Disodium fluorophosphate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

06/10/1974 - 02/11/1974

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

Meets generally accepted scientific standards with acceptable restrictions. Deficiencies: Food consumption not reported Uterine weights not determined One third used for visceral examination; should be 50% Test substance identification (Batch etc) missing No details on housing conditions/source of animals Administration only during periods of organogenesis, not until day before pregnancy This study is considered to be acceptable and to adequately satisfy both the guideline requirement and the regulatory requirement for this endpoint as supporting data in accordance with Regulation EC No. 1907/2006. This data is submitted to support the argument that the sodium and phosphate content of disodium fluorophosphate will not induce a developmental toxicity effect.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1975

Report date:

1975

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: no data

Deviations:

not specified

Principles of method if other than guideline:

Adult female albino CD-1 mice were mated with young adult males. Observation of a vaginal sperm plug was considered as Day 0 of gestation. Dosing by oral intubation with a control (Vehicle at level equivalent to group receiving the highest dose or aspirin at 150 mg/kg) or test article in a water suspension (10 mL/kg bw) at 3.7, 17.2, 79.7 or 370.0 mg/kg was carried out daily on Days 6 to 15 of gestation. Observations of body weight, appearence, behaviour, and food consumption were performed. Daily room temperature and humidity were recorded. On Day 17 of gestation all dams underwent Caesarean section. Sex, number of corpora lutea, implantation sites, resorption sites and live/dead foetuses recorded. Body weights of live pups recorded. Urogenital tract of each dam examined for anatomical normality. All foetuses examined grossly for presence of external congenital abnormalities. One third foetuses of each litter underwent detailed visceral examination and the remaining two thirds were cleared in potassium hydroxide, stained with alizarin red S dye and examined for skeletal defects.

GLP compliance:

no

Remarks:

Study predates GLP

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Sodium dihydrogenorthophosphate

EC Number:

231-449-2

EC Name:

Sodium dihydrogenorthophosphate

Cas Number:

7558-80-7

Molecular formula:

H3O4P.Na

IUPAC Name:

sodium dihydrogen phosphate

Details on test material:

- Name of test material (as cited in study report): FDA 73-2 (Monosodium phosphate, anhydrous)
- Physical state: Fine white powdered material

Test animals

Species:

mouse

Strain:

other: albino CD-1

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Outbred
- Age at study initiation: No data
- Weight at study initiation: 29 - 31 g
- Fasting period before study: No data
- Housing: Gang housing in disposable plastic cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: No data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): ave 21 - 26
- Humidity (%): 42 - 74%

IN-LIFE DATES: From: 06/10/1974 To: 02/11/1974

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
VEHICLE: Water
- Amount of vehicle (if gavage): 10 mL/kg bodyweight

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

- Impregnation procedure: cohoused
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy

Duration of treatment / exposure:

10 days (Day 6 to Day 15 of gestation)

Frequency of treatment:

Daily

Duration of test:

17 days

No. of animals per sex per dose:

Test material and vehicle control: 25 females / dose level
Positive control: 27 females
Table 1 Number of animals dosed
Material Dose (mg/kg) Total
Mated Pregnant
Sham 0.0 25 21
Aspirin 150.0 27 20
FDA 73-2 3.7 25 22
17.2 25 19
79.7 25 20
370.0 25 22

Control animals:

yes, sham-exposed

other: positive control: 150 mg/kg aspirin

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Appearence, behaviour, food consumption and weight observed daily.
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: Body weights recorded on days 0, 6, 11, 15 and 17.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 17
- Organs examined: uterus and urogenital tract

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes

Fetal examinations:

- External examinations: Yes: one third per litter
- Soft tissue examinations: Yes: one third per litter
- Skeletal examinations: Yes: two thirds per litter
- Head examinations: Yes: two thirds per litter

Statistics:

No data

Indices:

No data

Historical control data:

No

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

> 370 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

> 370 mg/kg bw/day

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Table 2 Reproduction data

Dose (mg/kg)	Sham	Aspirin	3.7	17.2	79.7	370.0
Pregnancies
Total No.	21	20	22	19	20	22
Died or aborted (before Day 17)	0	0	0	0	0	0
To term (on Day 17)	21	20	22	19	20	22
Corpora Lutea
Total no.	275	233	255	233	251	279
Average/dam mated	11.0	8.63	10.2	9.32	10.0	11.2
Live litters
Total No.*	21	20	22	19	20	22
Implant Sites
Total No.	259	218	240	224	236	255
Average/dam*	12.3	10.9	10.9	11.8	11.8	11.6
Resorptions
Total No*	8	8	5	9	10	13
Dams with 1 or more sites resorbed	8	6	5	4	9	11
Dams with all sites resorbed	--	--	--	--	--	--
Per cent partial resorptions	38.1	30.0	22.7	21.1	45.0	50.0
Per cent complete resorptions	--	--	--	--	--	--
Live foetuses				215
Total No	248	208	233	11.3	224	240
Average/dam*	11.8	10.4	10.6	1.01	11.2	10.9
Sex ratio (M/F)	1.04	0.84	0.82		0.84	1.07
Dead Foetuses				--
Total No.*	3	2	2	--	2	2
Dams with 1 or more dead	3	1	2	--	2	2
Dams with all dead	--	--	--	--	--	--
Per cent partial dead	14.3	5.00	9.09	--	10.0	9.09
Per cent all dead	--	--	--	--	--	--
Average foetus weight (g)	0.8	0.85	0.85	0.92	0.93	0.86

* Includes only those dams examined at term

** Positive control: 150 mg/kg

 

Table 3 Summary of skeletal findings

Findings	Dose (mg/kg)
	Sham	Aspirin	3.7	17.2	79.7	370.0
Live foetuses examined (at term)	173/21	144/20	165/22	148/149	156/20	167/22
Sternebrae
Incomplete oss.	60/19	65/19	32/14	51/16	13/5	81/19
Scrambled
Bipartite		1/1		3/2		3/2
Fused
Extra
Missing	39/12	36/11	19/9	13/7	2/2	20/12
Other
Ribs
Incomplete oss.
Fused/split				1/1
Wavy
Less than 12
More than 13	23/10	32/14	23/12	25/10	30/16	25/15
Other
Vertebrae
Incomplete oss.	4/2	11/5	4/3	1/1
Scrambled
Fused
Extra ctrs. oss.
Scoliosis
Tail defects
Other
Skull
Incomplete closure	2/2
Missing
Craniostosis
Other
Extremities
Incomplete oss.	6/4	15/5	2/2	1/1		1/1
Missing
Extra
Miscellaneous
Hyoid; missing	30/12	60/16	24/12	26/11	27/11	43/15
Hyoid; reduced	26/12	18/13	22/13	26/16	19/10	22/14

* Numerator = Number of foetuses affected; Denominator = Number of litters affected

** Positive control: 150 mg/kg

Summary of soft tissue abnormalities: 1 pup from a litter where the dam was dosed with 3.7 mg/kg test material showed exophthalmos and encephalmeningocele.

Applicant's summary and conclusion

Conclusions:

Under the conditions of the study, the test material administered to pregnant mice for 10 days up to a dose level of 370 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and foetoxicity is > 370 mg/kg bw.

This study is considered to be acceptable and to adequately satisfy both the guideline requirement and the regulatory requirement for this endpoint as supporting data in accordance with Regulation EC No. 1907/2006. This data is submitted to support the argument that the sodium and phosphate content of disodium fluorophosphate will not induce a developmental toxicity effect.

This study is considered to be of adequate reliability and relevance to be submitted as supporting data for this endpoint.