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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study is conducted to an appropriate guideline and under the conditions of GLP. The reliability has been amended (from reliability 1 to 2) to reflect the use of this study for read across. Read across justification: sodium and potassium orthophosphates. The following substances are considered to be similar enough to facilitate read across for systemic toxicity endpoints: Sodium dihydrogenorthophosphate, CAS: 7558-80-7 Disodium hydrogenorthophosphate, CAS: 7558-79-4 Trisodium orthophosphate, CAS: 7601-54-9 Potassium dihydrogenorthophosphate, CAS: 7778-77-0 Dipotassium hydrogenorthophosphate, CAS: 7758-11-4 Tripotassium orthophosphate, CAS: 7778-53-2 Potassium pentahydrogen bis(phosphate), CAS: 14887-42-4 All members of the group are structurally similar ionic inorganic compounds with the anion only changing by the number of hydrogen atoms to account for changes in charge due to increase in cation numbers. Progression through the group sees an increase in cation number from one to three followed by a change in cation from sodium to potassium and again an increase in number from one to three. Both cations are group 1 alkali metals with the same ionic charge, similar chemical behaviour and both sodium and calcium are essential biological elements. Both the Na+ and the K+ cation have a similar biological function and therefore orthophosphate salts of these types are not considered to differ in their systemic toxicity profile. No members of the group are classified for acute toxicity and generally exhibited no mortalities at the classification limit. Two members of the group are classified for local effects only (i.e. skin/eye irritation) which will not have an impact on the systemic toxicity of the compounds and all are highly water soluble. Read-across between these substances has also been justified for repeated dose toxicity.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report Date:
2005

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Potassium phosphate, dibasic (CAS No. 7758-11-4)
- Physical state: solid (messed colourless powder)
- Analytical purity: 1158906: 99.5%, 1118496:99.6%
- Impurities (identity and concentrations): See Appendix 21 for Certificate of Analysis
- Composition of test material, percentage of components: See Appendix 21 for Certificate of Analysis
- Purity test date: No data
- Lot/batch No.: 1158906, 1118496
- Storage condition of test material: Normal temperature, dehumidify
- Other: pH: 9.2

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Orient Co., Ltd
- Age at study initiation: 7 weeks
- Housing: Stainless steel wire cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 8 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C):21.5 - 25°C
- Humidity (%): 41.8 ± 68.7%
- Air changes (per hr): 10- 15 times per hr
- Photoperiod (hrs dark / hrs light): lighting: 12 hrs per day




Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Solution of test substance was prepared daily by suspending in water for injection after measurement of expected test substances expected consumption. Stability and homogeneity analysis of prepared test substance were not conducted after agreement with sponsor.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
Mating period was a 2 week period. Males and females were mated at a 1:1 ratio in each cage. Coitus was confirmed by dropping of vaginal plug at every morning and afternoon. Gestation day 0 was determined to be the coitus confirmation day.
Duration of treatment / exposure:
2 weeks before copulation to 4 days after parturition in female rats.
2 weeks before copulation to 2 weeks after copulation in male rats.

Frequency of treatment:
Daily (number of applications is not clearly defined in study report)

Doses / concentrations
Remarks:
Doses / Concentrations:
1000 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
22 Males and 22 Females in the control and test groups

Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Once a day, 30 minutes after mating
- Cage side observations checked in tables 2.1-2.2 were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once a day, 30 minutes after mating

BODY WEIGHT: Yes
- Time schedule for examinations: Female: Once a week during first administration, day 1 of dosing, gestational days 0, 7, 14, 20 and potst-partum days 0, 4 and just before necropsy.
Males: Once a week during first administration and just before necropsy

Bodyweights were not measure during mating period.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day:.Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Female: Food consumption, was measured once a week after first administration involved the day before administration, food and water were supplied in gestational day 0, 6, 13, 19 and postpartum day 0, 3 and residue was measured in the next day.
Male: Food consumption was measured once a week after first administration involved the day. Before administration, food and water were supplied in coitus confirm day and the day before necropsy, residue was measured in the next day.
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 early resorptions: No data
- Number of late resorptions: No data
Fetal examinations:
- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: Yes
Statistics:
The Levene’s test was conducted to compare the homogeneity of the variance for the data collected from the examinations of the body weight, food and water consumption, haematology, blood chemistry, organ weight, and body weight and crown lump length of neonates. If the variance is homogenous, one-way ANOVA test was performed and if the results showed significance, Dunnets T-test was conducted to find out significance. If the variance was homogeneity after repeat Levene’s test about transformed data, one-way ANOVA test was carried out and if the results showed significance, Dunnets T-test was conducted to find out significance.


Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
PRE AND POST IMPLANTATION LOSS (Table 17 and Appendix 17)
In the control and treatment group, group pre-implantation loss rates by calculation of numbers of corpus lutea verum and implantation sites were 43.59 and 42.54%. Individual pre-implantation loss rates were 39.96 and 39.99%. Group post-implantation loss rates were 6.82 and 4.76%. Individual pre-implantation loss rates were 7.77 and 4.60%.

OBSERVATIONS OF NEONATES (Tables, 18, 19, 20 and Appendix 18, 19-1, 19-2, 19-3, 19-4, 20 and Figures 7, 8, 9 and 10)
Mean litter sizes (No.) were 12.8 and 13.8, birth rates were 98.5 and 97.3%, postpartum 0 days survival rates were 100%, postpartum 4 days survival rates were 99.5% and 99.1%, sex ratio in postpartum 0 and 4 days body weight and crown lump length. There was no abnormalities about external examination of neonates in control and treatment groups.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
It is considered that the NOAEL for reproductive parameters of the parent animals (fertility) and the development of neonates is 1000 mg/kg bw because all animals in the control and treatment groups were successful in mating, pregnancy and parturition. No effects on neonatal development were noted.