Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.28 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

5

Dose descriptor starting point:

NOAEL

Value:

2 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

1.4 mg/m³

Explanation for the modification of the dose descriptor starting point:

The calculation of the DNEL is based on an oral NOAEL observed in a chronic oral toxicity study in mice (OECD 453; 2012).

To correct the interspecies difference between mouse and human the no observed effect level has to be corrected as follows:

Corrected starting point for the inhalative route for workers:

= NOAEL(oral) * (1/0.67 m³/kg bw/day) * (ABSoral-mouse/ABSinh-human) * 6.7 m³ (8h) /10 m³ (8h)* (7 days exposure mouse/5 days exposure worker)

= 2 mg/kg bw/day * (1/0.67 m³/kg bw/day) * (1/2) * 0.67 m³ * 1.4= 1.4 mg/m³

As worst case as recommended in the ECHA Guidance R.8 (2012), it is assumed that oral absorption rate is 50% of that of of inhalation absorption.

(ABSoral-mouse = oral absorption in mice, ABSinh-human = inhalation absorption rate in humans)

Thus, the corrected starting point for workers was 1.4 mg/m³ for inhalation.

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

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Hazard assessment conclusion:

medium hazard (no threshold derived)

Hazard assessment conclusion:

medium hazard (no threshold derived)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

35

Dose descriptor starting point:

NOAEL

Value:

2 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

140 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.

Dermal NOAEL = oral NOAEL*ABS(oral)/ABS(dermal) * (7 days exposure rat/5 days exposure worker) = 2 mg/kg bw/day *(50%/1%) * 1.4 = 140 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:

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

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Hazard assessment conclusion:

medium hazard (no threshold derived)

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	-	LD50 > 300 mg/kg bw; LD50 cut-off 500 mg/kg bw	-	Rat acute study
Dermal	Irritating effects noted	LD50 > 400 mg a.i./ kg bw (Although the substance has only been tested at 400 mg a.i./kg bw, the consideration of all available data on acute dermal toxicity, acute oral toxicity, toxicokinetics and dermal penetration leads to the conclusion, that the dermal LD50 will be > 2000 mg a.i./kg bw and thus no classification for acute dermal toxicity will be required (see EPS on acute dermal toxicity).	No effects, but no higher dose levels tested	Rat acute study
Irritation/corrosivity
Eye	Irreversible effects to the eye (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, H314 (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
Repeated dose toxicity (sub-acute/sub-chronic/chronic)
Oral	-	NOAEL = 2 mg a.i./kg bw/day (males) / LOAEL = 4 mg a.i./kg bw/day (females)	Degeneration with cellular reaction in skeletal muscle, bone and heart	Combined Chronic Toxicity / Carcinogenicity Study, mouse, OECD TG 453
Oral	-	NOAEL = 2.5 mg a.i./kg bw/day	Increase of leucocytes and neutrophile granulocytes and decrease of lymphocytes	90 day rat study, EPA OPP 82-1
Oral	-	NOAEL = 5 mg a.i./kg bw/day	Increase of leucocytes, decreased body weight and food consumption	90 day study, dog, OECD TG 409
Oral	-	NOAEL = 12 mg a.i./kg bw/day	Increase of leucocytes, platelets, neutrophilic granulocytes, lymphocytes and basophilic granulocytes, urea, aspartate aminotransferase and decrease in creatinine, decreased body weight and food consumption	90 day study, mouse, similar to OECD TG 408 (dose-range finder for OECD TG 453 Combined Chronic Toxicity / Carcinogenicity Study)
Developmental toxicity
Oral	-	NOAEL = 30 mg a.i./kg bw/day (rabbit) NOAEL = 50 mg a.i./kg bw/day (rat)	No developmental effects No developmental effects	OECD TG 414, rabbit OECD TG 414, rat
Fertility
Oral	-	NOAEL (parental) = 6 mg a.i./kg bw/day NOAEL (reproductive, development) = 20 mg a.i./kg bw/day	Decreases in body weight, body weight gain and relative food consumption No effects	Rat 2 generation study, OECD TG 416
Carcinogenicity
Oral	-	NOAEL(carcinogenicity) = 7 mg a.i./kg bw/day (males) / NOAEL(carcinogenicity) = 13 mg a.i./kg bw/day (females)	No carcinogenic effects	Combined Chronic Toxicity / Carcinogenicity Study, mouse, OECD TG 453

Oral absorption

The systemic bioavailability of 14C labelled registration substance 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 for absorbed dose in 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 the registration substance 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 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 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 the registration substance in diet for 78 weeks at dose levels of 0, 2, 6 and 20 (7) mg a.i./kg bw/day (males) and 0, 4, 12 and 40 (13) mg a.i./kg bw/day (females).

Histopathological examinations revealed the following treatment-related findings: degeneration with cellular reaction in skeletal muscle, bone and heart.

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

From the other available repeated dose toxicity studies there was no evidence that females could be more susceptible to toxic effects of the registration substance 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/day 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 by cytochrome 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.

Worker-DNEL long-term for dermal route (systemic): 4 mg/kg bw/day

Start value: 2.0 mg/kg bw/day

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 140 mg/kg bw/day

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

Worker-DNEL long-term for inhalation route (systemic): 0.28 mg/m³

Start value: 2.0 mg/kg bw/day

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 1.4 mg/m³

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

corrected inhalatory NOAEC = oral NOAEL x 1/sRV_mousex ABS_oral-mouse/ABS_inh-humanx sRV_human/wRV x (exposure duration mouse/exposure duration worker)

= 2.0 x 1/0.67 x 50/100 x 6.7/10 x 7day/week / 5day/week

The corrected inhalatory NOAEC_worker(8 h) is therefore:

= 1.4 mg/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.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.05 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Dose descriptor starting point:

NOAEL

Value:

2 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

0.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

The calculation of the DNEL is based on an oral NOAEL observed in a chronic oral toxicity study in mice (OECD 453; 2012).

To correct the interspecies difference between mouse and human the no observed effect level has to be corrected as follows:

Corrected starting point for the inhalative route for general population:

= NOAEL(oral) * (1/2.01 m³/kg bw/day) * (ABSoral-mouse/ABSinh-human)

= 2 mg/kg bw/day * (1/2.01 m³/kg bw/day) * (1/2) = 0.5 mg/m³

As worst case as recommended in the ECHA Guidance R.8 (2012), it is assumed that oral absorption rate is 50% of that of inhalation absorption.

(ABSoral-mouse = oral absorption in mice, ABSinh-human = inhalation absorption rate in humans)

Thus, the corrected starting point for workers was 0.5 mg/m³ for inhalation.

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

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Hazard assessment conclusion:

medium hazard (no threshold derived)

Hazard assessment conclusion:

medium hazard (no threshold derived)

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 derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

70

Dose descriptor starting point:

NOAEL

Value:

2 mg/kg bw/day

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.

Dermal NOAEL = oral NOAEL*ABS(oral)/ABS(dermal) = 2 mg/kg bw/day *(50%/5%) = 20 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

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

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 derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

70

Dose descriptor starting point:

NOAEL

Value:

2 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No modification of the dose descriptor starting point required as the NOAEL is based on a chronic oral toxicity study.

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

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

Hazard assessment conclusion:

medium hazard (no threshold derived)

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	-	LD50 > 300 mg/kg bw; LD50 cut-off 500 mg/kg bw	-	Rat acute study
Dermal	Irritating effects noted	LD50 > 400 mg a.i./ kg bw (Although the substance has only been tested at 400 mg a.i./kg bw, the consideration of all available data on acute dermal toxicity, acute oral toxicity, toxicokinetics and dermal penetration leads to the conclusion, that the dermal LD50 will be > 2000 mg a.i./kg bw and thus no classification for acute dermal toxicity will be required.(see EPS on acute dermal toxicity)	No effects, but no higher dose levels tested	Rat acute study
Irritation/corrosivity
Eye	Irreversible effects to the eye (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, H314 (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
Repeated dose toxicity (sub-acute/sub-chronic/chronic)
Oral	-	NOAEL = 2 mg a.i./kg bw/day (males) / LOAEL = 4 mg a.i./kg bw/day (females)	Degeneration with cellular reaction in skeletal muscle, bone and heart	Combined Chronic Toxicity / Carcinogenicity Study, mouse, OECD TG 453
Oral	-	NOAEL = 2.5 mg a.i./kg bw/day	Increase of leucocytes and neutrophile granulocytes and decrease of lymphocytes	90 day rat study, EPA OPP 82-1
Oral	-	NOAEL = 5 mg a.i./kg bw/day	Increase of leucocytes, decreased body weight and food consumption	90 day study, dog, OECD TG 409
Oral	-	NOAEL = 12 mg a.i./kg bw/day	Increase of leucocytes, platelets, neutrophilic granulocytes, lymphocytes and basophilic granulocytes, urea, aspartate aminotransferase and decrease in creatinine, decreased body weight and food consumption	90 day study, mouse, similar to OECD TG 408 (dose-range finder for OECD TG 453 Combined Chronic Toxicity / Carcinogenicity Study)
Developmental toxicity
Oral	-	NOAEL = 30 mg a.i./kg bw/day (rabbit) NOAEL = 50 mg a.i./kg bw/day (rat)	No developmental effects No developmental effects	OECD TG 414, rabbit OECD TG 414, rat
Fertility
Oral	-	NOAEL (parental) = 6 mg a.i./kg bw/day NOAEL (reproductive, development) = 20 mg a.i./kg bw/day	Decreases in body weight, body weight gain and relative food consumption No effects	Rat 2 generation study, OECD TG 416
Carcinogenicity
Oral	-	NOAEL(carcinogenicity) = 7 mg a.i./kg bw/day (males) / NOAEL(carcinogenicity) = 13 mg a.i./kg bw/day (females)	No carcinogenic effects	Combined Chronic Toxicity / Carcinogenicity Study mouse, OECD TG 453