Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
34 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
34 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 mg/m³
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 mg/m³
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 mg/kg bw/day
DNEL related information
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

Workers - Hazard for the eyes

Additional information - workers

Discussion

Overall, the systemic toxicity of carboxylic acid di C4 -C6 (AGS) 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:

Overall, the systemic toxicity of AGS-mixture is low. There is no dermal or inhalation repeated dose toxicity study available. The NOAEL of AGS-Mixturs in the 13-week study was 195 mg/kg-bw/day. No specific target organ could be identified in this study.

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 dicarboxylic acid mixture is well absorbed by the oral route)

The overall corrected systemic NOAEC for worker is 344 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 (glutaric acid and succinic acid are a central endogenous metabolites. In limited studies in animals and humans it was shown that adipic acid is absorbed after oral administration, partially metabolized to various metabolites and CO2 which are excreted via urine and breath, resp.)

- Time extrapolation 2 (suchronic study in animals)

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

Systemic long- and short-term inhalation DNEL (worker) = 344/10 = 34 mg/m3

Systemic toxicity dermal and oral exposure:

- Default intraspecies factor rat -> human: 4

- No factor for additional uncertainty will be applied because no specific toxicity and/or target organ was identified in animal experiments. Due to the irritation properties against mucosal membranes local irritation is likely to be the most sensitive effect of AGS-mixture.

- Default interspecies factor worker: 5

- Default factor for extrapolation suchronic to chronic: 2

Systemic long- and short-term oral/dermal DNEL (worker) = 200/40 = 5 mg/kg/day

Local toxicity:

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

Inhalation:

Respiratory irritation in animals is not examined, however, due to the acidic character of the dicarboxylic acid mixture, a local irritation potential can not be excluded.

No evidence of respiratory tract irritation was reported for adipic acid 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).

Reliable human data are not available in the literature. In one study the authors reported that clouds of adipic acid and other materials were routinely generated during charging of reaction vessels. In 7 of 12 workers exposed (for an average of 9.2 years) to various glycols, glycerine, other compounds, and adipic acid dust particles (8 h average concentration 0.47-0.79 mg/m3 [0.08-0.13 ppm]) complained of mucosal irritation (eye, nose, and throat). There was no local exhaust ventilation and the workers did not wear respiratory protection (Cummings and Roseman 1985). Due to the limitations mentioned this study is not reliable and can not be used to derive a threshold for local irritation.

A Threshold Limit Value (TLV-TWA) of 5 mg/m3 was established for adipic acid 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.

A threshold of 5 mg/m3 is supported by occupational medical experiences with adipic acid , glutaric acid and succininc acid available within the lead company, Lanxess. Regularly, medical examination of the staff (7 persons) is performed. Examination includes 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. Parallel to the medical examination the concentration of those hazardous substances in the air at the workplace were determined. The maximum concentration of adipic acid and glutaricacid were 11.6 mg/m3 and 1.23 mg/m3, respectively, between 2006 and 2009 (Currenta 2010).

A toxicological 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 the proposed DNEL long-term for local effects of 5 mg/m3 is consistent with the recommendations by this toxicological task force.

Overall, the TLV-TWA of 5 mg/m3 established by the American Conference of Governmental Industrial Hygienists (ACGIH) for adipic acid in 2001 is consistent with the available data for cicarboxylic acid and is taken as long-term inhalation DNEL. Concerning the short term exposure we recommend the same value as proposed for long-term exposure: 5 mg/m3.

Dermal exposure:

Dicarboxylic acid is only slightly irritating to the skin (no classification necessary).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEC

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
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:
2.5 mg/kg bw/day
DNEL related information
Overall assessment factor (AF):
80
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
80
Modified dose descriptor starting point:
NOAEL

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

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
DNEL related information
Overall assessment factor (AF):
80
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

See discussion above on worker.

Systemic toxicity by inhalation:

NOAEL of AGS-Mixturs in the 13-week study was 195 mg/kg-bw/day

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: 170 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 (see worker)

- Time extrapolation 2 (subchronic to chronic)

- 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) = 170 /20 = 8.5 mg/m3

Systemic effects oral and dermal exposure:

the default intraspecies factor for the general population is 10 (compared to 5 for worker). All other factors remain the same as for worker. Concerning the short-term DNEL a factor of 1 will be applied to the long-term DNEL.

Local effects:

Dicarboxylic acid mixture is an irritating compound labelled with R41. AGS-mixture 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” A qualitative risk characterisation approach is required when there is no basis for setting a DN(M)EL for a certain human health endpoint such as irritation. Carboxylic acids cause risk of serious damage to the eyes and no appropriate data are available to set a DNEL for general population. Therefore, a qualitative risk charaterisation has been done for this point. Compounds which cause “risk of serious damage to the eyes” should be allocated to the “moderate hazard category”.