 4 for acute toxicity (methyl undecenoate) or category 2 for eye irritation (undecylenic acid), indicating the generally limited hazardous effects exhibited by the two substances. We proposed therefore to use the same long term DNEL for undecylenic acid and methyl undecenoate :

In a 90-day repeated toxicity study performed in rats with undecylenic acid (Fabreguettes, 1999), the oral NOAEL for systemic toxicity was60 mg/kg bw/day: Cardiomyopathy was recorded at 180 mg/kg bw/d, myocardial degeneration / monocellular aggregation which was reversible during the treatment free period.

·        Step 1) Relevant dose-descriptor :NOAEL =60 mg/kg/day

·        Step 2) Modification of starting point :

-Conversion into inhalation NOAEC (in mg/m3) by using an 8 -hour respiratory volume for the rat = 0.38 m3/kg/bw

- Correcting for oral to inhalation absorption=1

Methyl Undecenoate has a low volatility (water solubility of less than 0.5 kPa, and a boiling point above 180°C) as undecylenic acid.For purpose of DNEL derivation, absorption by the oral and inhalation route will be assumed to be equivalent.

-Correction for activity driven differences of respiratory volumes in workers in rest= 6.7m3/10m3

NOAEC corrected = 60 x 1/0.38 x 6.7/10 = 105.79 mg/m3

·        Step 3) Assessment factors:

-Interspecies =2.5

-Intraspecies=5

-Exposure duration= 2

-Dose response=1

-Quality of database = 1

Global Uncertainty factor= 25

·        Step 4) DNEL derivation:

DNEL inhalation (long term, systemic effects) = 105.79 x 1/25 = 4.23 mg/m3

 

1-3 DNEL long term, systemic effects, dermal

Occupational exposure to undecylenic acid may also occur by dermal exposure. Although no dermal repeated dose toxicity studies is available as well as no information on dermal absorption, we derived a dermal DNEL based on the same Oral NOAEL selected for the derivation of the inhalation DNEL (extrapolation from oral to dermal route using the methodology described in the R8 ECHA document).

·        Step 1) Relevant dose-descriptor:  NOAEL= 60 mg/kg/day

·        Step 2) Modification of starting point:

-Correction for substances differences in dermal absorption= 1

Undecylenic acid has a high octanol/water particient coefficient (log Kow=4) which predicts a high dermal absorption. Furthermore, considering, the low molecular weight, the irritant properties of undecylenic acid, which may enhance penetration and the absence of dermal penetration studies, we will consider 100% absorption as a worst case. The correction factor will Then be equal to 1.

·        Step 3) Assessment factors:

-Interspecies = 2.5x4 = 10

-Intraspecies= 5

-Exposure duration= 2

-Dose response= 1

-Quality of database= 1

Global uncertainty factor=100

·        Step 4) DNEL derivation:

DNEL dermal (long term, systemic effects) = 60/100 = 0.6 mg/kg bw/d

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.04 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEC
Value:
52.17 mg/m³
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
89.7 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
75
Dose descriptor starting point:
LOAEC
AF for dose response relationship:
3
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.3 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):
200
Modified dose descriptor starting point:
NOAEL
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
AF for interspecies differences (allometric scaling):
4
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.3 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):
200
Modified dose descriptor starting point:
NOAEL
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
AF for interspecies differences (allometric scaling):
4
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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

2- GENERAL POPULATION

Methyl-10 -undecenoate is used as an intermediate in the synthesis of chemicals. It is further used as an additive for the formulation of fragrances and of ant-smell products. The anti-smell products are sold to the public as commercial goods and are used by consumers.

The main relevant routes are therefore the dermal and inhalation routes.

1-1 DNEL short term, local effects, inhalation

Provided the R20 "harmful by inhalation" classification of the test substance, the derivation of a DNEL (acute, inhalation route) is relevant. The acute inhalation rat toxicity study (TNO, 1999) was used for DNEL derivation, considering that the LC50 was equal to 3670 mg/m3 (over a 4‑hour exposure).

Irregular breathing was observed in all rats exposed to 2670 mg/m3 (group B) and 4540 mg/m3 (group C) during the third hour of exposure, and in all rats exposed to 3720 mg/m3 (group D) during the second and third hour of exposure.

Shallow breathing was seen in all rats exposed to 2670 mg/m3 (group B ) during the last hour of exposure and in all (surviving) rats exposed to 3720 or 4540 mg/m3 during the third and fourth hour of exposure. Wet fur (head, breast and/or nose) was observed after exposure in all surviving rats exposed to 2670, 3720 or 4540 mg/m3.

Animals that died during or shortly after exposure showed numerous abnormalities. Stiffly closed eyes were seen in several rats. Two male rats of each group exposed to 3720, 4540 or 5480 mg/m3 showed presence of white substance in the eye chamber of both eyes; one male and one female exposed to 5480 mg/m3 showed the same finding but in one eye chamber only. Upon autopsy, almost all rats showed dark and swollen livers and dark discoloured, occasionally blood-containing, lungs. In addition, upon removal of the organs (such as liver) in animals exposed to the highest concentration, much oedema was observed as confirmed by the presence of large amounts of fluid. Occasional findings consisted of swollen blood vessels in various organs such as stomach, caecum, intestines, testes and/or seminal vesicles. At terminal sacrifice of the surviving rats 14 days after exposure, no abnormalities were observed.

·        Step 1: Selection of the relevant dose descriptor:

LOAEC (4 hours) = 2670 mg/m3 based on irregular and shallow breathing.

·        Step 2: Modification of the starting point:

-Time extrapolation to the reference period of 15 minutes for acute effects, using the modified Haber's law (Cnx t = k) with acoefficient of 3 for extrapolation from a longer to shorter exposure duration:

LOAEC (15 minutes) = 6728 mg/m3

No correction should be applied for respiratory volume because the critical effects are local effects related to irritation.

·        Step 3: Assessment factors:

- Interspecies differences: as massive exposure by inhalation is considered, no toxicokinetic assessment factor is applied. However, a factor of2.5to correct for differences other than differences in metabolic rate is applied.

- Intraspecies differences: the default assessment factor of10is applied.

- Exposure duration:1(it’s an acute DNEL extrapoled to 15 minutes)

- Dose response:3(LOAEC)

- Quality of whole database:1

Total assessment factor = 75

·        Step 4: DNEL derivation:

 DNEL (acute inhalation, local effects) = 89.7 mg/m3

2-1 DNEL Long term, systemic toxicity, inhalation

For the selection of the starting point and the leading effects we used the same repeated dose toxicity study used for undecylenic acid DNEL derivation. We used a read across approach for evaluation of the long term toxicity endpoints of methyl undecenoate by

using data obtained on undecylenic acid.

The justification for read across is that we demonstrated in vitro the methyl undecenoate undergo rapid hydrolysis to undecylenic acid under simulated gastric conditions (pH hydrolysis study report Report reference: 09/ANA/14891/NFS-CPA, 2009, see section 5.1.2 of IUCLID), this major result should therefore indicate that the read-across for the repeated dose toxicity endpoint is relevant. It should also be noted that only some relatively minor toxic effects were being observed, not exceeding category 4 for acute toxicity (methyl-10-undecenoate) or category 2 for eye irritation (undecylenic acid), indicating the generally limited hazardous effects exhibited by the two substances.

We proposed therefore to use the same long term DNEL for undecylenic acid and methyl undecenoate :

In a 90-day repeated toxicity study performed in rats with undecylenic acid (Fabreguettes, 1999), the oral NOAEL for systemic toxicity was 60 mg/kg bw/day.: Cardiomyopathy was recorded at 180 mg/kg bw/d, myocardial degeneration / monocellular aggregation which was reversible during the treatment free period.

·        Step 1) Relevant dose-descriptor:NOAEL =60 mg/kg/day

·        Step 2) Modification of starting point :

-Conversion into inhalation NOAEC (in mg/m3) by using an 24-hour respiratory volume for the rat = 1.15 m3/kg/bw

-Correcting for oral to inhalation absorption=1

Methyl Undecenoate has a low volatility (water solubility of less than 0.5 kPa, and a boiling point above 180°C) as undecylenic acid. For purpose of DNEL derivation, absorption by the oral and inhalation route will be assumed to be equivalent.

NOAEC corrected = 60 x 1/1.15 = 52.17 mg/m3

·        Step 3) Assessment factors:

-Interspecies =2.5

-Intraspecies=10

-Exposure duration= 2

-Dose response=1

-Quality of database = 1

Global Uncertainty factor= 50

·        Step 4) DNEL derivation:

DNEL inhalation (long term, systemic effects) = 52.17 / 50 = 1.04 mg/m3

 

2-2 DNEL long term, systemic effects, dermal

Occupational exposure to undecylenic acid may also occur by dermal exposure. Although no dermal repeated dose toxicity studies is available as well as no information on dermal absorption, we derived a dermal DNEL based on the same Oral NOAEL selected for the derivation of the inhalation DNEL (extrapolation from oral to dermal route using the methodology described in the R8 ECHA document).

·        Step 1) Relevant dose-descriptor:  NOAEL= 60 mg/kg/day

·        Step 2) Modification of starting point :

Correction for substances differences in dermal absorption= 1

Undecylenic acid has a high octanol/water particient coefficient (log Kow=4) which predicts a high dermal absorption. Furthermore, considering, the low molecular weight, the irritant properties of undecylenic acid, which may enhance penetration and the absence of dermal penetration studies, we will consider 100% absorption as a worst case. The correction factor will Then be equal to 1.

·        Step 3) Assessment factors:

-Interspecies 2.5 x 4 = 10

-Intraspecies= 10

-Exposure duration= 2

-Dose response= 1

-Quality of database= 1

Global uncertainty factor=200

·        Step 4) DNEL derivation:

DNEL dermal (long term, systemic effects) = 60 / 200 = 0.3 mg/kg bw/d

 

2-3 DNEL long term, systemic effects, oral

·        Step 1) Relevant dose-descriptor:  NOAEL= 60 mg/kg/day

·        Step 2) Modification of starting point :no

·        Step 3) Assessment factors:

-Interspecies 2.5 x 4 = 10

-Intraspecies= 10

-Exposure duration= 2

-Dose response= 1

-Quality of database= 1

Global uncertainty factor=200

·        Step 4) DNEL derivation:

DNEL oral (long term, systemic effects) = 60 / 200 = 0.3 mg/kg bw/d