3,9-dicyclohex-3-enyl-2,4,8,10-tetraoxaspiro[5.5]undecane

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

29.3 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

18

Modified dose descriptor starting point:

NOAEC

Value:

528.9 mg/m³

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

AF for interspecies differences (allometric scaling):

1

AF for other interspecies differences:

1

AF for intraspecies differences:

3

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

146.5 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.16 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

72

Modified dose descriptor starting point:

NOAEL

Value:

4.16 mg/kg bw/day

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

AF for interspecies differences (allometric scaling):

4

AF for other interspecies differences:

1

AF for intraspecies differences:

3

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

20.8 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Vulkazon AFS (CAS 6600-31-3)

(3,9-Di-3-cyclohexen-1-yl-2,4,8,10-tetraoxaspiro[5,5]undecane)

DNELs (worker)

Repeated dose toxicity

A subacute oral gavage study rats was evaluated for the derivation of DNELs of Vulkazon AFS.

Basis for delineation of the DNEL:

Study (rat study) Repeated dose study rat, male, female, subacute oral gavage study for 28 days rat: 0 (control), 100, 300 or 1000 mg/kg bw/d – male, female via gavage

Effects, NOAEL

NOEL = 300 mg/kg bw/d (male + female rats)

Effects: Body weights were unaffected up to 300 mg/kg body weight in males and in all female dose groups. At 1000 mg/kg body weights of male rats were transiently significantly reduced. The test item had no effect on food and water intake of all treated females and of low and mid dose males. High dose males consumed more food and water related to body weight.

Reference

Wirnitzer U (2012 draft) Repeated Dose Systemic Toxicity Study in Wistar Rats (4-Weeks Daily Administration by Gavage)

Bayer Pharma AG GDD-GED General Toxicology 42096 Wuppertal Germany

Study n°: T3082698

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

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

NOEL(rat, male) from a subacute toxicity study:              300 mg/kg bw/day

Penetration oral compared to dermal:                                        1

For interspecies rat vs. human:                                                  4

For remaining interspecies differences:                                    1*

For intraspecies differences in workers:                                   3**

For extrapolation of exposure duration subacute to chronic:       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: 4.16 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. Overall it is likely that bioavailability is very low and consequently toxicodynamic 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. 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.

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

NOEL(rat) from a subacute toxicity study:300 mg/kg bw/day Correction of the starting point according TGD Figure R.8-3: Corrected inhalatory NOEC = Oral NOEL (300 mg/kg) x 1/0.38 m³/kg x 6.7 m³/10m³ => NOEC worker = 528.9 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 workers:                             3**

For extrapolation of exposure duration subacute to chronic:   6

For reliability of dose-response:                                           1

For quality of whole database:                                           1

Overall factor:                                                                    18

Worker DNEL long-term for inhalation exposure: 29.3 mg/m³

* 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. Overall it is likely that bioavailability is very low and consequently toxicodynamic 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. 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.

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

Concerning the systemic effects an exceeding factor of 5 based on the DNEL for long term exposure seems justified.

Worker DNELshort-term for oral or dermal route-systemic: 20.8 mg/kg bw/day

Worker DNEL short-term for inhalation exposure: 146.5 mg/m³

Conclusion (systemic effects):

Worker DNEL long-term for oral or dermal route-systemic:        4.16 mg/kg bw/day

Worker DNEL long-term for inhalation exposure:                      29.3 mg/m³

Worker DNELshort-term for oral or dermal route-systemic: 20.8 mg/kg bw/day

Worker DNEL short-term for inhalation exposure: 146.5 mg/m³

3.) Reproductive Toxicity – systemic effects (worker)

There was no fertility study with Vulkazon AFS (3,9-Di-3-cyclohexen-1-yl-2,4,8,10-tetraoxaspiro[5,5]undecane) available. No effects on reproductive organs were observed in a 28 day study in rats. The pathologic evaluation consisted of organ weight, gross and microscopic examination of reproductive organs, incl. testes, epididymis, prostate gland, seminal vesicle, vagina, cervix, uterus, ovary, and oviduct. No treatment-related changes were observed for any reproductive organ investigated during macroscopic and microscopic examination of all major organs (NOAEL, rat: 1000 mg/kg bw/day; males and females). On the basis of this study no effects on fertility were expected (NOAEL, rat: 1000 mg/kg bw/day).

In a OECD TG 414 study (pre-natal development toxicity study) in rats no adverse effects were reported and, consequently, the NOAEL for maternal, reproductive and developmental toxicity was found to be 1000 mg/kg/day (highest dose tested).

As no hazard for reproductive toxicity was reported the the NOAEL for reproductive toxicity (1000 mg/kg bw/day; highest dose tested) is higher than the NOAEL for repeated dose toxicity (300 mg/kg bw/day), the derivation of a separate DNEL for reproductive toxicity is not necessary, because the DNEL for repeated dose toxicity covers both endpoints.

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

In rabbits, Vulkazon AFS (3,9-Di-3-cyclohexen-1-yl-2,4,8,10-tetraoxaspiro[5,5]undecane) is not irritating to the skin, and not irritating to the eyes. 5. Sensitization Vulkazon AFS (3,9-Di-3-cyclohexen-1-yl-2,4,8,10-tetraoxaspiro[5,5]undecane) was not sensitising in a LLNA. Vulkazon AFS (3,9-Di-3-cyclohexen-1-yl-2,4,8,10-tetraoxaspiro[5,5]undecane) 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 exposureDNEL;        local effectDNEL;        systemic effect

Oral (long term)                        not applicable               4.16 mg/kg

Oral (short term)                      not applicable               20.8 mg/kg

Dermal (long term)                   not applicable               4.16 mg/kg

Dermal (short term)               not applicable               20.8 mg/kg

Inhalation (long term)               not applicable               29.3 mg/m³

Inhalation (short term)              not applicable               146.5 mg/m³

References:

• Wirnitzer U, 3,9-Di-3-cyclohexen-1-yl-2,4,8,10-tetraoxaspiro[5.5]undecane - Repeated Dose Systemic Toxicity Study in Wistar Rats (4-Weeks Daily Administration by Gavage) (draft), Bayer Pharma AG, GDD-GED General Toxicology, 42096 Wuppertal, Germany (2012)

•Loeser E, Kimmerle G, Ozonschutzmittel KAC 4196 - Akute toxikologische Untersuchungen, Bayer AG - Institut fuer Toxikologie, Wuppertal-Elberfeld, Germany, Report n° 6400, 1976

•Vohr HW, 3,9-Di-3-cyclohexen-1- yl-2,4,8,10-tetraoxaspiro (5.51 undecane - Local lymph node assay in mice (LLNA/IMDS Bayer Pharma AG - GDD-GED-Toxicology - 42096 Wuppertal, Germany, Report n° AT06363 (2012)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.7 mg/m³

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

30

Modified dose descriptor starting point:

NOAEC

Value:

260.8 mg/m³

AF for dose response relationship:

1

Justification:

see 'Discussion'

AF for differences in duration of exposure:

6

Justification:

see 'Discussion'

AF for interspecies differences (allometric scaling):

1

Justification:

see 'Discussion'

AF for other interspecies differences:

1

Justification:

see 'Discussion'

AF for intraspecies differences:

5

Justification:

see 'Discussion'

AF for the quality of the whole database:

1

Justification:

see 'Discussion'

AF for remaining uncertainties:

1

Justification:

see 'Discussion'

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

43.5 mg/m³

Route of original study:

Oral

DNEL related information

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.5 mg/kg bw/day

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

120

Modified dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

AF for dose response relationship:

1

Justification:

see 'Discussion'

AF for differences in duration of exposure:

6

Justification:

see 'Discussion'

AF for interspecies differences (allometric scaling):

4

Justification:

see 'Discussion'

AF for other interspecies differences:

1

Justification:

see 'Discussion'

AF for intraspecies differences:

5

Justification:

see 'Discussion'

AF for the quality of the whole database:

1

Justification:

see 'Discussion'

AF for remaining uncertainties:

1

Justification:

see 'Discussion'

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

12.5 mg/kg bw/day

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Justification:

see 'Discussion'

Justification:

see 'Discussion'

Justification:

see 'Discussion'

Justification:

see 'Discussion'

Justification:

see 'Discussion'

Justification:

see 'Discussion'

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.5 mg/kg bw/day

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

120

Modified dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

AF for interspecies differences (allometric scaling):

4

AF for other interspecies differences:

1

AF for intraspecies differences:

5

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

12.5 mg/kg bw/day

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

Vulkazon AFS (CAS 6600-31-3)

(3,9-Di-3-cyclohexen-1-yl-2,4,8,10-tetraoxaspiro[5,5]undecane)

DNELs (general population)

Repeated dose toxicity

A subacute oral gavage study rats was evaluated for the derivation of DNELs of Vulkazon AFS.

Basis for delineation of the DNEL:

Study (rat study)

Repeated dose study

rat, male, female,

subacute oral gavage study for 28 days

rat: 0 (control), 100, 300 or 1000 mg/kg bw/d – male, female via gavage

NOEL = 300 mg/kg bw/d (male + female rats)

Effects, NOAEL

Effects:

Body weights were unaffected up to 300 mg/kg body weight in males and in all female dose groups. At 1000 mg/kg body weights of male rats were transiently significantly reduced.

The test item had no effect on food and water intake of all treated females and of low and mid dose males. High dose males consumed more food and water related to body weight.

Reference

Wirnitzer U (2012 draft)

Repeated Dose Systemic Toxicity Study in Wistar Rats (4-Weeks Daily Administration by Gavage)

Bayer Pharma AG

GDD-GED General Toxicology

42096 Wuppertal

Germany

Study n°: T3082698

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

Long-term oral or dermal route-systemic effects (general population) using default extrapolation factors:

NOEL(rat, male) from a subacute toxicity study:               300 mg/kg bw/day

Penetration oral compared to dermal:                                   1

For interspecies rat vs. human:                                           4

For remaining interspecies differences:                                 1*

For intraspecies differences in general population:               5**

For extrapolation of exposure duration subacute to chronic: 6

For reliability of dose-response:                                          1

For quality of whole database:                                           1

Overall factor:                                                                120

DNEL long-term for oral or dermal route-systemic: 2.5 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. Overall it is likely that bioavailability is very low and consequently toxicodynamic 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. Overall it is likely that bioavailability is very low and intraspecies differences in humans based on differences in human toxicokinetic and metabolism is of limited significance.

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

NOEL(rat) from a subacute toxicity study: 300 mg/kg bw/day

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

Corrected inhalatory NOEC = Oral NOEL (300 mg/kg) x 1/1.15 m³/kg x 1.0

=> NOEC worker = 260.8 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 subacute to chronic: 6

For reliability of dose-response:                                           1

For quality of whole database:                                               1

Overall factor:                                                                       30

DNEL long-term for inhalation exposure: 8.7 mg/m³

* 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. Overall it is likely that bioavailability is very low and consequently toxicodynamic 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. Overall it is likely that bioavailability is very low and intraspecies differences in humans based on differences in human toxicokinetic and metabolism is of limited significance.

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.

General population DNEL short-term for oral or dermal route-systemic: 12.5 mg/kg bw/day

General population DNEL short-term for inhalation exposure: 43.5 mg/m³

Conclusion (systemic effects):

General population DNEL long-term for oral or dermal route-systemic: 2.5 mg/kg bw/day

General population DNEL long-term for inhalation exposure: 8.7 mg/m³

General population DNEL short-term for oral or dermal route-systemic: 12.5 mg/kg bw/day

General population DNEL short-term for inhalation exposure: 43.5 mg/m³

3.) Reproductive Toxicity – systemic effects (worker)

There was no fertility study with Vulkazon AFS (3,9-Di-3-cyclohexen-1-yl-2,4,8,10-tetraoxaspiro[5,5]undecane) available. No effects on reproductive organs were observed in a 28 day study in rats. The pathologic evaluation consisted of organ weight, gross and microscopic examination of reproductive organs, incl. testes, epididymis, prostate gland, seminal vesicle, vagina, cervix, uterus, ovary, and oviduct. No treatment-related changes were observed for any reproductive organ investigated during macroscopic and microscopic examination of all major organs (NOAEL, rat: 1000 mg/kg bw/day; males and females). On the basis of this study no effects on fertility were expected (NOAEL, rat: 1000 mg/kg bw/day).

In a OECD TG 414 study (pre-natal development toxicity study) in rats no adverse effects were reported and, consequently, the NOAEL for maternal, reproductive and developmental toxicity was found to be 1000 mg/kg/day (highest dose tested).

As no hazard for reproductive toxicity was reported the the NOAEL for reproductive toxicity (1000 mg/kg bw/day; highest dose tested) is higher than the NOAEL for repeated dose toxicity (300 mg/kg bw/day), the derivation of a separate DNEL for reproductive toxicity is not necessary, because the DNEL for repeated dose toxicity covers both endpoints.

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

In rabbits, Vulkazon AFS (3,9-Di-3-cyclohexen-1-yl-2,4,8,10-tetraoxaspiro[5,5]undecane) is not irritating to the skin, and not irritating to the eyes.

5. Sensitization

Vulkazon AFS (3,9-Di-3-cyclohexen-1-yl-2,4,8,10-tetraoxaspiro[5,5]undecane) was not sensitising in a LLNA.

Vulkazon AFS (3,9-Di-3-cyclohexen-1-yl-2,4,8,10-tetraoxaspiro[5,5]undecane) is not sensitizing and not irritating to the skin and eyes. Therefore no hazard was identified.

Conclusion (systemic and local effects – general population):

Route of exposure              DNEL; local effect        DNEL; systemic effect

Oral (long term)               No hazard identified                      2.5 mg/kg

Oral (short term)              No hazard identified                    12.5 mg/kg/day

Dermal (long term)           No hazard identified                      2.5 mg/kg

Dermal (short term)        No hazard identified                    12.5 mg/kg/day

Inhalation (long term)        No hazard identified                      8.7 mg/m³

Inhalation (short term)       No hazard identified                    43.5 mg/m³

References:

• Wirnitzer U, 3,9-Di-3-cyclohexen-1-yl-2,4,8,10-tetraoxaspiro[5.5]undecane - Repeated Dose Systemic Toxicity Study in Wistar Rats (4-Weeks Daily Administration by Gavage) (draft), Bayer Pharma AG, GDD-GED General Toxicology, 42096 Wuppertal, Germany (2012)

• Loeser E, Kimmerle G, Ozonschutzmittel KAC 4196 - Akute toxikologische Untersuchungen, Bayer AG - Institut fuer Toxikologie, Wuppertal-Elberfeld, Germany, Report n° 6400, 1976

• Vohr HW, 3,9-Di-3-cyclohexen-1- yl-2,4,8,10-tetraoxaspiro (5.51 undecane - Local lymph node assay in mice (LLNA/IMDS Bayer Pharma AG - GDD-GED-Toxicology - 42096 Wuppertal, Germany, Report n° AT06363 (2012)