Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Quality of whole database:
No study available. A developmental toxicity study on monosodium phosphate anhydrous in two species at dose-levels well above those at which human can be exposed on two species does not indicate reprotoxicity preoccupation.
Additional information

Polyphosphoric acid is a mixture of the corresponding acids to phosphate anion and its condensed phosphates as follows:

- orthophosphoric acid or phosphoric acid (17 -76%),

- pyrophosphoric acid (23 -50%),

- triphosphoric acid (1.5 -25%),

- tetraphosphoric acid (0 -12%)

- and pentaphosphoric acid (0 -7%).

 

A condensed phosphate anion M(n+2)PnO(3n+1)has one or several P-O-P bonds and has been obtained by heating (dehydration). When the substance polyphosphoric acid is in contact of excess of water, a rapid hydrolysis is observed with the longer chains (tri, tetra or penta) while a very slow hydrolysis is observed for the dimer form to ortho phosphate. The pyrophosphate ion is the simplest form of a condensed phosphate group. As the group contains only two phosphate groups, both of the phosphorus ions are classified as “terminal phosphorus”. The pyrophosphate can undergo ionisation with loss of H+ from each of the two –OH groups on each P and therefore can occur in the -1, -2 -3 or -4 state. The degree of ionisation is dependant upon the associated cations (if there are) and the ambient pH (if in solution).

No partition coefficient value was determined for these substances as they are inorganic phosphates that are highly ionic (depending on ambient pH). Because of this ionic nature the passive passage across biological membranes will be negligible. Pyrophosphate is an anion that occurs in all living cells and is formed mainly by the synthesis of DNA from Nucleotide triphosphates (DNAn + Deoxyribonucleotide triphosphate → DNAn+1 + pyrophosphate). Usually it is cleaved rapidly into two orthophosphate molecules by one of the different members of the alkaline phosphatase family which are present in all tissues. Pyrophosphate nevertheless is generally relatively stable against uncatalyzed hydrolysis (half life = 10 d in autoclaved Flat branch sediment (Blanchar RW and Riego DC, 1975, Tripolyphosphate and pyrophosphate hydrolysis in sediments, Soil sci. soc.Am. J 40: 225-229)).

Section 8.7.1. Adaptation

According to Annex VIII, Section 8.7.1, Column 2 of Regulation (EC) No. 1907/2006, a screening for reproductive/developmental toxicity study does not need to be conducted if a prenatal development toxicity study is available. A developmental toxicity study on monosodium phosphate anhydrous on two species is included in IUCLID Section 7.8.2 of this dossier and therefore a screening study is not considered to be scientifically justified.

Section 8.7.2. Adaptation

The standard requirement for chemicals manufactured or imported into the EU in quantities of 100- 1,000 tpa does not includes a two-generation reprotoxicity study (OECD 416) unless a potential for toxicity on reproduction is suspected. According to the Integrated Testing Strategy (ITS) proposed in the ECHA guidance document on the information requirements and chemical safety assessment, Chapter R. 7a: Endpoint specific guidance, Section 7.6.6, if there is sufficient data to permit a robust conclusion on reproductive toxicity testing then no further testing will be required. The justification for not conducting a two-generation is based on the evaluation of existing data in laboratory animals, available data on similar or parent compounds, historical data and general characteristics of the test material.

For the purpose of assessing the risk of reprotoxicity the following substances are considered to be similar enough to facilitate read across:

Laboratory studies:

- Negative In vitro mutagenicity and genotoxicity evidence on phosphoric acid suggests a low potential for germ cell mutagenicity.

- For the developmental toxicity/teratogenicity endpoint, read-across with monosodium phosphate, anhydrous was done based on structural similarities and as shown in the toxicokinetic assessment (as soon as phosphoric acid reaches the blood system, it hydrolysis in phosphate and therefore, cannot become systemically bio-available as such but in form of phosphates). The 10 days NOAEL for maternal and developmental toxicity, following oral (gavage) exposure, in male/female CD-1 mouse was > or = 370 mg/kg bw/day and in male/female Wistar rats was > or = 410 mg/kg bw/day. The test was performed according to a method similar to OECD Guideline 414. The results showed no evidence of developmental toxicity to the foetus of any species or any other adverse effects to the foetus or mother at any dose level.

In conclusion, an additional two generation reproduction study on phosphoric acid or its salts in the rat is unlikely to result in providing further evidence of reproductive toxicity as the existing studies have demonstrated a lack of effect at dose levels well in excess of expected human exposure. A study would therefore be scientifically and ethically unjustified.


Short description of key information:
No screening for reproductive/developmental toxicity study is available. A developmental toxicity study on monosodium phosphate anhydrous on two species did not show toxicity for reproduction at doses levels of at least 370 mg/kg bw/day.Therefore a screening study is not considered needed.

Effects on developmental toxicity

Description of key information
For the developmental toxicity/teratogenicity endpoint, read-across with monosodium phosphate, anhydrous was done based on structural similarities and as shown in the toxicokinetic assessment (as soon as phosphoric acid reaches the blood system, it hydrolysis in phosphate and therefore, cannot become systemically bio-available as such but in form of phosphates). The 10 days NOAEL for maternal and developmental toxicity, following oral (gavage) exposure, in male/female CD-1 mouse was > or = 370 mg/kg bw/day and in male/female Wistar rats was > or = 410 mg/kg bw/day. The test was performed according to a method similar to OECD Guideline 414. 
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
no data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study similar/equivalent to OECD Guideline 414 with acceptable restrictions.
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
: CAS# and purity of test substance not provided; no mention of acclimization, minimal data on environmental conditions were included, no data on macroscopic examination of dams was provided.
GLP compliance:
no
Limit test:
no
Species:
mouse
Strain:
CD-1
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: adult
- Weight at study initiation: average body weight on day 0 ranged from 29-31 g
- Fasting period before study: no data
- Housing: gang-housed in disposable plastic cages
- Diet: ad libitum
- Water: tap water ad libitum
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): controlled
- Humidity (%): controlled
- Air changes (per hr): no data .
- Photoperiod (hrs dark / hrs light): no data


IN-LIFE DATES: From: no data To: no data
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Administered as a water suspension (10 mL per kg of body weight)



Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: One male was not permitted to impregnate more than one female per group
- Length of cohabitation: no data.
- Further matings after two unsuccessful attempts: no data
- Verification of same strain and source of both sexes: no data
- Proof of pregnancy: pesence of a vaginal plug was referred to as day 0 of pregnancy
Duration of treatment / exposure:
10 days (Females were dosed beginning on day 6 through day 15 of gestation)
Frequency of treatment:
Daily
Duration of test:
17 days ( Day 17 of gestation)
Remarks:
Doses / Concentrations:
3.7, 17.2, 79.7, and 370.0 mg/kg
Basis:
actual ingested
No. of animals per sex per dose:
25 females per test substance dose group, 27 animals in the positive control group
Control animals:
yes, sham-exposed
Details on study design:
The study also included a positive control (Aspirin) at 150 mg/kg
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Observed daily for appearance and behavior with particular attention to food consumption and weight, in order to rule out any abnormalities which may have occurred as a result of anorexic effects in the pregnant female animal.


BODY WEIGHT: Yes
- Time schedule for examinations: Recorded on days 0, 6, 11, 15 and 17 of gestation.


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 17
- Organs examined: urogenital tract of each dam was examined in detail for anatomical normality.


OTHER: Daily room temperature and humidity were recorded.
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 resorptions: Yes
- Other: The sex, number of live and dead fetuses and the body weights of the live pups were recorded.
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: 1/3 per litter underwent detailed visceral examinations employing the Wilson technique.
- Skeletal examinations: Yes: remaining 2/3 were cleared in potassium hydroxide (KOH), stained with alizarin red S dye and examined for skeletal defects.
- Head examinations: No data
Statistics:
no data
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No appreciable effects were identified on the average body weight of any of the dose groups.

No deleterious observational effects were noted.

No effects were identified in regard to the number of pregnancies, corpora lutea, live litters, implant sites, or resorptions between the test substance dose groups and the sham control treated group.
Dose descriptor:
NOAEL
Effect level:
>= 370 mg/kg bw/day
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEL
Effect level:
>= 370 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No effects were identified in regard to the number of live fetuses, dead fetuses or the average fetal weight between the test substance dose groups and the sham control treated group.
The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
The administration of up to 370 mg/kg (body weight) of the test material to pregnant mice for 10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
370 mg/kg bw/day
Study duration:
subacute
Species:
mouse
Quality of whole database:
Study similar/equivalent to OECD Guideline 414 with acceptable restrictions.
Additional information

Polyphosphoric acid is a mixture of the corresponding acids to phosphate anion and its condensed phosphates as follows:

- orthophosphoric acid or phosphoric acid (17 -76%),

- pyrophosphoric acid (23 -50%),

- triphosphoric acid (1.5 -25%),

- tetraphosphoric acid (0 -12%)

- and pentaphosphoric acid (0 -7%).

 

A condensed phosphate anion M(n+2)PnO(3n+1)has one or several P-O-P bonds and has been obtained by heating (dehydration). When the substance polyphosphoric acid is in contact of excess of water, a rapid hydrolysis is observed with the longer chains (tri, tetra or penta) while a very slow hydrolysis is observed for the dimer form to ortho phosphate. The pyrophosphate ion is the simplest form of a condensed phosphate group. As the group contains only two phosphate groups, both of the phosphorus ions are classified as “terminal phosphorus”. The pyrophosphate can undergo ionisation with loss of H+ from each of the two –OH groups on each P and therefore can occur in the -1, -2 -3 or -4 state. The degree of ionisation is dependant upon the associated cations (if there are) and the ambient pH (if in solution).

No partition coefficient value was determined for these substances as they are inorganic phosphates that are highly ionic (depending on ambient pH). Because of this ionic nature the passive passage across biological membranes will be negligible. Pyrophosphate is an anion that occurs in all living cells and is formed mainly by the synthesis of DNA from Nucleotide triphosphates (DNAn + Deoxyribonucleotide triphosphate → DNAn+1 + pyrophosphate). Usually it is cleaved rapidly into two orthophosphate molecules by one of the different members of the alkaline phosphatase family which are present in all tissues. Pyrophosphate nevertheless is generally relatively stable against uncatalyzed hydrolysis (half life = 10 d in autoclaved Flat branch sediment (Blanchar RW and Riego DC, 1975, Tripolyphosphate and pyrophosphate hydrolysis in sediments, Soil sci. soc.Am. J 40: 225-229)).

The Food and Drug Research Laboratories, Inc (1975) performed a prenatal developmental toxicity study with monosodium phosphate anhydrous in male/female CD-1 mouse and Wistar rats. Sham-exposed animals served as concurrent control. CD-1 mouse were exposed via gavage to doses of 3.7, 17.2, 79.7 and 370.0 mg/kg and Wistar rats to 4.1, 19.0, 88.3 and 410 mg/kg. A positive control substance (Aspirin 150 mg/kg for test with mouse and 250 mg/kg for test with rats) was included in the test.

The administration of up to 370 mg/kg (body weight) of the test material to pregnant mice for 10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls. The NOAEL was > or = 370 mg/kg bw/day for maternal and developmental toxicity. The administration of up to 410 mg/kg (body weight) of the test material to pregnant rats for 10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls. The NOAEL was > or = 410 mg/kg bw/day for maternal and developmental toxicity.

Justification for classification or non-classification

Based on the available data on phosphoric acid and its salts and according to the criteria laid down in the CLP Regulation, polyphosphoric acid should not be classified for reproductive toxicity.

Additional information