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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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study.

Data source

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

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Qualifier:
according to
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): sodium formate
- Physical state: solid/crystalline
- Analytical purity: >99%.
- Storage: at room temperature under nitrogen

Test animals

Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
Animals
- Species: rat.
- Strain: Wistar.
- Sex: female.
- Age: 70-84 days at gestational day 0.
- Body weight: 141-202  grams on gestational day 0.
- Housing: singly in stainless steel wire mesh cages.
- Diet: ground Kliba maintenance diet rat/mouse and water ad libitum.

- Environment: fully air-conditioned rooms.
- Temperature range 20-24°C, relative humidity 30-70%.
- Dark/light cycle: 12/12 hours

Administration / exposure

Route of administration:
oral: gavage
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

The aqueous test substance solutions were prepared at the beginning of the administration period and thereafter at intervals which
took into account the analytical results of the stability verification . For the preparation of the solutions, an appropriate amount of the
test substance was weighed in a graduated measuring flask, topped up with doubly distilled water and subsequently thoroughly mixed
using a magnetic stirrer .


Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
HPLC with UV detection
Details on mating procedure:
- Mating: time-mated by the breeder.
Duration of treatment / exposure:
gestational days 6-19
Frequency of treatment:
7/week
Duration of test:
17 days
No. of animals per sex per dose:
25 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Due to technical reasons the study was conducted in three replicates.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: clinical symptoms and mortality: at least daily
- Cage side observations checked were included (Part A, Table IA-001).


DETAILED CLINICAL OBSERVATIONS: No


BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed on days 0, 1, 3, 6, 8, 10, 13, 15, 17, 19 and 20 p .c . . The body
weight change of the animals was calculated from these results.


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Parameters examined: gross pathology. Determination corrected body weight
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other:
- Placenta weight: Yes
- Number of live and dead fetuses: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No

Other:
fetal weight
Sex distribution
Statistics:
Statistical evaluation included the use of Dunnett's test, Fisher's exact test, and of the Wilcoxon test.
Historical control data:
Report Volume III, tables IIIB-001-IIIB-019

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No clinical signs of toxicty, no mortalities, food consumption and body weight not affected. Mean gravid uterus weight and reproduction data (concenption rate, corpora lutea, pre- and postimplantation loss, number of viable fetuses) not affected at any dose level. No findings at necropsy.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
945 mg/kg bw/day (actual dose received)
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Placenta weight, fetal weight, sex distribution not affected. External malformations inside historical control range; no soft tissue or skeletal malformations. Incidence and type of variations does not suggest a treatment-related effect at any dose level.

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEL
Effect level:
945 mg/kg bw/day (actual dose received)
Basis for effect level:
other: embryotoxicity
Dose descriptor:
NOAEL
Effect level:
945 mg/kg bw/day (actual dose received)
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables


EXAMINATION OF THE DAMS
Only pregnant dams were used for calculations. The number of pregnant  animals per group was as follows:
Table 1: dose levels and number of tested animals

==============================================
Group      Dose                number of
           (mg/kg bw /day)     pregnant animals
---------------------------------------------- 
0              0                  24           
1             59                  25
2            236                  23
3            945                  24 
============================================== 

Mortalities:  none in any of the groups.
Clinical signs: none in any of the groups.
Food consumption: similar across all groups, no difference in treated  groups compared to the control group.
Body weights: similar across all groups, no difference in treated groups  compared to the control group.
Corrected body weight gain (terminal body weight minus weight of the  unopened uterus minus body weight on gestational day 6): no difference 

of  biological relevance in treated groups compared to the control group.
Mean carcass weights: similar among all test groups 0-3.

Terminal examinations of dams:
Uterus weight: the mean gravid uterus weight of the treated test groups  1, 2, and 3 was not influenced by the treatment. The differences 

between  these groups and the control group revealed no dose-dependency and were  without biological relevance.

Necropsy findings: none.

Reproduction data: Conception rates were not affected by treatment. 

Table 2: conception rate
==============================================
Group      Dose                Conception rate
           (mg/kg bw /day)         (%)
---------------------------------------------- 
0              0                  96           
1             59                 100
2            236                  92
3            945                  96 
============================================== 

There were no substance-related and/or biologically significant  differences among the test group in the conception rate, the mean number  of corpora lutea and implantation sites, or in the values calculated for  the pre- and postimplantation losses as well as the number of resorptions  and viable fetuses.

EXAMINATION OF THE FETUSES

Sex distribution : nor affected.
Weight of placentae: mean weights in treated groups comparable to the  control group.
Fetal weight: mean weights in treated groups comparable to the control  group.

External examinations
External malformations were within the historical control range. There  was no external variation recorded in any of the fetuses.
Table 3: Incidence of external malformations

==============================================
Group      Dose             External malformations
           (mg/kg bw /day)    (incidence / %)
---------------------------------------------- 
0              0             0/213 fetuses / 0%          
1             59             0/220 fetuses / 0% 
2            236             0/212 fetuses / 0% 
3            945             1/212 fetuses / 0.5%
============================================== 

Soft tissue examinations
No soft tissue malformation was recorded for any of the fetuses.
Two soft tissue variations (uni- or bilateral dilatation of the renal  pelvis with or without dilated ureter) were detected in each group  including 

the controls without any dose-relationship.

Table 4: Incidence of soft tisue variations

==============================================
Group      Dose             Soft tissue variations
           (mg/kg bw /day)           (%)
---------------------------------------------- 
0              0                    5.6         
1             59                    3.6
2            236                    6.1 
3            945                    1.7
============================================== 

Skeletal examinations

There were no skeletal malformations in treated fetuses.

Table 5: Incidence of skeletal malformations

=====================================================
Group      Dose             Skeletal malformations
           (mg/kg bw /day)      (incidence / %)
----------------------------------------------------- 
0              0               1/113 fetuses / 0.9%        
1             59               0/116 fetuses / 0%
2            236               0/113 fetuses / 0% 
3            945               0/109 fetuses / 0%

===================================================== 
The incidence of skeletal variations does not suggest a treatment-related  effect. 

The observed pattern of skeletal variations was not different from that  seen in the historical controls. The scattered occurrence of  statistically 

significant differences compared to the control group was  not dose-related and not considered to be of toxicological relevance.


Table 6: Incidence of skeletal variations

=====================================================
Group      Dose             Skeletal variations
           (mg/kg bw /day)        (%)
----------------------------------------------------- 
0              0                   96.9%        
1             59                   91.4%
2            236                   96.7%
3            945                   96.7%
===================================================== 

Applicant's summary and conclusion

Conclusions:
No maternal toxicity, no embryo-/fetal toxicity or teratogenicity at any dose including the top dose, 945 mg/kg bw/day.
Executive summary:

 

Conclusion:

In a developmental study, time-mated female rats (25/dose, OECD TG 414) were given NaFo (sodium formate) via oral gavage at 0, 59, 236, and 945 mg/kg bw/day during gestation days 6 to 19.  Maternal toxicity was not seen. Gestational parameters were not influenced and there were no effects on the developing fetuses.  No malformations or skeletal variations were seen.  The NOAEL for maternal and developmental toxicity was 945 mg sodium formate/kg bw/day, the highest dose tested. 

 

The developmental toxicity study in the rabbit is classified acceptable and satisfies the guideline requirement for a developmental toxicity study (OECD 414) in rats.

 

Generally, formate salts are used as test material in studies requiring repeated dosing, due to the corrosivity of formic acid. NOAEL values obtained in such studies may be used to calculate the NOAEL for the formate anion which may be read across to other salts or formic acid, taking into account stoichiometry and formula weights. For the ease of the reader, this is tabulated below (calculation in brackets).

 

Table: calculation of NOAEL values

 

 

Formula

weight

NOAEL
maternal toxicity

NOAEL
developmental toxicity

NOAEL
teratogenicity

 

(mg/kg bw/day)

Sodium formate

69

945

945

945

Formate anion

45

616
(945/69x45)

616
(945/69x45)

616
(945/69x45)

Formic acid

46

630
(945/69x46)

630
(945/69x46)

630
(945/69x46)