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EC number: 423-340-5 | CAS number: 162881-26-7 CGI 819
- 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
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2013-2014
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: OECD 414 and GLP compliant study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 014
- Report date:
- 2014
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Phenyl bis(2,4,6-trimethylbenzoyl)-phosphine oxide
- EC Number:
- 423-340-5
- EC Name:
- Phenyl bis(2,4,6-trimethylbenzoyl)-phosphine oxide
- Cas Number:
- 162881-26-7
- Molecular formula:
- C26 H27 O3 P
- IUPAC Name:
- [phenyl(2,4,6-trimethylbenzoyl)phosphoryl](2,4,6-trimethylphenyl)methanone
- Details on test material:
- Physical state: Solid / light yellow
Expiry date: 25 Mar 2016
Storage conditions: Room temperature
Stability und er storage conditions: stable
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Crl:WI (Han)
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Age at study initiation: About 10-12 weeks
- Weight at study initiation: 141.7 – 193.4 g
- Housing: single caging
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: six days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30 - 70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 2013-02-13 To: 2013-03-12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: 1% carboxymethylcellulose in water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The specific amount of test substance was weighed, topped up with vehicle in a graduated flask and intensely mixed. The mixture was continuosly stirred until dosing.
VEHICLE
- Justification for use and choice of vehicle (if other than water): the test item can be suspended in the vehicle. It is not soluble in water.
- Amount of vehicle (if gavage): 10 ml/kg body weight - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- HPLC-method
- Details on mating procedure:
- - Impregnation procedure: purchased timed pregnant
The day of evidence of mating (= detection of vaginal plug/sperm) was referred to as GD 0. The animals arrived on the same day (GD 0) at the experimental laboratory. - Duration of treatment / exposure:
- gestation days 6- 19
- Frequency of treatment:
- daily
- Duration of test:
- 14 days
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 100,300 and 1000 mg/kg bw
Basis:
actual ingested
- No. of animals per sex per dose:
- 25
- Control animals:
- yes
- Details on study design:
- - Dose selection rationale: Based on range-finder study with pregnant rats
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Mortality/Morbidity, pertinent behavioral changes and/or signs of overt toxicity. were checked twice daily from Mondays to Fridays and once daily on Saturdays, Sundays and public holidays (GO 0 to 20).
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: GO 0, 1, 3, 6, 8, 10, 13, 15, 17, 19 and 20.
POST-MORTEM EXAMINATIONS: Gross pathology
- Sacrifice on gestation day: GD 20 - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: Site of implantations in the uterus - Fetal examinations:
- - External examinations: Yes: [all per litter ]
- Soft tissue examinations: Yes: [ half per litter ]
- Skeletal examinations: Yes: [ half per litter ]
In the present study the glossary of WISE et al. (1997) and its updated version of MAKRIS et al. (2009) was essentially used to describe findings in fetal morphology. Classification of these findings was based on the terms and definitions proposed by CHAHOUD et al. (1999) and SOLECKI et al. (2001, 2003):
Malformation
A permanent structural change that is likely to adversely affect the survival or health.
Variation
A change that also occurs in the fetuses of control animals and/or is unlikely to adversely affect the survival or health. This includes delays in growt or morphogenesis that have otherwise followed a normal pattern of development.
The term "unclassified observation" was used for those fetal findings, which could not be classified as malformations or variations. - Statistics:
- DUNNETT's test: Food consumption, body weight, body weight change, DUNNETT's test
corrected body weight gain, carcass weight, weight of
the unopened uterus, weight of the placentas and
fetuses, corpora lutea, implantations, pre- and
postimplantation losses, resorptions and live fetuses
FISHER's exact test
Number of pregnant animals at the end of the study, FISHER's exact test mortality rate (of the dams) and number of litters with fetal findings
WILCOXON test
Proportion of fetuses with findings per litter - Indices:
- sex ratio
conception rate (in %)
preimplantation loss (in %)
postimplantation loss (in %) - Historical control data:
- Included in the final report.
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
Details on maternal toxic effects:
The mean food consumption of the dams in test groups 1-3 (100 or 300 mg/kg bw/d) was generally comparable to the concurrent control throughout the entire study period. The mean food consumption of the high-dose dams (1000 mg/kg bw/d) was slightly and temporarily, but statistically significantly reduced on GD 8-13. The accumulated food consumption of these dams during the treatment (GD 6-19) was comparable to the control. Thus, the temporary decrease on GD 8-13 may well have been an incidental event.
No further effects were recorded.
Effect levels (maternal animals)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
See tables below.
Effect levels (fetuses)
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: teratogenicity
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Any other information on results incl. tables
The stability of the test substance suspensions over a period of 7 days in a refrigerator was demonstrated. The homogeneous distribution of the test substance in the vehicle (1% CMC) was demonstrated. The results of the analysis of the aqueous test substance preparations confirmed the correctness of the prepared concentrations. The analytical values of the samples corresponded to the expected values within the limits of the analytical method, i.e. were always above 90% and below 110% of the nominal concentrations.
The mean gravid uterus weights of the animals of test group 1-3 (100, 300 and 1000 mg/kg bw/d) were not influenced by the test substance. No necropsy findings which could be attributed to the test substance were seen in any dam.
There were no test substance-related and/or biologically relevant differences between test groups 0, 1, 2 and 3 (0, 100, 300 and 1000 mg/kg bw/d) in conception rate, in the mean number of corpora lutea and implantation sites or in the values calculated for the pre- and the postimplantation losses, the number of resorptions and viable fetuses. All observed differences are considered to reflect the normal range of fluctuations for animals of this strain and age.
The sex distribution of the fetuses in test groups 1-3 (100, 300 and 1000 mg/kg bw/d) was comparable to the control fetuses. So were the mean placental weights and the mean fetal weights of the low-, mid- and high-dose groups. No fetus showed external malformations, variations or unclassified variations. Fetal data for soft tissue and skeletal examinations are summarized below.
Table 1: Individual fetal soft tissue malformation
Test group | Dam No.-Fetus No., Sex | Finding |
0 (0 mg/kg bw/d) | none | |
1 (100 mg/kg bw/d) | 27-02 M | hydronephrosis, hydroureter |
2 (300 mg/kg bw/d) | none | |
3 (1000 mg/kg bw/d) | 86-08 F | anophthalmia |
mg/kg bw/d = milligram per kilogram bodyweight per day; No. = number; M = male; F = female
Table 2: Total soft tissue malformations
Test group 0 0 mg/kg bw/d |
Test group 1 100 mg/kg bw/d |
Test group 2 300 mg/kg bw/d |
Test group 3 1000 mg/kg bw/d |
||
Litter | N | 25 | 25 | 25 | 25 |
Fetuses | N | 117 | 116 | 121 | 121 |
Fetal incidence | N (%) | 0.0 | 1 (0.9) | 0.0 | 1 (0.8) |
Litter incidence | N (%) | 0.0 | 1 (4.0) | 0.0 | 1 (4.0) |
Affected fetuses/litter | Mean% | 0.0 | 1.3 | 0.0 | 0.8 |
mg/kg bw/d = milligram per kilogram body weight per day; N = number; % = per cent
Table 3: Total fetal soft tissue variations
Test group 0 0 mg/kg bw/d |
Test group 1 100 mg/kg bw/d |
Test group 2 300 mg/kg bw/d |
Test group 3 1000 mg/kg bw/d |
||
Litter | N | 25 | 25 | 25 | 25 |
Fetuses | N | 117 | 116 | 121 | 121 |
Fetal incidence | N (%) | 2 (1.7) | 3 (2.6) | 4 (3.3) | 2 (1.7) |
Litter incidence | N (%) | 2 (8.0) | 3 (12) | 4 (16) | 1 (4.0) |
Affected fetuses/litter | Mean% | 1.6 | 2.8 | 3.2 | 1.6 |
mg/kg bw/d = milligram per kilogram body weight per day; N = number; % = per cent
No unclassified soft tissue observations were recorded.
Table 4: Individual fetal skeletal malformations
Test group | Dam No.-Fetus No., Sex | Finding |
0 (0 mg/kg bw/d) | 6-01 M | misshapen basioccipital |
12-05 F | misshapen basioccipital | |
12-09 F | misshapen basisphenoid | |
17-06 F | misshapen basioccipital | |
1 (100 mg/kg bw/d) | 43-01 M | misshapen basisphenoid |
47-06 F | small cervical arch | |
2 (300 mg/kg bw/d) | 58-07 M | fused thoracic centrum, fused rib |
71-10 F | severely malformed vertebral column | |
3 (1000 mg/kg bw/d) | 82-04 M | shortened humerus |
86-06 F | exoccipital fused with 1stcervical arch, misshapen basioccipital, cervical hemivertebra | |
89-09 F | absent lumbar vertebra, intercostal rib, branched rib |
mg/kg bw/d = milligram per kilogram bodyweight per day; No. = number; M = male; F = female
Table 5: Total fetal skeletal malformations
Test group 0 0 mg/kg bw/d |
Test group 1 100 mg/kg bw/d |
Test group 2 300 mg/kg bw/d |
Test group 3 1000 mg/kg bw/d |
||
Litter | N | 25 | 25 | 25 | 25 |
Fetuses | N | 132 | 128 | 133 | 130 |
Fetal incidence | N (%) | 4 (3.0) | 2 (1.6) | 2 (1.5) | 3 (2.3) |
Litter incidence | N (%) | 3 (12) | 2 (8.0) | 2 (8.0) | 3 (12) |
Affected fetuses/litter | Mean% | 3.0 | 1.5 | 1.6 | 2.5 |
mg/kg bw/d = milligram per kilogram body weight per day; N = number; % = per cent
Table 6: Total fetal skeletal variations
Test group 0 0 mg/kg bw/d |
Test group 1 100 mg/kg bw/d |
Test group 2 300 mg/kg bw/d |
Test group 3 1000 mg/kg bw/d |
||
Litter | N | 25 | 25 | 25 | 25 |
Fetuses | N | 132 | 128 | 133 | 130 |
Fetal incidence | N (%) | 127 (96) | 127 (99) | 132 (99) | 129 (99) |
Litter incidence | N (%) | 25 (100) | 25 (100) | 25 (100) | 25 (100) |
Affected fetuses/litter | Mean% | 96.5 | 99.0 | 99.2 | 99.3 |
mg/kg bw/d = milligram per kilogram body weight per day; N = number; % = per cent
Table 7: Occurrence of statistically significantly increased fetal skeletal variations (expressed as mean percentage of affected fetuses/litter)
Finding | Test group 0 0 mg/kg bw/d |
Test group 1 100 mg/kg bw/d |
Test group 2 300 mg/kg bw/d |
Test group 3 1000 mg/kg bw/d |
HCD Mean % (range) |
Incomplete ossification of cervical arch; cartilage pre- sent | 0.0 | 0.8 | 2.1* | 3.0* | 0.1 (0.0 – 0.8) |
Incomplete ossification of thoracic centrum; unchanged cartilage | 0.0 | 1.8 | 2.4* | 1.5 | 1.0 (0.0 – 4.8) |
Incomplete ossification of sacral arch; cartilage present |
1.2 | 3.7 | 2.8 | 7.3* | 1.5 (0.0 – 6.0) |
Unossified sternebra; unchanged cartilage | 4.0 | 10.7* | 5.3* | 8.7 | 8.6 (2.6 – 20.7) |
Unilateral ossification of sternebra; unchanged cartilage |
1.0 | 2.0 | 0.8 | 4.9* | 1.2 (0.0 – 4.0) |
mg/kg bw/d = milligram per kilogram body weight per day; HCD = Historical control data; % = per cent
* = p ≤ 0.05 (Wilcoxon-test [one-sided])
All these minor changes may be indicative for a minimal delay of skeletal maturation, however, the slightness of these apparent effects makes it difficult to judge whether these are real effects or not. They are in any case not considered as adverse events.
Table 8: Total unclassified cartilage observations
Test group 0 0 mg/kg bw/d |
Test group 1 100 mg/kg bw/d |
Test group 2 300 mg/kg bw/d |
Test group 3 1000 mg/kg bw/d |
||
Litter | N | 25 | 25 | 25 | 25 |
Fetuses | N | 132 | 128 | 133 | 130 |
Fetal incidence | N (%) | 98 (74) | 88 (69) | 88 (66) | 99 (76) |
Litter incidence | N (%) | 25 (100) | 25 (100) | 25 (100) | 25 (100) |
Affected fetuses/litter | Mean% | 73.9 | 68.7 | 66.9 | 75.9 |
mg/kg bw/d = milligram per kilogram body weight per day; N = number; % = per cent
Applicant's summary and conclusion
- Conclusions:
- The substance does not cause developmental toxicity or teratogenicity in rats.
- Executive summary:
In a prenatal developmental toxicity study the test substance was administered to pregnant Wistar rats daily by gavage from implantation to one day prior to the expected day of parturition (GD 6-19) to evaluate its potential maternal and prenatal developmental
toxicity. Analyses confirmed the correctness of the prepared concentrations, the homogeneous distribution and the stability of the test substance in the vehicle.
Generally, clinical observations including food consumption and body weight gain revealed no toxicologically relevant difference between the animals receiving 100, 300 or 1000 mg/kg bw/d test substance and controls. No differences of toxicological relevance between the control and the treated groups (100, 300 or 1000 mg/kg bw/d) were determined for any reproductive parameters, such as
conception rate, mean number of corpora lutea, mean number of implantations, as well as pre- and postimplantation loss. Similarly, no influence of the test substance on fetal weight and sex distribution of the fetuses was noted at any dose. Overall, there was no evidence for toxicologically relevant adverse effects of the test substance on fetal morphology at any dose.
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