Hexanedioic acid, di-C16-18 (even numbered) alkyl esters

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

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

Remarks:

No data on haematology, clinical chemistry, urinalysis and behavioural analysis

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1982

Reference 2

Reference Type:

secondary source

Title:

Diesters Category of the Aliphatic Esters Chemicals (Test Plan and Robust Summaries for Substances in the HPV Test Plan)

Author:

US-EPA (American Chemistry Council's Aliphatic Esters Panel)

Year:

2010

Bibliographic source:

High Production Volume (HPV) Chemical Challenge Program (201-16837A and 201-16837B)

Reference 3

Reference Type:

secondary source

Title:

Bis(2-ethylhexyl)adipate (DEHA) CAS N°: 103-23-1

Author:

OECD

Year:

2000

Bibliographic source:

SIDS Initial Assessment Report for SIAM 10; Tokyo, Japan, 15-17 March 2000

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

no data on haematology and clinical chemistry

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Bis(2-ethylhexyl) adipate

EC Number:

203-090-1

EC Name:

Bis(2-ethylhexyl) adipate

Cas Number:

103-23-1

Molecular formula:

C22H42O4

IUPAC Name:

bis(2-ethylhexyl) adipate

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: NCI Frederick Cancer Research Center, Frederick, Maryland
- Age at study initiation: 3 weeks old
- Housing: 5 per cage in solid bottom suspended polycarbonate cages equipped with disposable nonwoven fiber filter sheets and Aspen-bed hardwood chips as bedding
- Diet: powdered Wayne Lab Blox diet, ad libitum
- Water: available via an Edstrom automatic watering system, ad libitum
- Acclimation period: 2 weeks

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

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): at least every 14 days
- Mixing appropriate amounts with (Type of food): chemical was mixed with aliquot of powdered Wayne Lab Blox animal feed, placing the mixture in a Petterson-Kelly twin-shell intensifier bar V-blender with the remainder of the feed and mix for 10 minutes
- Storage temperature of food: 4 °C for no longer than 14 days

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The amounts of the test substance in 12500 and 25000 ppm samples were determined by vapour phase chromatography. One-gram samples of each of the above mixtures were triturated twice with 50-mL portions of methanol. The supernatant solutions were combined and diluted to a volume of 100 mL and analyzed. The mean of the analytical concentration was usually within 10% of the theoretical.

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
1600, 3100, 6300, 12500, 25000 ppm
Basis:
nominal in diet

Doses / concentrations 2

Remarks:

Doses / Concentrations:
females: 140, 271, 551, 1094, 2187 mg/kg bw/day; males: 160, 310, 630, 1250, and 2500 mg/kg bw/day
Basis:
other: actual ingested (recalculated based on food consumption). Only the corresponding values to 6300 ppm were given in the study report. The other doses were calculated with the mean food consumption used to calculate these given values.

No. of animals per sex per dose:

10

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: doses used are based on an acute study and a 14 day study
(groups of five rats per sex were treated with five dose levels of the test substance in feed (up to 100000 ppm) for 14 days, followed by 1 day of observation with control diet. 1 group per sex were maintained as untreated controls. All surviving animals were killed after 15 days.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE & CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- no specifics given on how feed consumption was observed

Sacrifice and pathology:

GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

one female (1600 ppm) died,

Mortality:

mortality observed, treatment-related

Description (incidence):

one female (1600 ppm) died,

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

dose-related body weight depression up to 18% (males); no effects in females

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not specified

Details on results:

CLINICAL SIGNS AND MORTALITY
One female rat recieving 1600 ppm died, but its death was not considered to be compound-related.

BODY WEIGHT AND WEIGHT GAIN
Weight gain depression was 11% or more for male rats fed 12500 ppm or 25000 ppm.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
No compound-related reduction in feed consumption were observed.

HISTOPATHOLOGY: NON-NEOPLASTIC
No compound-related histopathological effects were observed.

Effect levels

1

Key result

Dose descriptor:

NOAEL

Effect level:

630 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: decreased body weight at 1250 mg/kg bw/day

2

Key result

Dose descriptor:

NOAEL

Effect level:

6 300 ppm

Based on:

test mat.

Sex:

male

Basis for effect level:

other: decreased body weight at 12500 ppm

3

Key result

Dose descriptor:

LOAEL

Effect level:

1 250 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: decreased body weight

4

Key result

Dose descriptor:

LOAEL

Effect level:

12 500 ppm

Based on:

test mat.

Sex:

male

Basis for effect level:

other: decreased body weight

5

Key result

Dose descriptor:

NOAEL

Effect level:

2 187 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: no effects observed at the highest dose

6

Key result

Dose descriptor:

NOAEL

Effect level:

25 000 ppm

Based on:

test mat.

Sex:

female

Basis for effect level:

other: no effects observed at the highest dose

Target system / organ toxicity

Key result

Critical effects observed:

not specified