Disodium dihydrogenpyrophosphate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

No data

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 or copora 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

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1973

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 golden hamsters were mated with mature males (1:1). Observation of motile sperm in the vaginal smear 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 250 mg/kg) or test article in a water suspension at 1.66, 7.71, 35.8 and 166.0 mg/kg was carried out daily on Days 6 to 10 of gestation. Observations of body weight, appearence, behaviour, and food consumption were performed. On Day 14 of gestation all dams underwent Caesarean section. Implantation sites, resorption sites and live/dead foetuses recorded. Body weights of live pups recorded. Genital 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:

Disodium dihydrogenpyrophosphate

EC Number:

231-835-0

EC Name:

Disodium dihydrogenpyrophosphate

Cas Number:

7758-16-9

Molecular formula:

H4O7P2.2Na

IUPAC Name:

Sodium acid pyrophosphate

Details on test material:

- Name of test material (as cited in study report): FDA 71-61 (sodium acid pyrophosphate)
- Physical state: Fine white powdered material

Test animals

Species:

hamster

Strain:

other: Golden

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Outbred
- Age at study initiation: No data
- Weight at study initiation: 122.2 - 133.4 g
- Fasting period before study: No data
- Housing: Individually housed in mesh-bottomed 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): 1 mL/kg bw at doses equal to or below 250 mg/kg bw and 2 mL/kg at doses up to 500 mg/kg bw

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

- Impregnation procedure: 1:1 mating
- Proof of pregnancy: appearence of motile sperm in vaginal smear

Duration of treatment / exposure:

5 days (Day 6 to Day 10 of gestation)

Frequency of treatment:

Daily

Duration of test:

14 days

No. of animals per sex per dose:

Table 1 Number of animals dosed
Material Dose (mg/kg) Total
Mated Pregnant
Sham 0.0 22 20
Aspirin 250 22 21
FDA 71-81 1.66 22 20
7.71 24 20
35.8 22 21
166.0 22 22

Control animals:

yes, sham-exposed

other: positive control: 250 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, 8, 10 and 14.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 14
- Organs examined: uterus and genital 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
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: Yes

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)

Dose descriptor:

NOAEL

Effect level:

> 166 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

Maternal abnormalities

Abnormalities:

no effects observed

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

> 166 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects noted

Fetal abnormalities

Abnormalities:

no effects observed

Overall developmental toxicity

Developmental effects observed:

no

Any other information on results incl. tables

Table 2 Reproduction data

Dose (mg/kg)	Sham	Aspirin	1.66	7.71	35.8	166.0
Pregnancies
Total No.	20	21	20	20	21	22
Died or aborted (before Day 14)	0	0	0	0	1	1
To term (on Day 14)	20	21	20	20	20	21
Live litters
Total No.*	20	21	20	20	20	21
Implant Sites
Total No.	298	311	292	289	290	300
Average/dam*	14.9	14.8	14.6	14.5	14.5	14.3
Resorptions
Total No*	1	8	1	1	1	8
Dams with 1 or more sites resorbed	1	6	1	1	1	5
Dams with all sites resorbed	--	--	--	--	--	--
Per cent partial resorptions	5.00	28.6	5.00	5.00	5.00	23.8
Per cent complete resorptions	--	--	--	--	--	--
Live foetuses
Total No	295	303	291	288	289	292
Average/dam*	14.8	14.4	14.6	14.4	14.5	13.9
Sex ratio (M/F)	0.89	0.94	0.81	0.78	0.75	0.75
Dead Foetuses
Total No.*	2	--	--	--	--	--
Dams with 1 or more dead	2	--	--	--	--	--
Dams with all dead	--	--	--	--	--	--
Per cent partial dead	10.0	--	--	--	--	--
Per cent all dead	--	--	--	--	--	--
Average foetus weight (g)	1.70	1.72	1.72	1.82	1.82	1.75

* Includes only those dams examined at term

** Positive control: 250 mg/kg

 

Table 3 Summary of skeletal findings

Findings	Dose (mg/kg)
	Sham	Aspirin	1.66	7.71	35.8	166.0
Live foetuses examined (at term)	204/20	209/21	200/20	199/20	202/20	202/21
Sternebrae
Incomplete oss.	131/20	85/20	124/20	69/17	88/18	80/20
Scrambled
Bipartite	18/9	16/11	22/14	20/11	15/9	25/13
Fused
Extra	8/2		1/1	6/3	5/3
Missing	53/14	48/13	49/12	39/10	33/10	51/14
Other
Ribs
Incomplete oss.
Fused/split						2/1
Wavy
Less than 12
More than 13	62/17	56/13	46/16	69/17	38/13	60/16
Other
Vertebrae
Incomplete oss.	2/2	15/5		1/1		8/2
Scrambled
Fused
Extra ctrs. oss.
Scoliosis
Tail defects
Other
Skull
Incomplete closure
Missing
Craniostosis
Other
Extremities
Incomplete oss.	4/4	17/6		6/4		13/3
Missing
Extra
Miscellaneous
Hyoid; missing	6/6	14/6	5/4	4/2	2/1	13/3
Hyoid; reduced	7/7	6/5	9/7	7/3	6/5	8/6

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

** Positive control: 250 mg/kg

 

Table 4 Summary of soft tissue abnormalities

Material	Dose level (mg/kg)	Dam	Number of pups	Description
Sham	0.0	S 5908	1	Meningoencephalocele
		S 5914	1	Hydrocephalus
Aspirin	250.0	A 5912	1	Hepatomegaly
FDA 71-61	1.66	M 5013	1	Hydrocephalus
FDA 71-61	166.0	M 5092	4	Hydrocephalus
			2	Hydromyelia

Applicant's summary and conclusion

Conclusions:

Under the conditions of the study, the test material administered to pregnant hamsters for 5 days up to a dose level of 166 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and fetotoxicity is > 166 mg/kg bw.