Registration Dossier

Administrative data

Description of key information

No relevant treatment-related findings were observed for clinical signs, clinical biochemistry, histopathological or reproductive parameters up to the dose-level of 180 mg/kg bw/day in an OECD 408 study.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
180 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
GLP study which meets the Annex IX chapter 8.6.2 requirements.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
REACH Guidance Document R.7.a, Chapter. 7.4 Acute toxicity, indicates that in principle no inhalation studies are needed when vapour pressure < 0.1 Pa at 20°C or particle size > 100 µm. The substance is a viscous liquid with a very negligible vapour pressure at 20°C. The use of the substance is limited to industrial and professional users and does not involve the forming of aerosols, particles or droplets of an inhalable size. Exposure to humans via the inhalation route is considered unlikely to occur. There is no justification to perform further animal studies.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Quality of whole database:
REACH Guidance Document R.7.a, Chapter. 7.4 Acute toxicity, indicates that in principle no inhalation studies are needed when vapour pressure < 0.1 Pa at 20°C or particle size > 100 µm. The substance is a viscous liquid with a very negligible vapour pressure at 20°C. The use of the substance is limited to industrial and professional users and does not involve the forming of aerosols, particles or droplets of an inhalable size. Exposure to humans via the inhalation route is considered unlikely to occur. There is no justification to perform further animal studies.

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

1,1'-isopropylidenebis(p-phenyleneoxy)dipropan-2 –ol was administered by daily oral gavage to male and female Wistar Han rats at dose levels of 125, 250 and 500 mg/kg/day. Males were exposed for 2 weeks prior to mating, during mating, and up to termination (for 29 days). The females were exposed for 2 weeks prior to mating, during mating, during post-coitum, and at least 4 days of lactation (for 43-54 days). Formulation analysis showed that the formulations were prepared accurately, were homogenous, and were stable for at least 6 hours at room temperature.

Parental results:

Treatment related toxicity was evident at 250 and 500 mg/kg including mortality (3 animals at 250 mg/kg and 10 animals at 500 mg/kg), clinical signs (hunched posture, salivation, piloerection and lethargy, among others), changes in body weights, food consumption, haematology and clinical biochemistry parameters, and organ weight and organ to body weight ratios. Macroscopic and microscopic findings in the heart, stomach, brain, pituitary gland, kidneys, liver thymus, skeletal muscle, prostate gland, seminal vesicles, coagulation gland and ovaries were also noted. Additionally, impaired spermatogenesis were noted for males at 250 and 500 mg/kg/d.

No toxicologically significant changes were noted in functional observations, and no toxicologically relevant effects were seen in any parameter at 125 mg/kg bw/day. Therefore, the parental NOAEL was set at 125 mg/kg bw/day.

An OECD 408 study (Sub-chronic toxicity study (90-day), oral route (gavage) in rats) was performed with the 1,1'-isopropylidenebis(p-phenyleneoxy)dipropan-2 –ol at the dose-levels of 0, 20, 60 and 180 mg/kg bw/day with approval of ECHA for the 2010 Reach registration dossier. The test substance, formulated in polyethylene glycol 400, was administered daily for at least 90 days by oral gavage to SPF-bred Wistar rats. One control group and three treated groups were tested, each consisting of 10 males and 10 females.

Chemical analyses of formulations preparations were conducted during the study to assess accuracy, homogeneity and stability over 6 hours.

The following parameters were evaluated: clinical signs daily; functional observation tests in Week 12; body weight and food consumption weekly; ophthalmoscopy at pretest and in Week 13; estrous cycle determination; clinical pathology and macroscopy at termination; organ weights and histopathology on a selection of tissues including spermatogenic staging profiles assessment.

 

Formulation analyses confirmed that formulations of test substance in polyethylene glycol 400 were prepared accurately and homogenously, and were stable over at least 6 hours.

Two animals given180 mg/kg (one male and one female) were found dead between approximately 1 and 3 hours after dosing on Day 84 and 52, respectively. Histopathology revealed no cause of death. Signs of imminent death were absent by these or other animals of the same dose group or lower dose groups, no further mortality occurred in this study and animals were found dead within a short time period after dosing. In the previous study (i.e. combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test) 3 animals at 250 mg/kg and 10 animals at 500 mg/kg were found dead/sacrificed. The microscopic lesions that were thought to contribute to their moribundity in that study were absent in this study. Overall, this suggests that these deaths were unrelated to a toxicological effect of the test substance. The presence of watery-clear fluid in the thoracic cavity in both of these animals may suggest that these deaths were due to a gavage incident (the formulation was a clear solution).

A number of changes in red blood cell parameters were noted in both sexes at 60 and 180 mg/kg, including lower red blood cell counts, lower haemoglobin and haematocrit level, and higher mean corpuscular volume and mean corpuscular haemoglobin. Means remained essentially within the range considered normal for rats of this age and strain, and no morphological correlates indicative of increased breakdown or production of red blood cells were noted. Therefore, these haematological changes were considered not indicative of an adverse effect on red blood cell turn over. The higher liver to body weight ratio in males at 180 mg/kg corresponded with the centrilobular hepatocellular hypertrophy of the liver observed in most at 180 mg/kg (up to slight degree). Given the low severity of liver hypertrophy, absence of morphological liver findings, and only slight potentially supportive clinical biochemistry changes (higher cholesterol and higher alanine aminotransferase activity in males), these findings were considered adaptive and not adverse in nature. The higher cholesterol levels of females at 180 mg/kg occurred without any apparent morphological correlates.

Other clinical biochemistry changes at 180 mg/kg included lower potassium level (males), higher urea and calcium level (females), and higher inorganic phosphate level (males). At 60 mg/kg, clinical biochemistry changes were confined to lower potassium level (males) and higher urea level (females).

As these changes were slight in nature and also occurred in the absence of any supportive morphological changes, these were considered not to be adverse in nature.

Reproductive parameters assessed in this study revealed no adverse changes. The trend towards higher ovary weight among female dose groups was considered to be related to the interstitial cell hypertrophy in the interstitial gland of the ovaries in most females at 60 and 180 mg/kg (up to slight degree). Ovaries are steroid synthezing organs and play a major role in the endocrine system and reproductive system. The main precursor for the production of all steroid hormone synthesis is cholesterol (or cholesterylesters), that can be stored intracellular as lipid droplets in the ovary. The

histologic morphology of the recorded interstitial cell hypertrophy, with fine vacuolar appearance is suggestive for an exaggerated lipid storage which can lead to increased organ weight. Since estrous cycle length was normal for all examined females at 20, 60 and 180 mg/kg and the interstitial gland hypertrophy was of a low severity, this finding was considered to be non-adverse.

Spermatogenic staging profiles were normal for all animals assessed.

No histopathological correlates were found for the higher adrenal and kidney to body weight ratio in males and lower heart weight in females at 180 mg/kg. Therefore, these changes were considered not to be of toxicological relevance.

No relevant clinical signs were noted during treatment. Functional observation tests revealed no abnormalities, and ophthalmoscopy showed no treatment-related changes. The slightly lower body weight gain of males at 180 mg/kg was only minor in nature and well within the range considered normal for rats of this age and strain, and was therefore considered to be of no toxicological relevance.

No changes in food intake occurred.

From the results presented above, a No Observed Adverse Effect Level (NOAEL) for 1,1'-isopropylidenebis(p-phenyleneoxy)dipropan-2 –ol of at least 180 mg/kg was established.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The study was conducted at a GLP accredited laboratory using OECD Testing Guideline 408.

Justification for classification or non-classification

Based on the results available, 1,1'-isopropylidenebis(p-phenyleneoxy)dipropan-2 –ol does not have to be classified currently and has no obligatory labelling requirement for repeated dose toxicity according to the:

- Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2007),

- Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures.