2,2-dimethylpropane-1,3-diyl dibenzoate

Toxicity to reproduction: other studies

Administrative data

Endpoint:

toxicity to reproduction: other studies

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Subacute repeated dose toxicicity study according to respective guideline under GLP conditions.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2015

Report date:

2015

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: OECD TG 407

GLP compliance:

yes

Type of method:

in vivo

Test material

Test material information

Constituent 1

Reference substance name:

2,2-dimethylpropane-1,3-diyl dibenzoate

EC Number:

224-081-9

EC Name:

2,2-dimethylpropane-1,3-diyl dibenzoate

Cas Number:

4196-89-8

Molecular formula:

C19H20O4

IUPAC Name:

3-(benzoyloxy)-2,2-dimethylpropyl benzoate

impurity 1

Reference substance name:

3-hydroxy-2,2-dimethylpropyl benzoate

Cas Number:

5522-92-9

Molecular formula:

C12H16O3

IUPAC Name:

3-hydroxy-2,2-dimethylpropyl benzoate

Test material form:

solid: crystalline

Details on test material:

Batch No.: GSOH 140121

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 6 weeks
- Housing: groups of 5 animals per sex
- Diet ad libitum
- Water ad libitum
- Acclimation period: 5 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24
- Humidity (%): 40-70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Details on exposure:

The test substance formulated in polyethylene glycol 400 and administered daily for 28 days by oral gavage.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Chemical analyses of formulations preparations were conducted once during the study to assess accuracy, homogeneity and stability over 5 hours.

Duration of treatment / exposure:

28 days

Frequency of treatment:

once daily

Duration of test:

After 28 days of treatment animals were sacrificed.

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 100, 300, 1000 mg/kg bw/day
Basis:

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Details on study design:

The test substance formulated in polyethylene glycol 400 and administered daily for 28 days by oral gavage.
The following parameters were evaluated:
- clinical signs
- functional observation test
- body weight and food consumption
- clinical pathology and macroscopy at termination
- organ weights and histopathology on a selection of tissues as required by the guideline

GROSS PATHOLOGY: Yes
- organ weights:
adrenal glands, brain, epididymides, heart, kidneys, liver, ovaries, spleen, testes, thymus, uterus including cervix, prostate, seminal vesicles, thyroid including parathyroid

HISTOPATHOLOGY: Yes
adrenal glands, aorta, brain, caecum, Cervix, clitoral gland, colon, duodenum, epididymides, eyes, female mammary gland, femur including joint, heart, ileum, jejunum, kidneys, larynx, lacrimal gland exorbital, liver, lung infused with formalin, lymph nodes mandibular and mesenteric, nasopharynx, oesophgus, ovaries, pancreas, Peyer's patches, pituitary gland, preputal gland, prostate gland, rectum, salivary gland, sciatic nerve, seminal vesicles including coagulating glands, skeletal muscles, skin spinal cord, spleen, sternum with bone marrow, stomach, testes, thymus, thyroid gland including parathyroid, trachea, urinary bladder, uterus, vagina

Statistics:

Dunnett's test, the Steel test, Fisher Exact test, Kruskal Walis test

Results and discussion

Effect levels

1

Dose descriptor:

other: NOAEL (reproductive organs)

Effect level:

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

Sex:

male/female

Basis for effect level:

other: Based on the results from organ weights and macroscopic and microscopic examination

2

Dose descriptor:

NOAEL

Effect level:

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

Sex:

male/female

Basis for effect level:

other: Referring to the parameters examined. The test item was tolerated up to 1000 mg/kg bw/day without toxicologically relevant effects.

Observed effects

CLINICAL SIGNS AND MORTALITY
No mortality occurred during the study period.
Salivation was observed in all females and most males at 1000 mg/kg bw/day and most males at 300 mg/kg bw/day on several days after dosing.

BODY WEIGHT AND WEIGHT GAIN
Body weights and body weight gain of treated animals remained in the same range as controls over the study period.

ORGAN WEIGHTS
Organ weights or organ to body weight ratios of treated animals were similar to those of control animals.

GROSS PATHOLOGY
Macroscopic observations at necropsy did not reveal any alterations that were considered to have arisen as a result of treatment.

HISTOPATHOLOGY: NON-NEOPLASTIC
There were no microscopic findings recorded that could be attributed to treatment with the test substance.

Applicant's summary and conclusion

Conclusions:

From the results presented in the report a definitive No Observed Adverse Effect Level (NOAEL) for 2,2-dimethylpropane-1,3-diyl dibenzoate of at least 1000 mg/kg bw/day was established due to the lack of general toxicity and due to the lack of affected male and female reproductive organs.

Executive summary:

Male and female Wistar rats received daily 0, 100, 300 or 1000 mg/kg bw/day dissolved in polyethylene glycol 400 by gavage over a period of 28 days. The examinations were done according to OECD TG 407 under GLP conditions. Considering male and female reproductive organs no adverse effects were reported. Therefore a NOAEL (reproductive organs) at least 1000 mg/kg bw/day was established.

Overall, from the results presented in the report a definitive No Observed Adverse Effect Level (NOAEL) for 2,2-dimethylpropane-1,3-diyl dibenzoate of at least 1000 mg/kg bw/day was established due to the lack of general toxicity and due to the lack of affected male and female reproductive organs.