Hexanedioic acid, 1,6-bis(2-propylheptyl) ester

Endpoint summary

Description of key information

Dipropylheptyladipat caused no toxicity in rats upon single oral dosing of 5000 mg/kg bw (BASFSE, 2014) and single dermal application of 5000 mg/kg bw (BASF 2014). Based on the experimental data available for the structural analogue Diethylhexyladipat, the target chemical Dipropylheptyladipat is considered to be of low toxicity after inhalation with a LC50 above 5700 mg/m³ air (BASF A G, 1998, read across from Diethylhexyladipat (for details please refer to chapter 13 of the IUCLID, Assessment reports). 

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:

2014

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: Japan MAFF 8147

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at study initiation: approx. 10 weeks old
- Weight at study initiation: Animals of comparable weight (± 20% of the mean weight) 170-181 g ( on day 0)
- Fasting period before study:Feed was withdrawn from the animals at least 16 hours before administration, but water was available ad libitum.
- Housing: Makrolon cage, type III, single housing
- Diet: VRF1(P); SDS Special Diets Services, 67122 Altrip, Germany
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22°C ± 3°C
- Humidity: 30 – 70%
- Air changes: approx. 10 per hour
- Photoperiod: 12 h / 12 h (6.00 a.m. – 6.00 p.m. / 6.00 p.m. – 6.00 a.m.)

IN-LIFE DATES: 2014-06-24 to 2014-07-09

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Doses:

5000 mg/kg bw/d (5.49 ml/kg bw undiluted substance)

No. of animals per sex per dose:

3 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Body weight determination:
Individual body weights shortly before administration (day 0), weekly thereafter and on the last day of observation.
Clinical observations:
Recording of clinical signs several times on the day of administration, and at least once daily thereafter each workday for the individual animals.
Mortality:
A check for any dead or moribund animals was made at least once each workday
- Necropsy of survivors performed: yes
Necropsy with gross-pathology examination on the last day of the observation period after sacrifice by CO2- inhalation in a chamber with increasing concentrations over time.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: no mortality was observed

Mortality:

No mortality occurred

Clinical signs:

other: Impaired general state and piloerection at hour 2 and 3 and on day 9 after administration was observed in one animal.

Gross pathology:

There were no macroscopic pathological findings.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

5 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP compliant 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 old
- Weight at study initiation: 206 g (females); 284 g (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: 20 - 24°C
- Humidity: 30-70%
- Air changes (per hr): 12 hours light/12 hours dark

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 AG, volume V ~ 55L).
Technical equipment:
piston metering pump KP 2000 (Desaga)
two-component atomizer Mod.970 (stainless steel, Schlick).
aerosol mixing vessel (glass, BASF AG)
cyclonic separator (glass, BASF AG).
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 rats

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:

Probit analysis.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.7 mg/L air

Based on:

test mat.

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.

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

Study period:

2014

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: Japan MAFF 8147

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: Charles River Wiga GmbH, Germany
- Age at study initiation: male animals approx. 8 weeks, female animals approx. 12 weeks
- Weight at study initiation: Animals of comparable weight (± 20% of the mean weight), males: 233-244g; females: 210-223g
- Fasting period before study: no
- Housing: Single housing, Makrolon cage, type III
- Diet (e.g. ad libitum): VRF1(P); SDS Special Diets Services, 67122 Altrip, Germany
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C +/- 3°C
- Humidity (%): 30-70%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 h / 12 h (6.00 a.m. – 6.00 p.m. / 6.00 p.m. – 6.00 a.m.)

IN-LIFE DATES: From: 23 June 2014 To: 08 July 2014

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: About 40 cm² (corresponds to at least 10% of the body surface)
- Type of wrap if used: semi-occlusive

REMOVAL OF TEST SUBSTANCE
- Washing (if done): warm water
- Time after start of exposure: 24h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 5.49 ml/kg bw or 5000 mg/kg bw
- Concentration (if solution): undiluted


VEHICLE: undiluted substance was tested

Duration of exposure:

24h

Doses:

5.49 ml/kg bw or 5000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: day 0, weekly thereafter and on the last day of observation
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,gross pathology, skin findings

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: no mortality observed

Mortality:

no mortality observed

Clinical signs:

other: no local or systemic clinical signs were observed.

Gross pathology:

No macroscopic pathologic abnormalities were noted in the animals (5 males and 5 females) examined on the last day of observation.

Other findings:

No local effects were observed.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

5 000 mg/kg bw

Additional information

Acute oral toxicity

In the key oral toxicity study (BASF SE 2014, according to OECD 423) three female fasted Wistar rats were exposed each by gavage to Dipropylheptyladipat at a dose level of 5000 mg/kg bw. Animals were observed for 14 days. No mortality and no clinical signs were observed. No macroscopic pathological findings could be found. The oral LD50 was determined to be > 5000 mg/kg bw.

In addition, experimental data from acute oral toxicity studies with Diethylhexyladipat, a structural analogue of Dipropylheptyladipat, are in line with this result as they indicated very low oral toxicity. The LD50 values were between 45000 mg/kg bw to 19044 mg/kg bw based on a densitiy of 0.9249 g/cm³ for Diethylhexyladipat) in rats (NTP, 1982; BASF AG, 1955). Acute oral toxicity studies with Dipropylheptyladipat in the mouse, rabbit and cat showed LD50 values in the range of 24600 to 4650 mg/kg bw (NTP 1982; BASF AG 1955).

Acute inhalation toxicity

A well perfomed OECD-guideline and GLP compliant inhalation (nose only) toxicity study (BASFAG, 1998) indicated an LC50 of >5700 mg/m³ for the structural analogue Diethylhexyladipat.

Acute dermal toxicity

In the key dermal toxicity study (BASF SE 2014, according to OECD 402) 5 male and 5 female Wistar rats were exposed dermally to Dipropylheptyladipat at a dose level of 5000 mg/kg bw. Animals were observed for 14 days. No mortality, no clinical signs and no local effects were observed. No macroscopic pathological findings could be found. The dermal LD50 was determined to be > 5000 mg/kg bw.

Justification for selection of acute toxicity – oral endpoint
most reliable study

Justification for selection of acute toxicity – inhalation endpoint
most reliable study

Justification for selection of acute toxicity – dermal endpoint
most reliable study

Justification for classification or non-classification

Based on the available acute oral, dermal and inhalation toxicity data, Dipropylheptyladipat does not have to be classified for acute toxicity according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP/GHS). The test item does not meet the criteria for specific target organ toxicity after single exposure (STOT SE) according to Regulation (EC) No 1272/2008 (CLP/GHS).