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Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

98 mg/m³

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

490 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Modified dose descriptor starting point:

NOAEC

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

14 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Modified dose descriptor starting point:

NOAEL

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

70 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Modified dose descriptor starting point:

NOAEL

Pigment Yellow FC 26290 (CAS 111071-53-5)

DNELs (worker)

Repeated dose toxicity

Basis for delineation of the DNEL:

Study

Repeated dose study (28 day oral)

Male and female Wistar rats received Pigment Yellow FC 26290 by gavage for 28 days.

rat: 0 (control), 40, 200 or 1000 mg/kg bw/d – male/female rats

Effects, NOAEL

NOAEL = 1000 mg/kg bw/day (male/female rats)

Appearance and general behaviour were not influenced by treatment up to and including 1000 mg/kg bw/d. The general condition was temporarily reduced in some animals of the dose group 1000 mg/kg bw/d., but this observation is not considered to be adverse.

Growth, mortality, feed and water intake were not affected by treatment.

Hematological and histopathological investigations gave no indication of toxicologically relevant damage to blood or hematopoietic organs up to and including 1000 mg/kg bw/d.

Neither clinico-chemical nor gross pathological or histopathological investigations produced any evidence of treatment-related metabolic or organ damage.

Under the conditions of this study, Pigment Yellow FC 26290 was tolerated without adverse effects in dosages of up to and including 1000 mg/kg bw/d.

Reference

Bomhard E, Rosenbruch M

Pigment Yellow FC 26290

Subacute toxicity study in Wistar rats (administration by gavage for 28 days with a subsequent recovery period of 14 days)

Report-no.: 22215 + 22215 A (1993)

Bayer AG,

Fachbereich Toxikologie, Wuppertal

1.) Long-term toxicity – systemic effects (worker)

Long-term oral or dermal route-systemic effects (worker) using extrapolation factors:

NOAEL(rat) from a 28 day study: 1000 mg/kg bw/day

Penetration oral compared to dermal: 1

For interspecies differences rat vs. human: 4

For remaining interspecies differences: 1*

For intraspecies differences in workers: 3**

For extrapolation of exposure duration: 6***

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 72

Worker DNEL long-term for oral or dermal route-systemic: 13.88 mg/kg bw/day

* An assessment factor of 1 is used for “remaining interspecies differences” because of the low absorption potential of the compound (see chapter toxicokinetic) and the low toxicity profile (NOAEL limit dose 1000 mg/kg in sub-acute and developmental screening study). Overall it is likely that bioavailability is very low and consequently toxikodynamic parameters are of minor significance.

** An assessment factor of 3 is used due because of the low absorption potential of the compound (see chapter toxicokinetic) and the low toxicity profile (NOAEL limit dose 1000 mg/kg in sub-acute and developmental screening study). Overall it is likely that bioavailability is very low and intraspecies differences in humans based on differences in human toxicokinetoc and metabolism is of limited significance.

*** An assessment factor of 6 is used although this factor seems to be very conservative, based on the low toxicity observed in the sub-acute toxicity studying rats after 28 days of exposure and in the developmental screening study in which the animals are longer exposed 36 days of exposure in male rats and 57 days of exposure in female rats.

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

NOAEL(rat) from a 28 day study: 1000 mg/kg bw/day

Correction of the starting point according TGD Figure R.8-3:

Corrected inhalatory NOAEC = Oral NOAEL (1000 mg/kg) x 1/0.38 m³/kg x 6.7 m³/10m³ x 1

=> NOAEC worker = 1763.15 mg/m³

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

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

For remaining interspecies differences: 1*

For intraspecies differences in worker: 3**

For extrapolation of exposure duration: 6***

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 18

Worker DNEL long-term for inhalation exposure: 97.95 mg/m³

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

Concerning the systemic effects an exceeding factor of 5 based on the DNEL for long term exposure seems justified based on the REACH Guidance documents and due to the low toxicity of the substance (NOAEL limit dose 1000 mg/kg in sub-acute and developmental screening study).

Therefore the

Worker DNELshort-term for oral or dermal route-systemic: 69.4 mg/kg bw/day

Worker DNEL short-term for inhalation exposure: 489.8 mg/m³

3.) Reproductive Toxicity – systemic effects (workers)

A reproduction/developmental toxicity screening test in rats to assess general toxicity and potential effects on fertility of the F0 generation as well as potential effects on pre- and early postnatal development of the F1 generation after oral exposure was conducted in compliance with the OECD Guideline for Testing of Chemicals, No. 421 „Reproduction/Developmental Toxicity Screening Test“.

In the reproduction/developmental toxicity screening test in rats the compound did not result in any signs of parental toxicity. Body weight and food consumption were not affected. Reproduction parameters did not indicate any effect on male or female reproductive function. In addition, no effects on developmental parameters in F0 females and on parameters measured in F1 pups were found indicating any signs of developmental toxicity. In the screening study,1000 mg/kg represents the NOEL for male and female reproductive function and for developmental toxicity.

In the subacute oral (gavage) toxicity study with Pigment Yellow FC 26290 in rats (28 days), no adverse effects in reproductive organs (testes, prostate glands, epididymis, vagina, uterus, ovaries with eviduct) were observed in histopathological examinations at any of the doses administered (up to about 1000 mg/kg bw/d in) (Bomhard, Bayer AG, 1993).

There is no evidence indicating a potential of Pigment Yellow FC 26290 to interfere adversely with reproduction. The NOAEL for reproductive toxicity in rats based on the histopathological examination of reproductive organs is therefore 1000 mg/kg bw/day as the lower limit.

Therefore the derivation of a separate DNEL for reproductive toxicity is not necessary, because the DNEL for repeated dose toxicty covers both endpoints.

Conclusion (systemic effects):

Worker DNEL long-term for oral or dermal route-systemic: 14 mg/kg bw/day

Worker DNEL long-term for inhalation exposure: 98 mg/m³

Worker DNEL short-term for oral or dermal route-systemic: 70 mg/kg bw/day

Worker DNEL short-term for inhalation exposure: 490 mg/m³

4. Sensitization

Pigment Yellow FC 26290 is not sensitising to the skin of guinea pigs.

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

Pigment Yellow FC 26290, tested according to OECD Guideline 404, is not irritating to the skin

Pigment Yellow FC 26290, tested according to OECD Guideline 405, is not irritating to the eye.

Pigment Yellow FC 29290 is not sensitizing and not irritating to the skin and eyes. Therefore a DNEL for local effects is not applicable.

Conclusion (systemic and local effects - worker):

Route of exposure DNEL; local effect DNEL; systemic effect

Oral (long term) not applicable 14 mg/kg

Oral (short term) not applicable 70 mg/kg

Dermal (long term) not applicable 14 mg/kg

Dermal (short term) not applicable 70 mg/kg

Inhalation (long term) not applicable 98 mg/m³

Inhalation (short term) not applicable 490 mg/m³

References:

• Bomhard E, Rosenbruch M. (1993). Pigment Yellow FC 26290 subacute toxicity study in Wistar rats (administration by gavage for 28 days with a subsequent recovery period of 14 days). Bayer AG. Testing Laboratory: Bayer AG, Fachbereich Toxicologie, Wuppertal. Report no.: 22215 + 22215 A. Study number: T2041179.

• Dreist M, Kolb J (1992). Pigment Yellow FC 26290 Study for skin sensitization effect on guinea pigs (Maximisation test as decribed by Magnusson and Kligman). Bayer AG. Testing Laboratory: Bayer AG, Fachbereich Toxicologie, Wuppertal. Report no.: 21597. Study number: T2041205

• Kroetlinger F (1992). Pigment Yellow FC 26290 Study for skin and eye irritation/corrosion in rabbits. Bayer AG. Testing Laboratory: Bayer AG, Fachbereich Toxikologie, Wuppertal. Report no.: 21529. Study number: T8041175.

• Popp L (2012) Reproduction/Developmental Toxicity Screening Test in Rats after Administration by Gavage (Following OECD Guideline 421) – draft, Bayer Pharma AG, GDD-GED Toxicology, 42096 Wuppertal, Germany, Study number: T5083211

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

28 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Modified dose descriptor starting point:

NOAEC

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

144 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Modified dose descriptor starting point:

NOAEC

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Modified dose descriptor starting point:

NOAEL

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

41 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Modified dose descriptor starting point:

NOAEL

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8 mg/kg bw/day

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

41 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Modified dose descriptor starting point:

NOAEL

Pigment Yellow FC 26290 (CAS 111071-53-5)

DNELs (general population)

Repeated dose toxicity

Basis for delineation of the DNEL:

Reference

Study

Repeated dose study (28 day oral)

Male and female Wistar rats received Pigment Yellow FC 26290 by gavage for 28 days.

rat: 0 (control), 40, 200 or 1000 mg/kg bw/d – male/female rats

Effects, NOAEL

NOAEL = 1000 mg/kg bw/day (male/female rats)

Appearance and general behavior were not influenced by treatment up to and including 1000 mg/kg bw/d. The general condition was temporarily reduced in some animals of the dose group 1000 mg/kg bw/d., but this observation is not considered to be adverse.

Growth, mortality, feed and water intake were not affected by treatment.

Hematological and histopathological investigations gave no indication of toxicologically relevant damage to blood or hematopoietic organs up to and including 1000 mg/kg bw/d.

Neither clinico-chemical nor gross pathological or histopathological investigations produced any evidence of treatment-related metabolic or organ damage.

Under the conditions of this study, Pigment Yellow FC 26290 was tolerated without adverse effects in dosages of up to and including 1000 mg/kg bw/d.

Bomhard E, Rosenbruch M

Pigment Yellow FC 26290

Subacute toxicity study in Wistar rats (administration by gavage for 28 days with a subsequent recovery period of 14 days)

Report-no.: 22215 + 22215 A (1993)

Bayer AG,

Fachbereich Toxikologie, Wuppertal

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

Long-term oral or dermal route-systemic effects (worker) using extrapolation factors:

NOAEL(rat) from a 28 day study: 1000 mg/kg bw/day

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

For interspecies differences rat vs. human: 4

For remaining interspecies differences: 1*

For intraspecies differences in general population: 5**

For extrapolation of exposure duration: 6***

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 120

General population DNEL long-term for oral or dermal route-systemic: 8.33 mg/kg bw/day

* An assessment factor of 1 is used for “remaining interspecies differences” because of the low absorption potential of the compound (see chapter toxicokinetic) and the low toxicity profile (NOAEL limit dose 1000 mg/kg in sub-acute and developmental screening study). Overall it is likely that bioavailability is very low and consequently toxikodynamic parameters are of minor significance.

** An assessment factor of 5 is used due because of the low absorption potential of the compound (see chapter toxicokinetic) and the low toxicity profile (NOAEL limit dose 1000 mg/kg in sub-acute and developmental screening study). Overall it is likely that bioavailability is very low and intraspecies differences in humans based on differences in human toxicokinetoc and metabolism is of limited significance.

*** An assessment factor of 6 is used although this factor seems to be very conservative, based on the low toxicity observed in the sub-acute toxicity studying rats after 28 days of exposure and in the developmental screening study in which the animals are longer exposed 36 days of exposure in male rats and 57 days of exposure in female rats.

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

NOAEL(rat) from a 28 day study: 1000 mg/kg bw/day

Correction of the starting point according TGD Figure R.8-3:

Corrected inhalatory NOEC = Oral NOEL (1000 mg/kg) x 1/1.15 m³/kg x 1.0

=> NOEC general population = 869.56 mg/m³

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

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

For remaining interspecies differences: 1*

For intraspecies differences in general population: 5**

For extrapolation of exposure duration: 6***

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 30

General population DNEL long-term for inhalation exposure: 28.98 mg/m³

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

Concerning the systemic effects an exceeding factor of 5 based on the DNEL for long term exposure seems justified based on the REACH Guidance documents and due to the low toxicity of the substance (NOAEL limit dose 1000 mg/kg in sub-acute and developmental screening study).

Therefore the

General population DNELshort-term for oral or dermal route-systemic: 41.65 mg/kg bw/day

General population DNEL short-term for inhalation exposure: 144.9 mg/m³

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

A reproduction/developmental toxicity screening test in rats to assess general toxicity and potential effects on fertility of the F0 generation as well as potential effects on pre- and early postnatal development of the F1 generation after oral exposure was conducted in compliance with the OECD Guideline for Testing of Chemicals, No. 421 „Reproduction/Developmental Toxicity Screening Test“.

In the reproduction/developmental toxicity screening test in rats the compound did not result in any signs of parental toxicity. Body weight and food consumption were not affected. Reproduction parameters did not indicate any effect on male or female reproductive function. In addition, no effects on developmental parameters in F0 females and on parameters measured in F1 pups were found indicating any signs of developmental toxicity. In the screening study, 1000 mg/kg represents the NOEL for male and female reproductive function and for developmental toxicity.

In the subacute oral (gavage) toxicity study with Pigment Yellow FC 26290 in rats (28 days), no adverse effects in reproductive organs (testes, prostate glands, epididymis, vagina, uterus, ovaries with eviduct) were observed in histopathological examinations at any of the doses administered (up to about 1000 mg/kg bw/d in) (Bomhard, Bayer AG, 1993).

There is no evidence indicating a potential of Pigment Yellow FC 26290 to interfere adversely with reproduction. The NOAEL for reproductive toxicity in rats based on the histopathological examination of reproductive organs is therefore 1000 mg/kg bw/day as the lower limit.

Therefore the derivation of a separate DNEL for reproductive toxicity is not necessary, because the DNEL for repeated dose toxicity covers both endpoints.

Conclusion (systemic effects):

General population DNEL long-term for oral or dermal route-systemic: 8.33 mg/kg bw/day

General population DNEL long-term for inhalation exposure: 28.98 mg/m³

General population DNEL short-term for oral or dermal route-systemic: 41.65 mg/kg bw/day

General population DNEL short-term for inhalation exposure: 144.9 mg/m³

4. Sensitization

Pigment Yellow FC 26290 is not sensitising to the skin of guinea pigs.

6. Long-term and short-term dermal or inhalation route - local effects (general population)

Pigment Yellow FC 26290, tested according to OECD Guideline 404, is not irritating to the skin

Pigment Yellow FC 26290, tested according to OECD Guideline 405, is not irritating to the eye.

Pigment Yellow FC 29290 is not sensitizing and not irritating to the skin and eyes. Therefore a DNEL for local effects is not applicable.

Conclusion (systemic and local effects – general population):

Route of exposure DNEL; local effect DNEL; systemic effect

Oral (long term) not applicable 8 mg/kg

Oral (short term) not applicable 41 mg/kg

Dermal (long term) not applicable 8 mg/kg

Dermal (short term) not applicable 41 mg/kg

Inhalation (long term) not applicable 28 mg/m³

Inhalation (short term) not applicable 144 mg/m³

References:

• Bomhard E, Rosenbruch M. (1993). Pigment Yellow FC 26290 subacute toxicity study in Wistar rats (administration by gavage for 28 days with a subsequent recovery period of 14 days). Bayer AG. Testing Laboratory: Bayer AG, Fachbereich Toxicologie, Wuppertal. Report no.: 22215 + 22215 A. Study number: T2041179.

• Dreist M, Kolb J (1992). Pigment Yellow FC 26290 Study for skin sensitization effect on guinea pigs (Maximisation test as decribed by Magnusson and Kligman). Bayer AG. Testing Laboratory: Bayer AG, Fachbereich Toxicologie, Wuppertal. Report no.: 21597. Study number: T2041205

• Kroetlinger F (1992). Pigment Yellow FC 26290 Study for skin and eye irritation/corrosion in rabbits. Bayer AG. Testing Laboratory: Bayer AG, Fachbereich Toxikologie, Wuppertal. Report no.: 21529. Study number: T8041175.

• Popp L (2012) Reproduction/Developmental Toxicity Screening Test in Rats after Administration by Gavage (Following OECD Guideline 421) – draft, Bayer Pharma AG, GDD-GED Toxicology, 42096 Wuppertal, Germany, Study number: T5083211