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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Peer reviewed near guideline study; a study report on acute and (sub)chronic studies, read-across.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1982

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
no data on heamatology and clinical chemistry
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Supplier: W.R. Grace Co.(Fords, NJ)
- Name of test material (as cited in study report): di(2-ethylhexyl)adipate
- Substance type: a clear colourless liquid
- Analytical purity: 100.4% (ester titration)
- Lot/batch No.: GC-2-27-76
- Storage condition of test material: at 4 degrees Celcius

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: NCI Frederick cancer institute
- Age at study initiation: 4 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

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Dietary preparation:
Test diets were prepared by mixing the chemical with an aliquot of powdered
Wayne® Lab Blox animal feed (Allied Mills, Chicago, IL), placing the
mixture in a Patterson-Kelly twin-shell intensifier bar V-blender with the
remainder of the feed, and mixing for 10 minutes . Test diets were sealed in
labelled plastic bags and stored at 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 di(2-ethylhexyl)adipate in selected batches of feed were measured by vapor-phase chromatography of 50-ml methanol extracts of 2-g samples. At each dietary concentration, the mean of the analytical concentration was usually within +/-10% of the theoretical.
Duration of treatment / exposure:
Duration of treatment: 91 days
Frequency of treatment:
Frequency of treatment: daily (ad libitum)
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
1600, 3100, 6300, 12500, 25000 ppm
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
1600 ppm = approx. 200 mg/kg bw/day
Basis:
other: recalculated based on REACH guidance
No. of animals per sex per dose:
10 male and 10 female mice per dose.
Control animals:
yes, plain diet
Details on study design:
No further details were described.
Positive control:
No positive control was used.

Examinations

Observations and examinations performed and frequency:
Survival, body weight, histopathologic analysis and and feed consumption were assessed.
Clinical observations were
made twice daily and animals were weighed weekly.
Sacrifice and pathology:
At the end of the 91-day
study, survivors were killed, necropsies were performed on all animals, and
tissues were taken for histopathologic analysis .
Other examinations:
No other examinations were performed.
Statistics:
Statistical analyses for a possible dose-related effect on survival used the method of Cox (1972) for testing two groups for equality and Tarone's (1975) extension of Cox's methods for testing for a dose-related trend . One-tailed P values have been reported for all tests except the departure from linearity test, which is reported only when its two-tailed P value is less than 0 .05.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
One female mouse died as a result of an accident . Weight gain
depression was 10% or more for male mice fed 3,100 ppm or more . Weight gain
depression was 10% or more for females fed 6,000 or 25,000 ppm . No compound-related
histopathologic effects or reduction in feed consumption were observed.
High and low doses selected for the chronic study with mice were 12,000
ppm and 25,000 ppm di(2-ethylhexyl)adipate in feed .

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 600 ppm
Sex:
male/female
Basis for effect level:
other: Decreased body weight gain. Recalculated to be approx. 200 mg/kg bw/day.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion