Aluminium dihydrogen triphosphate

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:

key study

Study period:

No data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Meets generally accepted scientific standards with acceptable restrictions. Deficiencies: Food consumption not reported Uterine weights and corpora lutea 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 JUSTIFICATION FOR READ ACROSS; calcium and magnesium orthophosphates. The following substances are considered to be similar enough to facilitate read across for systemic toxicity endpoints: Calcium bis(dihydrogenorthophosohate, EC No: 231-837-1 Calcium hydrogenorthophosphate. EC No: 231-826-1 Tricalcium bis(orthophosphate), EC No: 231-840-8 Pentacalcium hydroxide tris(orthophosphate), EC No: 235-330-6 Magnesium hydrogenorthophosphate, EC No: 231-823-5 Trimagnesium bis(orthophosphate), EC No. 231-824-0 Magnesium bis(dihydrogenorthophosphate), EC No. 236-004-6 All of the above substances have exhibited similar toxicity in acute oral and dermal studies. Read across is justified on the following basis: 1. Low systemic toxicity in acute oral studies. A number of studies are provided to show that calcium and/or magnesium inorganic orthophosphates exhibit low acute oral toxicity. These data are provided in Section 7.2.1 of this dossier. The information provided in these records is considered to be of suitable relevance and reliability to underpin the read across for the acute dermal and inhalation endpoints. 2. Substance similarities All substances are ionic and will readily dissociate to their ionic forms in aqueous environments. The orthophosphate ion can under go ionisation with loss of H+from each of the three –OH groups and therefore can occur in the -1, -2 or -3. The degree of ionisation is dependant upon the associated cation and the ambient pH (if in solution). The ionic form of the Group 1ii alkali metals is M2+.Calcium, magnesium and phosphate are key elements in various cellular processes their import and export over cell membranes is regulated via pore systems and usually tightly regulated. Orthophosphate salts of these types are not considered to differ in their systemic toxicity profiles. Differences arise in their local effects profile due differences in pH and buffering capacities. This does not have an effect on systemic toxicity.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1974

Report date:

1973

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 4.65, 21.6, 100.0 and 465.0 mg/kg was carried out daily on Days 6 to 15 of gestation. Observations of body weight, appearence, behaviour, and food consumption were performed. On Day 17 of gestation all dams underwent Caesarean section. 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:

calcium dihydrogenorthophosphate monohydrate

IUPAC Name:

calcium dihydrogenorthophosphate monohydrate

Constituent 2

Reference substance name:

10031-30-8

EC Number:

600-059-8

Cas Number:

10031-30-8

IUPAC Name:

10031-30-8

Details on test material:

- Name of test material (as cited in study report): FDA 71-81 (Monocalcium phosphate; monohydrate)
- Physical state: Fine white crystalline 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: 29.2 - 30.6 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): No data
- Humidity (%): No data

IN-LIFE DATES: No data

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

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
4.65 mg/kg
Basis:
nominal in water

Doses / concentrations 2

Remarks:

Doses / Concentrations:
21.6 mg/kg
Basis:
nominal in water

Doses / concentrations 3

Remarks:

Doses / Concentrations:
100.0 mg/kg
Basis:
nominal in water

Doses / concentrations 4

Remarks:

Doses / Concentrations:
465.0 mg/kg
Basis:
nominal in water

No. of animals per sex per dose:

Table 1 Number of animals dosed
Material Dose (mg/kg) Total
Mated Pregnant
Sham 0.0 25 22
Aspirin 150.0 25 20
FDA 71-81 4.65 25 24
21.6 26 19
100.0 23 22
465.0 25 23

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: No
- 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:

> 465 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

> 465 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	4.65	21.6	100.0	465.0
Pregnancies
Total No.	22	20	24	19	22	23
Died or aborted (before Day 17)	0	1	0	0	0	0
To term (on Day 17)	22	19	24	19	22	23
Live litters
Total No.*	22	19	24	19	22	22
Implant Sites
Total No.	261	224	283	225	244	265
Average/dam*	11.9	11.8	11.8	11.8	11.1	11.5
Resorptions
Total No*	8	20	19	4	12	28
Dams with 1 or more sites resorbed	7	9	13	3	10	12
Dams with all sites resorbed	--	--	--	--	--	1
Per cent partial resorptions	31.8	47.4	54.2	15.8	45.5	52.2
Per cent complete resorptions	--	--	--	--	--	4.35
Live foetuses
Total No	252	201	261	221	230	233
Average/dam*	11.5	10.6	10.9	11.6	10.5	10.1
Sex ratio (M/F)	1.02	0.88	0.78	0.92	1.13	0.93
Dead Foetuses
Total No.*	1	3	--	--	2	4
Dams with 1 or more dead	1	3	--	--	2	3
Dams with all dead	--	--	--	--	--	--
Per cent partial dead	4.55	15.8	--	--	9.09	13.0
Per cent all dead	--	--	--	--	--	--
Average foetus weight (g)	0.84	0.81	0.88	0.87	0.82	0.85

* Includes only those dams examined at term

** Positive control: 150 mg/kg

 

Table 3 Summary of skeletal findings

Findings	Dose (mg/kg)
	Sham	Aspirin	4.65	21.6	100.0	465.0
Live foetuses examined (at term)	179/22	141/19	186/24	155/19	162/22	164/22
Sternebrae
Incomplete oss.	10/8	31/10	18/9	27/15	22/10	28/15
Scrambled
Bipartite	8/7	3/3	11/8	9/7	10/8	9/6
Fused
Extra		6/3
Missing	23/10	28/11	13/9	13/6	32/14	23/7
Other
Ribs
Incomplete oss.						9/4
Fused/split		2/2
Wavy		1/1	2/2
Less than 12	1/1		1/1			1/1
More than 13	48/18	30/12	42/18	18/11	32/15	34/17
Other
Vertebrae
Incomplete oss.	9/6	9/3	2/2	1/1	11/4	13/4
Scrambled
Fused
Extra ctrs. oss.
Scoliosis
Tail defects
Other
Skull
Incomplete closure		2/2
Missing			1/1
Craniostosis
Other; facial bones, inc						2/1
Extremities
Incomplete oss.	7/5	5/3	2/2		10/5	14/4
Missing
Extra
Miscellaneous
Hyoid; missing	37/16	33/11	31/15	22/12	52/15	33/13
Hyoid; reduced	17/11	25/12	17/11	21/14	15/11	27/14

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

** Positive control: 150 mg/kg

 

Table 4 Summary of soft tissue abnormalities

Material	Dose level (mg/kg)	Dam	Number of pups	Description
Aspirin	150.0	A 6068	1	Cleft palate; gastroschisis

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 465 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and developmental toxicity is > 465 mg/kg bw.