Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Based on a reliable acute oral toxicity study (OECD 423) the LD50 is determined to be >300 mg/kg bw and <2000 mg/kg bw for calcium nitrate. No reliable acute dermal toxicity study is available. An acute dermal toxicity study with Nitcal-K showed an LD50>2000 mg/kg bw.  An acute inhalation study is not considered necessary as the vapour pressure is assumed to be very low and the particle size of calcium nitrate is very high with 50% of the particles > 2000 micrometer. The read-across rationale can be found in the document attached in the appropriate target record and is fully incorporated in the CSR (see Appendix A).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
20 May 2010 - 16 Juni 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese Ministery of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147, November 2000, including the most recent partial revisions
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River, Deutschland, Sulzfeld, Germany.
- Age at study initiation: approx. 12 weeks old
- Weight at study initiation: body weights variation did not exceed +/- 20% of the sex mean.
- Housing: Group housing of 3 animals per cage in labeled Macrolon cages (MIV type; height 18 cm.) containing sterilized sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil, France) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom).
- Diet (e.g. ad libitum): Free access to pelleted roden diet (SM R/M-Z from SSNIFF Spezialdiaten GmbH, Soest, Germany).
- Water (e.g. ad libitum): Free access to tap water.
- Acclimatization period: at least 5 days before start of treatment under laboratory conditions.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.5 – 21.5ºC
- Humidity (%): 41 - 81%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light and 12 hours darkness per day
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle:2000 mg/kg (10 mL/kg) body weight and 300 mg/kg (10 mL/kg) body weight in water.
- Justification for choice of vehicle:The vehicle was selected based on trial formulations performed at NOTOX and on test substance data supplied by the sponsor.
Doses:
2000 mg/kg (10 mL/kg) body weight.
300 mg/kg (10 mL/kg) body weight.
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Clinical signs At periodic intervals (0, 2 and 4 hours) on the day of dosing (Day 1) and once daily thereafter, until Day 15.
Body weights Days 1 (pre-administration), 8 and 15 and at death (if found dead after Day 1).
- Necropsy of survivors performed: yes
- Other examinations performed:Mortality/Viability, clinical signs, body weight,
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 - < 2 000 mg/kg bw
Based on:
test mat.
Mortality:
Two animals at 2000 mg/kg were found dead on Day 2 and no mortality occurred at 300 mg/kg.
Clinical signs:
Clinical signs observed during the study period were as follows:
Dose level Clinical signs
2000 mg/kg Lethargy, flat and/or hunched posture, slow breathing and/or piloerection were noted in all animals on Day 1. In addition the surviving animal showed hunched posture on Day 2 and 3.
300 mg/kg hunched posture and piloerection were noted in three animals (3/6) on Day 1
Body weight:
The body weight gain shown by the surviving animals over the study period was considered to be similar to that expected of normal untreated animals of the same age and strain.
Gross pathology:
One animal that died on Day 2 at 2000 mg/kg showed many dark red foci in the glandular mucosa of the stomach and gelatinous state of the glandular mucosa. No abnormalities were found at macroscopic post mortem examination of the animals at 300 mg/kg.
Interpretation of results:
Category 4 based on GHS criteria
Remarks:
Classified as Category 4 according to Regulation (EC) 1272/2008
Conclusions:
The oral LD50 value of CALCIUM NITRATE TETRAHYDRATE in Wistar rats was established to be within the range of 300-2000 mg/kg body weight.

According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 1000 mg/kg body weight.


Based on these results:
-according to the Globally Harmonized System of Classification and Labeling of Chemicals (GHS) of the United Nations (2007), CALCIUM NITRATE TETRAHYDRATE should be classified as: harmful if swallowed (Category 4) for acute toxicity by the oral route.
-according to the Regulation (EC) No 1272/2008 on classification, labeling and packaging of substances and mixtures, CALCIUM NITRATE TETRAHYDRATE should be classified as Category 4 and should be labeled as H302: Harmful if swallowed
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
300 mg/kg bw
Quality of whole database:
The study has klimisch code 1.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
18 April - 2 May 2007
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
The study was performed with a substance analogue and the data are read across.
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Principles of method if other than guideline:
not applicable
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Age at study initiation: 9 weeks
- Weight at study initiation:
- Fasting period before study:
- Housing: indivvidually in labeled Macrolon cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days before start of treatment

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.8-22.9
- Humidity (%): 31-68
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 18 April 2007 To: 02 May 2007
Type of coverage:
occlusive
Vehicle:
water
Remarks:
selection based on trial formulations
Details on dermal exposure:
TEST SITE
- Area of exposure: 25 square cm for males and 18 square cm for females
- % coverage: 10% of total body surface
- Type of wrap if used: surgical gauze patch

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes, with tap water
- Time after start of exposure: 24 hrs

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg (10 ml/kg) body weigh
- Constant volume or concentration used: yes

Duration of exposure:
24 hours
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: daily observation for clinical signs, weekly determination of body weight
- Necropsy of survivors performed: yes (macroscopic examination only)
- Other examinations performed: none
Preliminary study:
not performed
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred
Clinical signs:
Males (recovery from these signs by day 3): lethargy, flat/hunched posture, uncoordinated movements, shallow respiration, piloerection, chromodacryorrhoea (snout), ptosis, hypothermia; Females (recovery from these signs by day 3): hunched posture, chromodacryorrhea.
Treated skin showed signs of irritation (scales, scabs, maculate erythema) during observation period
Body weight:
The mean body weight gain during the observation period was within the expected range
Gross pathology:
No abnormalities
Interpretation of results:
GHS criteria not met
Remarks:
Not classified according to Regulation (EC) 1272/2008
Conclusions:
Based on the results of an acute dermal toxicity study in rats, Nitcal /K does not have to be classified and has no obligatory labelling requirement for dermal toxicity according to the CLP Regulation.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
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. The read-across rationale can be found in the document attached in the target record.

Additional information

Oral

In an acute oral toxicity study with rats performed according to OECD 423, EU B.1tris and EPA and JMAFF guidelines, calcium nitrate gave an LD50 of >300 and <2000 mg/kg bw. At 2000 mg/kg bw 2/3 animals died at Day 2, at 300 mg/kg bw no animals died (0/6). Clinical signs observed during the study period were at 2000 mg/kg bw lethargy, flat and/or hunched posture, slow breathing and/or piloerection were noted in all animals on Day 1. In addition the surviving animal showed hunched posture on Day 2 and 3. At 300 mg/kg bw hunched posture and piloerection were noted in three animals (3/6) on Day 1. One animal that died on Day 2 at 2000 mg/kg bw showed many dark red foci in the glandular mucosa of the stomach and gelatinous state of the glandular mucosa. No abnormalities were found at macroscopic post mortem examination of the animals at 300 mg/kg bw. At this dose also the bodyweight gain was as was to be expected of untreated animals.

Dermal

No reliable study with calcium nitrate is available. In an OECD 402 acute dermal toxicity study with rats, Nitcal-K (potassium pentacalcium nitrate decahydrate) did show some signs of toxicity, but no mortality was observed at 2000 mg/kg bw. Therefore, the LD50 >2000 mg/kg bw. Clinical signs that were noted in males (recovery from these signs by day 3): lethargy, flat/hunched posture, uncoordinated movements, shallow respiration, piloerection, chromodacryorrhoea (snout), ptosis, hypothermia; Females (recovery from these signs by day 3): hunched posture, chromodacryorrhea. Treated skin showed signs of irritation (scales, scabs, maculate erythema) during observation period. The mean body weight gain during the observation period was within the expected range, no abnormalities at gross pathology, and no mortalities were noted.

Inhalation

No study is considered necessary. Calcium nitrate has an assumed very low vapour pressure, and its particle size is very high. Only 2% has a size <100 micrometer, and 50% is >2000 micrometer. Therefore, inhalation is not a likely route of exposure.

Justification for selection of acute toxicity – oral endpoint

One acute oral study is available.

Justification for selection of acute toxicity – dermal endpoint

One acute dermal study on the read-across substance Nitcal/K is available.

Justification for classification or non-classification

Justification for classification or non classification (calcium nitrate)

Based on the available data, calcium nitrate does not have to be classified according to the CLP Regulation with regard to acute dermal and inhalation toxicity.

However, the substance does need to be classified according to the CLP Regulation with Cat.4, H302 'Harmful if swallowed'.

Justification for classification or non classification (reaction mass containing calcium nitrate, magnesium nitrate and nitric acid)

This water solution contains ca. 26.8% calcium nitrate, 24.5% magnesium nitrate, 8.9% nitric acid and 39.5% water. As the water solution potentially may contain up to 18% of nitric acid, the classification mentioned in Chapter 3 was derived using this concentration.

It is considered justified to use the formula presented in CLP section 3.1.3.6.1 for the inhalation exposure route, although magnesium nitrate and calcium nitrate have not been studied for their acute inhalation toxicity. The mixture is an aqueous solution. Magnesium nitrate and calcium nitrate are not volatile and have a very low vapor pressure. It is not considered justified to assume that vapor from these substances need to be taken into account, also given their high solubility in water and their low acute oral and dermal toxicity.

For the other 2 exposure routes, the formula presented in CLP section 3.1.3.6.2.3 is used, as the concentration of nitric acid is >10% and no data is available for nitric acid for these 2 exposure routes.

Applying the formula presented in CLP section3.1.3.6.1 for the inhalation exposure route, the formula presented in CLP section 3.1.3.6.2.3 for the oral and dermal exposure routes,the ATE (oral) of 500 mg/kg bw for calcium nitrate and the ATE (inhalation) of 2.65 mg/L for nitric acid, the following classification is obtained for this aqueous solution containing up to 18% nitric acid:

Acute oral toxicity: Acute Tox. 4; H302 (ATEmix: (100-18)*500/26.8: 1530 mg/kg bw)

Acute dermal toxicity: Non-classified (ATEmix: >2000 mg/kg bw)

Acute inhalation toxicity: Acute Tox. 4; H332 (ATEmix: 100*2.65/18: 14.7 mg/L at 18% nitric acid) (in case the concentration of nitric acid would be <13%, no classification would be needed; ATEmix: 20.4 mg/L at this concentration)

See the CSR for all details.