Cyclohexane, oxidized, aq. ext.

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

264 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):

5

Modified dose descriptor starting point:

NOAEC

Value:

1 321.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

Rat to Human (oral to inhalation) default factor from REACH guidance: 1/0.38 m3/kg/day; Additional default factor for light activity from REACH guidance: 0.67; Absorption (oral to inhalation) default factor from REACH guidance: 1

AF for dose response relationship:

1

Justification:

Default value from REACH Guidance R.8

AF for differences in duration of exposure:

1

Justification:

Default value from REACH Guidance R.8. Starting point is a chronic study.

AF for interspecies differences (allometric scaling):

1

Justification:

Default value from REACH Guidance R.8. Allometric Scaling already taken into account in route-to-route extrapolation above.

AF for other interspecies differences:

1

Justification:

See discussion. No symptoms reported after oral administration of up to 7 g of Adipic Acid per day for 10 days to human volunteers.

AF for intraspecies differences:

5

Justification:

Default value from REACH Guidance R.8

AF for the quality of the whole database:

1

Justification:

Robust database

AF for remaining uncertainties:

1

Justification:

No additional uncertainties noted.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

528 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):

2.5

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: Upper Boundry Limit based on work by a Task Force within the German VCI

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: Upper Boundry Limit based on work by a Task Force within the German VCI

Overall assessment factor (AF):

0.5

DNEL extrapolated from long term DNEL

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

38 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):

20

Modified dose descriptor starting point:

NOAEL

Value:

750 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Default value from REACH Guidance R.8.  Dermal route considered equivalent to oral route in the absence of contrary information.

AF for dose response relationship:

1

Justification:

Default value from REACH Guidance R.8

AF for differences in duration of exposure:

1

Justification:

Default value from REACH Guidance R.8. Starting point is a chronic study.

AF for interspecies differences (allometric scaling):

4

Justification:

Default value from REACH Guidance R.8

AF for other interspecies differences:

1

Justification:

See discussion. No symptoms reported after oral administration of up to 7 g of Adipic Acid per day for 10 days to human volunteers.

AF for intraspecies differences:

5

Justification:

Default value from REACH Guidance R.8

AF for the quality of the whole database:

1

Justification:

Robust database.

AF for remaining uncertainties:

1

Justification:

No additional uncertainties noted.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

76 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

low 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

The scientific literature supports that the major ingredient, adipic acid, represent the primary path of COP acids biological metabolism toxicokinetics, metabolism and distribution biochemical metabolism pathway. For example, the second major constituent present in COP acid, 6-Hydroxyhexanoic Acid, is converted to adipic acid, the first major constituent in COP acid, leading to more adipic acid metabolism. In other words, adipic acid is formed when 6-hydroxyhexanoic acid is oxidized to the corresponding dicarboxylic acid, which is adipic acid. Thus, adipic acid toxicokinetics represent the major route of metabolism of COP acid.

 

Overall, the systemic toxicity of COP acid is significantly comparable to the major ingredient, adipic acid, which is low; it is not sensitizing, not mutagen, not toxic to reproductive organs and fertility, not a developmental toxicant and not carcinogenic.

 

Systemic toxicity:

Starting point:

 

There is no dermal repeated dose toxicity study available. There is no reliable repeated inhalation toxicity study with histopathological examination of the nose available. In a 2-year oral study adipic acid was of low repeated dose toxicity. The NOAEL was 1% for female and male rats (approx. 750 mg/kg bw/day). Females were not dosed at higher concentrations, males dosed at higher concentrations (3 and 5%) caused body weight retardation with no indication of specific target organ toxicity (Horn et al. 1957).

 

Long-Term:

 

Systemic toxicity by inhalation:

 

A) Modification of starting point and route to route extrapolation (oral route to inhalation):

Taking into account the following factors:

- The default physiological parameter under allometric scaling principle in REACH guidance documentation for worker (8h): 1/0.38 m3/kg/day

- Default factor for worker “light activity” 6.7m3/10m3 = 0.67

- differences in absorption oral/inhalation = 1( toxicokinetic data indicate that adipic acid is well absorbed by the oral route)

The overall corrected systemic NOAEC for worker is 1321.5 mg/m3

 

B) Assessment factors:

- Allometric scaling (AS) factor not applied according to REACH guidance documentation chapter R. 8, table R. 8-4; page 32. (Already considered in step A)

- Remaining interspecies differences: 1 ( No additional assessment factor necessary due to the database covering experiments in animal species and humans; no symptoms were reported after oral administration of up to 7 g of adipic acid per day, for 10 days to human volunteers (Weitzel, 1942 and 1947).

- Intraspecies differences: 5 (default factor worker according to REACH guidance documentation chapter R. 8)

 

C)Systemic long- and short-term inhalation DNEL (worker): 1321.5 mg/m3 / 5 = 264 mg/m3

 

Systemic toxicity by oral or dermal route:

 

A) No modification of the starting point is necessary; corrected NOAEL 750 mg/kg/day. We used the REACH guidance documentation chapter R8 default assumption that oral absorption and dermal absorption are equal.

 

B) Assessment factors:

- Allometric scaling (AS) factor: 4 (default factor rat to human according to REACH guidance documentation chapter R. 8)

- Remaining interspecies differences: 1 ( No additional assessment factor necessary due to the database covering experiments in animal species and humans; no symptoms were reported after oral administration of up to 7 g of adipic acid per day, for 10 days to human volunteers (Weitzel, 1942 and 1947).

- Intraspecies differences: 5 (default factor worker according to REACH guidance documentation chapter R. 8)

 

C) Systemic long-term oral/dermal DNELs (worker): 750 mg/m3 / 20 = 38 mg/kg/day

 

Short-Term:

According to REACH TGD dermal and oral ‘short-term’ exposures should normally be assessed using the long-term DNEL. This is taken to mean that short-term exposures should not result in exceeding the long-term DNEL. Since adipic acid is of low systemic toxicity and only slightly irritating to the skin, an additional assessment factor of 0.5 (2 times the long-term DNEL) is proposed and would allow for multiple 15-minute excursions above the worker’s baseline exposures without exceeding the long-term DNEL.

 

Local effects:

 

Adipic acid should be included into the moderate hazard category according to REACH TGD Part E "Risk Characterisation" based on the local effects observed in animal eye irritation tests.

 

Inhalation:

 

In the REACH TGD the DNEL calculation for compounds without fully valid long term inhalation study is usually based on oral studies. This extrapolation covers the systemic effects of the compound. For non-irritating compounds it can be assumed that the potential local effects will be covered by the derived systemic DNEL. For compounds with irritating or corrosive properties the derived systemic DNEL might not cover potential local effects.

 

A toxicological Task Force (TF) within the German VCI discussed the derivation of DNEL for local irritating compound with a limited database. The experts developed upper boundary values for irritating and/or corrosive compounds based on available data. In particular the expert TF evaluated the German MAK-values published in the TRGS900 in 2009. For irritating compounds labelled with R36 or R38 but without relevant inhalation toxicity data available the TF developed a generic upper boundary value of 10 mg/m3; for compounds with corrosive properties (R34 or R35) a respective value of 1 mg/m3 is developed.

 

Adipic acid is an irritating compound labelled with R41. The expert TF did no indicate a threshold for compounds labelled with R41 but we would propose to set the DNEL long-term for local effects to 1 mg/m3. This value is still conservative compared to MAK values of corrosive compounds as formic acid (MAK value: 9.5 mg/m3), HCl (3 mg/m3), Ammonium (14 mg/m3) Chlorine (1.5 mg/m3) or nitric acid (5.2 mg/m3); but sulphuric acid (0.1 mg/m3). Concerning the short term exposure we propose 2 mg/m3 as the upper boundary value.

 

A DNEL long-term of 1 mg/m3 and a DNEL short-term of 2 mg/m3 is in line with acute animal experiments performed with adipic acid. No evidence of respiratory tract irritation was reported in an acute inhalation study where 20 rats were exposed to up to 7700 mg/m3 of adipic acid dust (MMAD 3.5 µm) for 4 hours (BASF 1981) or in an subacute study with limited documentation where four rats were exposed to 126 mg/m3 of adipic acid dust for 6 hours per day for 15 days. The reliability of the sub-acute study is limited because only four animals were investigated, the MMAD was not determined and histopathology was performed only on nine organs, including the lung (Gage 1970).

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

65 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):

10

Modified dose descriptor starting point:

NOAEC

Value:

652.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

Rat to human (oral to inhalation) default factor for general population from REACH guidance: 1/1.15 = 0.87 m3/kg/day;  Differences in absorption (oral to inhalation) default value from REACH guidance: 1

AF for dose response relationship:

1

Justification:

Default value from REACH Guidance R.8

AF for differences in duration of exposure:

1

Justification:

Default value from REACH Guidance R.8. Starting point is a chronic study.

AF for interspecies differences (allometric scaling):

1

Justification:

Default value from REACH Guidance R.8. Allometric Scaling already taken into account in route-to-route extrapolation above.

AF for other interspecies differences:

1

Justification:

See discussion. No symptoms reported after oral administration of up to 7 g of Adipic Acid per day for 10 days to human volunteers.

AF for intraspecies differences:

10

Justification:

Default value from REACH Guidance R.8

AF for the quality of the whole database:

1

Justification:

Robust database

AF for remaining uncertainties:

1

Justification:

No additional uncertainties noted

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

65 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):

10

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

19 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):

40

Modified dose descriptor starting point:

NOAEL

Value:

750 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Default value from REACH Guidance R.8.  Dermal route considered equivalent to oral route in the absence of contrary information.

AF for dose response relationship:

1

Justification:

Default value from REACH Guidance R.8

AF for differences in duration of exposure:

1

Justification:

Default value from REACH Guidance R.8. Starting point is a chronic study.

AF for interspecies differences (allometric scaling):

4

Justification:

Default value from REACH Guidance R.8

AF for other interspecies differences:

1

Justification:

See discussion. No symptoms reported after oral administration of up to 7 g of Adipic Acid per day for 10 days to human volunteers.

AF for intraspecies differences:

10

Justification:

Default value from REACH Guidance R.8

AF for the quality of the whole database:

1

Justification:

Robust database

AF for remaining uncertainties:

1

Justification:

No additional uncertainties noted.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

19 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):

40

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

19 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):

40

Modified dose descriptor starting point:

NOAEL

Value:

750 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Not applicable.

AF for dose response relationship:

1

Justification:

Default value from REACH Guidance R.8

AF for differences in duration of exposure:

1

Justification:

Default value from REACH Guidance R.8. Starting point is a chronic study.

AF for interspecies differences (allometric scaling):

4

Justification:

Default value from REACH Guidance R.8

AF for other interspecies differences:

1

Justification:

See discussion. No symptoms reported after oral administration of up to 7 g of Adipic Acid per day for 10 days to human volunteers.

AF for intraspecies differences:

10

Justification:

Default value from REACH Guidance R.8

AF for the quality of the whole database:

1

Justification:

Robuts database

AF for remaining uncertainties:

1

Justification:

No additional uncertainties noted

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

19 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):

40

DNEL extrapolated from long term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

Overall, the systemic toxicity of adipic acid is low; it is not sensitizing, not mutagen, not toxic to reproductive organs and fertility, not a developmental toxicant and not carcinogenic.

 

Systemic toxicity:

 

Starting point:

 

There is no dermal repeated dose toxicity study available for COP acid. There is no reliable repeated inhalation toxicity study with histopathological examination of the nose available. However, in a 2-year oral study adipic acid, the main ingredient in COP acid, a low repeated dose toxicity was observed. The NOAEL was 1% for female and male rats (approx. 750 mg/kg bw/day). Females were not dosed at higher concentrations, males dosed at higher concentrations (3 and 5%) caused body weight retardation with no indication of specific target organ toxicity Horn et al. 1957).

 

Systemic toxicity by inhalation:

 

A) Modification of starting point:

- The default physiological parameter under allometric scaling principle in REACH guidance documentation for the general population: 1/1.15 = 0.87 m3/kg/day

- Differences in absorption oral/inhalation = 1 (toxicokinetic data indicate that adipic acid is well absorbed by the oral route)

The overall corrected systemic NOAEC for the general population: 652.5 mg/m3

 

B) Assessment factors:

- Allometric scaling (AS) factor not applied according to REACH guidance documentation chapter R. 8, table R. 8-4; page 32. (Already considered in step A)

- Remaining interspecies differences: 1 ( No additional assessment factor necessary due to the database covering experiments in animal species and humans; no symptoms were reported after oral administration of up to 7 g of adipic acid per day, for 10 days to human volunteers (Weitzel, 1942 and 1947).

- Intraspecies differences: 10 (default factor the general population according to REACH guidance documentation chapter R. 8)

 

C) Systemic long- and short-term inhalation DNEL (general population): 1321.5 mg/m3 / 10 = 65 mg/m3

 

Systemic toxicity by oral or dermal route:

 

A) No modification of the starting point is necessary; corrected NOAEL 750 mg/kg/day mg/kg/day

 

B) Assessment factors:

- Allometric scaling (AS) factor: 4 (default factor rat to human according to REACH guidance documentation chapter R. 8)

- Intraspecies factor general population (REACH TGD default factor): 10

 

C) Systemic long- and short-term oral/dermal DNELs (general population): 750 mg/m3 / 40 = 19 mg/kg/day

Local effects:

 

COP acid is expected to have similar irritation potentials of adipic acid. Adipic acid has a local irritation potential; it is irritating to the eye with symptoms not reversible in animal experiments. According to the ECHA “Guidance on information requirements and chemical safety assessment Part E: Risk Characterisation Substances” compounds which cause “risk of serious damage to the eyes” should be allocated to the “moderate hazard category”. Overall no DNEL long-term (and short term) for local effects is proposed for the general population.