Diisopropyl sebacate

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Study period:

31 Jan - 10 Apr 1986

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well documented study report which meets basic scientific principles. Purity of test substance not given.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1986

Report date:

1986

Materials and methods

Test guideline

Test guideline 1

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

purity of test substance not given

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))

Version / remarks:

purity of test substance not given

Deviations:

yes

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

69275-01-0

Cas Number:

69275-01-0

IUPAC Name:

69275-01-0

Details on test material:

- Name of test material (as cited in study report): Di-(2-octyl-dodecyl)-sebacate
- Physical state: colorless liquid
- Storage condition of test material: room termperature
- Analytical purity: no data

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Strain as given in the study report: Sprague-Dawley CD SPF
- Source: Charles River Wiga, Sulzfeld, Germany
- Age at study initiation: 4 weeks
- Weight at study initiation: 56 - 72 g (males); 55 - 76 g (females)
- Housing: 2-3 animals per cage in Makrolon type III cages
- Diet: pelleted, low count, low nitrosamine Altromin 1324 diet, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 10 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 - 24.9
- Humidity (%): 43 -56
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: oleum Arachidis, DAB8

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
Dosing solutions were prepared daily shortly before applications by dissolving test substance in oleum arachidis, DAB8 yielding final concentrations of 2, 7 and 20 %

VEHICLE
- Concentration in vehicle: 20 mg/mL for 100 mg/kg bw dose group, 70 mg/mL for 350 mg/kg bw dose group, 200 mg/mL for 1000 mg/kg bw dose group
- Amount of vehicle (if gavage): 5 mL/kg

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

28 days (control and test groups)
Additional animals (5/sex/group) for both the control and the high dose group were maintained for further 28 treatment-free days, for purpose of recovery testing.

Frequency of treatment:

once daily, 5 days a week

Doses / concentrations

Remarks:

Doses / Concentrations:
100, 350 and 1000 mg/kg bw/d (group 2, 3 and 4, respectively)
Basis:
actual ingested

No. of animals per sex per dose:

test groups: 10
recovery groups (control, high dose group): 5

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Doses were selected to achieve the a maximal high safety margin, to determine a not cumulative toxic dose and to determine toxic ranges.
- Rationale for selecting satellite groups: Establish reversibility of possible cumulative effects.
- Post-exposure recovery period in satellite groups: 28 days

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily for mortality and clinical symptoms

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/animal/day: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: weekly

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: day before sacrifice
- Dose groups that were examined: groups 1 and 4

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 4 weeks of application
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all
- Parameters checked in table [No.1] were examined (erythrocytes number, haematocrit, middle cell volume, haemoglobin, leucocyte numbers, thrombocyte numbers, differential blood count).

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after 4 weeks of application
- How many animals: all animals
- Parameters checked in table [No.2] were examined (GGT, GOT, GPT, alkaline phosphatase, sodium, potassium, glucose, urea, protein, calcium, creatinine, cholesterol, chloride, bilirubine).

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, absolute and relative organs weights were determined for brain, testicles, heart, liver, spleen, adrenals, kidneys, thymus
HISTOPATHOLOGY: Yes, following organs were subjected to histopathological examinations: aorta thoracica, eye, colon, glandular stomach, cerebrum, urinary bladder, skin, heart, testicles, liver, cerebellum, trachea, lung, maxillar lymph node, mesenterial lymph node, spleen, epididymis, adrenal, peripheral nerve, kidney, ovaries, pancreas, prostate, seminal gland, thyroid, salivary gland, oesophagus, thymus, uterus, tongue, proventriculus, skeletal muscles

Statistics:

T-test for determination of significant differences for body weights, blood evaluation and biochemical examinations
U-test for determination of significant differences for organ and bone weights

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

non adverse

Mortality:

mortality observed, treatment-related

Description (incidence):

non adverse

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

treated females of all 3 test groups

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

increased food intake in females of the middle and high dose group

Food efficiency:

not specified

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

no effects observed

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

non adverse, significant reduction of GOT values in the middle and high dose groups of both sexes and in the females of the low dose group

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
thin fur, alopecia, chromodacryorrhoe, sporadically slight scrapes (considered not to be substance-related; no details on affected sex or groups)

BODY WEIGHT AND WEIGHT GAIN
Increased food consumption and increased body weight gain were observed in the females of middle and high dose group:
group 2 - slight increase during week 4, groups 3+4 - slight increase during week 3 and strong increase after week 4 (see table 3)

FOOD CONSUMPTION AND COMPOUND INTAKE
slightly increased (compared to the control group) for females of group 3 during week 2 - 4, for females of group 4 during week 1, 2 and 4

HAEMATOLOGY
no toxic or dose-dependent effects

CLINICAL CHEMISTRY
The significant reduction of GOT values in females of all test groups (26% to 35% reduction) and males of the middle and high dose group (16% to 22% reduction) may be explained by elevation of mean values of GOT compared to historical controls.

GROSS PATHOLOGY
Insidences of hydrometra and hydronephrosis as well as different forms of testicular atrophy and edema of the proventricular mucosa were observed. As these findings were incidental in control groups they were not considered substance-related. No gross pathological findings were observed in thw recovery group.

HISTOPATHOLOGY: NON-NEOPLASTIC
The observed incidental pathological findings could be histopathological verified. No other histopathological effects were evident.

Effect levels

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: NOAEL corresponding to the highest dose tested.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Table 3: Mean body weight and body weight gain values (g) of rats treated with the test item in the feed for 28 days:

body weight gain
	males				females
week	control	100 mg/kg bw	350 mg/kg bw	1000 mg/kg bw	control	100 mg/kg bw	350 mg/kg bw	1000 mg/kg bw
0	158	159	165	158	136	139	137	141
1	210	211	220	214	158	163	164	166
2	267	271	280	269	179	184	189	190
3	315	323	332	323	193	203	209*	209*
4	355	362	373	262	202	217*	225**	225**
gain 0-4	197	203	208	204	66	78	88	84

*significant different (p>0,05); **significant different (p>0.01)