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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented study report which meets basic scientific principles (no data on haematology, clinical chemistry, urinalysis and behavioural analysis).

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1982
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 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

Test material

Constituent 1
Chemical structure
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 / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
1600, 3100, 6300, 12500, 25000 ppm
Basis:
nominal in diet
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 males and 10 females
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 (if feeding study): 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

open allclose all
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
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
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
Dose descriptor:
LOAEL
Effect level:
12 500 ppm
Based on:
test mat.
Sex:
male
Basis for effect level:
other: decreased body weight
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
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

Critical effects observed:
not specified

Applicant's summary and conclusion