Bis(2-ethylhexyl) adipate

Endpoint summary

Description of key information

Acute oral toxicity:
NTP (1982, comparable to OECD 401):
rats: LD50 > 20000 mg/kg
mice: LD50 > 20000mg/kg (females), app. 15000mg/kg (males)
BASF (1955, comparable to OECD 401)
rats: LD50 app. 19100mg/kg (converted from 20.7ml/kg)
1 rabbit and 1 cat: no mortality at app. 4600mg/kg

Smyth (1951)

LD50: 9100 mg/kg bw

Acute inhalation toxicity

BASF (1998, OECD 403, GLP)
rats: LC50 >5.7mg/L

Acute dermal toxicity

Smyth (1951)

rabbits: LD50=16300 ml/kg bw (~15 076 mg/kg bw)

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

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)

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: NCI Frederick cancer institute
- Age at study initiation: 3 weeks
- Housing: 5 per cage
- Diet :e.g. ad libitum
- Water :e.g. ad libitum
- Acclimatisation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-31
- Humidity (%): 10-88
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

corn oil

Doses:

0.08, 0.16, 0.31, 0.63, 1.25, 2.5 , 5.0, 10, 20 g/kg

No. of animals per sex per dose:

5

Control animals:

not specified

Details on study design:

Ten groups of five males and five females were administered a single dose of the test substance in corn oil by
gavage. The high doses were initiated after the start of the low dose groups (0.08- 1.25 g/kg).
All surviving animals were killed after 14 days .

Statistics:

no data

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 20 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: The estimated LD50 was 45 g/kg for males and 24 .6 g/kg for females.

Mortality:

males and females: 1/5 at 20 g/kg
males: 2/5 at 10 g/kg

Clinical signs:

other: no data

Gross pathology:

no data

         Survival(a)

Dose(g/kg ) Male        Female

 

0.08            5/5           5/5

0.16            5/5           5/5

0.31            5/5           5/5

0.63            5/5           5/5

1.25            5/5           5/5

1.25(b)       5/5           5/5

2.50(b)       5/5           5/5

5.00(b)       5/5           5/5

10.00(b)     3/5          5/5

20.00(b)     4/5          4/5

(a) Number surviving/number per group

(b) The single dose acute toxicity study at these higher doses was initiated 1 week after the single dose acute toxicity study at lower doses .

Interpretation of results:

GHS criteria not met

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

20 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OTS 798.1150 (Acute inhalation toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: breeding facility Dr. K. Thomae GmbH, Biberach, FRG
- Age at study initiation: approx . 8 - 9 weeks
- Weight at study initiation: 206 gram (females); 284 gram (males)
- Housing:singly in cages type DK III (Becker, Germany).
- Diet: ad libitum
- Water:ad libitum
- Acclimatisation period:at least 1 week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30-70
- Air changes (per hr): 12/12

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose/head only

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

Exposure system: Head-nose inhalation system INA 20 (glass-steel construction, BASF Aktiengesellschaft, volume V ~ 55L).
Technical equipment:
piston metering pump KP 2000 (Desaga)
two-component atomizer Mod.970 (stainless steel, Schlick).
aerosol mixing vessel (glass, BASF)
cyclonic separator (glass, BASF).
Flow rate of the test substance to the atomizer: 35.0 ml/h.
Exposure: supply air flow of 1500 L/h, exhaust air flow of 1350 l/h.

Analytical determination method: Gravimetric determination of the inhalation atmosphere concentration.
In addition, particle size was analyzed.
Equipment:
Stack Sampler Mark III (Andersen)
Vacuum Compressed Air Pump (Millipore)
Sampling probe (internal diameter 6.9 mm)
Limiting orifice 3 L/min
Balance: Sartorius M3P and Sartorius LC 1201S.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

5.7 mg/L

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

Duration of observation period: 14 days.
Clinical examinations: body weight (prior to exposure, after 7 days and after 14 days). Other clinical signs and findings.
Pathology: gross-pathological examination.

Statistics:

Performance of a Probit analysis.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.7 mg/L air

Exp. duration:

4 h

Mortality:

No lethality occured at the tested concentration of 5.7 mg/L during the study period of 14 days. Therefore, the study satisfied the criteria of a limit test (LC50 > 5.7 mg/L).

Clinical signs:

other: Clinical examination revealed irregular and accelerated respiration as well as attempts to escape and piloerection. No clinical signs could be detected from post dosing day 5 onward.

Body weight:

Body weight development of the animals was not influenced.

Gross pathology:

No macroscopic pathological findings were noted in animals examined at the end of the study.

Other findings:

Particle size distribution, expressed as mass median aerodynamic diameter (MMAD), was calculated to be 1.4 µm.

Interpretation of results:

GHS criteria not met

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating conc.

Value:

5 700 mg/m³ air

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

Penetration of rabbit skin is estimated by a technique closely akin to the one-day, cuff Method of Draize and associates using groups of four male albino New Zealand rabbits weighing 2.5 to 3.5 kg. The fur is removed from the entire trunk by clipping, and the dose is retained beneath an impervious plastic film. Dosages greater than 20 ml/kg cannot be retained in contact with the skin. The animals are immobilized during the 24-hour contact period, after which the film is removed and the rabbits are caged for the subsequent 14-day observation period. Based upon mortalities during a 14-day observation period, the most probable LD50 value and its fiducial range are estimated by the method of Thompson using the Tables of Weil.

GLP compliance:

no

Test type:

standard acute method

Species:

rabbit

Strain:

New Zealand White

Sex:

male

Sex:

male

Dose descriptor:

LD50

Effect level:

16 300 mL/kg bw

Interpretation of results:

GHS criteria not met

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

15 076 mg/kg bw

Additional information

The acute oral toxicity of Diethylhexyladipate (DEHA) is very low. In a study performed similar to the OECD 401 guideline 5 rats and 5 mice per sex were orally exposed to various doses of the test substance up to 20g/kg (NTP 1982). The LD50 for rats and female mice was above 20g/kg, while it was estimated to be 15g/kg for male mice. In an older study, groups of 5 rats were treated with up to app. 37000mg/kg (converted from 40ml/kg) (BASF 1955). The LD50 was calculated to be app. 19100mg/kg. In the same study, one rabbit and one cat survived a single dose of app. 4600mg/kg DEHA.

A well performed inhalation OECD-guideline and GLP compliant study was available (BASF 1998), that elicited an LC50 of > 5.7 mg/L in rats after nose only exposure for 4 hours.

Regarding the dermal route of exposure a non guideline and non GLP compliant study by Smyth et al. (1951) is available.

The LD50 was calculated to be app. 15076 mg/kg.

Justification for classification or non-classification

Based on the available acute oral, dermal and inhalation toxicity data, DEHA does not have to be classified for acute toxicity according to Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.