Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.19 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: informed assessment factors
Overall assessment factor (AF):
5
Modified dose descriptor starting point:
NOAEC
Value:
0.95 mg/m³
Explanation for the modification of the dose descriptor starting point:
Long term inhalation studies are not available. The long term systemic DNEL for the inhalation route has been derived from the oral repeated dose toxicity study. For derivation of the dose descriptor starting point a factor of 2 has been included for route-to-route extrapolation from oral to inhalative.
AF for dose response relationship:
1
Justification:
Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
1
Justification:
Chronic study – no time extrapolation required
AF for interspecies differences (allometric scaling):
1
Justification:
Default corrections for respiratory rate and respiratory volume have been included in route-to-route extrapolation
AF for other interspecies differences:
1
Justification:
No additional AF for remaining interspecies differences is required: repeated dose toxicity data from several species (mouse, rat, dog) as well as developmental toxicity studies in two species (rat, rabbit) are available showing no remarkable differences in susceptibility.
AF for intraspecies differences:
5
Justification:
Default AF for intraspecies differences (worker)
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No uncertainties remaining
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.86 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: informed assessment factors
Overall assessment factor (AF):
35
Modified dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Long term dermal studies are not available. The long term systemic DNEL for the dermal route has been derived from the oral repeated dose toxicity study. Based on the available toxicokinetic data, an oral absorption rate of 50%, and a dermal absorption rate of 1% is applied for extrapolation from the oral route.
AF for dose response relationship:
1
Justification:
Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
1
Justification:
Chronic study – no time extrapolation required
AF for interspecies differences (allometric scaling):
7
Justification:
Allometric scaling mouse to humans AF 7 (ECHA 2008).
AF for other interspecies differences:
1
Justification:
No additional AF for remaining interspecies differences is required: repeated dose toxicity data from several species (mouse, rat, dog) as well as developmental toxicity studies in two species (rat, rabbit) are available showing no remarkable differences in susceptibility.
AF for intraspecies differences:
5
Justification:
Default AF for intraspecies differences (worker)
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No uncertainties remaining
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

NOAELs used for derivation of DNEL(s):

Correction of starting point and justification of assessment factors

 

Dose descriptors identified for the endpoints of concern:

Endpoint

Quantitative dose descriptor or other information on potency

Associated relevant effect

Remarks on the study

 

Local effect

Systemic effect

 

 

Acute Toxicity

oral

-

660 mg a.i./kg bw

 

Rat acute study

dermal

irritating effects noted

>400 mg a.i./ kg bw

no effects, but no higher dose levels tested

Rat acute study

Irritation/corrosivity

Eye

Irreversible effects to the eye (R41; Cat. 1, H318)

 

No systemic effect

20% a.i.:conjunctival redness grade 3, iridial reaction grade 2

 

Rabbit study, OECD TG 405

Skin

Category 1C (corrosive)

No systemic effect

full thickness destruction of the skin tissue in 1/3 animals;

study with 20% a.i.: irritating, Category 2

 

Rabbit studies, OECD TG 404

Skin sensitisation

Skin

not sensitising

-

not sensitising

OECD TG 406, GPMT

 

Repeated dose toxicity (sub-acute/sub-chronic)

Oral

 

 

 

 

 

 

-

 

 

 

 

 

 

NOAEL = 2 mg a.i./kg bw/d (males) / LOAEL = 4 mg a.i./kg bw/d (females)

 

 

degeneration with cellular reaction in skeletal muscle, bone and heart, large macrophages in mesenteric lymph nodes and the small intestine

Combined Chronic Toxicity / Carcinogenicity Study, rat, OECD TG 453

 

Oral

 

 

-

 

 

 

 

NOAEL = 2.5 mg a.i./kg bw/d

 

 

increase of leucocytes and neutrophile granulocytes and decrease of lymphocytes

90 d rat study, EPA OPP 82-1

 

Oral

 

 

 

 

-

 

 

 

 

NOAEL = 5 mg a.i./kg bw/d

 

increase of leucocytes,atrophy in the male and female genital system; decreased body weight and food consumption

90 d study, dog, OECD TG 409

 

 

Oral

 

-

NOAEL = 1.03 mg a.i/kg bw/d (males) / NOAEL = 1.38 mg/kg bw/d (females)

alterations in the mesenteric lymph nodes

 

 

 

 

Combined Chronic Toxicity / Carcinogenicity Study, mouse, comparable to EU method B.33;

Read-across

Developmental toxicity

oral

-

NOAEL = 30 mg a.i./kg bw/d (rabbit)

 

NOAEL = 8 mg a.i./kg bw/d (rat)

No developmental effects

 

increase in incidence of unilateral hydroureter, interparietal and supraoccipital delayed ossification, slight increase in unilateral renal pelvic cavitation

OECD TG 414, rabbit

 

OECD TG 414, rat

Fertility

oral

-

NOAEL (parental, reproductive) = 6 mg a.i./kg bw/day

 

 

 

 

 

 

 

NOAEL (development) = 20 mg a.i./kg bw/day.

 

decreases in body weight, body weight gain and relative food consumption;

reduced number of implantation sites + reduced numbers of living pups

 

 

no effects

 

rat 2 generation study, OECD TG 416

Carcinogenicity

Oral

 

 

 

 

 

 

Oral

 

-

 

 

 

 

 

 

-

NOAEL(carcinogenicity) = 7 mg a.i./kg bw/d (males) / NOAEL(carcinogenicity) = 13 mg a.i./kg bw/d (females)

 

NOAEL(carcinogenicity)= 12.1 mg a.i/kg bw/d (males) /NOAEL(carcinogenicity)= 15.5 mg/kg bw/d (females)

No carcinogenic effects

 

 

 

 

No carcinogenic effects

 

 

 

 

 

Combined Chronic Toxicity / Carcinogenicity Study, rat, OECD TG 453

 

 

Combined Chronic Toxicity / Carcinogenicity Study, mouse, comparable to EU method B.33;

Read-across

 

Modification of the relevant dose descriptors to the correct starting point (NOAEL from oral 90 d repeated dose study):

Oral absorption

The systemic bioavailability of 14C labelled DOPA-Glycinate was 34% following oral administration (rat).

The Guidance on Information requirements and Chemical Safety Assessment, R.7c (Nov. 2012) states:

“In practice, an adjustment in oral toxicity factor (to account forabsorbed dosein the dermal exposure pathway) is recommended when the following conditions are met: (1) the toxicity value derived from the critical study is based on an administered dose (e.g., delivery in diet or by gavage) in its study design; (2) a scientifically defensible database demonstrates that the GI absorption of the chemical in question, from a medium (e.g., water, feed) similar to the one employed in the critical study, is significantly less than 100% (e.g., <50%). A cut-off of 50% GI absorption is recommended to reflect the intrinsic variability in the analysis of absorption studies. Thus, this cut-off level obviates the need to make comparatively small adjustments in the toxicity value that would otherwise impart on the process a level of accuracy that is not supported by the scientific literature.”

Thus an oral absorption of 50% is used for safety assessment.

 

Oral to inhalatory

No data for absorption after inhalatory exposure are available. By default an assessment factor of 2 is introduced for extrapolation from the oral route in accordance with REACH TGD.

 

Oral to dermal

In an in vitro dermal absorption assay with human skin, the systemically available dose as defined in the Guidance on Information requirements and chemical safety assessment, R.7c* of DOPA-Glycinate was 0.6±0.6% for the high exposure scenario (20% a.i.), and 5.0±2.5% for the low exposure scenario (0.2% a.i.), respectively.

For the worker exposure scenarios only the value obtained with the high exposure scenario is relevant within the context of REACH.

Based on the available data, a dermal absorption rate of 1% is applied forextrapolation from the oral route.

* According to the Guidance on Information requirements and chemical safety assessment, R.7c:"Dermal absorption represents the amount of topically applied test substance that is found in the epidermis (stratum corneum excluded) and in the dermis, and this quantity is therefore taken as systemically available. Dermal absorption is influenced by many factors, e.g. physico-chemical properties of the substance, its vehicle and concentration, and the exposure pattern (e.g. occlusion of the application site) as well as the skin site of the body […]. The term percutaneous penetration refers to in vitro experiments and represents the amount of topically applied test substance that is found in the receptor fluid – this quantity is taken as systemically available."

 

Modification of the relevant dose descriptors to the correct starting point (derived from oral combined chronic toxicity / carcinogenicity test, OECD TG 453 in mouse)

CD1-mice were treated with DOPA-Glycinate in diet for 78 weeks at dose levels of 0, 2, 6 and 20 (7) mg a.i./kg bw/d (males) and 0, 4, 12 and 40 (13) mg a.i./kg bw/d (females).

Histopathological examinations revealed the following treatment-related findings: degeneration with cellular reaction in skeletal muscle, bone and heart, large macrophages in mesenteric lymph nodes and the small intestine, vacuolisation of epithelial cells in the epididymides, hyperplasia of the secretory cells of the bronchial epithelium in the lungs.

The chronic NOAEL derived from the combined chronic toxicity and carcinogenicity study in mice is established at 2 mg a.i./kg bw/d in males and was not identified in females (histological change to muscle at 4 mg a.i./kg bw/d).

From the other available repeated dose toxicity studies there was no evidence that females could be more susceptible to toxic effects of DOPA-Glycinate than males. Thus, an assessment factor of 2 was applied for the extrapolation from LOAEL to NOAEL resulting in an extrapolated NOAEL of 2 mg/kg bw/d for females.

 

Uncertainties

AF

REACH

Justification

Allometric scaling (inhalation)

1

Default corrections for respiratory rate and respiratory volume have been included in route-to-route extrapolation

Allometric scaling (dermal)

7

Allometric scaling mouse to humans AF 7 (ECHA 2008).

Remaining interspecies differences

1

No additional AF for remaining interspecies differences is required: repeated dose toxicity data from several species (mouse, rat, dog) as well as developmental toxicity studies in two species (rat, rabbit) are available showing no remarkable differences in susceptibility.

Intraspecies differences

5

Default AF for intraspecies differences (worker)

Differences in duration of exposure

1

Chronic study – no time extrapolation required

Dose response and endpoint specific/severity

 

1

Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.

Quality of whole database

1

The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

 

Remaining uncertainties

1

No uncertainties remaining

 

Justification for not applying an additional assessment factor of 2.5 for remaining interspecies differences:

In general, lower primary aliphatic amines are metabolised to the corresponding carboxylic acid and urea. The secondary/tertiary site would be expected to undergo oxidation mediated bycytochrome P-450 or mixed function amine oxidases. Based on this, no differences in toxicodynamics are expected. This is further supported by the availability ofrepeated dose toxicity studies in several species (mouse, rat, dog) which showed no remarkable differences in susceptibility. Thus, the use of the additional factor of 2.5 is not justified.

 

Worker-DNEL long-term for dermal route (systemic): 2.86 mg/kg bw/d

Start value: 2.0 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 100 mg/kg bw/d

Overall AF: 7*1*5*1*1*1*1 = 35

 

Worker-DNEL long-term for inhalation route (systemic): 0.19 mg/m³

Start value: 2.0 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 0.95 mg/m³

 

For workers the corrected inhalatory NOEC is calculated according to the following equation:

corrected inhalatory NOAEC  = oral NOAEL x 1/sRVratx ABSoral-rat/ ABSinh-humanx sRVhuman/ wRV

                                             = 2.0 x 1/0.384 x 50/100 x 6.7/10

The corrected inhalatory NOAECworker(8 h) is therefore:

                                             = 0.95mg/m³(8 h-TWA)

 

Overall AF: 1*1*5*1*1*1*1 = 5

 

These DNELs do not address the potential for local irritation. The risk characterisation will consider whether specific risk management measures are necessary to protect against local effects.

 

The NOAELs derived from the oral two generation study (OECD TG 416) as well as from the developmental toxicity studies (OECD TG 414) were higher than the NOAEL derived from this repeated dose toxicity study. As no higher Assessment factors need to be applied for reproductive and developmental effects, the DNELs for those endpoints would also be higher. Thus, the repeated dose toxicity-DNELs are also protective for fertility as well as for development.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.047 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: informed assessment factors
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC
Value:
0.47 mg/m³
Explanation for the modification of the dose descriptor starting point:
Long term inhalation studies are not available. The long term systemic DNEL for the inhalation route has been derived from the oral repeated dose toxicity study. For derivation of the dose descriptor starting point a factor of 2 has been included for route-to-route extrapolation from oral to inhalative.
AF for dose response relationship:
1
Justification:
Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
1
Justification:
Chronic study – no time extrapolation required
AF for interspecies differences (allometric scaling):
1
Justification:
Default corrections for respiratory rate and respiratory volume have been included in route-to-route extrapolation
AF for other interspecies differences:
1
Justification:
No additional AF for remaining interspecies differences is required: repeated dose toxicity data from several species (mouse, rat, dog) as well as developmental toxicity studies in two species (rat, rabbit) are available showing no remarkable differences in susceptibility.
AF for intraspecies differences:
10
Justification:
Default AF for intraspecies differences (general population)
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No uncertainties remaining
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.286 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: informed assessment factors
Overall assessment factor (AF):
70
Modified dose descriptor starting point:
NOAEL
Value:
20 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Long term dermal studies are not available. The long term systemic DNEL for the dermal route has been derived from the oral repeated dose toxicity study. Based on the available toxicokinetic data, an oral absorption rate of 50%, and a dermal absorption rate of 5% is applied for extrapolation from the oral route.
AF for dose response relationship:
1
Justification:
Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
1
Justification:
Chronic study – no time extrapolation required
AF for interspecies differences (allometric scaling):
7
Justification:
Allometric scaling mouse to humans AF 7 (ECHA 2008).
AF for other interspecies differences:
1
Justification:
No additional AF for remaining interspecies differences is required: repeated dose toxicity data from several species (mouse, rat, dog) as well as developmental toxicity studies in two species (rat, rabbit) are available showing no remarkable differences in susceptibility.
AF for intraspecies differences:
10
Justification:
Default AF for intraspecies differences (general population)
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No uncertainties remaining
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.029 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: informed assessment factors
Overall assessment factor (AF):
70
Modified dose descriptor starting point:
NOAEL
Value:
2 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
1
Justification:
Chronic study – no time extrapolation required
AF for interspecies differences (allometric scaling):
7
Justification:
Allometric scaling mouse to humans AF 7 (ECHA 2008).
AF for other interspecies differences:
1
Justification:
No additional AF for remaining interspecies differences is required: repeated dose toxicity data from several species (mouse, rat, dog) as well as developmental toxicity studies in two species (rat, rabbit) are available showing no remarkable differences in susceptibility.
AF for intraspecies differences:
10
Justification:
Default AF for intraspecies differences (general population)
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor
AF for remaining uncertainties:
1
Justification:
No uncertainties remaining
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

NOAELs used for derivation of DNEL(s):

Correction of starting point and justification of assessment factors

 

Dose descriptors identified for the endpoints of concern:

Endpoint

Quantitative dose descriptor or other information on potency

Associated relevant effect

Remarks on the study

 

Local effect

Systemic effect

 

 

Acute Toxicity

oral

-

660 mg a.i./kg bw

 

Rat acute study

dermal

irritating effects noted

>400 mg a.i./ kg bw

no effects, but no higher dose levels tested

Rat acute study

Irritation/corrosivity

Eye

Irreversible effects to the eye (R41; Cat. 1, H318)

 

No systemic effect

20% a.i.:conjunctival redness grade 3, iridial reaction grade 2

 

Rabbit study, OECD TG 405

Skin

Category 1C (corrosive)

No systemic effect

full thickness destruction of the skin tissue in 1/3 animals;

study with 20% a.i.: irritating, Category 2

 

Rabbit studies, OECD TG 404

Skin sensitisation

Skin

not sensitising

-

not sensitising

OECD TG 406, GPMT

 

Repeated dose toxicity (sub-acute/sub-chronic)

Oral

 

 

 

 

 

 

-

 

 

 

 

 

 

NOAEL = 2 mg a.i./kg bw/d (males) / LOAEL = 4 mg a.i./kg bw/d (females)

 

 

degeneration with cellular reaction in skeletal muscle, bone and heart, large macrophages in mesenteric lymph nodes and the small intestine

Combined Chronic Toxicity / Carcinogenicity Study, rat, OECD TG 453

 

Oral

 

 

-

 

 

 

 

NOAEL = 2.5 mg a.i./kg bw/d

 

 

increase of leucocytes and neutrophile granulocytes and decrease of lymphocytes

90 d rat study, EPA OPP 82-1

 

Oral

 

 

 

 

-

 

 

 

 

NOAEL = 5 mg a.i./kg bw/d

 

increase of leucocytes,atrophy in the male and female genital system; decreased body weight and food consumption

90 d study, dog, OECD TG 409

 

 

Oral

 

-

NOAEL = 1.03 mg a.i/kg bw/d (males) / NOAEL = 1.38 mg/kg bw/d (females)

alterations in the mesenteric lymph nodes

 

 

 

 

Combined Chronic Toxicity / Carcinogenicity Study, mouse, comparable to EU method B.33;

Read-across

Developmental toxicity

oral

-

NOAEL = 30 mg a.i./kg bw/d (rabbit)

 

NOAEL = 8 mg a.i./kg bw/d (rat)

No developmental effects

 

increase in incidence of unilateral hydroureter, interparietal and supraoccipital delayed ossification, slight increase in unilateral renal pelvic cavitation

OECD TG 414, rabbit

 

OECD TG 414, rat

Fertility

oral

-

NOAEL (parental, reproductive) = 6 mg a.i./kg bw/day

 

 

 

 

 

 

 

NOAEL (development) = 20 mg a.i./kg bw/day.

 

decreases in body weight, body weight gain and relative food consumption;

reduced number of implantation sites + reduced numbers of living pups

 

 

no effects

 

rat 2 generation study, OECD TG 416

Carcinogenicity

Oral

 

 

 

 

 

 

Oral

 

-

 

 

 

 

 

 

-

NOAEL(carcinogenicity) = 7 mg a.i./kg bw/d (males) / NOAEL(carcinogenicity) = 13 mg a.i./kg bw/d (females)

 

NOAEL(carcinogenicity)= 12.1 mg a.i/kg bw/d (males) /NOAEL(carcinogenicity)= 15.5 mg/kg bw/d (females)

No carcinogenic effects

 

 

 

 

No carcinogenic effects

 

 

 

 

 

Combined Chronic Toxicity / Carcinogenicity Study, rat, OECD TG 453

 

 

Combined Chronic Toxicity / Carcinogenicity Study, mouse, comparable to EU method B.33;

Read-across

 

Modification of the relevant dose descriptors to the correct starting point (NOAEL from oral 90 d repeated dose study):

Oral absorption

The systemic bioavailability of 14C labelled DOPA-Glycinate was 34% following oral administration (rat).

The Guidance on Information requirements and Chemical Safety Assessment, R.7c (Nov. 2012) states:

“In practice, an adjustment in oral toxicity factor (to account forabsorbed dosein the dermal exposure pathway) is recommended when the following conditions are met: (1) the toxicity value derived from the critical study is based on an administered dose (e.g., delivery in diet or by gavage) in its study design; (2) a scientifically defensible database demonstrates that the GI absorption of the chemical in question, from a medium (e.g., water, feed) similar to the one employed in the critical study, is significantly less than 100% (e.g., <50%). A cut-off of 50% GI absorption is recommended to reflect the intrinsic variability in the analysis of absorption studies. Thus, this cut-off level obviates the need to make comparatively small adjustments in the toxicity value that would otherwise impart on the process a level of accuracy that is not supported by the scientific literature.”

Thus an oral absorption of 50% is used for safety assessment.

 

Oral to inhalatory

No data for absorption after inhalatory exposure are available. By default an assessment factor of 2 is introduced for extrapolation from the oral route in accordance with REACH TGD.

 

Oral to dermal

In an in vitro dermal absorption assay with human skin, the systemically available doseas defined intheGuidance on Information requirements and chemical safety assessment, R.7c*of DOPA-Glycinate was 0.6±0.6% for the high exposure scenario (20% a.i.), and 5.0±2.5% for the low exposure scenario (0.2% a.i.), respectively. The low exposure scenario is relevant for the consumer uses. Based on the available data, a dermal absorption rate of 5% is applied for extrapolation from the oral route.

*According to the Guidance on Information requirements and chemical safety assessment, R.7c: "Dermal absorption represents the amount of topically applied test substance that is found in the epidermis (stratum corneum excluded) and in the dermis, and this quantity is therefore taken as systemically available. Dermal absorption is influenced by many factors, e.g. physico-chemical propertxies of the substance, its vehicle and concentration, and the exposure pattern (e.g. occlusion of the application site) as well as the skin site of the body […]. The term percutaneous penetration refers to in vitro experiments and represents the amount of topically applied test substance that is found in the receptor fluid – this quantity is taken as systemically available."

 

Modification of the relevant dose descriptors to the correct starting point (derived from oral combined chronic toxicity / carcinogenicity test, OECD TG 453 in mouse)

CD1-mice were treated with DOPA-Glycinate in diet for 78 weeks at dose levels of 0, 2, 6 and 20 (7) mg a.i./kg bw/d (males) and 0, 4, 12 and 40 (13) mg a.i./kg bw/d (females).

Histopathological examinations revealed the following treatment-related findings: degeneration with cellular reaction in skeletal muscle, bone and heart, large macrophages in mesenteric lymph nodes and the small intestine, vacuolisation of epithelial cells in the epididymides, hyperplasia of the secretory cells of the bronchial epithelium in the lungs.

The chronic NOAEL derived from the combined chronic toxicity and carcinogenicity study in mice is established at 2 mg a.i./kg bw/d in males and was not identified in females (histological change to muscle at 4 mg a.i./kg bw/d).

From the other available repeated dose toxicity studies there was no evidence that females could be more susceptible to toxic effects of DOPA-Glycinate than males. Thus, an assessment factor of 2 was applied for the extrapolation from LOAEL to NOAEL resulting in an extrapolated NOAEL of 2 mg/kg bw/d for females.

 

Uncertainties

AF

REACH

Justification

Allometric scaling (inhalation)

1

Default corrections for respiratory rate and respiratory volume have been included in route-to-route extrapolation

Allometric scaling (dermal)

7

Allometric scaling mouse to humans AF 7 (ECHA 2008).

Remaining interspecies differences

1

No additional AF for remaining interspecies differences is required: repeated dose toxicity data from several species (mouse, rat, dog) as well as developmental toxicity studies in two species (rat, rabbit) are available showing no remarkable differences in susceptibility.

Intraspecies differences

10

Default AF for intraspecies differences (general population)

Differences in duration of exposure

1

Chronic study – no time extrapolation required

Dose response and endpoint specific/severity

 

1

Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.

Quality of whole database

1

The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

 

Remaining uncertainties

1

No uncertainties remaining

 

Justification for not applying an additional assessment factor of 2.5 for remaining interspecies differences:

In general, lower primary aliphatic amines are metabolised to the corresponding carboxylic acid and urea. The secondary/tertiary site would be expected to undergo oxidation mediated bycytochrome P-450 or mixed function amine oxidases. Based on this, no differences in toxicodynamics are expected. This is further supported by the availability of repeated dose toxicity studies in several species (mouse, rat, dog) which showed no remarkable differences in susceptibility. Thus, the use of the additional factor of 2.5 is not justified.

 

General population-DNEL long-term for dermal route (systemic): 0.286 mg/kg bw/d

Start value: 2.0 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 20 mg/kg bw/d

Overall AF: 7*1*10*1*1*1*1 = 70

 

General population-DNEL long-term for oral route (systemic): 0.029 mg/kg bw/d

Start value: 2.0 mg/kg bw/d

Route of original study: oral

Overall AF: 7*1*10*1*1*1*1 = 70

 

General population -DNEL long-term for inhalation route (systemic): 0.047 m³

Start value: 2.0 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 0.47 mg/m³

 

For general population the corrected inhalatory NOEC is calculated according to the following equation:

corrected inhalatory NOAEC  = oral NOAEL x 1/sRVratx ABSoral-rat/ ABSinh-human

                                             = 2.0 x 1/1.152 x 50/100

The corrected inhalatory NOAECgeneral population (24 h) is therefore:

                                             = 0.47 mg/m³ (24 h)

Overall AF:1*1*10*1*1*1*1 = 10

 

These DNELs do not address the potential for local irritation. The risk characterisation will consider whether specific risk management measures are necessary to protect against local effects.

The NOAELs derived from the oral two generation study (OECD TG 416) as well as from the developmental toxicity studies (OECD TG 414) were higher than the NOAEL derived from this repeated dose toxicity study. As no higher Assessment factors need to be applied for reproductive and developmental effects, the DNELs for those endpoints would also be higher. Thus, the repeated dose toxicity-DNELs are also protective for fertility as well as for development.