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EC number: 204-707-7 | CAS number: 124-64-1
- 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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- From 12 April 1990 to 14 august 1991
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Comparable to guidelines.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 991
- Report date:
- 1991
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- yes
- Remarks:
- 5 females per dose instead of 20
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Tetrakis(hydroxymethyl)phosphonium chloride
- EC Number:
- 204-707-7
- EC Name:
- Tetrakis(hydroxymethyl)phosphonium chloride
- Cas Number:
- 124-64-1
- Molecular formula:
- C4H12O4P.Cl
- IUPAC Name:
- tetrakis(hydroxymethyl)phosphonium chloride
Constituent 1
Test animals
- Species:
- rabbit
- Strain:
- New Zealand White
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Hazleton Research Products Inc., Pennsylvannia 17517, USA
- Age at study initiation: no data
- Weight at study initiation: 3.19 to 4.27 kg for females at mating
- Fasting period before study: no data
- Housing: individually in anodised stainless stell cages
- Diet: ad libitum, SQC standard rabbit diet, special diets services Ltd, Witham
- Water: ad libitum, filtered mains water via non-return automatic drinking valves
- Acclimation period: at least 12 days before mating
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16 to 22
- Humidity (%): 40 to 70
- Air changes (per hr): 15
- Photoperiod : 10 hrs dark / 14 hrs light (6AM to 8PM°
IN-LIFE DATES: FROM 19 APRIL 1990 TO 18 MAY 1990
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Remarks:
- distilled water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: Solutions of the test article in distilled water were prepared daily. Nitrogen gas was bubbled through all test and control article preparations to reduce the dissolved oxygen content. Formulations were stored at ambient temperature, in containers purged with nitrogen, before use.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analysis of formulations:
- stability: samples (100ml) of test article solutions formulated at 0.2 and 12 mg/ml were taken and analysed to determine the stability over 24 hours
- analysis for achieved concentration: samples (100 ml) of the formulations prepared on the first and last day of dosing were analysed for achieved concentration. - Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: no data
- Proof of pregnancy: no data, the day of mating was referred to as day 0 of gestation
- Any other deviations from standard protocol: Females that successfully completed coitus were injected intravenously via the marginal ear vein 10 I.U. of chorionic gonadotrophin to ensure ovulation. - Duration of treatment / exposure:
- from day 7 to day 19 of gestation.
- Frequency of treatment:
- daily
- Duration of test:
- 29 days
- No. of animals per sex per dose:
- 5 females per dose
- Control animals:
- yes, concurrent vehicle
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes, twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily during gestation
BODY WEIGHT: Yes
- Time schedule for examinations: on days 0, 7, 8, 9, 12, 19, 24 29 of gestation
FOOD INTAKE ): Yes
The amount of food consumed by each female was recorded on days 3, 7, 8, 9, 12, 15, 17, 19, 21, 24, 27 and 29 of gestation and reported on the body weight interval
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Organs examined: The ovaries and uteri were examined. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes - Fetal examinations:
- - External examinations: Yes: all per litter
- Foetuses were weighed individually, examined externally and sexed by internal inspection of the gonads. Foetuses showing malformations and one control litter were fixed in industrial methylated spirit and retained, the remaining foetuses were discarded - Statistics:
- No statistics were performed
- Indices:
- - percentage pre-implantation loss was calculated as: (number of corpora lutea - number of implantations)/ number of corpora lutea x 100
- percentage post-implantation loss was calculated as: (number of implantations- number of live foetuses)/ number of implantations x 100
- percentage male foetuses was calculated as: number of male foetuses/ number of foetuses of determined sex x 100 - Historical control data:
- No historical control data were provided to allow comparison with concurrent controls.
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
One animal in the high dose group aborted and died on day 19 of gestation, having shown marked weight loss (15 %) and reduced food intake from the start of treatment. Necropsy revealed ulceration of the stomach and abnormal appearance of the duodenum, jejunum, liver and uterus. A small quantity of clear fluid was observed in the thoracic cavity.
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- 18 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
Sex ratio (percentage male foetuses) was within expected limits in all groups, given the small sample size.
Mean foetal weight was lower than controls in all treated groups. Values were comparable to the expected range (39.9 to 43.5 g) for the low and intermediate dose groups and significantly reduced in the high dose group.
Pre-implantation loss was lower than the control group in all treated groups. The control value was unusually high owing to one unilateral pregnancy, which is not uncommon in this strain of rabbit.
Post-implantation loss was lower than controls in the low and intermediate dose groups and significantly increased in the high dose group. Three of the 4 high dose litters showed early or late intrauterine deaths.
Characteristic eye and/or limb malformations were observed in foetuses from all high dose litters. There was no effect of treatment at the lower doselevels investigated. No malformations were observed at 18 mg/kg/day and only one foetus from the group treated at 6 mg/kg/day showed a malformation. No malformations were observed in the control group.
Litter size was consequently lower than controls in the high dose group and comparable in the low and intermediate dose groups.
Effect levels (fetuses)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 18 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: teratogenicity
- Dose descriptor:
- NOAEL
- Effect level:
- 18 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: embryotoxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 18 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: fetotoxicity
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Any other information on results incl. tables
Maternal toxicity
- Morbidity:
One female in the high dose group aborted and died on day 19 of gestation. This animal having shown marked weight loss (15%) and reduced food intake from the start of the treatment. At necropsy, ulceration of the stomach and abnormal appearance of the duodenum, jejunum, liver and uterus were revealed.
All other animals survived.
- Clinical signs:
No clinical signs related to treatment were observed.
- Bodyweight/food intake:
During all the study, mean bodyweight gain was comparable in the low dose group to controls. Weight losses were observed in the medium and high dose groups, with a dose relationship, -1.5% and -3.5% respectively. For the high dose group, bodyweight did not increase even if the dosing ceased.
Dosage-related reductions in food intake were observed in the medium and high dose groups during the treatment period. After dosing ceased, food intake was comparable to controls in the high dose group but remained lower in the medium dose group. Slight food consumption was observed for the low dose group during the days 24-29. No relation with clinical signs or necropsy findings was considered.
- Necropsy:
Necropsy revealed gastro-intestinal changes in 3 out of 5 animals from each treated groups. Findings in the digestive tracts were considered indicative of irritation due to the acidic test article (reddening of mucosa) rather than toxicityper se.
Foetal toxicity
- Uterine implantation (Table THPC RF Rabbit-1):
All animals in the treated groups were pregnant, and one control female was not.
Table THPC RF Rabbit-1: Implantation data of female rabbit daily administered with THPSat 3dose levels (low: 4.8 mg/kg bw, medium: 14.4 mg/kg bw, high: 48 mg/kg bw, main ingredient).
|
Control |
Low |
Medium |
High |
N females |
5 |
5 |
5 |
5* |
N pregnant |
4 |
5 |
5 |
5 |
Mean corpora lutea per female |
10.3 |
9.0 |
9.4 |
11.3 |
Mean pre-implantation loss (%) |
26.8 |
15.6 |
8.5 |
6.7 |
Mean post-implantation loss (%) |
6.7 |
0.0 |
4.7 |
38.1 |
N females with live foetuses on day 29 |
4 |
5 |
5 |
4 |
N foetus |
28 |
38 |
41 |
26 |
N foetus per female |
7 |
7.6 |
8.2 |
6.5 |
% male foetuses |
53.6 |
52.6 |
48.8 |
46.2 |
Pre-implantation loss was lower than the control group in all treated groups. The control value was unusually high owing to one unilateral pregnancy.
Post-implantation loss was lower than controls in the low and medium dose groups and significantly increased in the high dose group. Three of the 4 high dose litters showed early or late intrauterine deaths.
- Foetal data:
Sex ratio was within expected limits in all groups.
Mean foetal weight was lower than controls in all treated groups, but comparable to the expected range for the low and medium dose groups. It was significantly reduced in the high dose group.
Foetal malformations were observed in foetuses from all high dose litters. All the foetuses showed eye malformations (microphthalmia, retinal dysplasia) and a half exhibited limb malformations (malrotated limbs, (oligo)syndactyly). Concerning the other groups, only one foetus from the low dose group (4.8 mg/kg bw main ingredient) was malformed (arthrogryposis).
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of this test, treatment with THPC at 60 mg/kg/day elicited severe maternal toxicity and associated embryo/foetal toxicity, demonstrated by an increased incidence of intrauterine deaths, reduced foetal weight and a high incidence of foetuses showing characteristic eye and limb malformations.
- Executive summary:
In an oral (gavage) range-finding study (Hazleton UK, 1991), three groups of 5 mated New Zealand White rabbits were given THPC orally at dose levels of 6, 18 or 60 mg/kg daily from day 7 to day 19 of gestation. A similar group of rabbits, given the vehicle (distilled water) by the same route and over the same period served as controls. All animals were maintained until day 29 of gestation, killed and their uterine contents examined. At the highest dose, one animal aborted and died on day 19, having shown excessive weight loss and low food intake. Ulceration of the stomach was observed at necropsy. No other deaths were observed.
There were no treatment-related clinical changes. Signs indicative of irritation of the gastro-intestinal mucosa were observed in all treated groups but were considered to be a result of the acidic test article rather than toxicity per se. Treatment with THPC at 60 mg/kg/day elicited severe maternal toxicity and associated embryo/foetal toxicity, demonstrated by an increased incidence of intrauterine deaths, reduced foetal weight and a high incidence of foetuses showing characteristic eye and limb malformations. At 18 mg/kg/day, maternal toxicity to a lesser extent was also observed but there was no indication of an adverse effect on the developong embryo/foetus. There was no indication of toxicity, maternal or foetal, at 6 mg/kg/day.
Under the conditions of this test, THPC induced severe maternal toxicity, embryo/foetal toxicity and teratogenicity only at the highest dose level.
A maternal NOAEL of 18 mg/kg/day and a teratotoxicity and embryo/foetal toxicity NOAEL of 18 mg/kg/day were identified.
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