Registration Dossier

Administrative data

Description of key information

The NOAEC of AGS-Mixturs in the 13-week study was 3%. In this study the test item was dissolved in deionised water and the animals were dosed by gavage. The following parameters have to be taken into account to derive a NOAEL in mg/kg-bw:
- AGS-Mixture contains overall 65.5% acids; (adipic acid: 3.9%; Glutaric acid: 16.43%; succinic acid 4.77% and nitric acid 3.9%)
- Volume applied per gavage per day: 10 ml/kg bw/day
- NOAEC: 3%
NOAEL = 3% (w/w) x 10 ml/kg-bw x 65.5% (w/w) = 195 mg/kg-bw

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
195 mg/kg bw/day
Study duration:

Additional information

Different dicarboxylic acid mixtures were investigated in a 4-week range finding study in rats performed to define the doses for a subsequent sub-chronic main study. Test articles were administered by gavage to 10 male and 10 female CD rats per dose group and clinical behaviour, body weight and food consumption were recorded. After sacrifice body weight and organ weights (liver, kidney, heart, adrenal, ovary, testis and brain) were reported but no histopathology was performed.

All animals died after dosing with a 50 % aqueous solution of the test sample AGS-Concentrate (adipic acid 10.44%, glutaric acid 37.63%, succinic acid 10.10%, nitric acid 7.4%) or after dosing with the pure test sample AGS-Mixture (adipic acid: 3.9%; Glutaric acid: 16.43%; succinic acid 4.77% and nitric acid 3.9%). The mortalities typically occured within the first 3 days, while a few occurred as late as week 2. At necropsy virtually all rats had evidence of petechial hemorrhage and brown to black discoloration of the gastric mucosal surface.

After application of a 50% aqueous solution of AGS-Mixture 5/10 males and 7/10 females died or were sacrificed in extremis and similar antemortem and post-mortem findings as in the higher dose groups were reported. Animals that survived to the terminal sacrifice had about a 10% decrease in body weight gain and did not show the gastric mucosal changes seen in the animals that died during the study.

In the 25% AGS-Mixture group all animals survived. The males had a slight decrease in body weight gain (-6.4%) and the females' weight gain was normal. Some animals showed excessive salvation and labored breathing after dosing. At necropsy, no evidence of the gastric mucosal findings was seen.

The only evidence of an effect after dosing animals with 10 or 5% AGS-Mixture was salvation seen in less than one-half of the rats.

The main sub-chronic study was conducted similar to OECD TG 408 and performed under GLP. The test item AGS-Mixture (adipic acid: 3.9%; Glutaric acid: 16.43%; succinic acid 4.77% and nitric acid 3.9%) was administered daily by oral gavage to 15 male and 15 female CD rats at dose levels of 3, 10 and 30%. The vehicle used was deionized water and the dosing volume 10 ml/kg.

The following parameters were reported for all animals: weekly clinical observations, body weight and food consumption, organ weights (liver, kidney, heart,adrenal, ovary, testis, brain), gross observations during necropsy. Additional parameters were reported for 10 animals/sex and dose at the end of the 13-week study: hematology (mct, hgb, rbc,mch, mvv, mchc, tdiff.leuco, pltlets, retic), biochemistry (AST, ALT, SAP, Glu, BUN, T.BILI, T.chol, Alb, Glob, T. Prot, Creat, Na, K, Cl, Ca, P, GGT, OCT, CPK), urological parameters (vol,pH, S Grv, prot, glu, ket, urobil, nitriles, bili, occ bld, sedim) and ophthalmological examination at 13 weeks. histopathological investigation was performed on > 45 organs in the control and high dose groups.

Three high dose (30% AGS-Mixture) males and one high dose female died during the study. Apart from one animal which died as a result of a gavage injury, no cause of death could be determined. No mortalities occurred at the lower dose levels or in the control animals. Effects observed at the high dose (30%) included weight reduction in males and female, reduced food consumption, clinical observation of labored breathing and/or rate.

Similar findings were seen at the mid dose (10%), but these observations were not as severe in magnitude or did not affect as many animals. A statistically significant increase in leukocytes was seen in males the 30% group. Urinary pH was significantly decreased in both genders at the high dose and in males at the mid dose.

There was no test article related effects seen at necropsy or on histopathological examination.

In this study the No-Effect-Level (NOEL) was 3% AGS-Mixture based on reduced body weight gain (males and females) and a decrease in urinary pH (males only) at 10%.

There are no data available after dermal or inhalation exposure to dicarboxylic acid mixture. Oral studies indicate that the toxicological profile of the dicarboxylic acid mixture is based on the acid character of the test substance; i.e. local irritation at the site of first contact. No specific organ toxicity is anticipated after dermal application or inhalation.

Additional sources/reviews cited in chapter "Additional Toxicological Information" support that the local irritation is the critical effect of dicarboxylic acid mixture taking into account the no specific target organ was identified for adipic acid in repeated dose toxicity studies including a limited chronic study. Glutaric acid and succinic acid are a central endogenous metabolites in the amino-acid pathway and in the citric acid cycle, respectively.

Justification for classification or non-classification

No classification is required according to the classification criteria 67/548/EWG and regulation no. 1272/2008 (GHS).