Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
two-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2007-Jan-09 through 2007-May-22
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3800 (Reproduction and Fertility Effects)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.35 (Two-Generation Reproduction Toxicity Test)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): Sodium formate
- Physical state: solid
- Analytical purity: 100%
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH.
- Age at study initiation: (P) 7 wks
- Weight at study initiation: (P) Males: men 108.0 g; Females: mean 96.0 g
- Fasting period before study: ovenight; feed study
- Housing: individually in Macrolon type M III cages supplied by Becker & Co., Castrop-Rauxel, Germany (floor area of about 800 cm²)
- Diet: ground Kliba maintenance diet mouse/rat “GLP” meal, supplied by Provimi Kliba SA, Kaiseraugst, Switzerland, was available ad libitum
throughout the study.
- Water: tap water ad libitum
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: feed
Vehicle:
other: food
Details on exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): ground standard diet
- Storage temperature: room temperature
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: maximum two weeks
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Commercial test kit "Ameisensäure"; enzymatic test with UV/vis detection at 340 nm. Details: Study Part III, p. 882
Duration of treatment / exposure:
Exposure period: throughout the study
F0 and F1 generation: 75 days premating exposure; during mating and gestation until post natal day (PND) 21
Frequency of treatment:
daily
Details on study schedule:
- F1 parental animals not mated until 10 weeks after selected from the F1 litters.
Dose / conc.:
100 mg/kg bw/day (nominal)
Remarks:
Based on diet
Dose / conc.:
300 mg/kg bw/day (nominal)
Remarks:
Based on diet
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Remarks:
Based on diet
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on results of preceding studies
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: A check for moribund or dead animals was made twice daily on working days or once daily
(Saturday, Sunday or on public holidays).


DETAILED CLINICAL OBSERVATIONS: Yes
- Tim eschedule: daily


BODY WEIGHT: Yes
- Time schedule for examinations: weekly


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: Yes
Oestrous cyclicity (parental animals):
Estrous cycle length and normality were evaluated daily for all F0 and F1 female parental rats for a minimum of 3 weeks prior to mating. The evaluations were continued throughout the mating period until the female exhibited evidence of mating. Moreover, at the scheduled necropsy a vaginal smear was microscopically examined to determine the stage of the estrous cycle for each F0 and F1 female.
Sperm parameters (parental animals):
Parameters examined in [all/P/F1/F2] male parental generations:
testis weight, epididymis weight, sperm count in testes and in epididymides, sperm motility, sperm morphology
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 8 pups/litter (4/sex/litter as nearly as possible); excess pups were killed and discarded.


PARAMETERS EXAMINED
The following parameters were examined in F1 and F2 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight at birth and weight gain, physical or behavioural abnormalities, sexual maturation (vaginal openng, preputial separation).


GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was not determined for pups born or found dead. Determinationof pup organweight (brain, spleen, thymus).
Postmortem examinations (parental animals):
SACRIFICE
F0 and F1 animals:
- Male animals: All surviving animals after the F1 or F2 pups were weaned (PND 21).
- Maternal animals: All surviving animals after the F1 or F2 pups were weaned (PND 21).


GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in section 3.9.2 (page 51) were weighed and those in section 3.9.3 (page 52) were prepared for microscopic examination.
Tissues examined by light microscopy are tabulated in section 3.9.4.
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring not selected as parental animals were sacrificed at 4 days of age and all F2 offspring were sacrificed at 21 days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:


GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.


HISTOPATHOLOGY / ORGAN WEIGTHS
Brain, spleen, and thymus were weighed.
Statistics:
Extensive statistical evaaluations included Dunnett test; Fisher's exact test; Wilcoxon test; Kruskal-Wallis test (cf. report, section 3.8.3)
Reproductive indices:
Male mating index; male fertility index. Female mating index; female fertility index; gestation index. Live birth index; postimplantation loss.
Offspring viability indices:
Viability index day 4. Lactation index (viability on day 21)
Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
effects observed, treatment-related
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No findings in F0 and and F1 parental animals noted.


BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
No changes in F0 and and F1 parental animals noted.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
The mean test substance intake was close to the nominal values:
F0 males: 93 / 282 / 939 mg/kg bw/day in treated groups
F0 females: 97 / 291 / 977 mg/kg bw/day in treated groups

F1 males: 91 / 266 / 949 mg/kg bw/day in treated groups
F2 females: 98 / 295 / 980 mg/kg bw/day in treated groups


REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
No effect in F0 females (section 4.2.1.6) or F1 females (section 4.2.36)


REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
No treatment-related effct in F0 males (section 4.2.1.8) or F1 males (section 4.2.3.8)

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
No effect in male or female F0 and F1 animals

F0 animals:
Males:
The male mating index varied between 96% in the control and 100% in the test groups.
The male fertility index ranged between 92% and 100% without showing any effect of dosing.
Females:
The female mating index calculated after the mating period for F1 litter was 96% in the control group and 100% in test groups 01-03 (100, 300 and 1000 mg/kg bw/d).
The mean duration until sperm was detected (GD 0) varied between 4.4 and 5.6 days without any relation to dosing. The fertility index was 96% in test group 01, 92% in test group 02 and 100% in test groups 00 and 03. The mean duration of gestation varied between 22.0 and 22.2 days without any relation to dosing.
The gestation index was 100% for all test groups, indicating that all pregnant F0 females had live F1 pups in their litters. There were no statistically significant differences in postimplantation loss between the test groups and the control (see Tab. IA-028). The live birth index was 99%, 99%, 100% and 99% in test groups 00-03.

F1 parental aimals
Males:
The male mating index was 96% in the low-dose group and 100% in the remaining test groups.
The male fertility index ranged between 92% and 100% without showing any effect of dosing.

Females: The female mating index for the F2 litter was 96% in test group 11 (100 mg/kg bw/d) and 100% in test groups 10, 12 and 13 (0, 300 and 1000 mg/kg bw/d).
The fertility index was 92% in the control and 100% in the remaining test groups.
The gestation index was 100% in all test groups, indicating that all pregnant F1 females had live F2 pups in their litters. The mean duration of gestation was very similar in all F1 test groups and varied between 21.8 and 22.0 days, with no relation to dosing.
There were no statistically significant differences of postimplantation loss between the test and the control groups.
The live birth index varied between 99% (test group 10) and 100% (test groups 11, 12 and 13).
ORGAN WEIGHTS (PARENTAL ANIMALS)
F0 animals:
Mean absolute organ weight parameters did not show significant differences compared to the control groups. In females, the mean relative weights of the brain, kidneys, and ovaries significantly changed (up to p<0.01), but were attributed to the slight reduction of the terminal body weight.

F1 animals:
Some significant changes (increase and reduction) of the absolute and relative weight were seen (kidneys, liver, pituitary gland, cauda epididymis affected; cf. section 4.3.2). There was no relation to dose or histopathological correlate.

GROSS PATHOLOGY and HISTOPATHOLOGY (PARENTAL ANIMALS)
F0 animals:
No changes noted (section 4.3.1)
F1 animals:
No changes apart from incidental glandular stomach erosion/ulcer in one control and eight mid dose animals.


OTHER FINDINGS (PARENTAL ANIMALS)

Sperm parameters: unchanged.
Estrous cycle data: no treatment-related change noted.
Dose descriptor:
NOAEL
Remarks:
reproduction
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effect on reproductive performance and reproductive organs of F0 animals.
Dose descriptor:
NOAEL
Remarks:
reproduction
Effect level:
1 292 mg/kg bw/day
Based on:
other: read across to potassium formate
Sex:
male/female
Basis for effect level:
other: No adverse effect on reproductive performance and reproductive organs of F0 animals wth sodium formate
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
VIABILITY (OFFSPRING)

F1 pups:
The viability index indicating pup mortality during early lactation (PND 0-4) varied between 98% (test group 03 – 1000 mg/kg bw/d) and 99% (test groups 00, 01 and 02 – 0, 100 and 300 mg/kg bw/d).
The lactation index indicating pup mortality on PND 4-21 varied between 99% (test group 02 – 300 mg/kg bw/d) and 100% (test groups 00, 01 and 03 – 0, 100 and 1000 mg/kg bw/d).

F2 pups:
The viability index indicating pup mortality during early lactation (PND 0-4) varied between 99% (test groups 11, 12 and 13 – 100, 300 and 1000 mg/kg bw/d) and 100% (control group).
The lactation index indicating pup mortality on PND 4-21 varied between 98% (control group) and 100% (test groups 11, 12 and 13 – 100, 300 and 1000 mg/kg bw/d).

CLINICAL SIGNS (OFFSPRING)
There were no treatment related clinical signs in F0 and F1 pups.

BODY WEIGHT (OFFSPRING)
Mean body weights and mean body weight gain of the male and female F1 (Figure page 69) and F2 pups (Figure page 85) were not influenced by the test substance during the entire lactation period. All values in test groups at 100, 300 and 1000 mg/kg bw/d were comparable with the concurrent control group.

SEXUAL MATURATION (OFFSPRING)
F1 pups:
Males, preputial separation: the mean number of days to reach the separation was 41.4, 41.5, 41.2, and 42.0 days in controls and 100, 300 and 1000 mg/kg body weight/day test groups, indicating that the test substance did not influence male sexual maturation.
Females, vaginal opening: the mean number of days to reach the criterion amounted to 31.3, 30.8, 31.4, and 31.9 days in controls and 100, 300 and 1000 mg/kg body weight/day test groups, respectively, indicating that female sexual maturation was not influenced by the test substance.

F2 pups: not determined

ORGAN WEIGHTS (OFFSPRING)
F1 pups: mean absolute and relative pup organ weights did not show statistically significant differences to the control group, withth exception of statistically significantly increased absolute brain weights in groups at 100 and 300 mg/kg bw/day. Relative brain weight was not affected, and there was no dose relationship. Therefore, this finding was not considered to be of toxicological relevance.
F2 pups: mean absolute and relative pup organ weights did not show statistically significant differences to the control group, withth exception of statistically significantly decreased absolute and relative spleen weight in high dose males. Females were not affected. This finding was not considered to be of toxicological relevance.


GROSS PATHOLOGY (OFFSPRING)
There were spontaneous findings at necropsy of the F1 pups (Part III, tables IA-039 through IA-042) and F2 pups (Part III, tables IA-084 through IA-086), but these were without relation to dosing and/or could be found in the historical control data at comparable or even higher incidences.


OTHER FINDINGS (OFFSPRING)
Sex ratio was unchanged in the treated F1 and F2 pups.
Dose descriptor:
NOAEL
Remarks:
development
Generation:
F1
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects on pre- and postnatal survival, body weights, no clinical or necropsy findings.
Dose descriptor:
NOAEL
Remarks:
development
Generation:
F1
Effect level:
1 292 mg/kg bw/day
Based on:
other: read across to potassium formate
Sex:
male/female
Basis for effect level:
other: No effects on pre- and postnatal survival, body weights, no clinical or necropsy findings with sodium formate
Reproductive effects observed:
not specified
Conclusions:
Sodium formate was not a reproduction toxicant in a 2-generation rat feeding study. This result can be extrapolated to potaasium formate.
Executive summary:

The fertility toxicity potential of sodium formate was examined in a 2-Generation feed study using male and female Wistar rats (25/sex and dose) at dose levels of 0, 100, 300, and 1000 mg/kg bw/day. The study was conducted in accordance with current test guidelines including OECD guideline No. 416, and under GLP conditions.

 

Test substance consumption

The mean test substance intake was close to the nominal values:

Nominal dose
(mg/kg bw/day)

100

300

1000

F0 males

93.2

282

939.1

F0 females
- premating
- gestation


96.8
105.4


290.9
323.9


976.9
1081.4

F1 males

90.7

265.6

948.7

F1 females
- premating
- gestation


97.9
108.1


294.8
276.6


980.1
931.3

                                              

 

Clinical and pathological findings in parental animals

There were no clinical signs of toxicity or mortalities in any of the F0 or F1 parental dose groups. Food consumption and body weights were comparable to that of the concurrent controls. Necropsy and pathology revealed no gross findings or organ weight changes that could be treatment related.

 

Reproduction parameters in F0 and F1 parental animals
There were no indications that sodium formate adversely affected fertility or reproductive performance of the F0 and F1 parental animals at dose levels as high as 1000 mg/kg body weight/day. Mating behavior, conception, gestation, parturition, lactation and weaning as well as sexual organ weights and gross findings of these organs were comparable between the rats of the test substance-treated test groups and the corresponding controls, and ranged within the historical control data of the test facility. There were no effects on male and female reproduction organs. Sperm parameters and estrous cycle were not affected.

Reproduction and developmental parameters in F1 pups

No test substance induced signs of developmental toxicity were noted in the progeny of the F0 and F1 parents at dose levels as high as 1000 mg/kg body weight/day. The number of delivered pups/litter, the sex ratio, their postnatal survival on days 4 and 21 after parturition, their body weights, and their sexual maturation remained unaffected by the test substance.

 

Clinical and pathological findings in F1 and F2 pups

-      Clinical and/or gross necropsy examinations of the F1 and F2 pups revealed only findings which were considered to be spontaneous in nature.The type and incidence offindings was within the range of the concurrent and/or the historical controls. (BASF SE, 2008).

 

Based on the above, the NOAEL values were as follows:

-      NOAEL 1000 mg/kg bw/day for general systemic toxicity for F0 and F1 parental animals

-      NOAEL 1000 mg/kg bw/day for fertility and reproductive performance for the F0 and F1 parental rats

-      NOAEL 1000 mg/kg bw/day for developmental toxicity, in the F1 and F2 progeny.

 

 

The study is considered to be valid and can be used for assessment of this endpoint.

 

The NOAEL values derived in this study (1000 mg sodium formate per kg bw/day) corresponds a NOAEL of 1292 mg potassium formate/kg bw/day.

 

 

Effect on fertility: via oral route
Dose descriptor:
NOAEL
1 235 mg/kg bw/day
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

In the absence of studies with potassium formate, results obtained with a related substance, sodium formate, can be used as justified in section 7.1.1. The read across is based on the assumption that only the formate anion may have a potential for adverse effects whereas sodium and potassium are unlikely to contribute. Details of the calculation are contained below and in the table in the discussion of developmental toxicity findings.

The fertility toxicity potential of sodium formate was examined in a 2-Generation feed study using male and female Wistar rats (25/sex and dose) at dose levels of 0, 100, 300, and 1000 mg/kg bw/day. The study was conducted in accordance with current test guidelines including OECD guideline No. 416, and under GLP conditions.

 

Test substance consumption

The mean test substance intake was close to the nominal values:

Nominal dose
(mg/kg bw/day)

100

300

1000

F0 males

93.2

282

939.1

F0 females
- premating
- gestation


96.8
105.4


290.9
323.9


976.9
1081.4

F1 males

90.7

265.6

948.7

F1 females
- premating
- gestation


97.9
108.1


294.8
276.6


980.1
931.3

  

Clincal and pathological findings in parental animals

There were no clinical signs of toxicity or mortalities in any of the F0 or F1 parental dose groups. Food consumption and body weights were comparable to that of the concurrent controls. Necropsy and pathology revealed no gross findings or organ weight changes that could be treatment related.

 

 

Reproduction parameters in F0 and F1 parental animals
There were no indications that sodium formate adversely affected fertility or reproductive performance of the F0 and F1 parental animals at dose levels as high as 1000 mg/kg body weight/day. Mating behavior, conception, gestation, parturition, lactation and weaning as well as sexual organ weights and gross findings of these organs were comparable between the rats of the test substance-treated test groups and the corresponding controls, and ranged within the historical control data of the test facility. There were no effects on male and female reproduction organs. Sperm parameters and estrous cycle were not affected.

Reproduction and developmental parameters in F1 pups

No test substance induced signs of developmental toxicity were noted in the progeny of the F0 and F1 parents at dose levels as high as 1000 mg/kg body weight/day. The number of delivered pups/litter, the sex ratio, their postnatal survival on days 4 and 21 after parturition, their body weights, and their sexual maturation remained unaffected by the test substance.

 

Clinical and pathological findings in F1 and F2 pups

Clinical and/or gross necropsy examinations of the F1 and F2 pups revealed only findings which were considered to be spontaneous in nature.The type and incidence offindings was within the range of the concurrent and/or the historical controls. (BASF SE, 2008).

 

Based on the above, the NOAEL values were as follows:

-      NOAEL 1000 mg/kg bw/day for general systemic toxicity for F0 and F1 parental animals

-      NOAEL 1000 mg/kg bw/day for fertility and reproductive performance for the F0 and F1 parental rats

-      NOAEL 1000 mg/kg bw/day for developmental toxicity, in the F1 and F2 progeny.

 

 

The study is considered to be valid and can be used for assessment of this endpoint.

 

For read across purposes, the NOAEL for the formate anion may be calculated, taking into account formula weights. The calculation (1000 mg sodium formate/kg /69 x 45 = 650 mg/kg bw/day) gives a NOAEL of approx. 650 mg formate/kg bw/day, or 1235 mg potassium formate/kg bw/day.

 

 



Short description of key information:
No studies are known to exist for potassium formate for any route, but results may be read across from a sodium formate study which was made for the most relevant oral route: male and female reproduction parameters and progeny development were not affected by sodium formate (up to 1000 mg/kg bw/day) in a 2-generation rat feeding study performed according to OECD 416 and under GLP conditions. This result may be extrapolated to potassium formate. The mentioned dose compares to a NOAEL of 1235 mg potassium formate/kg bw/day.

Effects on developmental toxicity

Description of key information
No developmental toxicity studies are known to exist for potassium formate for any route, but results may be read across from a sodium formate study which was made for the most relevant oral route. Sodium formate showed no maternal or developmental toxicity in GLP, OECD No. 414 guideline studies using rabbits and rats at dose levels up to 1000 mg/kg bw/day, and this result may be extrapolated to potassium formate. The mentioned  dose compares to a NOAEL of 1235 mg potassium formate/kg bw/day.
Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): Sodium formate
- Analytical purity: 100%
Species:
rabbit
Strain:
Himalayan
Details on test animals or test system and environmental conditions:
- Species:  rabbit
- Strain:   Himalayan
- Source:  Charles River Laboratories, Research Models and Services, Germany GmbH (former Charles River Laboratories, Germany)
- Sex: female
- Number: 25 per group
- Age: 13-21 weeks at study initiation
- Body weight (group mean): 2560 g
- Mating: Insemination; day of insemination designated day 0 of the study
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
For the preparation of the solutions, an appropriate amount of the test substance was weighed in a graduated measuring flask depending
on the dose group, topped up with doubly distilled water and subsequently thoroughly mixed until it was completely dissolved.


VEHICLE
- Amount of vehicle (if gavage): dose volume: 10 mL/kg bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
HPLC with external calibration. Column Synergi 4µ Hydro-RP 80 A, 250 x 3 mm. Eluant: phsophate buffer pH 2.9. UV-detection at 200 nm (report, page 229 onwards).
Details on mating procedure:
Artificial insemination:
After an acclimatization period of at least 5 days, the does were fertilized by means of artificial insemination.
This implied that 0.2 ml of a synthetic hormone which releases LH and FSH from the anterior pituitary lobe (Receptal®) were
injected intramuscularly to the female rabbits about 1 hour before insemination. The ejaculate samples used for the artificial insemination
were derived from male Himalayan rabbits of the same breed as the females. Each female was inseminated with the sperm of a defined male donor as documented in the raw data. The male donors were kept under conditions (air conditioning, diet, water) comparable to those of
the females participating in this study.
The day of insemination was designated as day 0 (beginning of the study) and the following day as day 1 post insemination (p.i.).
Duration of treatment / exposure:
days 6-28 post implantation
Frequency of treatment:
daily
Duration of test:
22 days
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
25 females
Control animals:
yes, concurrent vehicle
Details on study design:
Sex: female
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Clinical signs: checked each day
- Mortality: checked twice daily on working days, once on Saturday, Sunday, at public holidays


DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule:


BODY WEIGHT: Yes
- Time schedule for examinations: recorded regularly throughout the entire study period, i.e. on days 0, 2, 4, 6, 9, 11, 14, 16, 19, 21, 23, 25, 28 and 29 p.i.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes.
Food consumption was recorded daily throughout the entire study period.


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 29
- Organs examined: all females were sacrificed and assessed by gross pathology (including weight determinations of the unopened uterus and the placentae). For each doe, corpora lutea were counted and number and distribution of implantation sites (differentiated by resorptions, live and dead fetuses) were determined. Number and distribution of implantations sites were classified as live fetuses and dead implantations. Dead implantations comprised early resorptions, late resorptions and dead fetuses.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Placenta weight: yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: half per litter
Statistics:
Simultaneous comparison of all dose groups with the control group using the DUNNETT-test (twosided) for the hypothesis of equal means * for p < 0.05, ** for p < 0.01: Food consumption, body weight, body weight change, corrected, body weight gain (net maternal, body weight change), carcass, weight, weight of unopened, uterus, number of corpora lutea, number of implantations, number of resorptions, number of live fetuses, proportions of preimplantation loss, proportions of postimplantation loss, proportions of resorptions, proportion of live fetuses in each litter, litter mean fetal body weight, litter mean placental weight. 
Pairwise comparison of each dose group with the control group using FISHER'S EXACT test (one-sided) for the hypothesis of equal proportions * for p < 0.05, ** for p < 0.01: Female mortality, females pregnant at terminal sacrifice, number of litters with fetal findings.
Pairwise comparison of each dose group with the control group using the WILCOXON-test (onesided) for the hypothesis of equal medians * for p < 0.05, ** for p < 0.01: Proportions of fetuses with malformations, variations and/or unclassified observations in each litter.
Indices:
Conception rate, pre- and postimplantation loss
Historical control data:
Included in Part III of the report
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No clinical signs of toxicity, no treatement-related mortalities. Food consumption, body weights, necropsy findings not affected.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEL
Effect level:
1 292 mg/kg bw/day
Based on:
other: potassium formate, calculated
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Fetal weight, sex distribution, placenta weight not affected. Pre- and postimplantation loss not affected. External, soft tissue and skeletal malformations not affected by treatment.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Basis for effect level:
other: embryotoxicity
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Basis for effect level:
other: teratogenicity
Dose descriptor:
NOAEL
Effect level:
1 292 mg/kg bw/day
Based on:
other: potassium formate, calculated
Basis for effect level:
other: embryotoxicity
Dose descriptor:
NOAEL
Effect level:
1 292 mg/kg bw/day
Based on:
other: potassium formate, calculated
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified

Analysis of Test Substance
By various analyses, the stability of the test substance solutions over a period of 13 days at room temperature was
demonstrated, and the correctness of the prepared concentrations was shown.


EFFECTS
1 - Parental animals

Mortalities: none in any of the groups.
Clinical signs: none in any of the groups (Report, p. 34)
Food consumption: comparable across all groups, no relevant difference in treated groups compared to the control group
(Report, p. 35).
Body weights: comparable across all groups, no difference in treated groups compared to the control group ((Report p. 36).
Corrected body weight gain: did not reveal statistically significant differences between the test substance-treated groups and the control group (Report p. 36)
Uterus weight: no effect; the mean uterus weights were comparable between all groups (Report p. 37)

Necropsy findings: no test-substance related effect noted (Report p. 37)

Table1: Selected results for does in test groups 0 - 3,  i.e. at 0, 100, 300, or 1000 mg/kg bw per day

===========================================================
Parameter        Group 0     Group 1    Group 2     Group 3
-----------------------------------------------------------
Females mated/   
pregnant/       25/24/24   25/23/23    25/22/22   25/23/23
with viable 
fetuses

Food con-
sumtion (g)      100.5       97.8         94.5       94.6
day 0-29                    (97%)         (94%)      (94%)

Body weight      306.0      323.5        260.5      297.7 
gain (g)                    (106%)       (85%)      (97%)
day 0-29

Necropsy         - - No treatment-related findings  - -        
findings 
in dams 

Conception         96          92          88         92
rate (%)

Abortions           0           0           0          0

Corpora lutea    201/24     196/23        193/22    185/23
total/number 
of dams                

Implantations    176/24     185/23        156/22    161/23
total/number 
of dams
        
Resorptions       13/24     16/23          19/22     22/23
total/number 
of dams

total number      163        169            137       139
of fetuses                

total number       24         23             22        23
of litters                

pre-implantation 12.5(19.1) 6.7(11.9)   18.4(24.9) 13.3(16.1)
loss (+/- SD) %                

post-implantation 7.3(10.1) 7.9(9.3)  13.0(16.4) 13.9(16.2)
loss (+/- SD) %

fetuses/litter  6.8(2.25)  7.3(1.7)  6.2(2.5)  6.0(2.0)
(+/- SD)
live fetuses/   92.7(10.1)  92.1(9.3) 87.0(16.4) 86.1(16.2)
litter (+/- SD) %                

placenta weight   4.7        4.5          4.6          4.3
(mean) [g]                  (96%)        (98%)       (92%)

fetus weight     37.8        36.4        36.7        35.2
(mean) [g]                  (96%)        (97%)       (93%)
 
Fetal sex ratio 38.7:61.3  50.9:49.1   54.0:46.0   51.1:48.9        
[ratio m : f]
===========================================================
SD = Standard Deviation


2 - Fetuses

There were no test substance-related effects in any of the test groups at 100, 300, and 1000 mg/kg bw/day. 

Table 2: Selected results for fetuses in test groups 0 - 3,  i.e. from does at 0, 100, 300, or 1000 mg/kg bw per day:

===========================================================
Parameter        Group 0     Group 1    Group 2     Group 3
-----------------------------------------------------------
Total external malformations [%]
Fetuses           0.0         0.0        0.7         0.7
Litter            0.0         0.0        4.5         4.3 
Affect. fetuses   0.0         0.0        0.6         0.5
per litter

Total external variations [%]
Fetuses           4.3         0.6        2.2         1.4
Litter            13          4.3        9.1         8.7
Affect. fetuses   2.3         0.9        2.0         1.4
per litter

Skeletal malformations [%]
Fetuses           1.8         1.8        1.5         3.6
Litter            13          13         9.1         22 
Affect. fetuses   2.3         2.0        1.0         3.4
per litter

Skeletal variations [%]
Fetuses           52          65         60          65
Litter           100          91         95          96
Affect. fetuses   53.5        61.8       62.2        65.7
per litter

Soft tissue malformations [%]
Fetuses           1.2         0.6       2.2         4.3
Litter            8.3         4.3       14          26
Affect. fetuses   1.5         0.5       2.1         4.5
per litter

Soft tissue variations [%]
Fetuses           4.3         11        11          10
Litter            21          48        41          39
Affect. fetuses   4.2        10.9       9.4         8.9
per litter
===========================================================

Conclusions:
Result: negative; no maternal and prenatal developmental toxicity, no  teratogenicity at any tested dose level up to 1000 mg sodium formate/kg bw/day. This can be eytrapolated to potassium formate.
Executive summary:

In a developmental toxicity study performed according to OECD test guideline No. 414 and under GLP conditions, sodium formate (in water) was administered to 25 female Himalayan rabbits by gavage at dose levels of 0, 100, 300, and 1000 mg/kg bw/day from days 6 through 28 of gestation.

 

There were no treatment-related effects in mortality, clinical signs, body weight, food consumption, cesarean parameters, and terminal necropsy in the does. The maternal NOAEL is therefore 1000 mg sodium formate/kg bw/day.

There were no treatment-related effects in developmental parameters. Fetal weight at birth, sex distribution, placenta weight, pre- and postimplantation loss were not affected. There were no unusual or increased incidences of external, soft tissue or skeletal malformations attributable to the treatment. The developmental NOAEL is therefore 1000 sodium formate mg/kg bw/day. The NOAEL for teratogenicity is also 1000 sodium formate mg/kg bw/day, the highest dose tested (BASF, 2008).

 

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

 

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). The NOAEL values for potassium formate are therefore 1292 mg/kg bw/day.

Table: calculation of NOAEL values

 

 

Formula

weight

NOAEL
maternal toxicity

NOAEL
developmental toxicity

NOAEL
teratogenicity

 

 

(mg/kg bw/day)

Sodium formate

68

1000

1000

1000

Potassium formate

84

1292

1292

1292

 

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
not specified
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): sodium formate
Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
Animals
- Species: rat.
- Strain: Wistar.
- Sex: female.
Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
gestational days 6-19
Frequency of treatment:
7/week
Duration of test:
17 days
Dose / conc.:
59 mg/kg bw/day (nominal)
Dose / conc.:
236 mg/kg bw/day (nominal)
Dose / conc.:
945 mg/kg bw/day (nominal)
No. of animals per sex per dose:
25 females
Control animals:
yes, concurrent vehicle
Details on maternal toxic effects:
Maternal toxic effects:no effects
Dose descriptor:
NOAEL
Effect level:
945 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
1 167 mg/kg bw/day
Based on:
other: potassium formate, calculated
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Dose descriptor:
NOAEL
Effect level:
945 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: embryotoxicity
Dose descriptor:
NOAEL
Effect level:
945 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Dose descriptor:
NOAEL
Effect level:
1 167 mg/kg bw/day
Based on:
other: potassium formate, calculated
Basis for effect level:
other: embryotoxicity
Dose descriptor:
NOAEL
Effect level:
1 167 mg/kg bw/day
Based on:
other: potassium formate, calculated
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
The result of sodium formate (no maternal toxicity, no embryo-/fetal toxicity or teratogenicity at any dose including the top dose, 945 mg/kg bw/day) can be extrapolated to other formate salts.
Executive summary:

In a developmental toxicity study, time-mated female rats (25/dose, OECD TG 414; study conducted under GLP conditions) received 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. 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 (BASF AG, 2005).

 

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

 

Generally, formate salts are often used as test material in studies requiring repeated dosing, whereas the corrosivity of formic acid does not allow repeated dosing. Both formic acid and formate salts dissocitae in aqueous solution and are almost exclusively present as teh formate anion at pH values near neutral. Therefore, systemic NOAEL values can be normalised for formate anion and be read across to other formate salts and formic acid if stoichiometry and formula weights are taken into account. 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)

 

Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
1 235 mg/kg bw/day
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

In the absence of studies with potassium formate, results obtained with a related substance, sodium formate, can be used as justified in section 7.1.1. The read across is based on the assumption that only the formate anion may have a potential for adverse effects whereas sodium and potassium are unlikely to contribute. Details of the calculation are contained below.

Studies in vivo

In a developmental toxicity study performed according to OECD test guideline No. 414 and under GLP conditions, sodium formate (in water) was administered to 25 female Himalayan rabbits by gavage at dose levels of 0, 100, 300, and 1000 mg/kg bw/day from days 6 through 28 of gestation.

There were no treatment-related effects in mortality, clinical signs, body weight, food consumption,cesarean parameters, and terminal necropsy in the does. The maternal NOAEL is therefore 1000 mg sodium formate/kg bw/day.

Likewise, there were no treatment-related effects in developmental parameters. Fetal weight at birth, sex distribution, placenta weight, pre- and postimplantation loss were not affected. There were no unusual or increased incidences of external, soft tissue or skeletal malformations attributable to the treatment. The developmental NOAEL is therefore 1000 sodium formate mg/kg bw/day. The NOAEL for teratogenicity is also 1000 sodium formate mg/kg bw/day, the highest dose tested (BASF, 2008). The developmental toxicity study in the rabbit is classified as acceptable and satisfies the guideline requirement for a developmental toxicity study (OECD 414) in rabbits.

 

The above is supported by a rat developmental toxicity study that is referenced in the publicly available OECD SIAP (cf. section 13). Time-mated female rats (25/dose, OECD TG 414; study conducted under GLP conditions) received 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 (BASF AG, 2005). This developmental toxicity study is also classified as acceptable and satisfies the guideline requirement for a developmental toxicity study (OECD 414) in rats.

Read across to related chemicals

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 to 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

1000

1000

1000

Formate anion

45

652
(1000/69x45)

652
(1000/69x45)

652
(1000/69x45)

Potassium formate

85

1232
(1000/69x85)

1232
(1000/69x85)

1232
(1000/69x85)

Justification for classification or non-classification

No classification. Criteria of regulations 67/548/EC and 1272/2008/EC are not met.

Additional information