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REACH

Sodium formate

EC number: 205-488-0 | CAS number: 141-53-7

Life Cycle description
Uses advised against

Toxicological information

Endpoint summary

Administrative data

Description of key information

Repeated dose oral toxicity data in the rat are available for the read-across substance potassium formate.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference 1

Endpoint:: chronic toxicity: oral
Type of information:: experimental study
Adequacy of study:: supporting study
Reliability:: 1 (reliable without restriction)
Rationale for reliability incl. deficiencies:: comparable to guideline study
Qualifier:: equivalent or similar to guideline
Guideline:: OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:: no
GLP compliance:: yes
Limit test:: no
Specific details on test material used for the study:: - Name of test material (as cited in study report): "Formi LHS-Super"
- Substance type: salt
- Physical state: powder
- Analytical purity: 98.44 and 99%.
Species:: rat
Strain:: other: Crl:HanWist(Glx:BRL)BR
Sex:: male/female
Details on test animals or test system and environmental conditions:: Test animals
- Species: rat.
- Strain: Crl:HanWist(Glx:BRL)BR.
- Sex: male and female.
- Age: approx. 8 weeks at commencement of the experiment.
- Body weight: males: 186 to 275 g; females: 132 to 200 g.
- Number of animals: 20 per sex and dose group in the chronic toxicity study
- Housing: in groups of 5, in stainless steel mesh cages.
- Environment: routinely 19 to 25°C, relative humidity 40 to 70%,
- Air changes: 15 air  changes/hour.
- Photo period: 12-h light/dark cycle.

Treatment
- Dosing:  TS mixed into the diet.
- Diet: ground diet SQC Rat and Mouse Maintenance Diet No. 1, free access  to feed and tap water.
- Stability of TS in diet: examined; at least 7 days.
- Dose levels: 0, 50, 400, 2000 mg/kg bw/day.
- Dose selection: based on results from preliminary studies including a  13-week study in rats
Route of administration:: oral: feed
Vehicle:: other: feed
Details on oral exposure:: PREPARATION OF DOSING FEED:

DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): ground diet; mixed with TS in a mortar to give a premix, to which further diet was added as required and mixed in a blendor for five minutes.
- Storage temperature of food: at room temperatur ein sealed containers
Analytical verification of doses or concentrations:: yes
Details on analytical verification of doses or concentrations:: Analysis was performed in week 1, and at 12 or 13 week intervals thereafter
Duration of treatment / exposure:: 104 weeks
52 weeks: interim report
104 weeks: final report
Frequency of treatment:: 7 days/week
Dose / conc.:: 50 mg/kg bw/day (nominal)
Remarks:: Based on amount in the diet
Dose / conc.:: 400 mg/kg bw/day (nominal)
Remarks:: Based on amount in the diet
Dose / conc.:: 2 000 mg/kg bw/day (nominal)
Remarks:: Based on amount in the diet
No. of animals per sex per dose:: Main study: 50
Interim kill: 20
Control animals:: yes, concurrent vehicle
Details on study design:: - Dose selection rationale: based on the results of a 13-week study
Positive control:: not required
Observations and examinations performed and frequency:: CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Mortality: recorded twice daily. Clinical signs: observed daily.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Detailed physical examination of each animal was performed at weekly intervals.

BODY WEIGHT: Yes
- Time schedule for examinations: recorded before first treatment, at weekly intervals for 16 weeks, once every 4 weeks thereafter and before necropsy.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal group determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes. Determined weekly for the first 16 weeks, then one week in every 4 weeks thereafter.
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: investigation in all animals pre-treatment and in all control and high dose animals in Week 50
- Dose groups that were examined: investigation in all animals pre-treatment and in all control and high dose animals in Week 50

HAEMATOLOGY: Yes
- Time schedule for collection of blood: weeks 26, 52 and 103
- Method: 0.5 ml samples were withdrawn from 10 animals per group and sex in Weeks 26 and 52. Blood was taken from the lateral caudal vein of fasted animals and from decedents where possible.
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals: 10/sex/dose; all at termination
- Parameters examined: hemoglobin concentration, packed cell volume, mean cell volume, mean cell hemoglobin concentration, red blood cell count, total and differential white blood cell count, mean cell hemoglobin, and platelet count was performed and clotting times were determined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: weeks 26 and 52, and 103
- Animals fasted: Yes
- How many animals: 10/sex/dose; all at termination
- Parameters examined: aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, sodium, potassium, calcium, chloride, inorganic phosphorus, total protein, albumin, globulin, albumin/globulin ratio, total cholesterol, glucose, urea, total bilirubin, creatinine.

URINALYSIS: Yes
- Time schedule for collection of urine: samples were collected from 10 animals per group and sex in Weeks 25, 51 and 102. Where possible, urine and blood samples were taken from the same animals.
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters examined: microscopy of sediment, volume, specific gravity, urobilinogen. Semi-quantitatively: pH, protein, glucose, ketones, bilirubin, blood, reducing substances.

NEUROBEHAVIOURAL EXAMINATION: No

OTHER:

PATHOLOGY:
all animals killed at termination in Week 52 or found dead during the scheduled terminal necropsy period were considered to have completed the study, and any data collected was treated as such. All animals including decedents were necropsied. Animals were weighed and tissues were preserved:

------------------------------------------------------------
Adrenals#, aorta, brain#, cecum#, colon#, duodenum#, eyes#, femur with marrow and articular surface, gross lesions#, Harderian glands*, head, heart#, ileum#, jejunum#, kidneys#, lacrimal glands*, larynx, liver#, lungs with mainstem bronchi#, mammary (females)#, mandibular lymph nodes#, mesenteric lymph nodes#, muscle quadriceps, nasal turbinates*, nasopharynx*, esophagus#, optic nerves#, ovaries#, pancreas#, pituitary#, prostate#, rectum, salivary glands#, sciatic nerves#, seminal vesicles, skin#, spinal cord (cervical, lumbar, thoracic)#, spleen#, sternum with bone marrow#, stomach#, testes and epididymides#, thymus#, thyroids and parathyroids#, tissue masses#, tongue, trachea#, urinary bladder#, uterus#, vagina#, Zymbal glands*.
------------------------------------------------------------
(# = microscopically examined; * = retained in situ with the head)

HISTOPATHOLOGY:
Histopathology was performed on gross lesions, tissue masses and stomach from all animals and tissues denoted by (#) in the tissue list from control and high dose animals, and decedents from all groups.
Sacrifice and pathology:: GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:: Data from treated animals were compared with control data. In-life data: body weight gains, organ weights, food consumption and hematology variables were analyzed using ANOVA, separately for each sex. Dunnett's multiple test was used for comparison between control and treated group. A regression test was performed to determine whether there was a linear relationship between increasing dose and response.
Clinical signs:: no effects observed
Mortality:: no mortality observed
Body weight and weight changes:: effects observed, treatment-related
Description (incidence and severity):: Treatment-related findings were noted at 2000 mg/kg bw/d and included a statistically significant depression of body weight gain (by 27% in males and 19% in females; no effect at the low and intermediate dose levels).
Food consumption and compound intake (if feeding study):: no effects observed
Food efficiency:: not examined
Water consumption and compound intake (if drinking water study):: not examined
Ophthalmological findings:: no effects observed
Haematological findings:: no effects observed
Clinical biochemistry findings:: no effects observed
Urinalysis findings:: no effects observed
Behaviour (functional findings):: not examined
Immunological findings:: not examined
Organ weight findings including organ / body weight ratios:: no effects observed
Gross pathological findings:: effects observed, treatment-related
Description (incidence and severity):: At terminal kill, a thickening of the stomach confirmed as basal cell hyperplasia or foveolar epithelium hyperplasia in the majority of the high dose animals.
Neuropathological findings:: not examined
Histopathological findings: non-neoplastic:: effects observed, treatment-related
Description (incidence and severity):: At terminal kill, a thickening of the stomach confirmed as basal cell hyperplasia or foveolar epithelium hyperplasia in the majority of the high dose animals.
Histopathological findings: neoplastic:: no effects observed
Description (incidence and severity):: The spectrum of tumours was generally consistent with that expected in rats of this strain. There were no tumours of unusual nature or incidence indicative of specific target organ carcinogenicity in the stomach or any other tissue.
Other effects:: not specified
Details on results:: CLINICAL SIGNS AND MORTALITY
Clinical signs: There were no clinical signs related to treatment.
Mortalities: There was no pattern to indicate that the test substance had any effect on survival. Also, the incidence and pattern of morbidity observed in this strain was not changed by the test substance.
The distribution of deaths at the end of Week 52 is tabulated below.

==============================
Dose level Males Females
(mg/kg bw/d) [number of deaths (% survival)]
----------------------------------------------
0 1 (95) 2 (90)
50 0 (100) 0 (100)
400 1 (95) 3 (85)
2000 0 (100) 1 (95)
==============================

The distribution of deaths at the end of Week 104 is tabulated below.
==============================
Dose level Males Females
(mg/kg bw/d) [number of deaths (% survival)]
----------------------------------------------
0 8 (84) 11 (78)
50 12 (76) 9 (82)
400 11 (78) 13 (74)
2000 7 (86) 12 (76)
==============================
BODY WEIGHT AND WEIGHT GAIN
Body weight ands body weight gain for low and intermediate dose animals were comparable with that of the controls.
High dose animals had significantly reduced body weights at week 52, and at week 104 (lower by 27% in males, lower by 19% in females;
up to p
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Food consumption was comparable between all groups, with a tendency of an approx. 5% reduction in the high dose groups.

OPHTHALMOSCOPIC EXAMINATION
There was no effect on the eye noted.

HAEMATOLOGY
There was no consistent pattern of variation to indicate an effect of treatment.

CLINICAL CHEMISTRY
There was no consistent pattern of variation to indicate an effect of treatment.

URINALYSIS
There was no consistent pattern of variation to indicate an effect of treatment.

ORGAN WEIGHTS
There was no consistent pattern of variation to indicate an effect of treatment.

GROSS PATHOLOGY
The only treatment-related finding was an increase in the number of high dose animals with thick stomach
when compared with the controls. This was attributable to local irritation. The NOAEL was 50 mg/kg bw/day in teh 104-week study.

Group incidence of findings in the stomach, Week 52
======================================
Males Females
Group 1M 2M 3M 4M 1F 2F 3F 4F
mg/kg/day 0 50 400 2000 0 50 400 2000
---------------------------------------------------------
n 20 20 19 20 20 20 18 20

Thick 4 2 2 16 0 0 1 13
stomach
======================================
n = number of animals examined

HISTOPATHOLOGY:

NON-NEOPLASTIC
The spectrum of microscopic findings was generally consistent with that expected for rats of this strain. Treatment-related changes
were noted in the stomach and the salivary gland of high dose animals. For details see table under "Any other information on results".

In the stomach, basal cell hyperplasia was restricted to the squamous epithelium of the limiting ridge and appeared to correlate
with the necropsy finding of thick stomach. Foveolar epithelial hyperplasia was seen in both high dose animal groups, as were
slightly increased incidences of hyperkeratosis.
Acinar cell hypertrophy of the salivary gland was considered to be a minor cytological change and as a physiological response with
no toxicological significance.
Increased incidences of pancreas lobular atrophy were noted in the high dose groups; however, the incidences were comparable
between the controls and the high dose groups in the 104 Week study.

The incidence of non-neoplastic histopathology findings in other tissues was generally comparable with the control group and did
not indicate a systemic target organ toxicity.

NEOPLASTIC LESIONS:
The spectrum of tumors was generally consistent with that expected in rats of this strain. There were no tumors of unusual nature
or incidence indicative of specific target organ carcinogenicity in the stomach or any other tissue.
Dose descriptor:: NOAEL
Remarks:: ; systemic toxicity; sodium formate
Effect level:: 2 120 other: mg/kg/day (calculated)
Sex:: male/female
Basis for effect level:: other: Read across from potassium diformate. Absence of systemic toxicity.
Dose descriptor:: NOAEL
Remarks:: ; systemic toxicity; potassium diformate
Effect level:: 2 000 mg/kg bw/day (actual dose received)
Sex:: male/female
Basis for effect level:: other: Absence of systemic toxicity or target organ.
Dose descriptor:: NOAEL
Remarks:: ; local irritation toxicity; potassium diformate
Effect level:: 400 mg/kg bw/day (actual dose received)
Sex:: male/female
Basis for effect level:: other: Changes in stomach at 2000 mg/kg bw/day: increased incidences of foveolar epithelium and squamous cell hyperplasia.
: Key result
Critical effects observed:: no
Conclusions:: Local effects were seen in the stomach in both sexes at 2000 mg/kg bw/day. Systemic toxicity was not seen at any dose, including 2000 mg/kg bw/day, the highest dose tested. The NOAEL for systemic toxicity was therefore 2000 mg potassium diformate/kg bw/day in the rat, equivalent to 2092 mg sodium formate/kg bw/day.
Executive summary:: The repeated dose toxicity and oncogenicity of potassium diformate(1:2) was examined in a combined chronic toxicity and 104-week oral feed oncogenicity study in the rat similar to the OECD guideline 453 and under GLP conditions. Read-across from potassium diformate is justified because potassium diformate decomposes in aqueous solution into one molecule of each formate and formic acid, and the potassium ion. Thus, potassium diformate gives two formate anions on a molar basis. Local effects are attributable to the formic acid formed and can be neglected because these are not expected with neutral salts (sodium, potassium, ammonium, calcium formate). Read across can therefore be limited to systemic effects. The oral dietary administration of potassium formate (1:2) in a combined chronic toxicity/carcinogenicity study (equivalent to OECD guideline 453 and under GLP) to male and female Wistar rats (50 animals/dose/sex) for 104 weeks to rats at dose levels of 50, 400, and 2000 mg/kg bw/d was well tolerated without effects on clinical condition or survival. Treatment-related findings were noted at 2000 mg/kg bw/d and included a statistically significant depression of body weight gain (by 27% in males and 19% in females; no effect at the low and intermediate dose levels) and, at terminal kill, a thickening of the stomach confirmed as basal cell hyperplasia or foveolar epithelium hyperplasia in the majority of the high dose animals. These changes were less pronounced than in a previous 90-day rat study. There was no evidence of systemic target organ toxicity due to test substance administration, including the eyes. The spectrum of tumours was generally consistent with that expected in rats of this strain. There were no tumours of unusual nature or incidence indicative of specific target organ carcinogenicity in the stomach or any other tissue (Covance Laboratories, 2002). Overall, the local toxicity NOAEL for 52 and 104 weeks of treatment was considered to be 400 mg/kg bw/d, based on the local effects in the stomach and reduced body weight of the high dose rats. As no signs of systemic effects were noted, the NOAEL (rat, 104 week) for systemic toxicity is considered to be 2000 mg/kg bw/d. Taking stoichiometry and formula weights into consideration, the systemic toxicity NOAEL (rat, oral, 104-week) was 2092 mg sodium formate/kg bw/d.

Reference 2

Endpoint:: sub-chronic toxicity: oral
Type of information:: experimental study
Adequacy of study:: key study
Reliability:: 1 (reliable without restriction)
Rationale for reliability incl. deficiencies:: guideline study
Remarks:: Justification of test substance: potassium diformate decomposes into one molecule of each formate and formic acid. Thus, potassium diformate gives two formate anions on a molar basis. Local effects of the formic acid formed can be neglected because these are not expected with neutral salts (sodium, potassium, ammonium, calcium formate). Read across can therefore be limited to systemic effects.
Justification for type of information:: Justification of test substance: potassium diformate decomposes into one molecule of each formate and formic acid. Thus, potassium diformate gives two formate anions on a molar basis. Local effects of the formic acid formed can be neglected because these are not expected with neutral salts (sodium, potassium, ammonium, calcium formate). Read across can therefore be limited to systemic effects.
Qualifier:: according to guideline
Guideline:: OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:: yes
Remarks:: ; absorption of TS and reversibility of effects over a 4 week treatment-free period.
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): Formi-LHS; Formi LHS-Super
- Molecular formula (if other than submission substance): C2H3O4 K
- Molecular weight (if other than submission substance): 130.14
- Substance type: double salt
- Physical state: white powder
- Analytical purity: not reported; information available at the sponsor
- Impurities (identity and concentrations):
- Storage condition of test material: in sealed container at room temperature (10-30°C) in the dark
Species:: rat
Strain:: other: Crl:CDBR
Sex:: male/female
Details on test animals or test system and environmental conditions:: TEST ANIMALS
- Age at study initiation: 6 weeks
- Weight at study initiation: males: 166 to 208 g; females; 136 to 173 g.
- Housing: groups of 5 rats per cage
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): routinely 19 to 25°C
- Humidity (%): 40 to 70%
- Air changes (per hr): minimum 15/hour
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:: oral: feed
Vehicle:: unchanged (no vehicle)
Details on oral exposure:: - Dosing: test substance was mixed into the diet.
- Diet: ground SQC Rat and Mouse Maintenance Diet No. 1, free access to diet and to tap water.
- Stability of TS in diet: at least 2 weeks
- Replacement of diet: regularly within 2 weeks
- Dose levels:
- Main study: 0, 600, 1200, 3000 mg/kg bw/day.
- Recovery study: 0 and 3000 mg/kg bw/day.
- Absorption study: 3000 mg/kg bw/day.
Analytical verification of doses or concentrations:: yes
Details on analytical verification of doses or concentrations:: The enzymatic method "Formic Acid" by Boehringen Mannheim was used
Duration of treatment / exposure:: 13 weeks
Frequency of treatment:: 7 days/week
Dose / conc.:: 600 mg/kg bw/day (nominal)
Dose / conc.:: 1 200 mg/kg bw/day (nominal)
Dose / conc.:: 3 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:: Main study: 10 per sex and dose group.
Recovery study: 10 per sex of the control and the high dose groups.
Absorption study: 10 per sex of the high dose group.
Control animals:: yes, concurrent no treatment
Details on study design:: Post-exposure period: Satellite group: 4 weeks
Positive control:: Not required
Observations and examinations performed and frequency:: CAGE SIDE OBSERVATIONS: Yes
Mortality, clinical signs: observed at least daily.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: recorded before first treatment, at weekly intervals and  before necropsy.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal group 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

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: before treatment and in week 12
- Dose groups that were examined: all main-study animals were examined before treatment and  all control and high dose animals in week 12.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: week 13 in main study, week 17 in recovery study
- How many animals: all animals

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: week 13 in main study, week 17 in recovery study
- How many animals: week 13 in main study, week 17 in recovery study

URINALYSIS: Yes
- Time schedule for collection of urine: week 13 in main study, week 17 in recovery study
- Metabolism cages used for collection of urine: yes

OTHER:

ABSORPTION
0.5 ml blood samples were taken on Day 1 of feeding and during weeks 13  and 17 by tail vein  puncture. Plasma was separated and stored at below  -10°C until analysis of formate using the Formic Acid method by  Boehringer Mannheim.

GROSS PATHOLOGY

- All animals except those of the absorption study  were subjected to terminal necropsy after sacrifice.
- Organ weights: adrenals, kidneys, liver, testes and epididymides were  weighed before fixation.

HISTOPATHOLOGY
Histopathology: samples of the following tissues were fixed in 10%  buffered formalin. Eyes were fixed in Davidson's fluid.

Adrenals, aorta#, brain, cecum, colon, duodenum, eyes, femur with marrow  and articular surface#, gross lesions, Harderian glands#*, head#, heart,  ileum, jejunum, kidneys, lacrimal glands#*, larynx, liver, lungs, mammary  (females)#, mandibular lymph nodes, mesenteric lymph nodes, muscle  quadriceps#, esophagus, optic nerves#, ovaries, pancreas, pituitary,  prostate#, rectum, salivary glands, sciatic nerves, seminal vesicles#,  skin#, spinal cord (cervical, lumbar, thoracic)#, spleen, sternum with  bone marrow, stomach, testes and epididymides, thymus, thyroids an  parathyroids, tongue#, urinary bladder, uterus, nasal turbinates#*,  nasopharynx#*, vagina#, Zymbal glands*#.

# = tissue retained in fixative but not examined. * = retained in situ with the head

All organs and tissues in the control and high dose group animals were  histopathologically examined following hematoxylin and eosin staining.  Additionally, kidneys, lungs and gross lesions from the intermediate  groups were examined. Following observations in the stomachs of high dose animals, the stomachs  of the low and intermediate dose group animals were also examined,  together with the stomachs from the animals at the end of the recovery  period.
Sacrifice and pathology:: GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:: Absorption and recovery within 4 weeks
Statistics:: Body weight gains, necropsy body weight, hematology and clinical chemistry variables were analyzed using ANOVA, separately for each sex. Dunnett's multiple test was used for comparison between control and treated group. A regression test was performed to determine whether there was a linear relationship between increasing dose and response. Organ weights were analyzed using ANCOVA and Dunnett's test.
All recovery study data were analyzed using ANCOVA.
Clinical signs:: no effects observed
Mortality:: no mortality observed
Body weight and weight changes:: effects observed, treatment-related
Description (incidence and severity):: Male body weight gain was significantly decreased in all treated groups, whereas in females, body weight reduction gained a level of significance only in the high dose group animals. A dose-related body weight decrease was seen in all treated males and in the high dose female group, possibly as a result of the reduced palatability of the diet
Food consumption and compound intake (if feeding study):: effects observed, treatment-related
Description (incidence and severity):: Slightly reduced food consumption was seen in groups with reduced body weights.
Food efficiency:: not examined
Water consumption and compound intake (if drinking water study):: not examined
Ophthalmological findings:: no effects observed
Haematological findings:: effects observed, treatment-related
Description (incidence and severity):: The small but statistically significant changes in haematology and clinical chemistry parameters in the high dose animals were not of toxicological significance, due to the small changes and the lack of target organ toxicity.
Clinical biochemistry findings:: effects observed, treatment-related
Description (incidence and severity):: The small but statistically significant changes in haematology and clinical chemistry parameters in the high dose animals were not of toxicological significance, due to the small changes and the lack of target organ toxicity.
Urinalysis findings:: effects observed, treatment-related
Behaviour (functional findings):: not examined
Immunological findings:: not examined
Organ weight findings including organ / body weight ratios:: no effects observed
Gross pathological findings:: effects observed, treatment-related
Description (incidence and severity):: A specific target organ was the stomach, based on local irritation in the forestomach which caused a dose-related thickening of the stomach at all dose levels
Neuropathological findings:: not examined
Histopathological findings: non-neoplastic:: effects observed, treatment-related
Histopathological findings: neoplastic:: not specified
Description (incidence and severity):: A specific target organ was the stomach, based on local irritation in the forestomach which caused a dose-related thickening of the stomach at all dose levels, and was confirmed to be squamous cell hyperplasia. This was considered to be a response to minor irritation by the test substance, rather than a toxic effect
Details on results:: CLINICAL SIGNS AND MORTALITY
There were no treatment-related clinical observations or mortalities. Of the 3 mortalities observed (2 controls, 1 high dose female), necropsy  confirmed that all were associated with the orbital sinus blood sampling.

BODY WEIGHT AND WEIGHT GAIN
In males, there was a significant and dose-related reduction of body  weight gain. The overall difference from the controls (Weeks 0-13) was  statistically significant in all three groups (p<0.05, <0.01, and <0.001  in the low, intermediate, and high dose, resp.). In females, body weight gain was also reduced. Significance  was gained  only in the high dose group (p<0.01).

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
A slight dose-related reduction of food intake was noted in all male  groups. In females, a reduction was seen only in the high dose group. No  level of statistical significance was reached in any group. In the treatment-free recovery groups food intake was comparable to the  control rats.
For details of resulting doses see "Remarks on results". The authors argued that reduced body weight gain and food intake were probabl relate to reduced palability of the test diets.

OPHTHALMOSCOPIC EXAMINATION
No treatment related effects noted.

HAEMATOLOGY
There were small but statistically significant differences from the  controls (cf. table in "Remarks on results"). Clotting times were unchanged. Fluctuations in  white blood cell counts were noted for both sexes in all groups with no  clear dose-relation or significant trends. Observed changes were not regarded to be of biological or toxicological relevance.

CLINICAL CHEMISTRY
There were small but statistically significant differences from the  controls  (cf. table in "Remarks on results"). Clotting times were unchanged. Fluctuations in  white blood cell counts were noted for both sexes in all groups with no  clear dose-relation or significant trends. Observed changes were not regarded to be of biological or toxicological relevance.

URINALYSIS
Urinary parameters were similar to the controls in all groups except pH.  There was a trend towards an increased urinary pH (pH 8 or 9) in the  intermediate and high dose groups of both sexes at the end of the  treatment period.

After the 4-wk treatment-free period the majority of the high dose rats  had a urine pH of 6.0 or 7.0.

ORGAN WEIGHTS
At the end of the treatment period, group mean adjusted kidney, liver,  testes and epididymides weights in males were similar to the controls, as  were the mean weights of kidneys and liver in females. Reduced adrenal  weights compared to controls were noted in males (not significant) and in  females (p<0.05).

At the end of the treatment-free period, the mean liver weight of the  high dose males was slightly higher (p<0.01) than in controls.

GROSS PATHOLOGY
No remarkable findings, except thickening of the stomach, usually  involving the limiting ridge, at the end of the 13-week treatment period.  The effect was more pronounced in males, probably due to the higher  concentration of the TS in the diet (cf. table in "Remarks on results").

The effect subsided within the 4-week recovery period.

HISTOPATHOLOGY: NON-NEOPLASTIC
There was no other finding than a dose-related increase in the severity  and incidence of squamous cell hyperplasia in the stomach. No squamous  cell hyperplasia was noted in any of the male and female controls. The  histopathological finding correlated with the thick stomach findings  during necropsy.

The effect was largely reversible within the 4-week treatment-free period.

OTHER FINDINGS

Absorption study
Formate plasma levels following 3000 mg/kg bw/day were below the LOD  (Level of Detection, i.e. 62.54 µg/ml) in all but few animals on Day 1. In Week 13, mean plasma levels were increased and slightly above the LOD  in animals from both sexes in the early morning, consistent with the  nocturnal feeding habit, but decreased within few hours to below the LOD.

In Week 17, formate levels were below the LOD at the end of the 4-week  recovery period. Thus, there was no accumulation of formate detectable in plasma over  time.

======================================================
Examination      LOD        Males        Females
at (time) (µg/ml)     (µg/ml)        (µg/ml)
--------------------------------------------------------------------------------
62.5
Day 1
18:00 h                   < LOD           < LOD
24:00 h               max. 88.3
Day 2
06:00 h                max. 114.4
15:00 h                    < LOD           < LOD

Week 13 18:00 h                   < LOD           < LOD
next day, 06:00 h     mean: 158         mean: 96.6
next day, 15:00 h          < LOD          < LOD

End of 4-week recovery period            < LOD          < LOD
======================================================
Dose descriptor:: NOAEL
Remarks:: systemic toxicity; sodium formate
Effect level:: 3 185 other: mg/kg/day (calculated)
Sex:: male/female
Basis for effect level:: other: Read across from potassium diformate (1:2). No systemic toxicity or target organ
Dose descriptor:: NOAEL
Remarks:: systemic toxicity; potassium diformate
Effect level:: 3 000 mg/kg bw/day (actual dose received)
Sex:: male/female
Basis for effect level:: other: No systemic toxicity or target organ
Dose descriptor:: NOAEL
Remarks:: local irritation; potassium diformate
Effect level:: < 600 mg/kg bw/day (actual dose received)
Sex:: male/female
Basis for effect level:: other: Local irritation. Squamous cell hyperplasia in the forestomach of male and female rats seen at all tested dose levels.
: Key result
Critical effects observed:: no
Conclusions:: Overall, dietary administration of potassium diformate (1:2) to rats at 600, 1200, and 3000 mg/kg bw/d d for 13 weeks did not produce any overt systemic toxicity. Minor local irritation occurred in the forestomach of both sexes, with effects being seen in the males at all dose levels. Recovery was not complete in all animals after the 4-week treatment-free period. The authors did not derive NOAEL values, but they may be considered as follows:
Local irritation: NOAEL below 600 mg/kg bw/d, based on the irritation of the forestomach and the squamous cell hyperplasia seen at 600 mg/kg bw/d in both sexes.
Systemic toxicity: NOAEL(rat, 90 day study) 3000 mg/kg bw/day, as no adverse effect was seen at the highest dose tested. Taking stoichiometry and formula weights into consideration, this is equivalent to 3138 mg sodium formate/kg bw/d.
Executive summary:: The repeated dose of potassium diformate (1:2) was examined in a subchronic rat study according to the OECD guideline 408 and under GLP conditions. The guideline requirements were exceeded in that an absorption study and a recovery study were also included. Read-across from potassium diformate is justified because potassium diformate decomposes in aqueous solution into one molecule of each formate and formic acid, and the potassium ion. Thus, potassium diformate gives two formate anions on a molar basis. Local effects of the formic acid formed can be neglected because these are not expected with neutral salts (sodium, potassium, ammonium, calcium formate). Read across can therefore be limited to systemic effects. In the 13-week oral fed study potassium diformate (1:2) was administered in the diet at dose levels of 0, 600, 1200, and 3000 mg/kg bw/d to 10 rats/sex/dose. The doses were selected based on the results of a 7-day range finding study. Additional animals were used in satellite studies, i.e. a 4-week recovery study (0 and 3000 mg/kg bw/d, 10 rats/sex/dose), and in an absorption study (3000 mg/kg bw/d, 10 rats/sex/dose). In the absorption study, formate blood levels were below the level of detection (LOD; 62.5 µg/mL) in most instances. Slightly increased levels in the range 66 to 158 µg/mL were occasionally seen in some animals few hours after the nocturnal food uptake, but these declined to below the detection limit within few hours. Blood levels were also below the LOD at the end of the 4-week recovery period. These findings indicate that formate is rapidly metabolised in the rat, and that there was no accumulation over the 13-week treatment period. In the main study: no mortality or clinical signs of toxicity were seen. Male body weight gain was significantly decreased in all treated groups, whereas in females, body weight reduction gained a level of significance only in the high dose group animals. Slightly reduced food consumption was seen in groups with reduced body weights. Test substance consumption was close to the nominal doses, i.e. 0, 590, 1180, and 2880 (males) and 2950 (females) mg/kg bw/d, respectively. Reduced body weight gain and food consumption resulted possibly from a reduced palatability of the diet, and from the local irritation. There were no effects in ophthalmology. No clear effects were seen on haematology and clinical chemistry; some parameters gained a level of statistical significance, but this was of no biological or toxicological relevance. Organ weights of male and female rats were similar to those of the controls. Pathology revealed no remarkable finding except from local irritation, evidenced by the observation of a thickening of the limiting ridge in the stomach in all male groups and in the female high dose group at the end of the 13-week period. Histopathology revealed a dose-related increase in the incidence and severity of squamous cell hyperplasia in the forestomach of male and female rats. This effect was largely reversible in the 4-week recovery group. Overall, there was no overt systemic toxicity or target organ in this study. A dose-related body weight decrease was seen in all treated males and in the high dose female group, possibly as a result of the reduced palatability of the diet. The small but statistically significant changes in haematology and clinical chemistry parameters in the high dose animals were not of toxicological significance, due to the small changes and the lack of target organ toxicity. A specific target organ was the stomach, based on local irritation in the forestomach which caused a dose-related thickening of the stomach at all dose levels, and was confirmed to be squamous cell hyperplasia. This was considered to be a response to minor irritation by the test substance, rather than a toxic effect (Covance Laboratories, 1998).

Overall, dietary administration of potassium diformate (1:2) to rats at 600, 1200, and 3000 mg/kg bw/d d for 13 weeks did not produce any overt systemic toxicity. Minor local irritation occurred in the forestomach of both sexes, with effects being seen in the males at all dose levels. Recovery was not complete in all animals after the 4-week treatment-free period. The authors did not derive NOAEL values, but they may be considered as follows:

Local irritation: NOAEL below 600 mg/kg bw/d, based on the irritation of the forestomach and the squamous cell hyperplasia seen at 600 mg/kg bw/d in both sexes.

Systemic toxicity: NOAEL(rat, 90 day study) 3000 mg/kg bw/day, as no adverse effect was seen at the highest dose tested. Taking stoichiometry and formula weights into consideration, this is equivalent to 3138 mg sodium formate/kg bw/d.

Reference 3

Endpoint:: chronic toxicity: oral
Type of information:: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:: supporting study
Reliability:: 1 (reliable without restriction)
Rationale for reliability incl. deficiencies:: comparable to guideline study
Justification for type of information:: REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Justification of test substance: potassium diformate decomposes into one molecule of each formate and formic acid. Thus, potassium diformate gives two formate anions on a molar basis. Local effects of the formic acid formed can be neglected because these are not expected with neutral salts (sodium, potassium, ammonium, calcium formate). Read across can therefore be limited to systemic effects.
Reason / purpose for cross-reference:: read-across source
Reason / purpose for cross-reference:: read-across: supporting information
Qualifier:: equivalent or similar to guideline
Guideline:: OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:: no
GLP compliance:: yes
Limit test:: no
Specific details on test material used for the study:: - Name of test material (as cited in study report): "Formi LHS-Super"
- Substance type: salt
- Physical state: powder
- Analytical purity: 98.44 and 99%.
Species:: rat
Strain:: other: Crl:HanWist(Glx:BRL)BR
Sex:: male/female
Details on test animals or test system and environmental conditions:: Test animals
- Species: rat.
- Strain: Crl:HanWist(Glx:BRL)BR.
- Sex: male and female.
- Age: approx. 8 weeks at commencement of the experiment.
- Body weight: males: 186 to 275 g; females: 132 to 200 g.
- Number of animals: 20 per sex and dose group in the chronic toxicity study
- Housing: in groups of 5, in stainless steel mesh cages.
- Environment: routinely 19 to 25°C, relative humidity 40 to 70%,
- Air changes: 15 air  changes/hour.
- Photo period: 12-h light/dark cycle.

Treatment
- Dosing:  TS mixed into the diet.
- Diet: ground diet SQC Rat and Mouse Maintenance Diet No. 1, free access  to feed and tap water.
- Stability of TS in diet: examined; at least 7 days.
- Dose levels: 0, 50, 400, 2000 mg/kg bw/day.
- Dose selection: based on results from preliminary studies including a  13-week study in rats
Route of administration:: oral: feed
Vehicle:: other: feed
Details on oral exposure:: PREPARATION OF DOSING FEED:

DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): ground diet; mixed with TS in a mortar to give a premix, to which further diet was added as required and mixed in a blendor for five minutes.
- Storage temperature of food: at room temperatur ein sealed containers
Analytical verification of doses or concentrations:: yes
Details on analytical verification of doses or concentrations:: Analysis was performed in week 1, and at 12 or 13 week intervals thereafter
Duration of treatment / exposure:: 104 weeks
52 weeks: interim report
104 weeks: final report
Frequency of treatment:: 7 days/week
Dose / conc.:: 50 mg/kg bw/day (nominal)
Remarks:: Based on amount in the diet
Dose / conc.:: 400 mg/kg bw/day (nominal)
Remarks:: Based on amount in the diet
Dose / conc.:: 2 000 mg/kg bw/day (nominal)
Remarks:: Based on amount in the diet
No. of animals per sex per dose:: Main study: 50
Interim kill: 20
Control animals:: yes, concurrent vehicle
Details on study design:: - Dose selection rationale: based on the results of a 13-week study
Positive control:: not required
Observations and examinations performed and frequency:: CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Mortality: recorded twice daily. Clinical signs: observed daily.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Detailed physical examination of each animal was performed at weekly intervals.

BODY WEIGHT: Yes
- Time schedule for examinations: recorded before first treatment, at weekly intervals for 16 weeks, once every 4 weeks thereafter and before necropsy.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal group determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes. Determined weekly for the first 16 weeks, then one week in every 4 weeks thereafter.
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: investigation in all animals pre-treatment and in all control and high dose animals in Week 50
- Dose groups that were examined: investigation in all animals pre-treatment and in all control and high dose animals in Week 50

HAEMATOLOGY: Yes
- Time schedule for collection of blood: weeks 26, 52 and 103
- Method: 0.5 ml samples were withdrawn from 10 animals per group and sex in Weeks 26 and 52. Blood was taken from the lateral caudal vein of fasted animals and from decedents where possible.
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals: 10/sex/dose; all at termination
- Parameters examined: hemoglobin concentration, packed cell volume, mean cell volume, mean cell hemoglobin concentration, red blood cell count, total and differential white blood cell count, mean cell hemoglobin, and platelet count was performed and clotting times were determined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: weeks 26 and 52, and 103
- Animals fasted: Yes
- How many animals: 10/sex/dose; all at termination
- Parameters examined: aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, sodium, potassium, calcium, chloride, inorganic phosphorus, total protein, albumin, globulin, albumin/globulin ratio, total cholesterol, glucose, urea, total bilirubin, creatinine.

URINALYSIS: Yes
- Time schedule for collection of urine: samples were collected from 10 animals per group and sex in Weeks 25, 51 and 102. Where possible, urine and blood samples were taken from the same animals.
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters examined: microscopy of sediment, volume, specific gravity, urobilinogen. Semi-quantitatively: pH, protein, glucose, ketones, bilirubin, blood, reducing substances.

NEUROBEHAVIOURAL EXAMINATION: No

OTHER:

PATHOLOGY:
all animals killed at termination in Week 52 or found dead during the scheduled terminal necropsy period were considered to have completed the study, and any data collected was treated as such. All animals including decedents were necropsied. Animals were weighed and tissues were preserved:

------------------------------------------------------------
Adrenals#, aorta, brain#, cecum#, colon#, duodenum#, eyes#, femur with marrow and articular surface, gross lesions#, Harderian glands*, head, heart#, ileum#, jejunum#, kidneys#, lacrimal glands*, larynx, liver#, lungs with mainstem bronchi#, mammary (females)#, mandibular lymph nodes#, mesenteric lymph nodes#, muscle quadriceps, nasal turbinates*, nasopharynx*, esophagus#, optic nerves#, ovaries#, pancreas#, pituitary#, prostate#, rectum, salivary glands#, sciatic nerves#, seminal vesicles, skin#, spinal cord (cervical, lumbar, thoracic)#, spleen#, sternum with bone marrow#, stomach#, testes and epididymides#, thymus#, thyroids and parathyroids#, tissue masses#, tongue, trachea#, urinary bladder#, uterus#, vagina#, Zymbal glands*.
------------------------------------------------------------
(# = microscopically examined; * = retained in situ with the head)

HISTOPATHOLOGY:
Histopathology was performed on gross lesions, tissue masses and stomach from all animals and tissues denoted by (#) in the tissue list from control and high dose animals, and decedents from all groups.
Sacrifice and pathology:: GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:: Data from treated animals were compared with control data. In-life data: body weight gains, organ weights, food consumption and hematology variables were analyzed using ANOVA, separately for each sex. Dunnett's multiple test was used for comparison between control and treated group. A regression test was performed to determine whether there was a linear relationship between increasing dose and response.
Clinical signs:: no effects observed
Mortality:: no mortality observed
Body weight and weight changes:: effects observed, treatment-related
Description (incidence and severity):: Treatment-related findings were noted at 2000 mg/kg bw/d and included a statistically significant depression of body weight gain (by 27% in males and 19% in females; no effect at the low and intermediate dose levels).
Food consumption and compound intake (if feeding study):: no effects observed
Food efficiency:: not examined
Water consumption and compound intake (if drinking water study):: not examined
Ophthalmological findings:: no effects observed
Haematological findings:: no effects observed
Clinical biochemistry findings:: no effects observed
Urinalysis findings:: no effects observed
Behaviour (functional findings):: not examined
Immunological findings:: not examined
Organ weight findings including organ / body weight ratios:: no effects observed
Gross pathological findings:: effects observed, treatment-related
Description (incidence and severity):: At terminal kill, a thickening of the stomach confirmed as basal cell hyperplasia or foveolar epithelium hyperplasia in the majority of the high dose animals.
Neuropathological findings:: not examined
Histopathological findings: non-neoplastic:: effects observed, treatment-related
Description (incidence and severity):: At terminal kill, a thickening of the stomach confirmed as basal cell hyperplasia or foveolar epithelium hyperplasia in the majority of the high dose animals.
Histopathological findings: neoplastic:: no effects observed
Description (incidence and severity):: The spectrum of tumours was generally consistent with that expected in rats of this strain. There were no tumours of unusual nature or incidence indicative of specific target organ carcinogenicity in the stomach or any other tissue.
Other effects:: not specified
Details on results:: CLINICAL SIGNS AND MORTALITY
Clinical signs: There were no clinical signs related to treatment.
Mortalities: There was no pattern to indicate that the test substance had any effect on survival. Also, the incidence and pattern of morbidity observed in this strain was not changed by the test substance.
The distribution of deaths at the end of Week 52 is tabulated below.

==============================
Dose level Males Females
(mg/kg bw/d) [number of deaths (% survival)]
----------------------------------------------
0 1 (95) 2 (90)
50 0 (100) 0 (100)
400 1 (95) 3 (85)
2000 0 (100) 1 (95)
==============================

The distribution of deaths at the end of Week 104 is tabulated below.
==============================
Dose level Males Females
(mg/kg bw/d) [number of deaths (% survival)]
----------------------------------------------
0 8 (84) 11 (78)
50 12 (76) 9 (82)
400 11 (78) 13 (74)
2000 7 (86) 12 (76)
==============================
BODY WEIGHT AND WEIGHT GAIN
Body weight ands body weight gain for low and intermediate dose animals were comparable with that of the controls.
High dose animals had significantly reduced body weights at week 52, and at week 104 (lower by 27% in males, lower by 19% in females;
up to p
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Food consumption was comparable between all groups, with a tendency of an approx. 5% reduction in the high dose groups.

OPHTHALMOSCOPIC EXAMINATION
There was no effect on the eye noted.

HAEMATOLOGY
There was no consistent pattern of variation to indicate an effect of treatment.

CLINICAL CHEMISTRY
There was no consistent pattern of variation to indicate an effect of treatment.

URINALYSIS
There was no consistent pattern of variation to indicate an effect of treatment.

ORGAN WEIGHTS
There was no consistent pattern of variation to indicate an effect of treatment.

GROSS PATHOLOGY
The only treatment-related finding was an increase in the number of high dose animals with thick stomach
when compared with the controls. This was attributable to local irritation. The NOAEL was 50 mg/kg bw/day in teh 104-week study.

Group incidence of findings in the stomach, Week 52
======================================
Males Females
Group 1M 2M 3M 4M 1F 2F 3F 4F
mg/kg/day 0 50 400 2000 0 50 400 2000
---------------------------------------------------------
n 20 20 19 20 20 20 18 20

Thick 4 2 2 16 0 0 1 13
stomach
======================================
n = number of animals examined

HISTOPATHOLOGY:

NON-NEOPLASTIC
The spectrum of microscopic findings was generally consistent with that expected for rats of this strain. Treatment-related changes
were noted in the stomach and the salivary gland of high dose animals. For details see table under "Any other information on results".

In the stomach, basal cell hyperplasia was restricted to the squamous epithelium of the limiting ridge and appeared to correlate
with the necropsy finding of thick stomach. Foveolar epithelial hyperplasia was seen in both high dose animal groups, as were
slightly increased incidences of hyperkeratosis.
Acinar cell hypertrophy of the salivary gland was considered to be a minor cytological change and as a physiological response with
no toxicological significance.
Increased incidences of pancreas lobular atrophy were noted in the high dose groups; however, the incidences were comparable
between the controls and the high dose groups in the 104 Week study.

The incidence of non-neoplastic histopathology findings in other tissues was generally comparable with the control group and did
not indicate a systemic target organ toxicity.

NEOPLASTIC LESIONS:
The spectrum of tumors was generally consistent with that expected in rats of this strain. There were no tumors of unusual nature
or incidence indicative of specific target organ carcinogenicity in the stomach or any other tissue.
Dose descriptor:: NOAEL
Remarks:: ; systemic toxicity; sodium formate
Effect level:: 2 120 other: mg/kg/day (calculated)
Sex:: male/female
Basis for effect level:: other: Read across from potassium diformate. Absence of systemic toxicity.
Dose descriptor:: NOAEL
Remarks:: ; systemic toxicity; potassium diformate
Effect level:: 2 000 mg/kg bw/day (actual dose received)
Sex:: male/female
Basis for effect level:: other: Absence of systemic toxicity or target organ.
Dose descriptor:: NOAEL
Remarks:: ; local irritation toxicity; potassium diformate
Effect level:: 400 mg/kg bw/day (actual dose received)
Sex:: male/female
Basis for effect level:: other: Changes in stomach at 2000 mg/kg bw/day: increased incidences of foveolar epithelium and squamous cell hyperplasia.
: Key result
Critical effects observed:: no
Conclusions:: Local effects were seen in the stomach in both sexes at 2000 mg/kg bw/day. Systemic toxicity was not seen at any dose, including 2000 mg/kg bw/day, the highest dose tested. The NOAEL for systemic toxicity was therefore 2000 mg potassium diformate/kg bw/day in the rat, equivalent to 2092 mg sodium formate/kg bw/day.
Executive summary:: The repeated dose toxicity and oncogenicity of potassium diformate(1:2) was examined in a combined chronic toxicity and 104-week oral feed oncogenicity study in the rat similar to the OECD guideline 453 and under GLP conditions. Read-across from potassium diformate is justified because potassium diformate decomposes in aqueous solution into one molecule of each formate and formic acid, and the potassium ion. Thus, potassium diformate gives two formate anions on a molar basis. Local effects are attributable to the formic acid formed and can be neglected because these are not expected with neutral salts (sodium, potassium, ammonium, calcium formate). Read across can therefore be limited to systemic effects. The oral dietary administration of potassium formate (1:2) in a combined chronic toxicity/carcinogenicity study (equivalent to OECD guideline 453 and under GLP) to male and female Wistar rats (50 animals/dose/sex) for 104 weeks to rats at dose levels of 50, 400, and 2000 mg/kg bw/d was well tolerated without effects on clinical condition or survival. Treatment-related findings were noted at 2000 mg/kg bw/d and included a statistically significant depression of body weight gain (by 27% in males and 19% in females; no effect at the low and intermediate dose levels) and, at terminal kill, a thickening of the stomach confirmed as basal cell hyperplasia or foveolar epithelium hyperplasia in the majority of the high dose animals. These changes were less pronounced than in a previous 90-day rat study. There was no evidence of systemic target organ toxicity due to test substance administration, including the eyes. The spectrum of tumours was generally consistent with that expected in rats of this strain. There were no tumours of unusual nature or incidence indicative of specific target organ carcinogenicity in the stomach or any other tissue (Covance Laboratories, 2002). Overall, the local toxicity NOAEL for 52 and 104 weeks of treatment was considered to be 400 mg/kg bw/d, based on the local effects in the stomach and reduced body weight of the high dose rats. As no signs of systemic effects were noted, the NOAEL (rat, 104 week) for systemic toxicity is considered to be 2000 mg/kg bw/d. Taking stoichiometry and formula weights into consideration, the systemic toxicity NOAEL (rat, oral, 104-week) was 2092 mg sodium formate/kg bw/d.

Reference 4

Endpoint:: sub-chronic toxicity: oral
Type of 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:: guideline study
Remarks:: Justification of test substance: potassium diformate decomposes into one molecule of each formate and formic acid. Thus, potassium diformate gives two formate anions on a molar basis. Local effects of the formic acid formed can be neglected because these are not expected with neutral salts (sodium, potassium, ammonium, calcium formate). Read across can therefore be limited to systemic effects.
Justification for type of information:: REPORTING FORMAT FOR THE ANALOGUE APPROACH
[Please provide information for all of the points below. Indicate if further information is included as attachment to the same record, or elsewhere in the dataset (insert links in 'Cross-reference' table)]

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Justification of test substance: potassium diformate decomposes into one molecule of each formate and formic acid. Thus, potassium diformate gives two formate anions on a molar basis. Local effects of the formic acid formed can be neglected because these are not expected with neutral salts (sodium, potassium, ammonium, calcium formate). Read across can therefore be limited to systemic effects.
Reason / purpose for cross-reference:: read-across source
Reason / purpose for cross-reference:: read-across: supporting information
Qualifier:: according to guideline
Guideline:: OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:: yes
Remarks:: ; absorption of TS and reversibility of effects over a 4 week treatment-free period.
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): Formi-LHS; Formi LHS-Super
- Molecular formula (if other than submission substance): C2H3O4 K
- Molecular weight (if other than submission substance): 130.14
- Substance type: double salt
- Physical state: white powder
- Analytical purity: not reported; information available at the sponsor
- Impurities (identity and concentrations):
- Storage condition of test material: in sealed container at room temperature (10-30°C) in the dark
Species:: rat
Strain:: other: Crl:CDBR
Sex:: male/female
Details on test animals or test system and environmental conditions:: TEST ANIMALS
- Age at study initiation: 6 weeks
- Weight at study initiation: males: 166 to 208 g; females; 136 to 173 g.
- Housing: groups of 5 rats per cage
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): routinely 19 to 25°C
- Humidity (%): 40 to 70%
- Air changes (per hr): minimum 15/hour
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:: oral: feed
Vehicle:: unchanged (no vehicle)
Details on oral exposure:: - Dosing: test substance was mixed into the diet.
- Diet: ground SQC Rat and Mouse Maintenance Diet No. 1, free access to diet and to tap water.
- Stability of TS in diet: at least 2 weeks
- Replacement of diet: regularly within 2 weeks
- Dose levels:
- Main study: 0, 600, 1200, 3000 mg/kg bw/day.
- Recovery study: 0 and 3000 mg/kg bw/day.
- Absorption study: 3000 mg/kg bw/day.
Analytical verification of doses or concentrations:: yes
Details on analytical verification of doses or concentrations:: The enzymatic method "Formic Acid" by Boehringen Mannheim was used
Duration of treatment / exposure:: 13 weeks
Frequency of treatment:: 7 days/week
Dose / conc.:: 600 mg/kg bw/day (nominal)
Dose / conc.:: 1 200 mg/kg bw/day (nominal)
Dose / conc.:: 3 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:: Main study: 10 per sex and dose group.
Recovery study: 10 per sex of the control and the high dose groups.
Absorption study: 10 per sex of the high dose group.
Control animals:: yes, concurrent no treatment
Details on study design:: Post-exposure period: Satellite group: 4 weeks
Positive control:: Not required
Observations and examinations performed and frequency:: CAGE SIDE OBSERVATIONS: Yes
Mortality, clinical signs: observed at least daily.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: recorded before first treatment, at weekly intervals and  before necropsy.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal group 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

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: before treatment and in week 12
- Dose groups that were examined: all main-study animals were examined before treatment and  all control and high dose animals in week 12.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: week 13 in main study, week 17 in recovery study
- How many animals: all animals

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: week 13 in main study, week 17 in recovery study
- How many animals: week 13 in main study, week 17 in recovery study

URINALYSIS: Yes
- Time schedule for collection of urine: week 13 in main study, week 17 in recovery study
- Metabolism cages used for collection of urine: yes

OTHER:

ABSORPTION
0.5 ml blood samples were taken on Day 1 of feeding and during weeks 13  and 17 by tail vein  puncture. Plasma was separated and stored at below  -10°C until analysis of formate using the Formic Acid method by  Boehringer Mannheim.

GROSS PATHOLOGY

- All animals except those of the absorption study  were subjected to terminal necropsy after sacrifice.
- Organ weights: adrenals, kidneys, liver, testes and epididymides were  weighed before fixation.

HISTOPATHOLOGY
Histopathology: samples of the following tissues were fixed in 10%  buffered formalin. Eyes were fixed in Davidson's fluid.

Adrenals, aorta#, brain, cecum, colon, duodenum, eyes, femur with marrow  and articular surface#, gross lesions, Harderian glands#*, head#, heart,  ileum, jejunum, kidneys, lacrimal glands#*, larynx, liver, lungs, mammary  (females)#, mandibular lymph nodes, mesenteric lymph nodes, muscle  quadriceps#, esophagus, optic nerves#, ovaries, pancreas, pituitary,  prostate#, rectum, salivary glands, sciatic nerves, seminal vesicles#,  skin#, spinal cord (cervical, lumbar, thoracic)#, spleen, sternum with  bone marrow, stomach, testes and epididymides, thymus, thyroids an  parathyroids, tongue#, urinary bladder, uterus, nasal turbinates#*,  nasopharynx#*, vagina#, Zymbal glands*#.

# = tissue retained in fixative but not examined. * = retained in situ with the head

All organs and tissues in the control and high dose group animals were  histopathologically examined following hematoxylin and eosin staining.  Additionally, kidneys, lungs and gross lesions from the intermediate  groups were examined. Following observations in the stomachs of high dose animals, the stomachs  of the low and intermediate dose group animals were also examined,  together with the stomachs from the animals at the end of the recovery  period.
Sacrifice and pathology:: GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:: Absorption and recovery within 4 weeks
Statistics:: Body weight gains, necropsy body weight, hematology and clinical chemistry variables were analyzed using ANOVA, separately for each sex. Dunnett's multiple test was used for comparison between control and treated group. A regression test was performed to determine whether there was a linear relationship between increasing dose and response. Organ weights were analyzed using ANCOVA and Dunnett's test.
All recovery study data were analyzed using ANCOVA.
Clinical signs:: no effects observed
Mortality:: no mortality observed
Body weight and weight changes:: effects observed, treatment-related
Description (incidence and severity):: Male body weight gain was significantly decreased in all treated groups, whereas in females, body weight reduction gained a level of significance only in the high dose group animals. A dose-related body weight decrease was seen in all treated males and in the high dose female group, possibly as a result of the reduced palatability of the diet
Food consumption and compound intake (if feeding study):: effects observed, treatment-related
Description (incidence and severity):: Slightly reduced food consumption was seen in groups with reduced body weights.
Food efficiency:: not examined
Water consumption and compound intake (if drinking water study):: not examined
Ophthalmological findings:: no effects observed
Haematological findings:: effects observed, treatment-related
Description (incidence and severity):: The small but statistically significant changes in haematology and clinical chemistry parameters in the high dose animals were not of toxicological significance, due to the small changes and the lack of target organ toxicity.
Clinical biochemistry findings:: effects observed, treatment-related
Description (incidence and severity):: The small but statistically significant changes in haematology and clinical chemistry parameters in the high dose animals were not of toxicological significance, due to the small changes and the lack of target organ toxicity.
Urinalysis findings:: effects observed, treatment-related
Behaviour (functional findings):: not examined
Immunological findings:: not examined
Organ weight findings including organ / body weight ratios:: no effects observed
Gross pathological findings:: effects observed, treatment-related
Description (incidence and severity):: A specific target organ was the stomach, based on local irritation in the forestomach which caused a dose-related thickening of the stomach at all dose levels
Neuropathological findings:: not examined
Histopathological findings: non-neoplastic:: effects observed, treatment-related
Histopathological findings: neoplastic:: not specified
Description (incidence and severity):: A specific target organ was the stomach, based on local irritation in the forestomach which caused a dose-related thickening of the stomach at all dose levels, and was confirmed to be squamous cell hyperplasia. This was considered to be a response to minor irritation by the test substance, rather than a toxic effect
Details on results:: CLINICAL SIGNS AND MORTALITY
There were no treatment-related clinical observations or mortalities. Of the 3 mortalities observed (2 controls, 1 high dose female), necropsy  confirmed that all were associated with the orbital sinus blood sampling.

BODY WEIGHT AND WEIGHT GAIN
In males, there was a significant and dose-related reduction of body  weight gain. The overall difference from the controls (Weeks 0-13) was  statistically significant in all three groups (p<0.05, <0.01, and <0.001  in the low, intermediate, and high dose, resp.). In females, body weight gain was also reduced. Significance  was gained  only in the high dose group (p<0.01).

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
A slight dose-related reduction of food intake was noted in all male  groups. In females, a reduction was seen only in the high dose group. No  level of statistical significance was reached in any group. In the treatment-free recovery groups food intake was comparable to the  control rats.
For details of resulting doses see "Remarks on results". The authors argued that reduced body weight gain and food intake were probabl relate to reduced palability of the test diets.

OPHTHALMOSCOPIC EXAMINATION
No treatment related effects noted.

HAEMATOLOGY
There were small but statistically significant differences from the  controls (cf. table in "Remarks on results"). Clotting times were unchanged. Fluctuations in  white blood cell counts were noted for both sexes in all groups with no  clear dose-relation or significant trends. Observed changes were not regarded to be of biological or toxicological relevance.

CLINICAL CHEMISTRY
There were small but statistically significant differences from the  controls  (cf. table in "Remarks on results"). Clotting times were unchanged. Fluctuations in  white blood cell counts were noted for both sexes in all groups with no  clear dose-relation or significant trends. Observed changes were not regarded to be of biological or toxicological relevance.

URINALYSIS
Urinary parameters were similar to the controls in all groups except pH.  There was a trend towards an increased urinary pH (pH 8 or 9) in the  intermediate and high dose groups of both sexes at the end of the  treatment period.

After the 4-wk treatment-free period the majority of the high dose rats  had a urine pH of 6.0 or 7.0.

ORGAN WEIGHTS
At the end of the treatment period, group mean adjusted kidney, liver,  testes and epididymides weights in males were similar to the controls, as  were the mean weights of kidneys and liver in females. Reduced adrenal  weights compared to controls were noted in males (not significant) and in  females (p<0.05).

At the end of the treatment-free period, the mean liver weight of the  high dose males was slightly higher (p<0.01) than in controls.

GROSS PATHOLOGY
No remarkable findings, except thickening of the stomach, usually  involving the limiting ridge, at the end of the 13-week treatment period.  The effect was more pronounced in males, probably due to the higher  concentration of the TS in the diet (cf. table in "Remarks on results").

The effect subsided within the 4-week recovery period.

HISTOPATHOLOGY: NON-NEOPLASTIC
There was no other finding than a dose-related increase in the severity  and incidence of squamous cell hyperplasia in the stomach. No squamous  cell hyperplasia was noted in any of the male and female controls. The  histopathological finding correlated with the thick stomach findings  during necropsy.

The effect was largely reversible within the 4-week treatment-free period.

OTHER FINDINGS

Absorption study
Formate plasma levels following 3000 mg/kg bw/day were below the LOD  (Level of Detection, i.e. 62.54 µg/ml) in all but few animals on Day 1. In Week 13, mean plasma levels were increased and slightly above the LOD  in animals from both sexes in the early morning, consistent with the  nocturnal feeding habit, but decreased within few hours to below the LOD.

In Week 17, formate levels were below the LOD at the end of the 4-week  recovery period. Thus, there was no accumulation of formate detectable in plasma over  time.

======================================================
Examination      LOD        Males        Females
at (time) (µg/ml)     (µg/ml)        (µg/ml)
--------------------------------------------------------------------------------
62.5
Day 1
18:00 h                   < LOD           < LOD
24:00 h               max. 88.3
Day 2
06:00 h                max. 114.4
15:00 h                    < LOD           < LOD

Week 13 18:00 h                   < LOD           < LOD
next day, 06:00 h     mean: 158         mean: 96.6
next day, 15:00 h          < LOD          < LOD

End of 4-week recovery period            < LOD          < LOD
======================================================
Dose descriptor:: NOAEL
Remarks:: systemic toxicity; sodium formate
Effect level:: 3 185 other: mg/kg/day (calculated)
Sex:: male/female
Basis for effect level:: other: Read across from potassium diformate (1:2). No systemic toxicity or target organ
Dose descriptor:: NOAEL
Remarks:: systemic toxicity; potassium diformate
Effect level:: 3 000 mg/kg bw/day (actual dose received)
Sex:: male/female
Basis for effect level:: other: No systemic toxicity or target organ
Dose descriptor:: NOAEL
Remarks:: local irritation; potassium diformate
Effect level:: < 600 mg/kg bw/day (actual dose received)
Sex:: male/female
Basis for effect level:: other: Local irritation. Squamous cell hyperplasia in the forestomach of male and female rats seen at all tested dose levels.
: Key result
Critical effects observed:: no
Conclusions:: Overall, dietary administration of potassium diformate (1:2) to rats at 600, 1200, and 3000 mg/kg bw/d d for 13 weeks did not produce any overt systemic toxicity. Minor local irritation occurred in the forestomach of both sexes, with effects being seen in the males at all dose levels. Recovery was not complete in all animals after the 4-week treatment-free period. The authors did not derive NOAEL values, but they may be considered as follows:
Local irritation: NOAEL below 600 mg/kg bw/d, based on the irritation of the forestomach and the squamous cell hyperplasia seen at 600 mg/kg bw/d in both sexes.
Systemic toxicity: NOAEL(rat, 90 day study) 3000 mg/kg bw/day, as no adverse effect was seen at the highest dose tested. Taking stoichiometry and formula weights into consideration, this is equivalent to 3138 mg sodium formate/kg bw/d.
Executive summary:: The repeated dose of potassium diformate (1:2) was examined in a subchronic rat study according to the OECD guideline 408 and under GLP conditions. The guideline requirements were exceeded in that an absorption study and a recovery study were also included. Read-across from potassium diformate is justified because potassium diformate decomposes in aqueous solution into one molecule of each formate and formic acid, and the potassium ion. Thus, potassium diformate gives two formate anions on a molar basis. Local effects of the formic acid formed can be neglected because these are not expected with neutral salts (sodium, potassium, ammonium, calcium formate). Read across can therefore be limited to systemic effects. In the 13-week oral fed study potassium diformate (1:2) was administered in the diet at dose levels of 0, 600, 1200, and 3000 mg/kg bw/d to 10 rats/sex/dose. The doses were selected based on the results of a 7-day range finding study. Additional animals were used in satellite studies, i.e. a 4-week recovery study (0 and 3000 mg/kg bw/d, 10 rats/sex/dose), and in an absorption study (3000 mg/kg bw/d, 10 rats/sex/dose). In the absorption study, formate blood levels were below the level of detection (LOD; 62.5 µg/mL) in most instances. Slightly increased levels in the range 66 to 158 µg/mL were occasionally seen in some animals few hours after the nocturnal food uptake, but these declined to below the detection limit within few hours. Blood levels were also below the LOD at the end of the 4-week recovery period. These findings indicate that formate is rapidly metabolised in the rat, and that there was no accumulation over the 13-week treatment period. In the main study: no mortality or clinical signs of toxicity were seen. Male body weight gain was significantly decreased in all treated groups, whereas in females, body weight reduction gained a level of significance only in the high dose group animals. Slightly reduced food consumption was seen in groups with reduced body weights. Test substance consumption was close to the nominal doses, i.e. 0, 590, 1180, and 2880 (males) and 2950 (females) mg/kg bw/d, respectively. Reduced body weight gain and food consumption resulted possibly from a reduced palatability of the diet, and from the local irritation. There were no effects in ophthalmology. No clear effects were seen on haematology and clinical chemistry; some parameters gained a level of statistical significance, but this was of no biological or toxicological relevance. Organ weights of male and female rats were similar to those of the controls. Pathology revealed no remarkable finding except from local irritation, evidenced by the observation of a thickening of the limiting ridge in the stomach in all male groups and in the female high dose group at the end of the 13-week period. Histopathology revealed a dose-related increase in the incidence and severity of squamous cell hyperplasia in the forestomach of male and female rats. This effect was largely reversible in the 4-week recovery group. Overall, there was no overt systemic toxicity or target organ in this study. A dose-related body weight decrease was seen in all treated males and in the high dose female group, possibly as a result of the reduced palatability of the diet. The small but statistically significant changes in haematology and clinical chemistry parameters in the high dose animals were not of toxicological significance, due to the small changes and the lack of target organ toxicity. A specific target organ was the stomach, based on local irritation in the forestomach which caused a dose-related thickening of the stomach at all dose levels, and was confirmed to be squamous cell hyperplasia. This was considered to be a response to minor irritation by the test substance, rather than a toxic effect (Covance Laboratories, 1998).

Overall, dietary administration of potassium diformate (1:2) to rats at 600, 1200, and 3000 mg/kg bw/d d for 13 weeks did not produce any overt systemic toxicity. Minor local irritation occurred in the forestomach of both sexes, with effects being seen in the males at all dose levels. Recovery was not complete in all animals after the 4-week treatment-free period. The authors did not derive NOAEL values, but they may be considered as follows:

Local irritation: NOAEL below 600 mg/kg bw/d, based on the irritation of the forestomach and the squamous cell hyperplasia seen at 600 mg/kg bw/d in both sexes.

Systemic toxicity: NOAEL(rat, 90 day study) 3000 mg/kg bw/day, as no adverse effect was seen at the highest dose tested. Taking stoichiometry and formula weights into consideration, this is equivalent to 3138 mg sodium formate/kg bw/d.

Endpoint conclusion

Endpoint conclusion:: no adverse effect observed
Dose descriptor:: NOAEL
: 3 138 mg/kg bw/day
Study duration:: subchronic
Species:: rat
Quality of whole database:: Good quality 90-day and chronic toxicity studies are available for the read-across substance, potassium formate.
System:: gastrointestinal tract
Organ:: stomach

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:: no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:: no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:: no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:: no study available

Additional information

No repeated dose study on sodium formate was located, but the results from the read-across (analogue) potassium formate salt are used.

Subchronic oral feed rat study

The repeated dose toxicity of potassium diformate (1:2) was examined in a subchronic rat study according to OECD guideline 408 and GLP. The guideline requirements were exceeded in that an absorption study and a recovery study were also included. A read across from potassium diformate is justified because potassium diformate decomposes in aqueous solution into one molecule of each formate and formic acid, and the potassium ion. Thus, potassium diformate gives two formate anions on a molar basis. Local effects of the formic acid formed can be neglected because these are not expected with neutral salts (sodium, potassium, ammonium, calcium formate). Read across can therefore be limited to systemic effects. In the 13-week oral fed study potassium diformate (1:2) was administered in the diet at dose levels of 0, 600, 1200, and 3000 mg/kg bw/d to 10 rats/sex/dose. The doses were selected based on the results of a 7 day range finding study. Additional animals were used in satellite studies, i.e. a 4-week recovery study (0 and 3000 mg/kg bw/d, 10 rats/sex/dose), and in an absorption study (3000 mg/kg bw/d, 10 rats/sex/dose). In the absorption study, formate blood levels were below the level of detection (LOD; 62.5 µg/mL) in most instances. Slightly increased levels in the range 66 to 158 µg/mL were occasionally seen in some animals few hours after the nocturnal food uptake, but these declined to below the detection limit within few hours. Blood levels were also below the LOD at the end of the 4-week recovery period. These findings indicate that formate is rapidly metabolised in the rat, and that there was no accumulation over the 13-week treatment period. In the main study, no mortality or clinical signs of toxicity were seen. Male body weight gain was significantly decreased in all treated groups, whereas in females body weight reduction gained a level of significance only in the high dose group animals. A slightly reduced food consumption was seen groups with reduced body weights. Test substance consumption was close to the nominal doses, i.e. 0, 590, 1180, and 2880 (males) and 2950 (females) mg/kg bw/day, respectively. Reduced body weight gain and food consumption resulted possibly from reduced palatability of the diet, and from the local irritation. There were no effects on ophthalmology. No clear effects were seen on haematology and clinical chemistry; some parameters gained a level of statistical significance, but this was of no biological or toxicological relevance. Organ weights of male and female rats were similar to those of the controls. Pathology revealed no remarkable findings except from local irritation, evidenced by the observation of a thickening of the limiting ridge in the stomach in all male groups and in the female high dose group at the end of the 13-week period. Histopathology revealed a dose-related increase in the incidence and severity of squamous cell hyperplasia in the forestomach of male and female rats. This effect was largely reversible in the 4-week recovery group. Overall, there was no overt systemic toxicity or target organ in this study. A dose-related body weight decrease was seen in all treated males and in the high dose female group, possibly as a result of the reduced palatability of the diet. The small but statistically significant changes in haematology and clinical chemistry parameters in the high dose animals were not of toxicological significance, due to the small changes and the lack of target organ toxicity. A specific target organ was the stomach, based on local irritation in the forestomach which caused a dose-related thickening of the stomach at all dose levels, and was confirmed to be squamous cell hyperplasia. This was considered to be a response to minor irritation by the test substance, rather than a toxic effect (Covance Laboratories, 1998). Overall, dietary administration of potassium diformate (1:2) to rats at 600, 1200, and 3000 mg/kg bw/d for 13 weeks did not produce any overt systemic toxicity. Minor local irritation had occurred in the forestomach of both sexes, with effects being seen in the males at all dose levels. Recovery was not complete in all animals after the 4-week treatment-free period. The authors did not derive NOAEL values, but they may be considered as follows: Local irritation: NOAEL below 600 mg/kg bw/d, based on the irritation of the forestomach and the squamous cell hyperplasia seen at 600 mg/kg bw and day in both sexes. Systemic toxicity: NOAEL (rat, 90 day study) 3000 mg/kg bw/d, as no adverse effect was seen at the highest dose tested. Taking stoichiometry and formula weights into consideration, this is equivalent to 2077 mg formate anion/kg bw/day, or 3185 mg sodium formate/kg bw/d. This subchronic toxicity study in the rat is acceptable and satisfies the guideline requirement for a subchronic oral study (OECD 408).

Chronic oral feed rat study

The repeated dose toxicity and oncogenicity of potassium diformate(1:2) was examined in a combined chronic toxicity and 104-week oral feed oncogenicity study in the rat similar to the OECD guideline 453 and under GLP conditions. Read-across from potassium diformate is justified because potassium diformate decomposes in aqueous solution into one molecule of each formate and formic acid, and the potassium ion. Thus, potassium diformate gives two formate anions on a molar basis. Local effects are attributable to the formic acid formed and can be neglected because these are not expected with neutral salts (sodium, potassium, ammonium, calcium formate). Read across can therefore be limited to systemic effects. The oral dietary administration of potassium formate (1:2) in a combined chronic toxicity /carcinogenicity study (equivalent to OECD guideline 453 and under GLP) to male and female Wistar rats (50 animals/dose/sex) for 104 weeks to rats at dose levels of 50, 400, and 2000 mg/kg bw/d was well tolerated without effects on clinical condition or survival. Treatment related findings were noted at 2000 mg/kg bw/d and included a statistically significant depression of body weight gain (lower by 27% in males and 19% in females; no effect at the low and intermediate dose levels) and, at terminal kill, a thickening of the stomach confirmed as basal cell hyperplasia or foveolar epithelium hyperplasia in the majority of the high dose animals. These changes were less pronounced than in a previous 90-day rat study. There was no evidence of systemic target organ toxicity due to test substance administration, including the eyes. The spectrum of tumours was generally consistent with that expected in rats of this strain. There were no tumours of unusual nature or incidence indicative of specific target organ carcinogenicity in the stomach or any other tissue (Covance Laboratories, 2002). Overall, the local toxicity NOAEL for 52 and 104 weeks of treatment was considered to be 400 mg/kg bw/d, based on the local effects in the stomach and reduced body weight of the high dose rats. As no signs of systemic effects were noted, the NOAEL (rat, 104 week) for systemic toxicity is considered to be 2000 mg/kg bw/d. Taking stoichiometry and formula weights into consideration, this is equivalent to 1385 mg formate anion/kg bw/d, or systemic toxicity NOAEL(rat, oral, 104-week) 2120 mg sodium formate/kg bw/d. No target organ was identified. This study in the rat is acceptable and satisfies the guideline requirement for a chronic oral study (OECD 453).

Justification for classification or non-classification

Based on data for the read-across substance (analogue) potassium diformate, it can be concluded that sodium diformate is of low toxicity following repeated dosing and does not meet the criteria for classification for STOT-RE under CLP.

Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.

Target dose (mg/kg bw/d)	Consumption of TS (mg/kg bw/d)
	males	females
50	50.1	50.2
400	401.1	402.1
2000	2013.3	2015.3

Dose group	Nominal dose (mg/kg/day	Males	Females
Low	600	591	589
Intermediate	1200	1177	1178
High	3000	2879	2951

	Males			Females
	Low	Intermediate	High	Low	Intermediate	High
RBC			Incr*
MCV			Decr***		Decr*	Decr***
MCH			Decr**			Decr*
MCHC						Incr**
Platelet			Incr***
WBC			Incr**

	Males			Females
	Low	Intermediate	High	Low	Intermediate	High
Hb						Incr*
RBC						Incr*
HK						Incr*

	Males			Females
	Low	Intermediate	High	Low	Intermediate	High
AST			Incrtrend
AP			Incrtrend
Total bilirubin						Decr*
Total protein						Decr*

K			Decr***
Ca						Decr*

Creatinine			Decr***	Incr.*		Decr*
Urea				Incr.*	Incr.*
Total cholesterol				Incr.*	Incr.*

Globulin						Decr*
Albumin/globulin ratio						Decr*

Registration Dossier

Registration Dossier

Diss Factsheets

Sodium formate

Endpoint summary

Administrative data

Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen all close all

Reference 1

Reference 2

Reference 3

Reference 4

Endpoint conclusion

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Additional information

Justification for classification or non-classification

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	Males				Females
Dose group (mg/kg bw/day)	0	50	400	2000	0	50	400	2000
Stomach n	20	20	19	20	20	20	18	20
Basal/squamous cell hyperplasia	0	0	1	12	0	0	0	12
Foveolar epithelium hyperplasia	0	1	0	14	0	0	0	11
Erosion /ulcer	1	0	1	1	0	0	0	0
parakeratosis	1	0	1	2	0	0	0	0

Salivary gland n	20	0	0	20	20	0	0	20
Acinar cell hypertrophy	0			7	0			3

Pancreas n	20	0	0	20	20	0	0	20
Lobular atrophy	5			10	0			2

	Males			Females
	Low	Intermediate	High	Low	Intermediate	High
Week 13	1/10	3/10	7/10	0/10	2/10	5/10

Week 17	0/10	0/10	2/10	0/10	0/10	0/10

	Males			Females
	Low	Intermediate	High	Low	Intermediate	High
Week 13
n	10	10	10	10	10	10
Grade 0	6	1	0	6	2	0
Grade 1	2	6	4	4	6	5
Grade 2	2	3	5	0	2	3
Grade 3	0	0	1	0	0	2

Week 17
n			10			10
Grade 0			6			7
Grade 1			4			3
Grade 2			0
Grade 3			0			0

	Males			Females
	Low	Intermediate	High	Low	Intermediate	High
Week 13	1/10	3/10	7/10	0/10	2/10	5/10

Week 17	0/10	0/10	2/10	0/10	0/10	0/10

	Males			Females
	Low	Intermediate	High	Low	Intermediate	High
Week 13
n	10	10	10	10	10	10
Grade 0	6	1	0	6	2	0
Grade 1	2	6	4	4	6	5
Grade 2	2	3	5	0	2	3
Grade 3	0	0	1	0	0	2

Week 17
n			10			10
Grade 0			6			7
Grade 1			4			3
Grade 2			0
Grade 3			0			0

Registration Dossier

Registration Dossier

Diss Factsheets

Sodium formate

Endpoint summary

Administrative data

Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Reference 1

Reference 2

Reference 3

Reference 4

Endpoint conclusion

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Additional information

Justification for classification or non-classification

EU Privacy Disclaimer

Referenceopen all close all