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EC number: 246-904-0 | CAS number: 25371-54-4
- 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
Toxicity to reproduction
Administrative data
- Endpoint:
- toxicity to reproduction
- Remarks:
- other: combined repeated dose and reproductive/developmental toxicity screening test
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- July 2012 to March 2013
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP guideline study
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to other study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 013
- Report date:
- 2013
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes
Test material
- Reference substance name:
- Dimethyl octadecylphosphonate
- EC Number:
- 246-904-0
- EC Name:
- Dimethyl octadecylphosphonate
- Cas Number:
- 25371-54-4
- Molecular formula:
- C20H43O3P
- IUPAC Name:
- dimethyl octadecylphosphonate
- Reference substance name:
- M-5925
- IUPAC Name:
- M-5925
- Test material form:
- other: white waxy solid
- Details on test material:
- Identification : M-5925
Molecular formula C20H43O3P
Molecular weight 362.54
Batch number B10-11648
Purity: 100%
Storage: Ambient, in the dark
Expiry Date: 07 May 2013 (1 year shelf-life after receipt arbitrarily allocated by the testing laboratory)
Constituent 1
Constituent 2
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approximately 11 weeks
- Weight at study initiation: Males weighed ca. 292 to 299 g (mean group weights), females weighed ca. 201 to 204 g (mean group weights)
- Fasting period before study: No
- Housing: Housed in groups of 5 with the exception of the mating period when 1 female was housed with 1 male and post mating when females were housed individually
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24
- Humidity (%): 40-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: To: 02 September 2012 to 01 November 2012
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- propylene glycol
- Details on exposure:
- VEHICLE
- Justification for use and choice of vehicle (if other than water): based on trial formulations at Wil Research Europe
- Concentration in vehicle: 20, 60 and 200 mg/g nominal
- Amount of vehicle (if gavage): 5 ml/kg body weight - Details on mating procedure:
- Following a minimum of 21 days of exposure for the males and females, one female was cohabitated with one male of the same treatment group,
avoiding sibling mating (Macrolon plastic cage). Detection of mating was confirmed by evidence of sperm in the vaginal lavage or by the appearance of an intravaginal copulatory plug. This day was designated Day 0 post-coitum. Once mating occurred, the males and females were separated. A maximum of 14 days was allowed for mating, after which females who had not shown evidence of mating were separated from their males.
Detection of mating was not confirmed for animal no. 53 which did deliver live offspring. The mating date of this animal was estimated at 21 days prior to the actual delivery date. This day was designated Day 0 postcoitum. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analysis performed on samples prepared for use on 03 September 2012. No test substance was found in the Group 1 formulations (control group). The concentrations analysed in the formulations of Group 2, 3 and 4 were in agreement with target concentrations (i.e. mean accuracies between 90% and 110%).
The formulations of Group 2 and 4 were homogeneous (i.e. coefficient of variation ≤ 10%). Group 3 was not tested for homogeneity.
Formulations at the entire range were stable when stored at room temperature under normal laboratory light conditions for at least 5 hours (i.e. relative difference ≤ 10%).
The long term storage samples were stable at ≤-70°C for at least 12 days. - Duration of treatment / exposure:
- Treatment: daily oral gavage dosing
Males were exposed for 36 days, i.e. 3 weeks prior to mating, during mating, and up to the day prior to scheduled necropsy. Females were exposed for 47-60 days, i.e. during 3 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation (up to the day prior to scheduled necropsy).
Pups were not treated directly but were potentially exposed to the test substance in utero and through lactational transfer. - Frequency of treatment:
- Once daily
- Details on study schedule:
- - F0 parental animals were mated after a minimum of 21 days exposure and 14 days was allowed for mating. The females were allowed to litter normally. Day 1 of lactation was defined as the day when a litter was found completed (i.e. membranes and placentas cleaned up, nest build up and/or feeding of pups started). Females that were littering were left undisturbed.
Study schedule:
Start treatment: 02 September 2012
Start mating: 23 September 2012
Blood sampling: 08 October 2012 (selected males), 19, 22-24 October 2012 (selected females)
Delivery of litters: 14-18, 26 and 27 October 2012
Necropsy: 8 October 2012 (selected males), 19, 22-24 October and 01 November 2012 (selected females)
Experimental completion date: 01 November 2012 (end of in-life phase)
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
0
Basis:
other: mg/kg body weight/day
- Remarks:
- Doses / Concentrations:
100
Basis:
other: mg/kg body weight/day
- Remarks:
- Doses / Concentrations:
300
Basis:
other: mg/kg body weight/day
- Remarks:
- Doses / Concentrations:
1000/600
Basis:
other: mg/kg body weight/day
- No. of animals per sex per dose:
- 10 males and 10 females
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Dose levels were selected based on results of a 10-day dose ranging finding study
- Rationale for animal assignment (if not random): random assignment
- Rationale for selecting satellite groups: not selected.
- Post-exposure recovery period in satellite groups: not applicable
- Section schedule rationale (if not random):
Examinations
- Parental animals: Observations and examinations:
- General repeat dose toxicity study observations include: Mortality/viability, clinical signs (daily within the cage and weekly with animal outside of the cage), functional observations, body weights, food consumption, visual assessment of water consumption, haematology, clinical chemistry, necropsy examination, organ weight collection and histopathology of a full range of protocol listed tissues. Testes from the 5 males selected for histological examination in the control and high dose group and from any males suspected of being infertile was also processed to allow staging of spermatogenesis.
General reproductive data:
Male number paired with, mating date, confirmation of pregnancy, and delivery day were recorded.
Pregnant females were examined to detect signs of difficult or prolonged parturition, and cage debris of pregnant females was examined to detect signs of abortion or premature birth. Any deficiencies in maternal care (such as inadequate construction or cleaning of the nest, pups left scattered and cold, physical abuse of pups or apparently inadequate lactation or feeding) were examined. - Oestrous cyclicity (parental animals):
- Not specifically investigated.
- Sperm parameters (parental animals):
- Not examined
- Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no
- If yes, maximum of [...] pups/litter ([...]/sex/litter as nearly as possible); excess pups were killed and discarded.
PARAMETERS EXAMINED
The following parameters were examined in [F1] offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain (pups weighed on days 1 and 4 of lactation)
GROSS EXAMINATION OF DEAD PUPS: Pups surviving to planned terminated were killed by decapitation on Days 5-7 of lactation. All pups were sexed and descriptions of all external abnormalities were recorded. The stomach for pups not surviving to the scheduled necropsy date was examined for the presence of milk. If possible, defects or cause of death were evaluated. - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals were examined macroscopically following completion of the mating period (a minimum of 28 days dose administration)
- Maternal animals - Day of necropsy: Females which delivered: lactation days 5-7, female which failed to deliver: post coitum days 25-26 (females with evidence of mating), females with total litter loss: within 3 days of litter loss.
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal tissues and organs with special attention paid to reproductive organs.
The numbers of former implantation sites and corpora lutea were recorded for all paired females. In case no macroscopically visible implantation sites were present, nongravid uteri were stained using the Salewski technique (Ref. 1) in order to detect any former implantation sites (Salewski staining prepared at WIL Research Europe using Ammoniumsulfide-solution 20% (Merck, Darmstadt, Germany) and Milli-Ro water (Millipore Corporation, Bedford, USA)).
HISTOPATHOLOGY / ORGAN WEIGHTS
A full range of tissues and organs were collected and preaserved in formalin. this is also described in detail in IUCLID summary 7.5.1. Organs were weighed from 5/sex and included the following reproductive organs: testes, epididymides, prostate, seminal vesicles including coagulating glands, ovaries and uterus (including cervix). In the remaining males testes and epididymides were weighed. Tissues and organs associated with reproductive/developmental toxicity screen are tabulated in Table 1. - Postmortem examinations (offspring):
- Pups surviving to planned termination were killed by decapitation on Days 5-7 of lactation.
All pups were sexed and descriptions of all external abnormalities were recorded. The stomach for pups not surviving to the scheduled necropsy date was examined for the presence of milk. If possible, defects or cause of death were evaluated. - Statistics:
- The following statistical methods were used to analyze the data:
– If the variables could be assumed to follow a normal distribution, the Dunnett-test (Ref. 2; many- to-one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex.
– The Steel-test (Ref. 3; many-to-one rank test) was applied if the data could not be assumed to follow a normal distribution.
– The Fisher Exact-test (Ref. 4) was applied to frequency data.
– The Kruskal-Wallis nonparametric ANOVA test (Ref. 5) was applied to motor activity data.
All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance. Group means were calculated for continuous data and medians were calculated for discrete data (scores). - Reproductive indices:
- the following calculations were performed:
Mating index (%); number of females mated/number of females paired x 100
Fertility index (%); number of pregnant females/number of females paired x100
Conception index (%); number of pregnant females/number of females mated x100
Gestation index (%); number of females bearing live pups/number of pregnant females x100
Duration of gestation; number of days between confirmation of mating and the beginning of parturition - Offspring viability indices:
- Percentage of live males at first litter check; number of live male pups at first litter check/number of live pups at first litter check x100
Percentage of live females at first litter check; number of live female pups at first litter check/ number of live pups at first litter check x100
Percentage of postnatal loss; number of dead pups before planned necropsy/number of live pups at first litter check x100
Viability index; number of live pups before planned necropsy/number of pups born live
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Hunched posture, piloerection, diarrhoea, salivation, lethargy, lean appearance recorded at 1000 mg/kg. Resolution of these symptoms noted after dose level reduced to 600 mg/kg.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Weight loss and lower food intake recorded at 1000 mg/kg. After reducing the dose to 600 mg/kg the animals' food intake increased and they regained body weight but remained lighter than controls.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Weight loss and lower food intake recorded at 1000 mg/kg. After reducing the dose to 600 mg/kg the animals' food intake increased and they regained body weight but remained lighter than controls.
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Stomach - local iritation noted - all treated groups. Mesenteric lymph nodes congestion/sinus histiocytosis at 600 mg/kg, Adrenals vacuolation zona glomerulosa 600 mg/kg
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- Animals mated on a 1 male to 1 female basis without specific oestrus cycle monitoring.
- Reproductive function: sperm measures:
- not examined
- Description (incidence and severity):
- no specific sperm measures performed.
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- Mating, fertility and conception indices, precoital time, number of corpora lutea and implantation sites were unaffected by treatment.
Details on results (P0)
No toxicologically relevant effects on reproductive parameters were noted. The mating, fertility and conception indices, precoital time, and number of corpora lutea and implantation sites were unaffected by treatment. The spermatogenic staging profiles were normal for all examined males. No abnormalities were seen in the reproductive organs of the rats who failed to sire or deliver healthy pups, which could account for their infertility.
No toxicologically relevant effects on the gestation index and duration, parturition, maternal care and early postnatal pup development (mortality, clinical signs, body weight and macroscopy) were observed.
Gestation
The gestation index and duration of gestation were unaffected by treatment. There were 9, 10, 9 and 10 pregnant females in the control, 100, 300 and 600 mg/kg groups, respectively. The gestation index was 88.9, 90, 100, and 100% for these groups.
Parturition/maternal care
No signs of difficult or prolonged parturition were noted among the pregnant females.
Examination of cage debris of pregnant females revealed no signs of abortion or premature birth and no deficiencies in maternal care were observed.
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOAEL
- Remarks:
- reproduction
- Effect level:
- > 600 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Dose descriptor:
- NOAEL
- Remarks:
- developmental
- Effect level:
- > 600 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No treatment related findings
- Mortality / viability:
- no mortality observed
- Description (incidence and severity):
- No treatment related effect on number of dead and living pups at the first litter check, postnatal loss, viability index and sex ratio recorded.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No teatment related findings
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No treatment related findings
- Histopathological findings:
- not examined
Details on results (F1)
Number of dead and living pups at first litter check, postnatal loss, viability index and sex ratio were unaffected by treatment, and clinical signs, body weight and external macroscopy did not reveal treatment-related findings.
Mortality
One, two and two pups in the 100, 300 and 600 mg/kg groups, respectively, died or went missing in the first days of lactation. No pups died in the control group. One female at 600 mg/kg (no. 72) had a total litter loss after her single pup went missing. This pup was most likely cannibalized. No toxicological relevance was attributed to these dead/missing pups since the mortality incidence did not show a dose-related trend and remained within the range considered normal for pups of this age.
Clinical signs
Scab/scabs on the head were noted for two pups at 300 mg/kg. Abnormal posture of the right hind leg was recorded for one pup at 600 mg/kg. These were the only clinical sign noted and were considered incidental in nature.
Body weights
Body weights of pups were unaffected by treatment up to 600 mg/kg.
Macroscopy
The only macroscopic findings that were noted were considered to be incidental in nature.
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
REPRODUCTION DATA SUMMARY
|
Group 1 Control |
Group 2 100 mg/kg |
Group 3 300 mg/kg |
Group 4 600 mg/kg |
Females paired |
10 |
10 |
10 |
10 |
Females mated |
10 |
10 |
10 |
10 |
Females pregnant |
9 |
10 |
9 |
10 |
Non-pregnant females |
1 |
0 |
0 |
0 |
Females with living pups on Day1 |
8 |
9 |
9 |
10 |
Mating index(%) (Females mated /Females paired) *100 |
100.0 |
100.0 |
100.0 |
100.0 |
Fertility index(%) (Pregnant females/Females paired) *100 |
90.0 |
100.0 |
90.0 |
100.0 |
Conception index(%) (Pregnant females/Females mated) *100 |
90.0 |
100.0 |
90.0 |
100.0 |
Gestation index(%) (Females with living pups on Day1 /Pregnant females) *100 |
88.9 |
90.0 |
100.0 |
100.0 |
Precoital time: F0-Generation – Post coitum
DAYOFTHE PAIRINGPERIOD |
GROUP1 CONTROL |
GROUP2 100MG/KG |
GROUP3 300MG/KG |
GROUP4 600MG/KG |
NUMBER OF FEMALES MATED |
||||
1 |
3 |
3 |
4 |
3 |
2 |
1 |
2 |
1 |
5 |
3 |
3 |
3 |
4 |
2 |
4 |
2 |
− |
1 |
− |
11 |
− |
1 |
− |
− |
12 |
− |
1 |
− |
− |
13 |
1 |
− |
− |
− |
MEDIAN PRECOITAL TIME |
3 |
3 |
3 |
2 |
MEAN PRECOITAL TIME |
3.5 |
3.9 |
2.2 |
1.9 |
N |
10 |
10 |
10 |
10 |
Not significant by Steel-test
Corpora lutea and implantation sites summary
|
|
Group 1 Control |
Group 2 100 mg/kg |
Group 3 300 mg/kg |
Group 4 600 mg/kg |
NECROPSY CorporaLutea |
MEAN |
15.2 |
13.0 |
13.8 |
10.6 |
|
ST.DEV |
5.0 |
6.1 |
5.5 |
3.4 |
|
N |
9 |
10 |
9 |
10 |
Implantations |
MEAN |
11.6 |
8.7 |
11.1 |
9.8 |
|
ST.DEV |
3.0 |
4.8 |
3.0 |
3.4 |
|
N |
9 |
10 |
9 |
10 |
not significant by Steel test
Developmental data – F0-Generation – Lactation
|
Group 1 Control |
Group 2 100 mg/kg |
Group 3 300 mg/kg |
Group 4 600 mg/kg |
LITTERS - TOTAL |
8 |
9 |
9 |
10 |
DURATION OF GESTATION |
||||
MEAN(+) |
20.9 |
21.4 |
21.2 |
21.1 |
ST.DEV. |
0.8 |
0.7 |
0.4 |
0.3 |
N |
8 |
9 |
9 |
10 |
DEAD PUPS AT FIRST LITTER CHECK |
||||
LITTERS AFFECTED (#) |
0 |
1 |
0 |
0 |
TOTAL |
0 |
1 |
0 |
0 |
MEAN (+) |
0.0 |
0.1 |
0.0 |
0.0 |
ST. DEC. |
0.0 |
0.3 |
0.0 |
0.0 |
N |
8 |
9 |
9 |
10 |
LIVING PUPS AT FIRST LITTER CHECK |
||||
% OF MALES / FEMALES (#) |
52/ 48 |
54/ 46 |
49/ 51 |
59/ 41 |
TOTAL |
87 |
80 |
102 |
93 |
MEAN(+) |
10.9 |
8.9 |
11.3 |
9.3 |
ST.DEV. |
3.2 |
3.6 |
3.3 |
3.6 |
N |
8 |
9 |
9 |
10 |
POSTNATAL LOSS |
||||
% OF LIVING PUPS |
0.0 |
0.0 |
2.0 |
2.2 |
LITTERS AFFECTED(#) |
0 |
0 |
2 |
2 |
TOTAL(#) |
0 |
0 |
2 |
2 |
MEAN(+) |
0.0 |
0.0 |
0.2 |
0.2 |
ST.DEV. |
0.0 |
0.0 |
0.4 |
0.4 |
N |
8 |
9 |
9 |
10 |
VIABILITY INDEX(#) |
100.0 |
100.0 |
98.0 |
97.8 |
Viability index= (Number of alive pups before planned necropsy/ Number of pups born alive)*100
+/++Steels test significant at 5% (+) or 1% (++) level
#/##Fisher's Exact test significant at 5% (#) or 1% (##) level
BODY WEIGHTS OF PUPS (G) F0-GENERATION - LACTATION
Day |
Sex |
|
Group 1 Control |
Group 2 100 mg/kg |
Group 3 300 mg/kg |
Group 4 600 mg/kg |
1 |
M |
MEAN |
6.3 |
6.9 |
6.5 |
6.1 |
|
|
ST.DEV. |
0.8 |
1.1 |
0.8 |
0.5 |
|
|
N |
8 |
9 |
9 |
9 |
|
F |
MEAN |
6.1 |
6.5 |
6.3 |
5.7 |
|
|
ST.DEV. |
0.7 |
0.9 |
0.7 |
0.5 |
|
|
N |
8 |
9 |
9 |
10 |
|
M+F |
MEAN |
6.2 |
6.8 |
6.4 |
5.9 |
|
|
ST.DEV. |
0.7 |
1.0 |
0.7 |
0.5 |
|
|
N |
8 |
9 |
9 |
10 |
4 |
M |
MEAN |
9.6 |
10.5 |
9.4 |
9.0 |
|
|
ST.DEV. |
1.5 |
2.2 |
1.2 |
0.9 |
|
|
N |
8 |
9 |
9 |
9 |
|
F |
MEAN |
9.3 |
9.9 |
9.3 |
8.6 |
|
|
ST.DEV. |
1.3 |
1.7 |
1.0 |
0.8 |
|
|
N |
8 |
9 |
9 |
9 |
|
M+F |
MEAN |
9.5 |
10.3 |
9.4 |
8.8 |
|
|
ST.DEV. |
1.4 |
2.0 |
1.1 |
0.8 |
|
|
N |
8 |
9 |
9 |
9 |
Not significant by Dunnett's test
Applicant's summary and conclusion
- Conclusions:
- In conclusion, treatment with Dimethyl octadecylphosphonate (DMOP) by oral gavage in male and female Wistar Han rats at dose levels of 100, 300, 600 and 1000 mg/kg body weight/day revealed parental toxicity at 600 mg/kg body weight/day. No reproduction and developmental toxicity was observed for treatment up to 600 mg/kg body weight/day.
Based on these results, the following No Observed Adverse Effect Level (NOAEL) was derived:
Reproduction: at least 600 mg/kg bw/day
Developmental: at least 600 mg/kg bw/day - Executive summary:
Dimethyl octadecylphosphonate (DMOP) was administered by daily oral gavage to male and female Wistar Han rats at dose levels of 0, 100, 300 and 1000 (Days 1-13 of treatment) mg/kg. Due to toxicity observed at 1000 mg/kg, the dose level of Group 4 was lowered to 600 mg/kg from Day 14 of treatment onwards. Males were exposed for 36 days, i.e. 3 weeks prior to mating, during mating, and up to termination. Females were exposed for 47-60 days, i.e. during 3 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation. Pups were not treated directly but were exposed to the test substance in utero and through lactational transfer.
Formulation analysis showed that the formulations were prepared accurately, were homogenous, and were stable for at least 5 hours at room temperature.
General reproductive data for the parenteral animals was recorded. This included male number paired with, mating data, confirmation of pregnancy and delivery date. Pregnant females were examined to detect signs of difficult or prolonged parturition and cage debris of pregnant females was examined top detect signs of abortion or premature birth. Any deficiencies in maternal care (such as inadequate construction or cleaning of the nest, pups left scattered and cold, physical abuse of pups or apparently inadequate lactation or feeding) were examined.
Each litter of pups was examined for mortality and viability. The numbers of live and dead pups on Day 1 of lactation and daily thereafter was determined and if possible, cause of death was evaluated. Clinical signs examinations were performed at least once daily. On lactation days 1 and 4 the pups were weighed and their sex determined. The pups were sacrificed on Days 5 to 7 of lactation. Sex was confirmed and descriptions of any external abnormalities recorded. The stomach of any pup not surviving to the scheduled termination was examined for the presence of milk and cause of death established if possible.
The following indices were calculated: mating index, fertility index, conception index, gestation index, duration of gestion, percentage of live males at first litter check, percentage of live females at first litter check, percentage of postnatal loss, viability index.
No toxicologically relevant effects on reproductive parameters such as mating, fertility and conception indices, precoital time, number of corpora lutea and implantation sites. The spermatogenic staging profiles were normal for all examined males. No abnormalities were seen in the reproductive organs of the rats who failed to sire or deliver healthy pups, which could account for their infertility. For developmental data, no toxicologically relevant effects on gestation index and duration, parturition, maternal care and early postnatal pup development (mortality, clinical signs, body weight and macroscopy) were observed. It was concluded that based on these results the NOAEL for reproductive and developmental effects was at least 600 mg/kg bw/day.
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