Nitric acid, ammonium calcium salt

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No reliable study with nitric acid, ammonium calcium salt is present. An OECD 422 study with rats shows no effects at all up to doses of 1500 mg/kg bw/day of potassium nitrate. No effects were found on reproduction parameters, neither embryotoxic or developmental effects were seen.

No further studies are considered necessary. No fertility effects or effects on reproductive organs were observed up to and including the highest dose tested of 1500 mg/kg bw/d in an oral OECD 422 study in rats with potassium nitrate. In a repeated dose toxicity study with Nitcal-K (potassium pentacalcium nitrate) also no effects on reproduction organs were found. Calcium is an essential element for humans and the acceptable daily intake for calcium is 1-2.5 g/day (Dutch Voedingscentrum). After intestinal absorption of ammonium ion, ammonium is converted to urea by the liver, and subsequently excreted in urine. Urea is also an endogenous product of protein and amino acid catabolism, and consequently 20-35 g of urea is excreted daily in human urine. In relation to these ADI/background values exposure due to use as regulated under REACH is considered minimal.

JECFA and the former SCF derived an ADI of 3.7 mg/kg bw/d for nitrate, which was left unchanged by EFSA (EFSA, Nitrate in vegetables. Scientific opinion of the panel on contaminants in the food chain, 2008). This ADI was based on a 2-y study in rats with a NOEL of 500 mg sodium nitrate/kg bw/ (= 370 mg/kg bw/d nitrate)and a subchronic study with sodium nitrate in dogs with a NOEL of 370 mg/kg bw/d for nitrate. The OECD study with potassium nitrate in this dossier has a NOAEL of 1500 mg/kg bw/d which is equivalent to 62/101.1 x 1500 = 920 mg nitrate/kg bw/d, which is higher than the study on which the ADI was based. As the exposure assessment using this value indicates safe use, it is also considered safe for reproductive and developmental toxicity.

Moreover, nitric acid, ammonium calcium salt, has been used in fertilizers for over decades without an identifiable relation to reproductive or developmental effects.

Short description of key information:

No reliable study with CN-Nitcal is present. In a reliable OECD 422screening study in rats with potassium nitrate no effects were found up to the highest dose tested (1500 mg/kg bw/d). In addition, in repeated dose studies with potassium nitrate and Nitcal-K no effects on reproduction organs were found.  Nitric acid, ammonium calcium salt dissociates into Ca2+, NH4+ and nitrate ions. Nitrates are regulated within the body. The ammonium cation is not an essential ion, but a waste product from animal metabolism that is re-used in protein synthesis via glutamate. Depending on the species, ammonium will be directly excreted to the environment or converted to urea, which is less toxic. Ca2+ is also a necessary element of which the accepted daily dose is 1-2.5 g/day (Dutch Voedingscentrum). Together with the available data showing no effects, an additional study is therefore not considered necessary. The overall conclusion for CN-Nitcal is that there is no evidence that the substance may present a risk to fertility. The read-across rationale can be found in the document attached to the appropriate target record.

Justification for selection of Effect on fertility via oral route:

One study on the read-across substance Potassium nitrate is available. An expert statement has been written to justify the waiving of a one generation reproductive toxicity study.

Link to relevant study records

Reference

Reference 1

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: According to OECD 422 and GLP procedures

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

not specified

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

not specified

Details on mating procedure:

- Length of cohabitation: 14 days

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Animals on the study were divided between two subgroups (toxicity and reproductive subgroups). The exposure period for males and females in the toxicity subgroup was 28 days. The exposure period for reproductive subgroup males was at most 28 days. The exposure period for reproductive subgroup females was at most 53 days (14 days pre-mating, 14 days mating, and gestational and lactational periods up to lactation day 4).

Frequency of treatment:

daily

Remarks:

Doses / Concentrations:
0, 250, 750, and 1,500 mg/kg/day
Basis:

No. of animals per sex per dose:

5 males/group
10 females/group

Control animals:

yes

Details on study design:

- Dose selection rationale: Doses were selected based on parameters assessed in a range-finding study at concentrations up to 1,000 mg/kg/day.

Positive control:

not applicable

Parental animals: Observations and examinations:

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION: Yes

gestation length
gestation index
litter size

Litter observations:

PARAMETERS EXAMINED
The following parameters were examined in offspring:
number and sex of pups, survival indices, presence of gross anomalies, weight gain

Postmortem examinations (parental animals):

HISTOPATHOLOGY
Histology for reproductive subgroup animals was restricted to retained reproductive organs (and any other abnormalities observed at necropsy).

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

Reproductive performance:

no effects observed

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS):
all animals mated within 4 days

Dose descriptor:

NOAEL

Effect level:

>= 1 500 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects at highest dose tested

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Gross pathological findings:

no effects observed

Remarks on result:

not measured/tested

Reproductive effects observed:

not specified

Reproductive subgroup: There were no treatment-related deaths and no signs of overt clinical toxicity. There were no effects on body weight, food consumption, or food efficiency. Mating performance and fertility were unaffected by treatment. All animals mated within 4 days. There were no treatment-related effects on gestation length, gestation index, litter size, offspring survival indices, sex ration, offspring bodyweight, or macropathology for offspring.

 

Conclusions:

NOAEL:  1,500 mg/kg/day (general toxicity)
               1,500 mg/kg/day (reproduction/developmental toxicity)
LOAEL:  No adverse effects were seen on general toxicity endpoints. No adverse effects were seen on  reproduction/developmental toxicity endpoints.

Reference 2

Endpoint:

extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)

Type of information:

other: Expert statement

Adequacy of study:

key study

Study period:

2017

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Expert statement based on toxicity data available.

Principles of method if other than guideline:

Expert statement based on toxicity data available.

GLP compliance:

no

Justification for study design:

Expert statement based on toxicity data available.

Remarks on result:

not measured/tested

Remarks on result:

not measured/tested

Reproductive effects observed:

not specified

Conclusions:

Based on the expert statement provided as attached study report, an extended one-generation reproductive toxicity study does not need to be conducted for nitric acid, ammonium calcium salt.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 500 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The study has been performed according to OECD and/or EC guidelines and according to GLP principles. However, since the study was performed with a substance analogue and the data are read across, the Klimisch score is 2.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Description of key information

No reliable study with CN-Nitcal is present. In a reliable OECD422 screening study in rats with potassium nitrate no effects were found up to the highest dose tested (1500 mg/kg bw/d).  Nitric acid, ammonium calcium salt dissociates into Ca2+, NH4+ and nitrate ions. Nitrates are regulated within the body. The ammonium cation is not an essential ion, but a waste product from animal metabolism that is re-used in protein synthesis via glutamate. Depending on the species, ammonium will be directly excreted to the environment or converted to urea, which is less toxic. Ca2+ is also a necessary element of which the accepted daily dose is 1-2.5 g/day (Dutch Voedingscentrum).  The overall conclusion for nitric acid, ammonium calcium salt is that there is no evidence that the substance may present a risk for developmental toxicity. The read-across rationale can be found in the document attached to the appropriate target record.

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

January 7, 2002 – October 14, 2002

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study has been performed according to OECD and/or EC guidelines and according to GLP principles. However, since the study was performed with a substance analogue and the data are read across, the Klimisch score is 2.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

other: OECD 422

Deviations:

not specified

GLP compliance:

yes

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, NC
- Age at study initiation: males were 64 days of age on day of arrival; females were 61 days of age on day of arrival
- Weight at study initiation: 225 – 325 grams for male rats; 161 – 219 for female rats
- Fasting period before study:
- Housing: Animals were individually housed except for during the cohabitation and lactation period in wire mesh suspended stainless steel cages which conformed with GLP requirements, During cohabitation each pair of rats were housed in the male rat’s cage. Beginning no later than Day 20 of gestation, female rats were individually housed in polyethylene shoebox cages containing nesting material with wire mesh lids. Each dam and litter was housed in a common nesting box during the lactation/postnatal period.
- Diet (e.g. ad libitum): Purina Certified Rodent Diet #5002; as libitum
- Water (e.g. ad libitum): automatic dispenser; ad libitum and when females and litters were housed in shoebox cages via water bottle; ad libitum
- Acclimation period: 12 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 – 22
- Humidity (%): 43 – 66
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 hrs

IN-LIFE DATES: Jan 8, 2002 – Feb 23, 2002

Route of administration:

oral: gavage

Vehicle:

other: distilled water

Details on exposure:

Dose calculations: Individual doses were calculated based on the most recent weekly body weights and were adjusted each week to maintain the targeted dose level for all rats in the General Toxicity groups (i.e., mg/kg/day). For female rats in te Reproduction groups, individual doses were calculated based on the most recent body weights and were adjusted to maintain the targeted dose level (i.e., mg/kg/day). All doses were administered by volume of 10 mL/kg after correcting for concentration of the test mixture. Control animals received the vehicle only at the same volume as the test groups.

Dose preparations: The test substance (011101-3D) was ground in a Krups coffee mill (Model 203) prior to use and again upon receipt of additional test substance (020122-1D). A quantity sufficient to cover the grinding blade was added to the coffee mill and ground to a fine powder. Appropriate amounts of ground test material were accurately weighed into a 100 mL volumetric flask and diluted to volume with distilled water for each of the low, mid and high concentrations. Given that there was visual evidence (i.e. settling of test substance to bottom of cup) of a small amount of precipitate , the dosing mixtures were constantly stirred on a magnetic stir plate while being sampled to dose the test animals during the study.

Dose frequency: Each animal was dosed by oral intubation using a stainless steel balltipped gavage needle attached to an appropriate syringe. Dose administration was daily (7 days/week) for all adult animals as follows:
Male rats: Reproduction/General toxicity groups: during two-week premating and two-week mating periods for at least 28 days of exposure.
Female rats: Reproduction groups: during two-week premating, two-week mating, gestational and lactational periods. General Toxicity groups: for at least 28 days of exposure.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The test substance was assumed to be homogenous and stable at the time drawn by syringe to dose the test animals. Analysis of dosing mixtures, therefore, were limited to concentration verification of representative preparations intended for the control, low, intermediate and high dose levels in the study. Representative dosing mixtures of each concentration during the study were provided to the analytical department at three time points during the study (prior to animal exposure, near the middle (Test days 24 and 28) and near the end of the study (Test day 45). Vehicle control samples were inadvertently not submitted for analysis. Each dose preparation was evaluated by flame atomic absorption spectroscopy for total potassium (SOAC Official Method 975.03)(1988). A reference standard of potassium (999 ug/ml) , supplied by EM Science, was used for calibration.

Details on mating procedure:

- Length of cohabitation: 14 days

Duration of treatment / exposure:

Animals on the study were divided between two subgroups (toxicity and reproductive subgroups). The exposure period for males and females in the toxicity subgroup was 28 days. The exposure period for reproductive subgroup males was at most 28 days. The exposure period for reproductive subgroup females was at most 53 days (14 days pre-mating, 14 days mating, and gestational and lactational periods up to lactation day 4).

Frequency of treatment:

daily

Duration of test:

tox group: 28 days
repro group: 53 days

Remarks:

Doses / Concentrations:
0, 250, 750, and 1,500 mg/kg/day (Doses were selected based on parameters assessed in a range-finding study at concentrations up to 1,000 mg/kg/day)
Basis:
other: Doses were selected based on parameters assessed in a range-finding study at concentrations up to 1,000 mg/kg/day

No. of animals per sex per dose:

5 males and 5 females

Control animals:

yes, concurrent vehicle

Details on study design:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily for viability and cage-side observations were performed daily during acclimation, premating and mating, gestation, and lactation periods, except when scheduled detailed observations were conducted. All observations were recorded.


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Observations were performed and recorded at least once during the acclimation period for all male and female rats. Observations were performed and recorded approximately once per week during the premating and mating periods for females of the reproduction groups during the gestational days (GD7, GD14 and GD20) and lactational (LD4 only) periods. Female rats were evaluated for adverse clinical signs during parturition. Maternal behavior was checked on LD0 and LD4 and recorded. The date and clock time of all observations and/or mortality checks was recorded.

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were recorded at least twice during the acclimation period (including the day after receipt) before pairing and mating. All male rats were weighed weekly during the premating and mating periods and at the time of sacrifice. Mated females were weighted on GD0, 7, 14 and 20, and on the day of delivery (LD0) and LD4 (prior to terminal sacrifice). Females showing no evidence of mating were assigned a GD0 after cessation of cohabitation and body weights were measured accordingly. Females in the General Toxicity Groups were weighed weekly and at the time of sacrifice. Body weight gains were calculated for males and females during each appropriate interval.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Although not a feeding study, food consumption was determined weekly during the premating period (no mating period) for all males and females. Individual food consumption was measured and recorded weekly thereafter for the females in the general toxicity groups and during the gestational period for the females in the reproductive groups. Food consumption was also recorded on LD0 and LD4. The data were then used to calculate food efficiency for the associated intervals.

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Data from food consumption were used to determine food efficiency for associated intervals.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: See detailed clinical observations
- Dose groups that were examined:

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Day 28 of treatment
- Anaesthetic used for blood collection: Yes. (Isoflourane anesthesia ) collected via orbital sinus bleeding.
- Animals fasted: Yes, 18 hours prior to blood collection
- How many animals: 5 males and 5 females/dose level
- Parameters examined: hematocrit, hemoglobin concentration, erythrocyte count, total and differential leukocyte count, platelet count, prothrombin time and activated partial thromboplastin time.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on Day 28 of treatment
- Animals fasted: Yes. 18 hours prior to blood collection
- How many animals: 5 males and 5 females/dose level
- Parameters examined: calcium, phosphorus, chloride, sodium, potassium, fasting glucose, serum alanine aminotransferase (SGPT), serum aspartate aminotransferase (SGOT), gamma glutamyl transpeptidase, urea nitrogen, albumin, blood creatinine, total bilirubin, total serum protein, globulin, total cholesterol, alkaline phosphatase and magnesium measurements.

URINALYSIS: Yes / No / No data
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters examined:

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: during the final days of treatment
- Dose groups that were examined: Five male and five females/dose group (including controls).
- Battery of functions tested: sensory activity / grip strength / motor activity: excitability, autonomic function, gait and sensorimotor coordination (open field and manipulative evaluations), reactivity and sensitivity (elicited behavior) and other abnormal clinical signs including but not limited to convulsions, tremors, unusual or bizarre behavior, emaciation, dehydration, and general appearance. The rats were observed in random without the observer aware of the dose group.

Motor activity was also evaluated. Each animal was evaluated for a single one-hour phase, with photobeam counts accumulated over six, 10-minute intervals. Total movements (consisting of fine and active movements) was considered an appropriate measure for the assessment of potential behavior effects in this screening level study.)

Maternal examinations:

Necropsy: Gross necropsy of all males and females included an initial examination of
external surfaces and orifices, as well as the cranial, thoracic and abdominal cavities and
their contents. Rats were examined for gross lesions. Gross lesions were retained in
neutral buffered. 10% formalin (NBF).
• Reproductive Groups: Special attention was paid to the organs of the
reproductive system. For male rats, the testes and epididymides. seminal vesicles
with coagulating gland and prostate were retained. The testes and epididymides
were weighed. The testes were fixed in Bouin's solution for 4-12 hours
(depending on size) before being retained in 70% alcohol For females, special
care was taken to examine the uterus for the presence of conceptuses .. For each
female, the ovaries were weighed; the ovaries, uterus and accompanying
structures, and a mammary gland were retained in NBF. Subsequently, the fixed
uteruses from all adult female rats (including those that did not deliver litters and
those that delivered pups) were stained with potassium ferricyanide to confirm
pregnancy status and to determine post-implantation toss.

Rats were evaluated for gross lesions. Pregnancy status and uterine contents of
female rats were recorded.. Aborted fetuses and/or delivered pups were
examined to the extent possible. Organs and tissues were excised, weighed,
preserved and/or stained and implantation sites counted as described for 1hose
animals sacrificed by design.

• General Toxicology Groups: At scheduled sacrifice, all survivors were
euthanized by exsanguination from the abdominal aorta under isoflourane
anesthesia. All animals were subjected to a full necropsy that included
examination of the external surface of the body, all orifices and the thoracic.
abdominal and cranial cavities and their contents. The liver, kidneys, adrenals,
brain, heart, thymus, spleen. ovaries, testes and epididymides (of all animals
sacrificed by design) were weighed wet as soon as possible after dissection to
avoid drying. The following organs and tissues from all animals were preserved
in NBF for possible future histopathological examination: all gross lesions,
lungs, brain~ including sections of the medulla/pons. cerebellar cortex and
cerebral cortex, spinal cord (3 levels: cervical, mid-thoracic, and lumbar), eyes,
pituitary. thyroid/parathyroid, thymus, trachea, heart. sternum with bone marrow,
salivary glands, liver, spleen, kidneys, adrenals, pancreas, ovaries, testes, uterus
(with attached urinary bladder, cervix and vagina), accessory sex organs
(epididymides, prostate, and seminal vesicles). female mammary gland., skin.
aorta. esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum,
representative lymph node, and peripheral nerve (sciatic).

HISTOPATHOLOGY: Yes
Organs: Histopathologic examination was performed on the preserved organs and tissues of the Reproductive and General Toxicity Group animals from the control (Groups I and II) and high dose (Groups VII and VIII). In addition, gross lesions of potential toxicological significance noted in any test groups were also examined. Microscopic findings were graded.

Statistics:

Mean and standard deviations were calculated for all quantitative data. Except for clinical pathology data were the contract laboratory, Huntingdon Life Sciences, elected to use statistics to aid in the data interpretation; no further statistical treatment of the study was conducted due to small group sizes.

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
see IUCLID 7.8.1 and 7.5.1

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 500 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 500 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Remarks on result:

not measured/tested

Abnormalities:

not specified

Developmental effects observed:

not specified

Reproductive subgroup: There were no treatment-related deaths and no signs of overt clinical toxicity. There were no effects on body weight, food consumption, or food efficiency. Mating performance and fertility were unaffected by treatment. All animals mated within 4 days. There were no treatment-related effects on gestation length, gestation index, litter size, offspring survival indices, sex ration, offspring bodyweight, or macropathology for offspring.

WATER CONSUMPTION AND COMPOUND INTAKE

There were no effects of test-substance treatment on food consumption in males. There were no effects of food consumption on females during pre-mating; during Weeks 3, 4, and 5 for females in the General Toxicity Group; or during gestation and lactation. Food consumption was not measured during the mating period. Food efficiency was also unaffected by treatment.

 

ORGAN WEIGHTS:

Mean organ weights and organ-to-body weight ratios for both the Reproduction and General Toxicity test groups, in general, were considered comparable to their respective control groups. Any slight increases or decreases from the control were incidental, not dose-related and judged not to be of toxicological importance.

 

GROSS PATHOLOGY:

There were a number of gross observations correlated to microscopic findings. The dilatation of the uterus (horns) observed in several female rats from the General Toxicology Group (Group II", Animal #8133 and 8134, Group VIII - Animal #8205, 8206, 8207 and 8208) was considered to be a function of the· estrus stage (generally proestrus, but sometimes early estrus). These gross observations and others, along with their microscopic correlates, were all considered incidental background findings not attributable to administration of the test substance.

Conclusions:

Based on the results of a combined repeated dose toxicity study with a reproduction/ developmental toxicity screening performed according to OECD 422 guideline and GLP principles, the NOAEL of potassium nitrate was found to be >= 1,500 mg/kg/day for developmental toxicity.

Reference 2

Endpoint:

developmental toxicity

Type of information:

other: Expert statement

Adequacy of study:

key study

Study period:

2017

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Expert statement based on toxicity data available

Principles of method if other than guideline:

Expert statement based on toxicity data available.

GLP compliance:

no

Species:

rabbit

Remarks on result:

not measured/tested

Remarks on result:

not measured/tested

Developmental effects observed:

not specified

Conclusions:

Based on the expert statement provided as attached study report, a developmental toxicity study does not need to be conducted for nitric acid, ammonium calcium salt.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 500 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The study has been performed according to OECD and/or EC guidelines and according to GLP principles. However, since the study was performed with a substance analogue and the data are read across, the Klimisch score is 2.

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

No reliable study with nitric acid, ammonium calcium salt is present. An OECD 422 study with rats shows no effects at all up to doses of 1500 mg/kg bw/day of potassium nitratee. No effects were found on reproduction parameters, neither embryotoxic or developmental effects were seen.

No further studies are considered necessary. No developmental effects were observed up to and including the highest dose tested of 1500 mg/kg bw/d in an oral OECD 422 study in rats with potassium nitrate. Calcium is an essential element for humans and the acceptable daily intake for sodium is 1-2.5 g/day (Dutch Voedingscentrum). In relation to this value exposure due to use as regulated under REACH is considered minimal.

JECFA and the former SCF derived an ADI of 3.7 mg/kg bw/d for nitrate, which was left unchanged by EFSA (EFSA, Nitrate in vegetables. Scientific opinion of the panel on contaminants in the food chain, 2008). This ADI was based on a 2-y study in rats with a NOEL of 500 mg sodium nitrate/kg bw/ (= 370 mg/kg bw/d nitrate) and a subchronic study with sodium nitrate in dogs with a NOEL of 370 mg/kg bw/d for nitrate. The OECD study with potassium nitrate in this dossier has a NOAEL of 1500 mg/kg bw/d which is equivalent to 62/101.1 x 1500 = 920 mg nitrate/kg bw/d, which is higher than the study on which the ADI was based. As the exposure assessment using this value indicates safe use, it is also considered safe for reproductive and developmental toxicity.

Moreover, nitric acid, ammonium calcium salt, has been used in fertilizers for over decades without an identifiable relation to reproductive or developmental effects.

Justification for selection of Effect on developmental toxicity: via oral route:

One study on the read-across substance potassium nitrate is available. An expert statement has been written to justify the waiving of a developmental study.

Justification for classification or non-classification

The available data do indicate that no classification is required for nitric acid, ammonium calcium salt according to Regulation (EC) 1272/2008.