Registration Dossier

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

75 mg/kg bw/day

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Modified dose descriptor starting point:

NOAEL

Value:

15 000 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 dermal DNEL has been derived from the oral 91 day repeated dose toxicity study with the structurally very similar source substance MDEA-Esterquat C16-18 and C18 satd.. Based on toxicokinetic data, an assessment factor for the route to route extrapolation (oral to dermal) of 30 has been applied.

AF for dose response relationship:

1

Justification:

In a reliable, adequate and relevant subchronic study in rats there were no toxicological effects relevant to humans up to and including the highest administered dose of 500 mg/kg bw/d. The NOAEL is reliable. No adjustment is required.

AF for differences in duration of exposure:

2

Justification:

Default assessment factor for extrapolation from subchronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling rat to humans AF 4 (ECHA 2008).

AF for other interspecies differences:

2.5

Justification:

Default AF for remaining interspecies differences

AF for intraspecies differences:

5

Justification:

Default AF for workers

AF for the quality of the whole database:

1

Justification:

The key study was conducted according to modern regulatory standards and was adequately reported. The tested dose range included the highest administered dose of 500 mg/kg bw/day. 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:

2

Justification:

To account for a lower sensitivity and the limited scope of the repeated dose toxicity studies for detecting effects on reproductive organs an additional assessment factor of 2 was applied.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Route-to-route extrapolation

Oral absorption

No data exist on differences in bioavailability following oral or dermal exposure between experimental animals and humans, and a similar bioavailability is assumed by default.

Oral to dermal

For systemic effects available in vivo toxicokinetic data of the structurally similar source substance MDEA-Esterquat C16-18 and C18 unsatd. will be taken into account for the route to route extrapolation.

Absorption after oral application: 48 ± 6 %

Absorption after dermal application: < 1.4%

Proposed assessment factor for the route to route extrapolation (oral to dermal): 30

A factor of 34 would have suggested a higher accuracy than the data actually provide; the use of a factor of 30 result in a more conservative dermal DNEL.

DERIVATION OF DNELs

DNELs long term systemic effects

Uncertainties	AF	Justification
Interspecies differences, dermal + oral	4	Allometric scaling rat to humans (ECHA 2008).
Interspecies differences, inhalation	1	No allometric scaling animals to humans as inhalation; differences in respiratory volume already included in route-to-route extrapolation (ECHA 2008).
Remaining interspecies differences	2.5	Default AF for remaining interspecies differences
Intraspecies differences, worker	5	Default AF for workers
Differences in duration of exposure	2 (OECD 408, general toxicity and fertility)	Default AF for extrapolation from sub-chronic to chronic (ECHA 2008).
	1 (OECD 414 developmental toxicity)	No time extrapolation factor has to be applied because the susceptible window is fully covered.
Dose response and endpoint specific/severity	1	The NOAEL is reliable. No adjustment is required.
Quality of whole database	1	The key studies were conducted according to modern regulatory standards and were adequately reported.
Remaining uncertainties	1 (OECD 408 general toxicity, OECD 414)	No remaining uncertainties
Remaining uncertainties	2 (OECD 408 fertility)	To account for a lower sensitivity and the limited scope of the repeated dose toxicity studies for detecting effects on reproductive organs an additional assessment factor of 2 was applied.

DNELs for general toxicity and fertility derived from the oral subchronic study NOAEL (OECD guideline 408; source substance MDEA-Esterquat C16 -18 and C18 unsatd.)

In a subchronic toxicity study comparable to OECD guideline 408, the source substance MDEA-Esterquat C16-18 and C18 unsatd. (10 % a.i.) was administered to 15 Charles River CD rats / sex/ dose by gavage at dose levels of 1, 10 and 500 mg/kg bw/ day for a period of 13- weeks. One control group received the vehicle, deionized water, and a second control group received pH-adjusted, deionized water (pH 2.5). The regimen for both control groups was identical to treatment groups.

No test substance-related findings were detected or observed in clinical examinations, body weights, food consumption values, haematology, urinalysis, neurobehavior, clinical biochemistry or pathology evaluations, including absolute and relative organ weights of ovary and testis and the histopathology of the reproductive organs (gonads, mammary gland (females only), prostate and seminal vesicle, uterus with cervix and vagina). The no effect level (NOEL) for this study is the highest tested dose level of 500 mg/kg bw/day of the test article.

An additional AF of 2 has been included for the derivation of the DNEL fertility taking account the lower sensitivity and the limited scope of the repeated dose toxicity studies for detecting effects on reproductive organs.

DNEL general toxicity worker, long-term dermal route (systemic): 150 mg/kg bw/d

Start value: NOEL(general toxicity) = 500 mg/kg bw/d

Route of original study: oral, rat

Dose descriptor starting point after route-to-route extrapolation: 15000 mg/kg bw/d

Overall AF: 4*2.5*5*2*1*1*1 = 100

DNEL fertility worker, long-term dermal route (systemic): 75 mg/kg bw/d

Start value: NOEL (fertility) = 500 mg/kg bw/d

Route of original study: rat, oral

Dose descriptor starting point after route-to-route extrapolation: 15000 mg/kg bw/d

Overall AF: 4*2.5*5*2*1*1*2 = 200

DNELs for development derived from the prenatal development study NOAEL (OECD guideline 414; source substance MDEA-Esterquat C16 -18 and C18 unsatd.)

In the developmental toxicity study (OECD guideline 414), groups of 25 mated female Wistar rats were treated with the structurally similar source substance MDEA-Esterquat C16-18 and C18 unsatd. orally by gavage once daily from day 6 through 15 post coitum, at dose levels of 0, 50, 250 and 1000 mg/kg bw/day. Females were sacrificed on day 21 post coitum and the fetuses were removed by Caesarean section.

At 50, 250, and 1000 mg/kg, for the dams no test substance-related deaths or clinical signs as were noted as reaction to treatment. Up to and including the highest dose level of 1000 mg/kg, food consumption and body weight development of the dams were not affected by treatment with the test substance. At necropsy, no test substance-related abnormal findings in the dams were noted in any group.

DNEL development worker, long-term dermal route (systemic): 600 mg/kg bw/d

Start value: NOAEL (development): 1000 mg/kg bw/d

Route of original study: rat, oral

Dose descriptor starting point after route-to-route extrapolation: 30000 mg/kg bw/d

Overall AF: 4*2.5*5*1*1*1*1 = 50

Conclusion

Strictly conservative DNELs long-term systemic effects have been derived from results of the available test data, which include a pre-natal developmental study and sub acute and sub-chronic studies with evaluation of reproductive endpoints.To account for a lower sensitivity and the limited scope of the repeated dose toxicity studies for detecting effects on reproductive organs an additional assessment factor of 2 was applied. The additional assessment factor of 2 was chosen in accordance with the REACH TGD (Chapter R8) and on the basis of the results of a retrospective analysis of the added value of the rat two-generation reproductive toxicity study versus the rat subchronic toxicity study. In this analysis on 47 reproductive toxic and 75 non reproductive toxic substances, it could be demonstrated, that on average, only a small difference of less than twofold in overall NOAELs was found between the rat two-generation study and the rat 90-day study (Janner et al. 2007).

The 28-day subacute studies according to OECD 407 with the target and the source substance showed a comparable low systemic toxicity after repeated exposure for both substances. Together with the high structural similarity between the source substance and the target substance an additional assessment factor for remaining uncertainties due to the read-across approach is not justified.

No DNELs for the inhalation route were derived as inhalation is not a relevant route of exposure to MDEA Esterquat C18 satd. due to the physicochemical properties of the substance and the nature of its uses. MDEA Esterquat C18 unsatd. is a waxy solid. Generation of inhalable particles such as dust or aerosols is therefore not to be expected. Vaporization needs not to be considered due to the substance’s very low vapour pressure of 7.33E-18 Pa at 25°C. The generation of dusts and aerosols is prevented by appropriate RMMs, and the substance is not used in spray applications.

The critical long term DNEL for workers is the DNEL worker fertility for dermal route (systemic) of 75 mg/kg bw/day.

A DNEL for acute toxicity is not established because no acute toxicity hazard (leading to classification and labelling) has been identified. Results of laboratory animal studies show a low acute toxicity after oral and dermal exposure. Therefore the acute intrinsic toxic activity of MDEA Esterquat C18 satd. is considered to be low. The occurrence of a systemic toxicity relevant to humans after inhalation is unlikely.

A DNEL local effects via dermal and inhalation route is not established because the substance is not classified dangerous for respiratory or skin irritation/corrosion and respiratory or skin sensitisation. The substance is not classified for eye irriation therefore there is no hazard identified for eyes.

References

Janer et al. (2007): A retrospective analysis of the added value of the rat two-generation reproductive toxicity study versus the rat subchronic toxicity study.Reprod Toxicol. 2007 Jul; 24(1):103-13

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.25 mg/kg bw/day

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

400

Modified dose descriptor starting point:

NOAEL

Value:

500 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

no route to route extrapolation required

AF for dose response relationship:

1

Justification:

In a reliable, adequate and relevant subchronic study in rats there were no toxicological effects relevant to humans up to and including the highest administered dose of 500 mg/kg bw/d. The NOAEL is reliable. No adjustment is required.

AF for differences in duration of exposure:

2

Justification:

Default assessment factor for extrapolation from subchronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling rat to humans AF 4 (ECHA 2008).

AF for other interspecies differences:

2.5

Justification:

Default AF for remaining interspecies differences

AF for intraspecies differences:

10

Justification:

Default AF for 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. The tested dose range included the highest administered dose of 500 mg/kg bw/day. 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:

2

Justification:

To account for a lower sensitivity and the limited scope of the repeated dose toxicity studies for detecting effects on reproductive organs an additional assessment factor of 2 was applied.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Route-to-route extrapolation

Oral absorption

No data exist on differences in bioavailability following oral or dermal exposure between experimental animals and humans, and a similar bioavailability is assumed by default.

Oral to dermal

For systemic effects available in vivo toxicokinetic data of the structurally similar source substance MDEA-Esterquat C16-18 and C18 unsatd. will be taken into account for the route to route extrapolation.

Absorption after oral application: 48 ± 6 %

Absorption after dermal application: < 1.4%

Proposed assessment factor for the route to route extrapolation (oral to dermal): 30

A factor of 34 would have suggested a higher accuracy than the data actually provide; the use of a factor of 30 result in a more conservative dermal DNEL.

DERIVATION OF DNELs

DNELs long term systemic effects

Uncertainties	AF	Justification
Interspecies differences, dermal + oral	4	Allometric scaling rat to humans (ECHA 2008).
Interspecies differences, inhalation	1	No allometric scaling animals to humans as inhalation; differences in respiratory volume already included in route-to-route extrapolation (ECHA 2008).
Remaining interspecies differences	2.5	Default AF for remaining interspecies differences
Intraspecies differences, general population	10	Default AF for general population.
Differences in duration of exposure	2 (OECD 408, general toxicity and fertility)	Default AF for extrapolation from sub-chronic to chronic (ECHA 2008).
	1 (OECD 414 developmental toxicity)	No time extrapolation factor has to be applied because the susceptible window is fully covered.
Dose response and endpoint specific/severity	1	The NOAEL is reliable. No adjustment is required.
Quality of whole database	1	The key studies were conducted according to modern regulatory standards and were adequately reported.
Remaining uncertainties	1 (OECD 408 general toxicity, OECD 414)	No remaining uncertainties
Remaining uncertainties	2 (OECD 408 fertility)	To account for a lower sensitivity and the limited scope of the repeated dose toxicity studies for detecting effects on reproductive organs an additional assessment factor of 2 was applied.

DNELs for general toxicity and fertility derived from the oral subchronic study NOAEL (OECD guideline 408; source substance MDEA-Esterquat C16 -18 and C18 unsatd.)

In a subchronic toxicity study comparable to OECD guideline 408, the source substance MDEA-Esterquat C16-18 and C18 unsatd. (10 % a.i.) was administered to 15 Charles River CD rats / sex/ dose by gavage at dose levels of 1, 10 and 500 mg/kg bw/ day for a period of 13- weeks. One control group received the vehicle, deionized water, and a second control group received pH-adjusted, deionized water (pH 2.5). The regimen for both control groups was identical to treatment groups.

No test substance-related findings were detected or observed in clinical examinations, body weights, food consumption values, haematology, urinalysis, neurobehavior, clinical biochemistry or pathology evaluations, including absolute and relative organ weights of ovary and testis and the histopathology of the reproductive organs (gonads, mammary gland (females only), prostate and seminal vesicle, uterus with cervix and vagina). The no effect level (NOEL) for this study is the highest tested dose level of 500 mg/kg bw/day of the test article.

An additional AF of 2 has been included for the derivation of the DNEL fertility taking accountthe lower sensitivity and the limited scope of the repeated dose toxicity studies for detecting effects on reproductive organs.

DNEL general toxicity general population, long-term for oral route (systemic): 2.5 mg/kg bw/d

Start value: NOEL(general toxicity) = 500 mg/kg bw/d

Route of original study: oral

Overall AF 4*2.5*10*2*1*1*1 = 200

DNEL fertility general population, long-term for oral route (systemic): 1.25 mg/kg bw/d

Start value: NOEL (fertility) = 500 mg/kg bw/d

Route of original study: rat, oral

Overall AF 4*2.5*10*2*1*1*2 = 400

DNELs for development derived from the prenatal development study NOAEL (OECD guideline 414; source substance MDEA-Esterquat C16 -18 and C18 unsatd.)

In the developmental toxicity study (OECD guideline 414), groups of 25 mated female Wistar rats were treated with the structurally similar source substance MDEA-Esterquat C16-18 and C18 unsatd. orally by gavage once daily from day 6 through 15 post coitum, at dose levels of 0, 50, 250 and 1000 mg/kg bw/day. Females were sacrificed on day 21 post coitum and the fetuses were removed by Caesarean section.

At 50, 250, and 1000 mg/kg, for the dams no test substance-related deaths or clinical signs as were noted as reaction to treatment. Up to and including the highest dose level of 1000 mg/kg, food consumption and body weight development of the dams were not affected by treatment with the test substance. At necropsy, no test substance-related abnormal findings in the dams were noted in any group.

DNEL development General population, long-term for oral route (systemic): 10 mg/kg bw/d

Start value: NOAEL (development) = 1000 mg/kg bw/d

Route of original study: rat, oral

Overall AF 4*2.5*10*1*1*1*1 = 100

Conclusion

Strictly conservative DNELs long-term systemic effects have been derived from results of the available test data, which include a pre-natal developmental study and sub acute and sub-chronic studies with evaluation of reproductive endpoints.To account for a lower sensitivity and the limited scope of the repeated dose toxicity studies for detecting effects on reproductive organs an additional assessment factor of 2 was applied. The additional assessment factor of 2 was chosen in accordance with the REACH TGD (Chapter R8) and on the basis of the results of a retrospective analysis of the added value of the rat two-generation reproductive toxicity study versus the rat subchronic toxicity study. In this analysis on 47 reproductive toxic and 75 non reproductive toxic substances, it could be demonstrated, that on average, only a small difference of less than twofold in overall NOAELs was found between the rat two-generation study and the rat 90-day study (Janner et al. 2007).

The 28-day subacute studies according to OECD 407 with the target and the source substance showed a comparable low systemic toxicity after repeated exposure for both substances. Together with the high structural similarity between the source substance and the target substance an additional assessment factor for remaining uncertainties due to the read-across approach is not justified.

No DNELs for the inhalation route were derived as inhalation is not a relevant route of exposure to MDEA Esterquat C18 satd. due to the physicochemical properties of the substance and the nature of its uses. MDEA Esterquat C18 unsatd. is a waxy solid. Generation of inhalable particles such as dust or aerosols is therefore not to be expected. Vaporization needs not to be considered due to the substance’s very low vapour pressure of 7.33E-18 Pa at 25°C. The generation of dusts and aerosols is prevented by appropriate RMMs, and the substance is not used in spray applications.

DNELs for general population for the oral route were only derived for assessment of risk related to exposure to man via the environment. No REACH-relevant consumer use has been identified. The only consumer use is as cosmetic product, which is not within the scope of REACH.

The DNELs for general and developmental toxicity are higher than those for fertility. Thus, the fertility-DNELs are also protective for general toxicity and development.

The critical long term DNEL for the general population is the DNEL general population fertility for oral route of 1.25 mg/kg bw/day.

A DNEL for acute toxicity is not established because no acute toxicity hazard (leading to classification and labelling) has been identified. Results of laboratory animal studies show a low acute toxicity after oral and dermal exposure. Therefore the acute intrinsic toxic activity of MDEA Esterquat C18 satd. is considered to be low. The occurrence of a systemic toxicity relevant to humans after inhalation is unlikely.

A DNEL local effects via dermal and inhalation route is not established because the substance is not classified dangerous for respiratory or skin irritation/corrosion and respiratory or skin sensitisation. The substance is not classified for eye irriation therefore there is no hazard identified for eyes.

References

Janer et al. (2007): A retrospective analysis of the added value of the rat two-generation reproductive toxicity study versus the rat subchronic toxicity study.Reprod Toxicol. 2007 Jul; 24(1):103-13