Carboxylic acids, di-, C4-6

Endpoint summary

Description of key information

Dicarboxylic acid mixture is of low acute toxicity after oral or dermal exposure. Although no reliable inhalation study is available low toxicity by inhalation is also anticipated based on low acute toxicity data reported for adipic acid.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1979

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

not specified

Principles of method if other than guideline:

Animals were observed for 14 days

GLP compliance:

no

Test type:

standard acute method

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

water

Doses:

6 dose level; 3160; 3980; 5010; 6310; 7940; 10000 mg/kg bw

No. of animals per sex per dose:

2-3 males; 2-3 females; overall 5 animals per dose group

Control animals:

no

Sex:

male/female

Dose descriptor:

LD0

Effect level:

3 980 mg/kg bw

Sex:

male/female

Dose descriptor:

LD50

Effect level:

6 000 mg/kg bw

95% CL:

>= 5 400 - <= 6 720

Mortality:

see Table 1

Signs of intoxication: weight loss (one day in survivors), increasing weakness, salvation, collapse and death.

Gross autopsy:

5010 and 6310 mg/kg group: Hemorrhagic lungs, liver, kidney and spleen discoloration and acute gastrointestinal inflamation.

7940 and 10000 mg/kg group: Lung and liver hyperemia

Survivors (day 14): Viscera appeared normal.

Table 1: mortalities

Dosage (mg/kg bw)	mortality males	mortality females	mortality combined
3160	0/3	0/2	0/5
3980	0/2	0/3	0/5
5010	1/3	0/2	1/5
6310	0/2	3/3	3/5
7940	3/3	2/2	5/5
10000	2/2	3/3	5/5

Interpretation of results:

GHS criteria not met

Executive summary:

An oral LD50 value of 6000 mg/kg (95% confidence limits 5400 - 6720 mg/kg) was reported in rats in study similar to OECD TG 401 with doses up to 10000 mg/kg. In this study a 20% aqueous solution of a dicarboxylic acid mixture was tested and mortality was seen during the first 4 days; most deaths were reported within the first day. Signs of intoxication were weight loss (one day in survivors), increased weakness, salvation, collapse and death. Lethal doses caused hemorrhagic lungs, liver, kidney and spleen discoloration and acute gastrointestinal inflamation. Animals that survived to termination (day 14) appeared normal.

Endpoint conclusion

Dose descriptor:

LD50

Value:

6 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substance have similar toxicological properties because they share structural similarities with common functional groups, varying solely in their length. This prediction is supported by experimental data for environmental fate, ecotoxicity and human health toxicology on the multi-constituent target substance, the source substance and on further constituents of the target substance.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The target Glutaric acid, tech. (CAS No. 68603-87-2) is a multi-constituent substance, consisting of C4-, C5- and C6- dicarboxylic acids. The source substance Adipic acid (CAS No 124-04-9, C6-dicarboxylic acid) is one of the main components of the target substance. Additionally, target and source exhibit the same core structure as they are based on linear carbon chains with same acidic moieties, varying solely in chain lengths. Adipic acid thus serves as a structural representative of glutaric acid, tech.. No relevant impurity was identified for the boundary composition of Glutaric acid tech. and adipic acid.

3. ANALOGUE APPROACH JUSTIFICATION
The prediction is supported by experimental data on the multi-constituent target substance and the source substance showing comparable properties regarding physico-chemistry, ecotoxicology and human health toxicology. Therefore, read-across from toxicity studies on the source substance is considered as an appropriate adaption to the standard information requirements for the target substance.

For detailed information see the RAAF document attached to the IUCLID:
‘Justification for a read-across approach from Adipic acid (cAS no. 124-04-9) [Source] to Glutaric acid, tech. (CAS No 68603-87-2) [Target]

Reason / purpose for cross-reference:

read-across source

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Key result

Sex:

male/female

Dose descriptor:

LC0

Effect level:

7 700 mg/m³ air

Exp. duration:

4 h

Remarks on result:

other: no mortalities observed

Mortality:

No mortalities observed at a concentration of 7700 mg/m³ of the source adipic acid. It can be concluded that for the target dicarboxylic acid mixture no relevant toxic effects up to the limit concentration are expected.

Clinical signs:

other: Nothing abnormal observed

Gross pathology:

Nothing abnormal observed

Neither mortality nor symptoms were observed during and after exposure.  No pathological changes were reported at necropsy.

Conclusions:

In the acute inhalation toxicity study with the constituent adipic acid at the maximal attainable concentration of 7700 mg/m³ no signs of toxicity and also no macroscopic pathological changes were observed. This concentration can therefore be regarded as LC0.

Executive summary:

The concentration of 7700 mg/m³ can be regarded as LC0 in the source acute inhalation toxicity study. As explained in the justification for type of information, the differences in molecular structure between the target and the source are unlikely to lead to distinct differences in acute inhalation toxicity. The acidic nature of target and source is expected to be the critical effect in acute inhalation toxicity studies and no relevant quantitative differences in local effects and thus no acute inhalation toxicity of dicarboxylic acid mixture can be expected.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1979

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

no guideline followed

Principles of method if other than guideline:

Animals were dosed with 40% aqueous solutions for 24 hours and observed for 14 days.
one female rabbit was dosed with 5010 mg/kg.
one female and one male rabbit were dosed with 7940 mg/kg

GLP compliance:

no

Test type:

standard acute method

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Type of coverage:

not specified

Vehicle:

water

Duration of exposure:

24 hours

Doses:

5010 and 7940 mg/kg

No. of animals per sex per dose:

5010 group: one female
7940 mg/kg group: one female and one male

Control animals:

not required

Sex:

male/female

Dose descriptor:

LD0

Effect level:

7 940 mg/kg bw

Signs of intoxication: wieght loss (two to four days)

Gross autopsy: viscera appeared normal

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

LD0 > 7940 mg/kg

Executive summary:

No mortality was reported in an acute dermal toxicity experiment in rabbits following administration of 5010 mg/kg (n=1) or 7940 mg/kg (n=2) of a 40% aqueous solution/suspension of dicarboxylic acid mixture. The only clinical signs reported were weight loss during the first 2 to 4 days. The viscera appeared normal at termination after 14 days. The LD50 was thus > 7940 mg/kg bw.

Endpoint conclusion

Dose descriptor:

LD50

Value:

7 940 mg/kg bw

Additional information

An oral LD50 value of 6000 mg/kg (95% confidence limits 5400 - 6720 mg/kg) was reported in rats in a study similar to OECD TG 401 with doses up to 10000 mg/kg. In this study a 20% aqueous solution of a dicarboxylic acid mixture was tested and mortality was seen during the first 4 days; most deaths were reported within the first day. Signs of intoxication were weight loss (one day in survivors), increased weakness, salvation, collapse and death. Lethal doses caused hemorrhagic lungs, liver, kidney and spleen discoloration and acute gastrointestinal inflammation. Animals that survived to termination (day 14) appeared normal (Monsanto, 1979). Two additional studies report LD50 values of 5000 mg/kg and 2207 mg/kg and support the low acute oral toxicity of dicarboxylic acid mixture.

 

No mortality was reported in an acute dermal toxicity experiment in rabbits following administration of 5010 mg/kg (n=1) or 7940 mg/kg (n=2) of a 40% aqueous solution/suspension of dicarboxylic acid mixture. The only clinical signs reported were weight loss during the first 2 to 4 days. The viscera appeared normal at termination after 14 days.

 

There are no reliable data studies available to evaluate the acute inhalation toxicity of dicarboxylic acid mixture. In a study with limited reliability five rats per sex were whole body exposed for 4 hours to dicarboxylic acid mixture aerosols at a single analytical concentration of 0.03 mg/l. The filters used avoids particles > 5 µm. All animals were observed for 14 days for mortality and clinical signs of toxicity. Body weights were recorded before exposure and at weekly intervals. No clinical signs or body weight effects as well as no adverse necropsy findings were recorded (BASF, 1979).

Reliable data on acute inhalation toxicity are available for the read-across source adipic acid. In a study similar to OECD TG 403 no mortality, toxicity or macroscopic pathological changes were observed in 20 rats exposed for 4 h (nose only) to the maximal attainable concentration of 7700 mg/m³ of adipic acid dust. 50% of the particles had a MMAD below 3.5 µm.
The concentration of 7700 mg/m³ can be regarded as LC0 in the source acute inhalation toxicity study. As explained in the justification for type of information, the differences in molecular structure between the target and the source unlikely to lead to substantial differences in acute inhalation toxicity. The acidic nature of target and source is expected to be the critical effect in acute inhalation toxicity studies and no relevant quantitative differences in local effects and thus no acute inhalation toxicity of dicarboxylic acid mixture can be expected.

The neat glutaric acid (C5-dicarboxylic acid) and succinic acid (C4-dicarboxylic acid) also showed a very low acute oral toxicity with LD₅₀ values of well above 2000 mg/kg bw. The acute dermal toxicity was determined with > 7000 mg/kg bw for the neat glutaric acid. No data are available for acute dermal toxicity of succinic acid and acute inhalation toxicity of glutaric and succinic acid.

Justification for classification or non-classification

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