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EC number: 444-860-9 | CAS number: 474510-57-1
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 22 July 2011 - 15 May 2012
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 012
- Report date:
- 2012
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- 22 March 1996
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: EPA OPPTS 870.3650 Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test
- Version / remarks:
- July 2000
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- -
- EC Number:
- 444-860-9
- EC Name:
- -
- Cas Number:
- 474510-57-1
- Molecular formula:
- C21 H24 O4
- IUPAC Name:
- 2-hydroxy-1-(4-{[4-(2-hydroxy-2-methylpropanoyl)phenyl]methyl}phenyl)-2-methylpropan-1-one
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- - Source: Harlan Laboratories, B.V. Kreuzelweg 53 5961 NM Horst / Netherlands
- Age at study initiation: 11 weeks
- Weight at study initiation: Males: 291 to 371 g, Females: 182 to 213 g
- Housing: singly
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7d
- Fasting: 16h before administration
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 30-70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
-The dose formulations were prepared weekly
- Homogeneity of the test item in the vehicle was maintained during the daily administration period using a magnetic stirrer.
VEHICLE
- Justification for use and choice of vehicle (if other than water): As used in previous dose range-finding study - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The samples were analyzed following an analytical procedure provided by the Sponsor and adapted at Harlan Laboratories. The test item was used as the analytical standard. Analyzed samples were not discarded without written consent from the study director. Duplicates were taken of all samples and were stored at Harlan Laboratories Ltd., Füllinsdorf / Switzerland. The samples were not discarded without written consent from the study director.
- Duration of treatment / exposure:
- Males: 4 weeks
Females: Approximately 7 weeks - Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 10 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 30 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 90 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels were selected based on a previous dose range-finding toxicity study in Han Wistar rats
- Positive control:
- no
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly
BODY WEIGHT: Yes
- Time schedule for examinations: daily
HAEMATOLOGY: Yes
- Time schedule for collection of blood: on the day of the scheduled necropsy from 5 males from each group, blood samples from 5 lactating females from each group were obtained on day 5 post partum
- Anaesthetic used for blood collection: Yes, isoflurane
- Animals fasted: Yes, 18h
- How many animals: 5 per sex and group
- Parameters checked in table [1] were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on the day of the scheduled necropsy from 5 males from each group, blood samples from 5 lactating females from each group were obtained on day 5 post partum
- Animals fasted: Yes, 18h
- How many animals: 5 per sex and group
- Parameters checked in table [2] were examined.
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: one time during the study
- Dose groups that were examined: 5 animals per sex and group
- Battery of functions tested: cage side observations, hand-held observations, open field observations, reflexes, hind / fore limb strength - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table)
HISTOPATHOLOGY: Yes (see table) - Statistics:
- The Dunnett-test (many to one t-test) based on a pooled variance
estimate was applied if the variables could be assumed to follow a normal distribution
for the comparison of the treated groups and the control groups for each sex.
• The Steel-test (many-one rank test) was applied instead of the
Dunnett-test when the data could not be assumed to follow a normal distribution.
• Fisher's exact-test was applied if the variables could be
dichotomized without loss of information.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- DAILY
Test item-related clinical signs were observed of males and females receiving 90 mg/kg body weight/day of Irgacure 127. Hunched posture, ruffled fur and discoloured feces were seen.
At the dose level of 90 mg/kg body weight/day, the male animal killed in extremies (no. 35) showed clinical signs such as ruffled fur from day 6 of treatment and hunched posture, ruffled fur and yellowish discoloured feces from day 8 of treatment. At necropsy no macroscopical finding was noted for this animal. Female no. 78, treated at the dose level of 90 mg/kg body weight/day and found dead on day 2 of the pairing period, had ruffled fur from day 6 of treatment and yellowish discoloured feces from day 9 of treatment. At necropsy examination, dark red iscoloration of the thymus, enlarged stomach and redish brown firm nodule in the jejunum were found. After histopathological examination it was concluded that the cause of death was likely the thrombosis of jejunum therefore this death was considered to be incidental.
At the dose level of 90 mg/kg body weight/day additional males were noted with ruffled fur and yellowish discoloured feces (no. 34 and 40) in the pre-pairing and pairing period. Male no. 37 had scabs and reddish sore on the right shoulder appearing in the pairing period and the scabs were noted in the after pairing period too.
Three additional females in this group (nos. 72, 73, 74) had ruffled fur starting in the pre-treatment period through pairing period. Female no. 73 had yellowish discoloured feces from the second week of pre-pairing period up to and including the gestation period. Female no. 72 also had huched posture on the first two days of the gestation period.
In groups 3 and 2 no clinical signs were noted in any sex during the study.
In group 1, male no. 10 had reddish sore at the cervical region for a short period in the pairing
period.
WEEKLY
At the dose level of 90 mg/kg body weight/day, the ruffled fur noted during the detailed weekly
clinical observations of males and females indicated a test item-related effect.
No test item-related effect was found in the other dose groups. - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- At 90 mg/kg body weight/day, one male was killed for ethical reason on day 9 of treatment in the pre-pairing period and one female died spontaneously on day 2 of pairing period (on day 16 of treatment). After histopathological examination it was concluded that the cause of death of the female was likely the thrombosis in jejunum and, therefore, this death was considered to be incidental and not test item related. Histopathological examination of the male showed slight diffuse hyperkeratosis in forestomach and minimal erosion in glandular stomach, signs of moderate stress in thymus and adrenal glands as well as slight diffuse atrophy in the prostate, coagulating gland and seminal vesicles. The body weight and food consumption of this male was rapidly decreasing from the second day of treatment onwards probably due to individual sensitivity. Since other males at 90 mg/kg body weight/day, started to show body weight and food consumption reduction later in the treatment period (the body weight started to decrease from the pairing period onwards and the food consumption was decreased in the second week of pre-pairing period), relationship to the treatment could not be excluded.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- BODY WEIGHT MALES
Pre-pairing and Pairing Periods
From day 5 of the pre-pairing period the mean body weight of males receiving 90 mg/kg body weight/day of Irgacure 127 was minimally decreased throughout the study when compared to the control group, although not reaching a level of statistical significance.
The mean body weight gain of males receiving 90 mg/kg body weight/day of Irgacure 127 was lower from day 5 of pre-pairing period when compared to controls and it was statistically significantly reduced between days 8 and 14. In correlation with the low food consumption this was considered to be a test item-related effect. Thereafter mean values similar to the control group were achieved during the pairing and after pairing periods.
In groups 30 and 10 mg/kg body weight/day, mean body weights and mean body weight gains of the males were similar to that of the control group during the study.
BODY WEIGHT FEMALES
Pre-pairing, Pairing, Gestation and Lactation Periods
During the pre-pairing period the mean body weights of females at the dose level of 90 mg/kg body weight/day were minimally below of the control level achiving levels of occasional statistical significance from day 9 onwards. During the pairing, gestation and lactation periods mean body weights comparable to those of the control group were noted.
Significantly lower mean body weight gain was recorded from day 4 of the pre-pairing period was considered to be a test item-related effects. During the gestation period, minimally increased mean body weight gain values were found while there was no difference in mean body weight gain noted during the lactation period.
In groups 30 and 10 mg/kg body weight/day, mean body weights and mean body weight gains of the females were similar to that of the control group during the study. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- FOOD CONSUMPTION MALES
The mean food consumption of males receiving 90 mg/kg body weight/day of Irgacure 127 was statistically significantly lower between days 8 and 14 in the pre-pairing period and it was lower during the whole pre-pairing period. This was considered to be a test item-related effect.
The mean food consumption of males was at control level for each test item-treated groups after the pairing period.
In groups 30 and 10 mg/kg body weight/day, food consumption of males was not affected by the treatment of the test item.
FOOD CONSUMPTION FEMALES
The mean food consumption of females receiving 90 mg/kg body weight/day of Irgacure 127 was statistically significantly lower during the pre-pairing period which was considered to be a test item-related effect.
There was no effect of treatment with Irgacure 127 on the food consumption of females in the gestation or lactation periods.
In groups 30 and 10 mg/kg body weight/day, the mean food consumption of females was not affected by the treatment of the test item.
- 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):
- MALES
No changes to be of toxicological relevance were noted in males in any dose group.
FEMALES
No changes were noted in females in any dose group. - Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The assessment of the biochemistry data did not reveal any test item-related effect in any dose
group in any sex.
MALES
No changes were noted in males in any dose group.
FEMALES
The total cholesterol level was statistically significantly higher in females treated at the dose level of 90 mg/kg body weight/day and lying slightly outside the range of historical control data, thus, test item-realted relationship cannot be excluded. The creatinine level was statistically significantly higher in females treated at the dose level of 10 mg/kg body weight/day however the value was within the historical background range. In absence of dose relationship no experimental relevance was attributed to this finding.
At the dose level of 30 mg/kg body weight/day no changes were noted. - Endocrine findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- effects observed, treatment-related
- Description (incidence and severity):
- FUNCTIONAL OBSERVATIONAL BATTERY
None of the parameters under investigation during the functional observational battery gave an indication of a test item-related effect.
Mean values of grip strength (fore- and hind paws) and landing foot splay gave no indication of
test item-related effects.
BODY TEMPERATURE
Mean body temperature in males was statistically significantly lower at the dose level of 90 mg/kg body weight/day compared to the control group (37.3 °C compared to 38.1 in the control group) and it was marginally lower when compared to historical control data range (37.5 - 39.1 °C). Additionally, slightly lower locomotor activity of this group was seen, thus a treatment-related effect can not be excluded. - Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Absolute and relative mean liver weights (both relative to body weight and relative to brain weight) were statistically increased in males and females of group 4 (90 mg/kg body weight/day). This finding correlated to diffuse hepatocellular hypertrophy associated with follicular hypertrophy of thyroid glands on some males and females of group 4.
Additionally, absolute and relative mean thymus weights were statistically significantly decreased in females of group 4, correlated with the observation of reduced size of thymus and thymic atrophy noted at histopathological examination.
No experimental relevance was attributed to increased relative mean kidney and heart weights in males and females of group 4 as the mean values were within the range of historical control data and no corroborative histopathological findings were recorded. - Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- The relevant macroscopical change in the stomach recorded as crateriform retraction was noted in one female at 30 mg/kg body weight/day, correlating with ulceration and submucosal inflammation.
One, three and four females receiving 10, 30 and 90 mg/kg body weight/day of the test item had reduced sized thymus correlating with thymic atrophy and reduced organ weights at 90 mg/kg body weight/day only. This thymus finding was considered to be likely stress-related. Other isolated macroscopical findings were considered to be within the range of normal background alterations.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Under the conditions of this experiment, the following treatment-related local irritative effects were induced:
Forestomach: hyperkeratosis in some females receiving 30 mg/kg body weight/day and all males receiving 90 mg/kg body weight/day and a single female at 90 mg/kg body weight/day, squamous cell hyperplasia with submucosal inflammation in a female at 30 mg/kg body weight/day; glandular stomach: focal erosion in one male at 10 mg/kg body weight/day and one male and female each at 90 mg/kg body weight/day, in the female associated with submucosal inflammation, mucosal atrophy.
Under the conditions of this experiment, the following treatment-related adaptive findings that are commonly seen in rats exposed with xenobiotics were induced:
Minimal to slight diffuse hepatocellular hypertrophy, characterized by an increase in
endoplasmic reticulum, was recorded in liver in all males and females at 90 mg/kg body
weight/day. This finding was considered to be adaptive.
Diffuse follicular cell hypertrophy in thyroid gland was noted in some males and females at 90 mg/kg body weight/day. This finding was considered to be consequent to the hepatocellular hypertrophy.
Histopathological examination of female no. 78 which died spontaneously receiving 90 mg/kg
body weight/day revealed that the cause of death was likely the thrombosis of jejunum and,
therefore, this death was considered to be incidental and not test item related.
Histopathological examination of the male no. 35 in the 90 mg/kg body weight/day group, which was killed in extremis, showed slight diffuse hyperkeratosis in forestomach and minimal erosion in glandular stomach, signs of moderate stress in thymus and adrenal glands as well as slight diffuse atrophy in the prostate, coagulating gland and seminal vesicles. The cause of moribundity could not be determind from the organs and tissues determined. - Histopathological findings: neoplastic:
- not examined
- Other effects:
- effects observed, non-treatment-related
- Description (incidence and severity):
- LOCOMOTOR ACTIVITY
For females at the dose level of 90 mg/kg body weight/day, total level of locomotor activity was statistically significantly reduced. In males the total level of activity was lower when compared to controls or other test item-treated groups but it did not reach statistical significance. The reduced locomotor activity in animals receiving 90 mg/kg body weight/day of Irgacure 127 was considered to be a test item-related effect.
In females at the dose level of 30 mg/kg body weight/day the low beam count at 30 minutes was
lower when compared to control but the total level of activity was not affected in this dose group.
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 30 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- clinical signs
- food consumption and compound intake
- mortality
- organ weights and organ / body weight ratios
Target system / organ toxicity
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 30 mg/kg bw/day (nominal)
- System:
- other: not reported
- Organ:
- liver
- thymus
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
Applicant's summary and conclusion
- Conclusions:
- Based on the observed mortality, clinical symptoms, decreased body weight, decreased food consumption, increased liver and decreased thymus weights at the dose level of 90 mg/kg body weight/day the NOAEL (No Observed Adverse Effect Level) for general toxicity in parental males and females was considered to be 30 mg/kg body weight/day.
A NOAEL (No Observed Adverse Effect Level) for the local irritative effect of the test item in
stomach could not be established for males and was established at 10 mg/kg bw/day for females based on the microscopic findings detected. - Executive summary:
The purpose of this guideline (OECD 422) study conducted with GLP certification, of the test material (EC: 444 -860 -9) was to generate preliminary information concerning the effects of the test item on the possible health hazards likely to arise from repeated exposure over a relatively limited period of time. In addition it provides information on possible effects on male and female reproductive performance such as gonadal function, mating behavior, conception, development of the conceptus and parturition.
The test item was administered orally by gavage to male rats for 28 days and to female rats for 14 days prior to pairing, through the pairing and gestation periods until the F1 generation reached day 4 post partum.
The test was conducted at three dose levels (10, 30, & 90 mg/kg bw/day). The duration of treatment covered a 2-week premating and a mating period in both sexes, approximately 1 week post-mating in males, and the entire gestation period as well as 4 days of lactation and 2 weeks thereafter in females. Treatment related toxicity was observed - the pups were shown to have a lower bodyweight and a decreased viability index. The NOAEL was determined to be 30 mg/kg bw/day.
A standard dose volume of 10 mL/kg body weight with a daily adjustment to the actual body weight was used. Control animals were dosed with the vehicle alone (Carboxymethylcellulose sodium salt 0.5%).
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