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

Endpoint summary

Description of key information

There is no subchronic study available. In the subacute oral study in rats no relevant hazard was identified resulting in a NOAEL of 1000 mg/kg bw/day. It is assumed that prolongation of treatment time does not provide additional information on toxic effects.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study under GLP condition

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes

Limit test:

no

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

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Details on oral 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

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

Positive control:

no

Observations and examinations performed and frequency:

The following parameters were evaluated:
- clinical signs daily
- functional observation test in week 4
- body weight and food consumption weekly
- clinical pathology at termination
- hematology: white blood cells, different leucocyte count, red blood cells, reticulocytes, red blood cell distribution width, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin concentration, platelets
- clotting potential: prothrombin time, activated partial thromboplastin time
- clinical biochemistry: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total protein, albumin, total bilirubin, urea, creatinine, glucose, cholesterol, sodium, potassium, chloride, calcium, inorganic phosphate, bile acids
- macroscopy at termination
- organ weights and histopathology on a selection of tissues as required by the guideline

Sacrifice and pathology:

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

Other examinations:

no ophthalmoscopic examination

Statistics:

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

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Salivation was observed among 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.
No other clinical signs considered to be related to treatment or abnormalities during weekly arena observations were noted during the observation period.

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

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

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Food consumption before or after correction for body weight remained similar to the control level over the study period.

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

Haematological parameters of treated rats were considered not to have been affected by treatment.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

Males at 1000 mg/kg bw/day showed a statistically significantly lower creatinine level (male (mean): 34.0 μmol/l (significant at 5%, but remaining within the range considered normal for rats of this age and strain) versus 38,5 μmol/l of control males (mean)).

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

Hearing ability, pupillary reflex and static righting reflex were normal in all examined animals. Grip strength was similar between control and high dose animals.

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Description (incidence and severity):

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

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

There were no microscopic findings recorded which could be attributed to treatment with the test substance.

Histopathological findings: neoplastic:

no effects observed

Other effects:

no effects observed

Details on results:

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.

FOOD CONSUMPTION
Food consumption before or after correction for body weight remains similar to the control level over the study period.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
no effect/no data

OPHTHALMOSCOPIC EXAMINATION
not done

HAEMATOLOGY
Hematological parameters of treated rats were considered not to have been affected by treatment.

CLINICAL CHEMISTRY
Males at 1000 mg/kg bw/day showed a statistically significantly lowered creatinine level:
male(mean): 34.0 µmol/l (sign. at 5%) versus 38,5 µmol/l of control males (mean)
This value remained within the range considered normal for rats of the age and strain.
Furthermore there is no morphological change in the kidneys to support the lower creatinine level. These changes were therefore considered not to be of toxicological relevance.

URINALYSIS
not done

NEUROBEHAVIOUR
no effect

ORGAN WEIGHTS
Males at 300 and at 1000 mg/kg bw/day showed slightly higher kidney weights (not statistically significant for absolute weights).
100, 300, 1000 mg/kg bw/day versus control
Males, mean kidney weights: 2.18 g, 2.37 g, 2.34 g versus 2.11 g of control
Males, mean organ/body weight ratios: 0.81 %, 0.87 % (sign at 5%), 0.86 % (sign at 5%) versus 0.77% of control
As there were no histopathological correlates these changes were considered not to be of toxicological relevance
Other 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.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
no effects

HISTORICAL CONTROL DATA (if applicable)
Available for hematology and clinical chemistry.

Key result

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 significant changes.

Key result

Critical effects observed:

not specified

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.

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. Except salivation of 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 which is considered as a physiological response, treatment was well tolerated. Males at 1000 mg/kg bw/day showed a statistically significantly lowered creatinine level and males at 300 and at 1000 mg/kg bw/day showed slightly higher kidney weights (not statistically significant for absolute weights), but these values remained within the range considered normal for rats of the age and strain. Furthermore there is no morphological change in the kidneys to support these observations. Therefore these changes were considered not to be of toxicological relevance. Other parameters investigated in this study were considered to have been unaffected by treatment.

 

CONCLUSION

From the results presented in this 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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

There is only one study available which could be considered. This study is performed according to OECD TG 407 and GLP and is, therefore, evaluated with Klimisch score 1. Male and female rats received up to and including 1000 mg/kg bw/day. No toxicological relevant effects were observed during the total treatment period resulting in a NOAEL of 1000 mg/kg bw/day (limit dose).

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

In a subacute oral study 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. Except salivation of 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 which is considered as a physiological response, treatment was well tolerated. Males at 1000 mg/kg bw/day showed a statistically significantly lowered creatinine level and males at 300 and at 1000 mg/kg bw/day showed slightly higher kidney weights (not statistically significant for absolute weights), but these values remained within the range considered normal for rats of the age and strain. Furthermore there is no morphological change in the kidneys to support these observations. Therefore these changes were considered not to be of toxicological relevance. Other parameters investigated in this study were considered to have been unaffected by treatment.

Overall, from the results presented in the report for the available 28 day study no hazard could be identified and a No Observed Adverse Effect Level (NOAEL) for 2,2-dimethylpropane-1,3-diyl dibenzoate of at least 1000 mg/kg bw/day was established.

 

There is no subchronic study available as required by Regulation (EC) No.1907/2006 (REACH), ANNEX IX, section 8.6. However, according to ANNEX IX, section 8.6, column 2 of Regulation (EC) No.1907/2006 (REACH) a subchronic study needs not to be conducted, if the substance is unreactive, insoluble and not inhalable and there is no evidence of absorption and no evidence of toxicity in a 28 day 'limit test' , particularly, if such a pattern is coupled with limited human exposure.

2,2-Dimethylpropane-1,3-diyl dibenzoate is an unreactive white or yellowish solid with mild odor and a melting point of 49 °C. 2,2-Dimethyl-1,3-diyl dibenzoate is not inhalable, because it is a waxy solid with a low vapor pressure, which is estimated to be < 0.0001 hPa at 25 °C. Additionally it is nearly insoluble in water (1.16 mg/l). 2,2-Dimethylpropane-1,3-diyl dibenzoate is used within polymer matrices and thus provides only limited human exposure. Furthermore, in the available 28 day study (OECD TG 407 and GLP) male and female rats were given daily doses up to and including 1000 mg/kg bw/day (limit dose) resulting in a NOAEL of 1000 mg/kg bw/day due to the lack of adverse effects.

 

In conclusion, based on these considerations the requirements of Regulation (EC) No.1907/2006 (REACH), ANNEX IX, section 8.6, column 2 (Specific rules for adaption from column 1) are fulfilled.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
There is only one study available which could be considered. This study is performed according to OECD TG 407 and GLP and is, therefore, evaluated with Klimisch score 1.

Justification for classification or non-classification

In a subacute oral study 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. No toxicological relevant effects were observed during the total treatment period resulting in a NOAEL of 1000 mg/kg bw/day (limit dose). A No Observed Adverse Effect Level (NOAEL) for 2,2-dimethylpropane- 1,3-diyl dibenzoate of at least 1000 mg/kg bw/day was established.

According to CLP classification criteria (Regulation (EC) No 1272/2008) a classification is not justified.