Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

A combined repeated dose toxicity study with the reproduction/developmental toxicity screening test was performed with 1,1-isopropylidenebis(p-phenyleneoxy)dipropan-2-ol. Treatment by oral gavage in male and female Wistar Han rats revealed parental toxicity at 250 and 500 mg/kg/day, and reproduction toxicity at 500 mg/kg/day.

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
250 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
GLP study which meets the Annex IX chapter 8.7.1 requirements.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
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. No toxicologically significant changes were noted in functional observations, and no toxicologically relevant effects were seen in any parameter at 125 mg/kg.

Reproductive results:

The mating, fertility and conception indices were lower for females at 500 mg/kg, along with a lower number of corpora lutea. The high mortality and limited number of litters available for evaluation likely contributed to this, though when also taking into account the evidence of impaired spermatogenesis, a treatment related effect cannot be excluded. There were no toxicologically significant changes noted in any of the remaining reproductive parameters investigated in this study (i.e. gestation index, precoital time, and number of implantation sites).

In conclusion, treatment with 1,1'-isopropylidenebis(p-phenyleneoxy)dipropan-2-ol by oral gavage in male and female Wistar Han rats at dose levels of 125, 250 and 500 mg/kg body weight/day revealed parental toxicity at 250 and 500 mg/kg body weight/day, and reproduction toxicity at 500 mg/kg body weight/day.

However, in the OECD 408 study (Sub-chronic toxicity study (90-day), oral route (gavage) in rats) performed with 1,1'-isopropylidenebis(p-phenyleneoxy)dipropan-2-ol at the dose-levels of 0, 20, 60 and 180 mg/kg, some reproductive parameters were examined. In this study, oestrous cycle length was normal for all examined females in any group except for one control female showing an extended oestrous cycle length. Minimal interstitial cell hypertrophy in the interstitial glands of the ovaries of females starting in the 60 mg/kg group was observed and considered as non-adverse. In addition, the spermatogenic staging profiles were normal for all males assessed at any dose-level, confirming that the impaired spermatogenesis and histopathological findings in the prostate gland, seminal vesicles, coagulation gland and ovaries observed concomitantly with non reproductive organs in the parental generation of the OECD 422 study were linked to the observed high toxicity.


Short description of key information:
In an oral repeated dose toxicity study, performed according to OECD422/421 test guidelines and GLP principles, reproduction toxicity was observed in the presence of parental toxicity, resulting in a NOAEL of 250 mg/kg bw/day for reproduction toxicity. No effects on reproductive parameters (estrous cycle length, spermatogenic staging profiles or histopathological study ) were observed in an oral 90-day repeated toxicity study up to 180 mg/kg/day.

Justification for selection of Effect on fertility via oral route:
The study was conducted at a GLP accredited laboratory using OECD Testing Guideline 422.

Effects on developmental toxicity

Description of key information

A prenatal developmental toxicity study (OECD 414) was performed in rats by oral gavage with 1,1'-isopropylidenebis(p-phenyleneoxy)dipropan-2-ol. The maternal No Observed Adverse Effect Level (NOAEL) was established as being 100 mg/kg bw and the developmental NOAEL was established as 250 mg/kg bw.

A prenatal developmental toxicity study (OECD 414) was performed in rabbits by oral gavage with 1,1'-isopropylidenebis(p-phenyleneoxy)dipropan-2-ol. A maternal and developmental No Observed Adverse Effect Level (NOAEL) of at least 75 mg/kg was established.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
75 mg/kg bw/day
Species:
rabbit
Quality of whole database:
GLP study which meets the Annex IX chapter 8.7.2 requirements.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

A prenatal developmental toxicity study (OECD 414) was performed in rats by oral gavage with 1,1'-isopropylidenebis(p-phenyleneoxy)dipropan-2-ol. Eighty-eight mated female Wistar Han rats were assigned to four dose groups. The test item was administered once daily by oral gavage from Days 6 to 19 post-coitum at doses of 40, 100 and 250mg/kg. The rats of the control group received the vehicle, polyethylene glycol 400, alone. Females were checked daily for the presence of clinical signs. Food consumption and body weight were determined daily during treatment and at periodic intervals in the other periods. All animals surviving to Day 20 post-coitum were subjected to an examinationpost-mortemand external, thoracic and abdominal macroscopic findings and weights of the kidneys, liver and thymus were recorded.

A microscopic examination of the thymus was also performed for selected females.

A laparohysterectomy was performed on each surviving female of the groups. The uteri, placentae and ovaries were examined, and the numbers of fetuses, early and late resorptions, totalimplantations and corpora lutea were recorded. Gravid uterine weights were recorded, and corrected

body weights (changes) were calculated. The fetuses were weighed, sexed and examined forexternal, visceral and skeletal malformations and developmental variations. All live fetuses wereeuthanized. One half of the fetuses were decapitated and the heads were fixed in Bouin’s fixative, all

fetuses were dissected and examined for visceral anomalies. All fetuses of control and high-dose groups were subsequently fixed in 96% aqueous ethanol and stained with Alizarin Red S for skeletal examinations.

Formulations prepared on one day during treatment were analyzed for accuracy, homogeneity andstability.

 Accuracy, homogeneity and stability of formulations were demonstrated by analyses.

Maternal toxicity was noted at 250 mg/kg and consisted of clinical signs (piloerection, salivation forseveral animals, and laboured respiration, rales and hunched posture at lower frequencies), and lowerbody weights, body weight gains and food consumption through most of the treatment period.No developmental toxicity was observed in the 40, 100 and 250 mg/kg groups.

Based on the results in this prenatal developmental toxicity study the maternal No Observed AdverseEffect Level (NOAEL) for 1,1'-isopropylidenebis(p-phenyleneoxy)dipropan-2-ol was established as being 100mg/kg and the developmental NOAEL was established as 250 mg/kg.

A prenatal developmental toxicity study (OECD 414) was performed in rabbits by oral gavage with 1,1'-isopropylidenebis(p-phenyleneoxy)dipropan-2-ol. The objectives of this study were todetermine the potential of the substance to induce developmental toxicity after maternal exposure during the critical period of organogenesis and to characterize maternal toxicity at the exposure levels tested when given orally by gavage to time-mated female New Zealand White rabbits from Day 6 to 28 post-coitum, inclusive. In addition, theNo Observed Adverse Effect Levels(NOAELs) for maternal toxicity and developmental toxicity were evaluated.

The dose levels in this study were selected to be 0 (0.5% aqueous carboxymethyl cellulose with 1.25% Tween 80), 8, 25 and 75 mg/kg/day, based on the results of a dose range finder.

The following parameters and end points were evaluated in this study for the F0-generation: mortality/moribundity, clinical signs, body weights, food consumption, gross necropsy findings, number of corpora lutea, (gravid)uterine weight and uterine contents. In addition, the following parameters were determined for the F1-generation: the number of fetuses, early and late resorptions, total implantations, fetal body weights, sex ratio, and external visceral and skeletal malformations and developmental variations.

No mortality occurred during the study period that was considered to be related to treatment with the test item. Treatment at 75 mg/kg resulted in slight body weight loss (average weight loss of 1%) on post-coitum Day 9 and significantly reduced food consumption over post-coitum Days 6-13 (relative food consumption about 38% lower than controls). As during the remaining of the treatment period, body weight and food consumption values returned back to normal, these effects were transient and therefore considered not to be adverse.

No maternal toxicity was observed in the 8 and 25 mg/kg groups.

No developmental toxicity was observedin the 8, 25 and 75 mg/kg groups.

In conclusion, based on the results in this prenatal developmental toxicity study in rabbit a maternal and developmental No Observed Adverse Effect Level (NOAEL) for 1,1’-isopropylidenebis(p-phenyleneoxy)dipropan-2-ol of at least 75 mg/kg was established.

The high dose of 75 mg/kg was considered to be the highest tolerated dose, as in the dose range finder treatment at 100 mg/kg resulted in mortality of one female, piloerection noted for all females, body weight loss with an average of -4% on post-coitum Days 9 and 13, and significantly reduced food consumption of 70% over post-coitum Days 6 to 20.


Justification for selection of Effect on developmental toxicity: via oral route:
The studies were conducted at a GLP accredited laboratory using OECD Testing Guideline 414

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 reproduction and developmental 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.