Disodium adipate

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 mg/m³

Explanation for the modification of the dose descriptor 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).

AF for dose response relationship:

1

AF for differences in duration of exposure:

1

Justification:

chronic studies available

AF for interspecies differences (allometric scaling):

1

Justification:

taken into account for NOAEC derivation

AF for other interspecies differences:

1

Justification:

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).

AF for intraspecies differences:

5

Justification:

default factor worker

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

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:

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

AF for dose response relationship:

1

AF for differences in duration of exposure:

1

Justification:

chronic studies available

AF for interspecies differences (allometric scaling):

4

Justification:

rat -> humans

AF for other interspecies differences:

1

Justification:

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).

AF for intraspecies differences:

5

Justification:

default for worker

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

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

Local toxicity:

Disodium adipate is no irritating to the skin or eyes.

Systemic toxicity:

Overall, the systemic toxicity of disodium adipate is low; it is not sensitizing, not mutagen, not toxic to reproductive organs and fertility, not a developmental toxicant and not carcinogenic. The DNEL calculations are based on adipic acid data.

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).

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)

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 absorbtion is equal to dermal absorbtion.

B)

- Assessment factors see above; including allometric scaling from rat to humans (4) and intraspecies differences for workers (5)

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

According to REACH TGD dermal and oral ‘short-term’ exposures should normally be assessed using the long-term DNEL and application of an additional factor. Since adipic acid is of low systemic toxicity and only slightly issitating to the skin an additional factor of 2 is applied to calculate short term DNEL.

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

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:

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)

AF for dose response relationship:

1

AF for differences in duration of exposure:

1

Justification:

chronic studies available

AF for interspecies differences (allometric scaling):

1

Justification:

taken into account for NOAEC calculation

AF for other interspecies differences:

1

Justification:

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).

AF for intraspecies differences:

10

Justification:

default

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

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:

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:

oral absorption assumed to be equal to dermal absorption as a conservative approach.

AF for dose response relationship:

1

AF for differences in duration of exposure:

1

Justification:

chronic studies available

AF for interspecies differences (allometric scaling):

4

Justification:

rats -> humans

AF for other interspecies differences:

1

Justification:

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).

AF for intraspecies differences:

10

Justification:

default

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

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:

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

AF for dose response relationship:

1

AF for differences in duration of exposure:

1

Justification:

chronic studies available

AF for interspecies differences (allometric scaling):

4

Justification:

rats -> humans

AF for other interspecies differences:

1

Justification:

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).

AF for intraspecies differences:

10

Justification:

default

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

Local toxicity:

Disodium adipate is not irritating to the skin or eyes.

Systemic toxicity:

Overall, the systemic toxicity of disodium adipate is low; it is not sensitizing, not mutagen, not toxic to reproductive organs and fertility, not a developmental toxicant and not carcinogenic. The DNEL calculations are based on adipic acid data.

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).

Systemic toxicity by inhalation:

A) Modification of starting point:

Taking into account the following factors:

- 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)

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 see above; including allometric scaling from rat to humans: 4

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

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