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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
other: read-across from supporting substance (structural analogue or surrogate)
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

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
Details on test material:
- Name of test material (as cited in study report): di(2-ethylhexyl)adipate
- Physical state: clear, colorless liquid
- Analytical purity: 100.5 % for Lot. No. 0-62-494 and 101.4 % for No. GC-2-27-76 (determined by ester titration)
- Lot/batch No.: GC-2-27-76
- Storage condition of test material: at 4°C

Test animals

Species:
mouse
Strain:
B6C3F1
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: 4 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: 18 - 31 °C.
- Humidity: 10 - 88 %.
- Air changes: 10 per hr.
- Photoperiod12 hrs dark /12 hrs light.

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:
200, 387, 787, 1562, and 3125 mg/kg bw
Basis: actual ingested (recalculated based on food consumption). Only the corresponding value to 1600 ppm were given in the study report. The other doses were calculated with the mean food consumption used to calculate this given value.
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 mice per sex were treated with five dose levels of the test substance in feed -up to 25000 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):
- 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:
no effects observed
Mortality:
mortality observed, treatment-related
Description (incidence):
1 female died (12500 ppm)
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
body weight depression in males (from 3100 ppm) and females (from 6300 ppm)
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 specified
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
One mouse died as a result of an accident.

BODY WEIGHT AND WEIGHT GAIN
Weight gain depression was 10 % or more for male mice fed 3100 ppm or more. Weight gain depression was 10 % or more for female mice fed 6300 or 25000 ppm.

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

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

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: decreased body weight gain at 387 mg/kg bw/day
Dose descriptor:
NOAEL
Effect level:
1 600 ppm
Based on:
test mat.
Sex:
male
Basis for effect level:
other: decreased body weight gain at 3100 ppm
Dose descriptor:
LOAEL
Effect level:
387 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: decreased body weight gain
Dose descriptor:
LOAEL
Effect level:
3 100 ppm
Based on:
test mat.
Sex:
male
Basis for effect level:
other: decreased body weight gain
Dose descriptor:
NOAEL
Effect level:
387 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: decreased body weight gain at 787 mg/kg bw/day
Dose descriptor:
NOAEL
Effect level:
3 100 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
other: decreased body weight gain at 6300 ppm
Dose descriptor:
LOAEL
Effect level:
787 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: decreased body weight gain
Dose descriptor:
LOAEL
Effect level:
6 300 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
other: decreased body weight gain

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
NOAEL (males, mice) = 200 mg/kg bw/day
LOAEL (males, mice) = 387 mg/kg bw/day
NOAEL (females, mice) = 387 mg/kg bw/day
LOAEL (females, mice) = 787 mg/kg bw/day
Executive summary:

A subchronic oral toxicity study similar to OECD 408 was performed with the structurally analogue substance in B6C3F1 mice at dose levels of 1600, 3100, 6300, 12500 and 25000 ppm for a period of 90 days. Ten animals per sex and dose received the test substance daily via diet, whereas a similar constituted control group was administered the plain diet.

No signs of toxic effects and no mortality were observed in any of the animals during the study period. An adverse decrease in body weight gain compared to controls was noted starting at 3100 ppm in males and at 6300 or 25000 ppm in females, respectively. Average food consumption was not altered between treated and control groups of both genders. No adverse effects were noted at histopathological examination while clinical chemistry and haematological parameters were not reported in this study.

Based on these results, a NOAEL of 1600 ppm was derived for male B6C3F1 mice, corresponding to an actual ingested dose of 200 mg/kg bw/day. NOAEL for female mice was found to be 387 mg/kg bw/day.