Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

74.1 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

12.5

Dose descriptor starting point:

NOAEC

Value:

750 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

926 mg/m³

Explanation for the modification of the dose descriptor starting point:

The oral NOAEL of 750 mg/kg bw/day, obtained in a chronic study on rats with continuous diet exposure (7 days/week; Horn, 1957), was considered relevant for human risk assessment purposes and is taken forward for DNEL derivation.

For the inhalation route there is no animal study available. Therefore, oral rat data is used to calculate a corresponding air concentration for humans and a route-to-route extrapolation for systemic effects is necessary to derive the correct starting point. In the case of oral-to-inhalation the inclusion of a default factor of 2 is recommended according to chapter R.8.4.2 of the ECHA Guidance on Information Requirements and Chemical Safety Assessment, chapter R.8: Characterisation of dose [concentration]-response for human health (version 2.1, November 2012). According to Figure R. 8-3 in the ECHA Guidance additional correction is needed for scaling issues: Corrected inhalation NOAEC = oral NOAEL * 50%/100% * 1/0.38 m³ per kg and day * 6.7 m³/10 m³ * 1.4 (for differences in experimental/human exposure conditions, i.e. 7 days/week in animal study versus 5 days/week for workers, see Appendix R.8-6 of ECHA Guidance R8). Based on the oral NOAEL of 750 mg/kg bw/day for systemic toxicity obtained in a study on rats with chronic treatment the starting point is calculated with 926 mg/m³.

AF for dose response relationship:

1

Justification:

Since the starting point for the DNEL calculation is a NOAEL according to chapter R.8.4.3.1 of ECHA Guidance R.8 the default assessment factor for dose response relationship is 1.

AF for differences in duration of exposure:

1

Justification:

For differences in experimental exposure duration (= chronic) and the duration of exposure for the population and scenario under consideration (= chronic) according to Table R.8-5 of ECHA Guidance R.8 no specific assessment factor is considered.

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is already included in the route-to-route extrapolation for dose descriptor calculation as described in ECHA Guidance R.8.

AF for other interspecies differences:

2.5

Justification:

A factor of 2.5 for remaining interspecies differences is suggested in ECHA guidance R.8.

AF for intraspecies differences:

5

Justification:

According to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor to be applied for intraspecies differences in workers is 5.

AF for the quality of the whole database:

1

Justification:

The default assessment factor is used as suggested by ECHA Guidance R.8, based on the available toxicological studies for adipic acid, the listing as ,GRAS’ in the US (FDA 1982), the establishment of a group ADI (JECFA, 1977) and the fact that no safety concerns at current levels of intake were seen for adipic acid when used as a flavoring agent (JECFA 1999). See ‘Additional Information’

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

21 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

NOAEL

Value:

750 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 050 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The oral NOAEL of 750 mg/kg bw/day, obtained in a chronic study on rats with continuous diet exposure (7 days/week; Horn, 1957), was considered relevant for human risk assessment purposes and is taken forward for DNEL derivation.

For the dermal route there is no animal study available. Therefore, oral rat data is used to calculate a corresponding dermal exposure dose for humans. On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor (i.e. factor 1) should be introduced when performing oral-to-dermal extrapolation (ECHA Guidance R.8, chapter 8.4.2). Thus, no modification of the dose descriptor starting point is warranted. However, since there are differences in experimental/human exposure conditions (7 days/week in animal study versus 5 days/week for workers) adaption with a factor of 1.4 seems appropriate (Appendix R.8-6 of ECHA Guidance R8). Based on the oral NOAEL of 750 mg/kg bw/day for systemic toxicity obtained in a study on rats with chronic treatment, the starting point is calculated with 1050 mg/kg bw/day.

AF for dose response relationship:

1

Justification:

Since the starting point for the DNEL calculation is a NOAEL according to chapter R.8.4.3.1 of ECHA Guidance R.8 the default assessment factor for dose response relationship is 1.

AF for differences in duration of exposure:

1

Justification:

For differences in experimental exposure duration (= chronic) and the duration of exposure for the population and scenario under consideration (= chronic) according to Table R.8-5 of ECHA Guidance R.8 no specific assessment factor is considered.

AF for interspecies differences (allometric scaling):

4

Justification:

According to Table R.8-3 of ECHA Guidance R.8 the allometric scaling factor for the rat when compared with humans is 4.

AF for other interspecies differences:

2.5

Justification:

A factor of 2.5 for remaining interspecies differences is suggested in ECHA Guidance R.8.

AF for intraspecies differences:

5

Justification:

According to chapter R.8.4.3.1 of ECHA Guidance R.8 the default assessment factor to be applied for intraspecies differences in workers is 5.

AF for the quality of the whole database:

1

Justification:

The default assessment factor is used as suggested by ECHA Guidance R.8, based on the available toxicological studies for adipic acid, the listing as ,GRAS’ in the US (FDA 1982), the establishment of a group ADI (JECFA, 1977) and the fact that no safety concerns at current levels of intake were seen for adipic acid when used as a flavoring agent (JECFA 1999). See ‘Additional Information’

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

medium hazard (no threshold derived)

Overall, the systemic toxicity of adipic acid is low; it is not sensitizing, not mutagen, not toxic to reproductive organs, not a developmental toxicant and showed no carcinogenic activity in a limited 2-year feeding study.

In a two-year feeding study, groups of 20 male rats were given 0.1, 1, 3 and 5 % of adipic acid in the diet (equivalent to doses of approximately 75, 750, 2250 and 3750 mg/kg bw/day). Groups of 10 or 19 female rats received food containing 0 or 1 % adipic acid, respectively (approx. 750 mg/kg bw/day). Body weights, food consumption and general appearance were recorded weekly throughout the experimental period. After 2 years, surviving rats were weighed, killed, and examined grossly. The brain, thyroid, lung, heart, liver, spleen, kidneys, adrenals and stomach of the animals were weighed. Microscopic examination of thyroid, lung, heart, liver, spleen, kidneys, adrenals, stomach, pancreas, bone marrow, large and small intestine uterus, ovaries and testes on a representative number of animals (no further information) was performed. The percent survival for each test group was higher than for the control group. There were no body weight differences during the test period in female and male rats treated with 0, 0.1 and 1 % adipic acid. The weight gains of the male rats receiving 3 and 5 % adipic acid were significantly less than the control groups. At necropsy there was no treatment related effect observed. Results of microscopic examination of the organs revealed no compound related effect. The NOAEL was 1 % for male and female rats (approx. 750 mg/kg bw/day) (Horn et al. 1957).

The dose of 750 mg/kg bw/day is thus considered as basis for DNEL derivation.

No reliable repeated inhalation or dermal toxicity studies are available for adipic acid.

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (MAK Commission) has evaluated adipic acid and derived a maximum concentration at the workplace (MAK value, 2016) of 2 mg/m³ (inhalable fraction). This value was established by analogy to phosphorus acid until suitable data become available. ‘Taking into account the lower acidity (of adipic acid), this value is to be considered as the ‘worst-case’ for adipic acid.’

With regard to peak limitation an excursion factor of 2 is applied by MAK, also in analogy to phosphoric acid.

(The MAK collection for Occupational Health and Safety 2018, Vol 3, No 3)

A Threshold Limit Value (TLV-TWA) of 5 mg/m3 was established by the American Conference of Governmental Industrial Hygienists (ACGIH) in 2001, based on the data reported by Krapotkina et al (1981) that the threshold for irritation of the human eye was 20 mg/m3. Clinical examinations of worker engaged in adipic acid manufacture found that inhaling adipic acid produced functional disorders of the autonomic nervous system and gastrointestinal tract and in the mucosa of the upper respiratory tracts.

Occupational medical examination of the staff at Lanxess (7 persons) was performed. Examinations included medical history, physical examination, lung function, ECG/Ergometry, vision-testing and audiometry. Occupational medical surveillance did not reveal any health effects like irritations of the eyes, skin, mucosa membranes or upper respiratory tract which could be derived to be from possible exposure at workplace.

Adipic acid is listed as a GRAS (Generally Recognized as Safe) food additive by the FDA (Code of Federal Registrations, Title 21 - Food and Drugs, Part 184, FDA 1982)

General use (1977): A Group ADI (Acceptable Daily Intake) of 0-5 mg/kg bw was established for adipic acid and its potassium, sodium and ammonium salts in 1977 by JECFA (Joint FAO/WHO Expert Committee on Food Additives).

No safety concern at current levels of intake were seen by JECFA when used as a flavouring agent (FLAVOUR USE, JECFA 1999).

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

13 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Dose descriptor starting point:

NOAEL

Value:

750 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

326 mg/m³

Explanation for the modification of the dose descriptor starting point:

The oral NOAEL of 750 mg/kg bw/day, obtained in a chronic study on rats with continuous diet exposure (7 days/week; Horn, 1957), was considered relevant for human risk assessment purposes and is taken forward for DNEL derivation.

For the inhalation route there is no animal study available. Therefore, oral rat data is used to calculate a corresponding air concentration for humans and a route-to-route extrapolation for systemic effects is necessary to derive the correct starting point. In the case of oral-to-inhalation the inclusion of a default factor of 2 is recommended according to chapter R.8.4.2 of ECHA Guidance R.8. According to Figure R. 8-3 of ECHA Guidance R.8 additional correction is needed for scaling issues: Corrected inhalation NOAEC = oral NOAEL * 0.5 * 1/1.15 m³ per kg and day (based on the oral NOAEL of 750 mg/kg bw/day for systemic toxicity).

AF for dose response relationship:

1

Justification:

As the starting point for the DNEL calculation is a NOAEL according to chapter R.8.4.3.1 of ECHA Guidance R.8 the default assessment factor for dose response relationship is 1.

AF for differences in duration of exposure:

1

Justification:

For differences in the experimental exposure duration (= chronic) and the duration of exposure for the population and scenario under consideration (= chronic) according to Table R.8-5 of ECHA Guidance R.8 a factor of 1 is considered.

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is already included in the route-to-route extrapolation for dose descriptor calculation as described in ECHA Guidance R.8.

AF for other interspecies differences:

2.5

Justification:

A factor of 2.5 for remaining interspecies differences is suggested in ECHA Guidance R.8.

AF for intraspecies differences:

10

Justification:

According to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor to be applied for intraspecies differences in the general population is 10.

AF for the quality of the whole database:

1

Justification:

The default assessment factor is used as suggested by ECHA Guidance R.8, based on the available toxicological studies for adipic acid, the listing as ,GRAS’ in the US (FDA 1982), the establishment of a group ADI (JECFA, 1977) and the fact that no safety concerns at current levels of intake were seen for adipic acid when used as a flavoring agent (JECFA 1999). See ‘Additional Information’

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

7.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEL

Value:

750 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

750 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The oral NOAEL of 750 mg/kg bw/day, obtained in a chronic study on rats with continuous diet exposure (7 days/week; Horn, 1957), was considered relevant for human risk assessment purposes and is taken forward for DNEL derivation.

For the dermal route there is no animal study available. Therefore, oral rat data are used to calculate a corresponding dermal exposure dose for humans. On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor (i.e. factor 1) should be introduced when performing oral-to-dermal extrapolation (ECHA Guidance R.8, chapter 8.4.2). Thus, no modification of the dose descriptor starting point is warranted.

AF for dose response relationship:

1

Justification:

As the starting point for the DNEL calculation is a NOAEL according to chapter R.8.4.3.1 of ECHA Guidance R.8 the default assessment factor for dose response relationship is 1.

AF for differences in duration of exposure:

1

Justification:

For differences in experimental exposure duration (= chronic) and the duration of exposure for the population and scenario under consideration (= chronic) according to Table R.8-5 of ECHA Guidance R.8 no specific assessment factor is considered.

AF for interspecies differences (allometric scaling):

4

Justification:

According to Table R.8-3 of ECHA Guidance R.8 the allometric scaling factor for the rat when compared with humans is 4.

AF for other interspecies differences:

2.5

Justification:

A factor of 2.5 for remaining interspecies differences is suggested in ECHA Guidance R.8.

AF for intraspecies differences:

10

Justification:

According to chapter R.8.4.3.1 of ECHA Guidance R.8 the default assessment factor to be applied for intraspecies differences in the general population is 10.

AF for the quality of the whole database:

1

Justification:

The default assessment factor is used as suggested by ECHA Guidance R.8, based on the available toxicological studies for adipic acid, the listing as ,GRAS’ in the US (FDA 1982), the establishment of a group ADI (JECFA, 1977) and the fact that no safety concerns at current levels of intake were seen for adipic acid when used as a flavoring agent (JECFA 1999). See ‘Additional Information’

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:

7.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEL

Value:

750 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The oral NOAEL of 750 mg/kg bw/day, obtained in a chronic study on rats with continuous diet exposure (7 days/week; Horn, 1957), was considered relevant for human risk assessment purposes and is taken forward for DNEL derivation.

Oral data from the rat are used to decide on a corresponding oral dose for humans. Therefore, a route-to-route extrapolation is not necessary and the NOAEL from the rat study is used as starting point.

AF for dose response relationship:

1

Justification:

As the starting point for the DNEL calculation is a NOAEL according to chapter R.8.4.3.1 of ECHA Guidance R.8 the default assessment factor for dose response relationship is 1.

AF for differences in duration of exposure:

1

Justification:

No difference in the experimental exposure duration (= chronic) and the duration of exposure for the population and scenario under consideration (= chronic) according to Table R.8-5 of ECHA Guidance R.8.