Registration Dossier

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Administrative data

Description of key information

Lime (chemical) hydraulic is not acutely toxic via oral, inhalation or dermal routes.

Acute oral toxicity:

LD50 (rat) > 2000 mg/kg bw for calcium dihydroxide (Arcelin, 2007); read across to lime (chemical) hydraulic

LD50 (rat) > 2000 mg/kg bw for calcium carbonate (Bradshaw, 2008)

Acute inhalation toxicity:

4 -h LC50 (rat) >6.04 mg/L air for Flue dust, Portland cement (EC 270 -659 -9)(TNO, 2010); read across to lime (chemical) hydraulic

4 -h LC50 (rat) >3 mg/L air (highest technically achievable concentration) for calcium carbonate (Schuler, 2010)

Acute dermal toxicity:

LD50 (rabbit) > 2500 mg/kg bw for calcium dihydroxide (Kietzmann, 1994); read across to lime (chemical) hydraulic

LD50 (rat) > 2000 mg/kg bw for calcium carbonate (Bradshaw, 2010)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2007-03-22 to 2007-04-26
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Version / remarks:
, adopted 2006-03-23
Deviations:
yes
Remarks:
see "rationale for reliability"
GLP compliance:
yes (incl. QA statement)
Remarks:
signed November 2005
Test type:
up-and-down procedure
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: RCC Ltd, Laboratory Animal Services, CH-4414 Füllinsdorf/Switzerland
- Age at study initiation: 11 weeks
- Weight at study initiation: 185.1 to 206.5 g
- Fasting period before study: Approximately 16 to 19 hours; Food was provided again approximately 3 hours after dosing
- Housing: Individually in Makrolon type-3 cages with standard softwood bedding ("Lignocel", Schill AG, CH-4132 Muttenz) during treatment and observations
- Diet (ad libitum): Pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, batch no. 80/06 or 89/06 (Provimi Kliba AG, CH-4303 Kaiseraugst/Switzerland)
- Water (ad libitum): Community tap water from Füllinsdorf
- Acclimation period: Seven days under laboratory conditions

ENVIRONMENTAL CONDITIONS
- Temperature: 22 +/- 3°C
- Humidity: 30-70 %
- Air changes: 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12/12
No further information on the test animals was stated.
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Details on oral exposure:
VEHICLE: Polyethylene glycol 300 (PEG 300)
- Description: Colourless viscous liquid
- Source: FLUKA Chemie GmbH, CH-9471 Buchs
- Stability of vehicle: Stable under storage conditions
- Expiration date: October 2007
- Storage conditions: At room temperature (range of 20 +/- 5°C), light protected
- Justification for choice of vehicle: The vehicle was chosen after a non-GLP solubility trial which was performed before the study initiation date. Polyethylene glycol 300 was the most suitable vehicle selected for the test item.
- Lot no.: 1300225
- Concentration in vehicle: 0.2 g/mL

MAXIMUM DOSE VOLUME APPLIED: The application volume was 10 mL/kg body weight.

DOSAGE PREPARATION:
The dose formulations were made shortly (i.e. less than 30 minutes) before each dosing occasion using a magnetic stirrer and a spatula. The test item was weighed into tared glass beaker on a suitable precision balance and the vehicle added (weight:volume). The pH of the freshly prepared dose formulations was mesaured at each occasion following preparation and was found to be between pH 6-7 for the test item. Temperature of the freshly prepared dose formulations were generally between 20-23 °C. Homogeneity of the test item in the vehicle was maintained during administration using a magnetic stirrer. The stability of the test item in the vehicle was not determined in this test. This is not considerd to be required because of the short period between dose preparation and administration to the animals.
No further information on oral exposure was stated.
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
5 female rats
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations of mortality/viability was made daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on the day of dosing (test day 1; with the clinical signs) and twice daily during days 2 - 15. Observations of body weight were made on the day prior to the administration of the test item, on the day of administration of the test item (prior to administration of the test item), and on days 8 and 15. Observations on clinical signs were made daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after the administration on test day 1. Once daily during days 2-15.
- Necropsy of survivors performed: Yes
All animals were killed by carbon dioxide asphyxiation and discarded after macroscopic examinations have been performed.
- Other examinations performed: For clinical signs all abnormalities were recorded.
No further information on the study design was stated.
Statistics:
No statistical analysis was performed.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No deaths occured during the study.
Clinical signs:
other: Slightly ruffled fur was noted at the 30-minutes reading up to day 2, 4, 5 or 7 in four animals. Hunched posture was observed at the 30-minutes reading up to the 1-, 3- or 5-hour reading in these animals. Slightly to moderately ruffled fur at the 30-minut
Gross pathology:
No macroscopic findings were observed at necropsy.
Interpretation of results:
GHS criteria not met
Conclusions:
The median lethal dose for the test item Precal 50S (Calcium dihydroxide (hydrated lime)) after single oral administration to female rats, observed over a period of 14 days is: LD50 (rat): greater than 2000 mg/kg body weight.
According to the criteria specified by Directive 67/548/EEC and subsequent regulations, the test item is not classified.
According to the EC Regulation No. 1272/2008 and subsequent regulations, the test item is not classified.
The results can be read-across to lime (chemical) hydraulic, of which calcium hydroxide is the main constituent governing the toxicological properties.
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
The study examined whether the bioavailability of calcium carbonate and calcium citrate could be improved by reducing the particle size. Because nanoscale supplements are novel formulas in health foods, the acute toxicity, sub-chronic toxicity (see separate IUCLID entry) and bioavailability (see separate IUCLID entry) needs to be determined in both sexes of mice in advance.
Standard acute toxicological evaluations of the ICR mice were performed in the initial assessment of the effects of nanoscale calcium carbonate internalisation. Micro calcium carbonate and nano calcium carbonate were administered in a single dose by gavage using a gastric intubation tube. The animals were then observed for a period of 7 days.
GLP compliance:
no
Species:
mouse
Strain:
ICR
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: National Taiwan University Hospital, Taipei, Taiwan
- Age at study initiation: 8-10 weeks
- Fasting period before study: Animals were fasted overnight
- Diet: Pelleted mouse feed available ad libitum
- Water: Reverse osmosis water available ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-25 °C
- Humidity (%): 30-70%
- Photoperiod (hrs dark / hrs light): 12 h/12 h day/night cycle


Sham surgery (n = 6, SHAM) or bilateral ovariectomy (n = 30, OVX) was performed from a dorsal approach at 6 to 8 week old mice. Surgical removal of the ovaries is a well-represented approach to mimic the postmenopausal condition in mice. In the sham operation, ovaries were exteriorised and then replaced.
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
The test materials were administered in a single dose by gavage using a gastric intubation tube.
Doses:
Vitamin D3 (261 U/ kg bw) plus micro calcium carbonate: 1.3g/kg bw
Vitamin D3 (261 U/ kg bw) plus nano calcium carbonate: 1.3g/kg bw
No. of animals per sex per dose:
8 animals/sex/dose
Control animals:
yes
Details on study design:
On day seven, all the animals were weighed and any signs of toxicity were noted.
Sex:
male/female
Dose descriptor:
other: NOAEL
Effect level:
1 300 mg/kg bw
Mortality:
No mortality was observed.
Clinical signs:
other: Throughout the study, no unusual behaviour or differences between groups were observed (i.e. no laboured breathing, difficulty moving, hunching or unusual interactions with cage mates were observed).

Table 1: Body weight and mortality during the 7-day acute toxicity test

Dose

Sex (n)

Initial body weight

(g)

Final body weight

(g)

Mortality

dead/treated

Control

Male (8)

Female (8)

33.2 ± 3.3

32.5 ± 3.7

35.3 ± 3.9

34.2 ± 3.8

0/8

0/8

Micro calcium carbonate

(1.3 g/kg bw)

Male (8)

Female (8)

33.4 ± 3.2

32.7 ± 3.4

34.9 ± 3.2

34.3 ± 3.6

0/8

0/8

Nano calcium carbonate

(1.3 g/kg bw)

Male (8)

Female (8)

32.5 ± 3.6

33.1 ± 2.9

33.7 ± 4.1

34.9 ±3.8

0/8

0/8

Data are mean ± SE values

 

Conclusions:
No mortality or unusual behaviour were observed during the course of the study. The NOAEL for both micro calcium carbonate and nano calcium carbonate were reported to be 1.3 g/kg bw.
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
19 November 2007 to 11 December 2007
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate, Kent, UK
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: 205-237 g
- Fasting period before study: overnight prior to dosing
- Housing: suspended polypropylene cages furnished with soft woodflakes and fitted with stainless steel lids.
- Diet: ad libitum (except overnight prior to dosing and 3-4 hours after dosing)
- Water: ad libitum
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25 °C
- Humidity (%): 30 to 70%
- Air changes (per hr): At least 15 changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours of continuous artificial light in each 24 hour period.
Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg
Doses:
2000 mg/kg
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: general observations - at 0.5, 1, 2 and 4 hours after dosing then again at least once daily for 14 days; bodyweights were recorded on days 0, 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs.
Statistics:
No data
Preliminary study:
The female test animal did not die during the study following a single oral dose of 2000 mg/kg bw. There were no clinical signs during the preliminary study.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Sex:
female
Dose descriptor:
LD0
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortalities occurred.
Clinical signs:
other: No clinical signs of systemic toxicity were observed.
Gross pathology:
No adverse effects were observed.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral median lethal dose (LD50) of the test material in the female Sprague-Dawley rat was estimated to be > 2000 mg/kg bw
Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Common functional groups/mechanism of action.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Target: Lime (chemical) hydraulic [CAS 85117-09-5; See section 1.2 for information on purity.
Source: calcium dihydroxide [CAS 1305-62-0; EC 215-137-3] 98.2%

3. ANALOGUE APPROACH JUSTIFICATION
When administered via the oral route, lime (chemical) hydraulic dissociates in aqueous solutions to calcium- and hydroxyl ions, whereas calcium carbonate will be decomposed into calcium and CO2, and calcium silicate remains largely undissolved. The acute oral toxicity of the lime compound calcium dihydroxide (hydrated lime) was tested in a GLP compliant study according to OECD guideline 425 (Arcelin 2007). This test substance represents the main constituent of lime (chemical) hydraulic that governs any potential toxicological effects (pH shift). Calcium dihydroxide is therefore considered as functionally equivalent to the target substance (lime (chemical), hydraulic).

4. DATA MATRIX
Source: No studies available
Target: LD50 (rat) > 2000 mg/kg bw
Reason / purpose for cross-reference:
read-across source
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
22 march 2010 to 30 July 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
fixed concentration procedure
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
Adult, male and female Wistar outbred (Crl:WI[WU]) rats were obtained from a colony maintained under SPF-conditions by Charles River Laboratories. Three male and three female animals arrived on 7 April 2010 at an age of 7 weeks. They were taken in their unopened shipping containers to animal room 5.2.10, were checked for overt signs of ill health and anomalies, and were kept in quarantine. After approval of the lot (negative titers to micro-organisms tested in a few animals), quarantine was raised on 9 April 2010 and the animals were moved to 6.0.04, a similar animal room. The rats were separated by sex and uniquely identified by ear tattoo. Just before the start of the study on 21 April 2010, the animals were weighed. The average body weights of the rats on day 0 before exposure were 277.7 g and 190.3 g for the males and females, respectively. The duration of the acclimatization period was 12 days.

The animals were housed under conventional conditions in macrolon cages with bedding of wood shavings (Lignocel, type ¾, Rettenmaier, Rosenberg, Germany) and strips of paper (Enviro-dri, Lillico, Betchworth, England) as environmental enrichment. The number of air changes was about 10 per hour. The animals were housed three males or three females to a cage. During the exposure, the animals had no access to feed or water and were housed individually in the holders. After exposure, the animals returned to their living cages and were held for an observation period of 15 days before sacrifice and necropsy.

The temperature in the animal room was within the range of 20 – 24°C, except on 14 April 2010 when temperature was above 24°C (25.3°C at maximum) for a maximum period of 20 minutes, most probably due to cleaning activities with hot water. Relative humidity occasionally exceeded the range of 45 – 65% for short periods of time, probably due to cleaning activities or meteorological circumstances. On 24 April 2010, relative humidity in the animal room was below 45% (43.4% at minimum) for a maximum period of 20 minutes. A 12-hour light and 12-hour dark cycle was maintained.
Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
The animals were exposed to the test atmosphere in a nose-only inhalation chamber, a modification of the design of the chamber manufactured by ADG Developments Ltd., Codicote, Hitchin, Herts, SG4 8UB, United Kingdom (see Figure 1). The inhalation chamber consisted of a cylindrical stainless steel column, surrounded by a transparent cylinder. The column had a volume of ca. 50 liters and consisted of a top assembly with the entrance of the unit, a rodent tube section and at the bottom the base assembly with the exhaust port. The rodent tube section had 20 ports for animal exposure. Several empty ports were used for test atmosphere sampling, particle size analysis, measurement of oxygen concentration, temperature and relative humidity. The animals were secured in plastic animal holders (Battelle), positioned radially through the outer cylinder around the central column. Male and female rats were placed in alternating order. The remaining ports were closed. Only the nose of the rats protruded into the interior of the column.

The inhalation equipment was designed to expose rats to a continuous supply of fresh test atmosphere. To generate the test atmosphere, Flue Dust T –fine (REACH) was aerosolized using a dust feeder (Hethon Nederland BV, Hengelo, The Netherlands), a venturi and a jet mill (Institute’s design). The latter two were supplied with humidified compressed air. The resulting test atmosphere was led to the top inlet of the exposure chamber and from there to the noses of the animals. At the bottom of the unit, the test atmosphere was exhausted .

During the generation of the test atmosphere, the settings of the dust feeder and the air pressure on the jet mill were recorded at regular intervals (approximately each half hour). The airflow through the exposure chamber at the pressure settings of the jet mill and the venturi was determined in a preliminary experiment and was established to be 89.25 L/min. The animals were placed in the exposure unit after stabilization of the test atmosphere. The period between the start of the generation of the test atmosphere and the start of exposure of the animals was 27 minutes. The concentration C in a perfectly stirred test atmosphere in a chamber with volume V (L) and flow F (L/min) increases according to C = C ∞* (1 – e -(F*T/V) ), in which T (min) is the time and C ∞is the steady state concentration. Hence T 95 , the time it takes to reach 95% of the steady state concentration is given by e -(F*T95/V) = 0.05, from which it follows that T 95 was approximately 1.7 minutes. In practice, after the start of the generation the aerosol will spread from the top to the bottom and T 95 will be shorter than in a perfectly stirred chamber.


Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
ca. 4 h
Concentrations:
Actual concentration
The actual concentration (± standard deviation, number of measurements) of Flue Dust T –fine (REACH) in the test atmosphere during exposure was 6.04 g/m
3 (± 0.54, n=14; indicating that the concentration in the test atmosphere was amply above the target limit concentration of 5 g/m3.

Nominal concentration
The nominal concentration, calculated from the total amount of test material used (by weighing) and the air flow was 14.51 g/m3. This indicates a generation efficiency of 42%, which is within the range expected for aerosol generation.

No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
Behaviour, clinical signs, and mortality
The rats were visually inspected just before exposure, for reactions to treatment during the exposure, shortly after exposure, and at least once daily during the observation period.

Body weights
Body weights of the animals were recorded just before exposure (day 0), on days 1, 3 and 7, and on day 15 prior to necropsy. In addition, animals were weighed on day 2, because of their ill health.

Pathology
At the end of the 15-day observation period, animals were killed by exsanguination from the abdominal aorta under pentobarbital anaesthesia (intraperitoneal injection of sodium pentobarbital) and examined for gross pathological changes.
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 6.04 mg/L air (nominal)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
One female animal (No. 3) was found dead after approximately three hours of exposure.
Clinical signs:
other: All animals demonstrated a decreased breathing rate during exposure, which became more severe with time. Clinical signs observed shortly after exposure in surviving animals included slight to moderate laboured breathing, slight to moderate rales, slight
Body weight:
All animals showed substantial body weight loss during the first few days after exposure (Table 3). Although a small decrease in body weight gain is expected due to the constraint of the animals during exposure, effects of this magnitude are considered treatment-related. Body weights recovered during the second week of the 15-day observation period.
Gross pathology:
The nose of the female animal that died during exposure seemed blocked, with brown powder on the exterior of the nose. In addition, the animals’ lungs were red discoloured with several petechiae .
Necropsy of the surviving rats at the end of the observation period revealed petechiae in the medial lung lobe of one male animal, which was not considered to be related to the exposure. No other macroscopic abnormalities were observed at necropsy.
Interpretation of results:
Category 5 based on GHS criteria
Conclusions:
One female animal died during exposure. All other animals survived the 14-day observation period. It is therefore concluded that the 4-hour LC50 of Flue Dust T –fine (REACH) is above 6.04 g/m3 for male and female rats. According to the OECD Guideline for Testing of Chemicals 436, the test material should be classified as Category 5 of the Globally Harmonized Classification System (GHS); according to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) regulation (EC) No. 1272/2008, the test material does not need to be classified.
Executive summary:

The aim of the present study was to investigate the acute inhalation toxicity of Flue Dust T –fine (REACH) in rats for REACH registration and classification purposes. Therefore, three male and three female animals were exposed to a target limit concentration of 5 g/m 3 during a single period of four hours. Animals were kept for an observation period of 15 days before sacrifice. To characterize the toxicity, the animals were observed during exposure, shortly after exposure and daily thereafter, body weight was measured before exposure and 1, 2, 3, 7 and 15 days after exposure and the animals were examined for gross pathological changes at necropsy.

The actual concentration during exposure was 6.04 ± 0.54 g/m 3 . The mass median aerodynamic diameter was 3.5 and 3.8 µm (duplicate measurements) and the distribution of particle sizes had a geometric standard deviation (gsd) of 2.2 and 2.1, respectively.

Animals demonstrated a decreased breathing rate during exposure, which became more severe with time. One female was found dead after 3 hours of exposure. At necropsy, the nose of this animal seemed blocked and the animals’ lungs were red discoloured with several petechiae. Clinical signs observed after exposure in surviving animals included breathing abnormalities, soiled eyes, nose and fur, blepharospasm, encrustations around the eyes, nose and mouth, dark eyes, and sluggishness. Female animals were slightly more affected than males. Generally, abnormalities were no longer seen after 5 to 6 days. Substantial body weight loss was observed during the first few days after exposure, which recovered in the second week of the 15-day recovery period.

Macroscopic examination at necropsy revealed red discoloured lungs with several petechiae in the animal that died during exposure, and the animals’ nose seemed blocked. No treatment-related gross abnormalities were found in the surviving animals at the end of the recovery period.

Physical obstruction of the nose may well have played a role in the observed respiratory abnormalities and mortality. Since rats are obligatory nose breathers, the relevance of this model for human exposure may be questioned for these effects.

Endpoint:
acute toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Common breakdown products/mechanism of action.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Source: Flue dust, Portland cement (EC 270-659-9). UVCB inorganic substance. Contains approximately 26% calcium oxide, 5.5% calcium carbonate, 9% tricalcium silicate and 24% dicalcium silicate (Full composition provided in TMI).
Target: natural hydraulic lime [CAS 85117-09-5; See section 1.2 for information on purity.

3. ANALOGUE APPROACH JUSTIFICATION

Flue dust, Portland cement (Source substance) contains calcium oxide, which hydrolyses to calcium dihydroxide in aqueous systems, and calcium carbonate, as well as salts, such as tricalcium silicate and dicalcium silicate which also hydrolyse to form calcium dihydroxide as one of the products in aqueous solution. Calcium dihydroxide, calcium carbonate and dicalcium silicate are all constituents of lime (chemical) hydraulic (Target substance).
For Flue dust, Portland cement, the pH is described as >11.5, due to hydration reaction (See RSS for acute inhalation; TNO 2010). This compares to a pH of 12.3 determined for a saturated solution of lime (chemical) hydraulic (see section 4.8, O'Connor and Woolley, 2010). Both substances are classified as Skin Irritant 2 (H315: Causes skin irritation) and STOT SE3 (H335: May cause respiratory irritation). On the basis of the similar pH, the hydrolysis of the main constituents of Flue dust, Portland cement to calcium dihydroxide and similar skin and respiratory irritation potentials, it is concluded that it is acceptable to read-across from Flue dust, Portland cement (Source) to lime (chemical) hydraulic (Target) for acute inhalation toxicity and that the Source and the Target will have a common mode of action upon inhalation, particularly for short term exposure, i.e. local effects due to irritation caused by alkalinity.
This approach is supported by the Scientific Committee on Occupational Exposure Limits in their recommendation for calcium oxide and calcium hydroxide (SCOEL/SUM/137, February 2008) in which the alkaline effects of Portland cement are used as a surrogate for the alkaline effects of calcium oxide and hydroxide. In turn, this approach can also be applied to lime (chemical) hydraulic.
According to the SCOEL, systemic effects of CaO and Ca(OH)2 are negligible at normal occupational exposure levels, since exposure by inhalation (7.1 and 5.4 mg Ca/day, respectively) adds a negligible body burden of calcium compared to the tolerable upper intake level of 2500 mg/day.

Reason / purpose for cross-reference:
read-across source
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 6.04 mg/L air (nominal)
Based on:
test mat.
Exp. duration:
4 h
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
20 April 2010 to 04 May 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories B.V., Kreuzelweg 53, 5961 NM Horst, Netherlands
- Age at study initiation: 9 weeks
- Weight at study initiation: Males: 254.7 - 271.5 g; Females: 177.3 - 200.3 g
- Housing: Optimal Hygienic Conditions (OHC) inside a barrier system. Animals were housed in groups of 5 of the same sex in Makrolon® type-IV cages with wire mesh tops and standard softwood bedding including paper enrichment.
- Diet: Pelleted standard Harlan Teklad 2914C rat maintenance diet available ad libitum except during the period when the animals were restrained in exposure tubes.
- Water: Community tap water from Füllinsdorf available ad libitum in water bottles, except during the period when they were restrained in exposure tubes.
- Acclimation period: Seven days under laboratory conditions

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 30 - 70%
- Air changes: 10-15 per hour
- Photoperiod: 12 hour fluorescent light / 12 hour dark cycle
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Remarks:
Flow past exposure
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Inhalation exposure was performed using a flow-past, nose-only exposure system. The inhalation exposure system is located inside a ducted extraction cabinet.
- Exposure chamber volume: Not specified
- Method of holding animals in test chamber: The animals were confined separately in restraint tubes which were positioned radially around the exposure chamber.
- Source and rate of air: The flow of air at each tube was 0.97 L/min, which is sufficient to minimize re-breathing of the test aerosol as it is more than twice the respiratory minute volume of rodents. The actual airflow rate through the exposure chamber was recorded at approximately 30 minute intervals from the start of the inhalation exposure.
- Method of conditioning air: Not specified
- System of generating particulates/aerosols: A dust aerosol was generated from the test item using a CR3020 rotating brush aerosol generator connected to a micronizing jet mill. The aerosol generated was then discharged into the exposure chamber through a 63Ni charge neutralizer.
- Method of particle size determination: The particle size distribution of the test aerosol was determined three times during exposure using a 7 stage Mercer cascade Impactor. The particle size distribution was measured by gravimetrically analyzing the test item deposited on each stage of the cascade impactor.
Mass Median Aerodynamic Diameters (MMAD) and Geometric Standard Deviations (GSD) were calculated on the basis of the results from the impactor, using Microsoft Excel Software. The target range was 1 to 4 μm for the MMAD and between 1.5 and 3 for the GSD.
- Treatment of exhaust air: The exhaled air is exhausted through the gap near each feed tube out of the exposure chamber.
- Temperature, humidity, pressure etc in air chamber: The oxygen concentration, airflow rate, temperature and relative humidity of the test atmosphere was measured continuously during exposure using a calibrated device. The results were recorded manually and were reported at 30 minute intervals from the start of exposure and additionally at the end of exposure. The oxygen concentration was maintained above 19% during each exposure period.
Mean oxygen concentration: 20.9 vol%, Mean temperature: 22.4 °C; Mean relative humidity: 7.3%

TEST ATMOSPHERE
- Brief description of analytical method used:
Gravimetric determinations of aerosol concentration were performed eight times during exposure. The samples were collected on a Millipore®durapore filter, Type HVLP loaded in a 47 mm inline stainless steel filter sampling device. The filters were weighed before and immediately after sampling using a calibrated balance. The test aerosol concentration was calculated from the amount of test item present on the filter and the sample volume.
Chemical determinations of aerosol concentration were performed eight times during exposure using the filters collected for gravimetric determination. The filters were transferred into appropriate labeled vials, forwarded at ambient temperature the scientist responsible for formulation analysis and stored at room temperature (20 ± 5 °C) until analysis. The samples were analyzed using an AAS method as follows:
Instrument: Perkin-Elmer Model PE 2100 (software 4100) atomic absorption spectrometer
Flame: Acetylene flame/nitrogen(I) oxide
Slit Width: 0.7 nm high
Wavelength: Calcium: 422.7 nm
- Samples taken from breathing zone: yes

TEST ATMOSPHERE
- Particle size distribution: See table; the particle size of the generated aerosol was fairly stable during the whole exposure period.
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): The Mass Median Aerodynamic Diameters (MMAD) obtained from three gravimetric measurements of particle size distribution during the exposure were similar (MMAD between 2.28 μm and 2.89 μm).The MMADs were well within the target range of 1 to 4 μm, thus deposition of the particles can be assumed to have occurred in both the upper and the lower respiratory tract. In addition, the Geometric Standard Deviations (GSD) were within the target range of 1.5 to 3. Hence, the particle size distributions obtained were considered to be appropriate for acute inhalation toxicity testing.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
Atomic absorption spectrometry
Duration of exposure:
4 h
Remarks on duration:
Exposure was interrupted three times for a total of 8 minutes for cleaning purpose. Nevertheless, the animals were exposed for a period of 4 hours as those interruptions were accounted for.
Concentrations:
Target aerosol concentration: 5 mg/L air
Nominal aerosol concentration: 9.4 mg/L air
Mean measured gravimetric aerosol concentration: 3.0 mg/L air
Mean measured chemical aerosol concentration: 3.0 mg/L air

It was not possible to achieve the target concentration of 5 mg/L air as the achieved level was at the technical limit. Therefore, some variations in the aerosol concentrations occurred. The chemical aerosol concentration compared favourably to the gravimetrically determined concentration. This was in accordance with the high purity of the test item.
No. of animals per sex per dose:
5 animals/ sex
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations for viability were recorded once before exposure on the day of exposure (test day 1), three times during exposure, immediately and 1 h after exposure on test day 1 and twice daily during the observation period.
- Necropsy of survivors performed: yes: All animals were necropsied and examined for macroscopic abnormalities.
- Other examinations performed: Clinical signs: Each animal was examined three times during exposure, immediately and 1 h after exposure on test day 1 and once daily during the observation period. Only grossly abnormal signs were detectable during exposure, as the animals were restrained in the exposure tubes; Body weight: The body weight of each animal was recorded on test days 1 (before exposure), 2, 4, 8 and 15 (before necropsy).
Statistics:
No statistical analysis was performed as only one group was allocated to the study.
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 3 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
All animals survived the scheduled observation period.
Clinical signs:
other: Clinical signs consisted of ruffled fur only and were recorded for all animals starting one hour after exposure. This observation was noted for up to a maximum of test day 4. From test day 5 onwards all animals were free of clinical signs.
Body weight:
The body weight of animal No. 1 on test day 1 was considered to be incorrect, probably due to a weighing error. The body weight of this animal from test day 2 onwards was within the range of the other male animals. These animals showed slight body weight loss from test day 1 to test day 2. Marginal to slight body weight loss was also noted in three females from test day 1 to test day 2 and in one female up to test day 4. All these animals showed normal body weight thereafter as well as the remaining female animal.
Gross pathology:
There were no macroscopic findings during this study.

Table 1: Test atmosphere conditions

Recording time

(hours:min)

O2 concentration

(vol %)

Temperature

(° C)

Relative humidity

(% RH)

08:10

20.7

22.5

6.4

08:40

20.6

22.5

6.2

09:10

20.7

22.5

6.7

09:45

20.6

22.5

13.8

10:15

20.7

22.5

7.7

10:45

20.7

22.6

6.7

11:15

20.7

22.5

6.2

11:45

20.6

22.3

6.0

12:15

20.7

22.3

6.8

12.18

20.7

22.2

6.8

MEAN

20.6

22.4

7.3

St. Dev.

0.0

0.1

2.3

N

10

10

10

 

 

Table 2: Chemical determination of aerosol concentrations

Sampling time

(hours:min)

Sampling volume

(L)

Amount of test item on the filter

(mg)

Chemical aerosol concentration

(mg/L air)

08:25-08:30

5.1

29.49

5.8

09:25 - 09:30

5.1

10.84

2.1

09:44 - 09:48

4.0

5.799

1.4

10:03 - 10:07

4.0

7.885

2.0

10:25 - 10:29

4.0

14.14

3.5

10:56 - 11:00

4.0

11.90

2.9

11:30 - 11:34

4.0

13.11

3.2

11:55 - 11:59

4.0

12.37

3.1

Mean

3.0

St. Dev.

1.3

N

8

 

 

Table 3: Particle size distribution

Time

Total amount collected

(µg)

Percentages:

Stage No.

Effective cut-off diameter (µm)

MMAD

(µm)

GSD

Corr. Coeff.

(R)

%<4 µm

1

--

2

4.6

3

3.0

4

2.13

5

1.6

6

1.06

7

0.715

8

0.325

08:36

754

15.4

25.6

27.1

17.4

8.0

3.6

1.1

2.0

2.61

2.11

0.946

71.6

10:32

849

22.0

26.3

19.4

15.4

9.2

3.2

2.5

2.0

2.89

2.37

0.965

64.7

11:37

735

6.9

34.3

25.9

16.2

11.2

2.3

0.3

3.0

2.28

1.94

0.913

80.2

 

Table 4: Body weights

Day

Animal body weight (g)

1

2

3

4

5

Males

1

140.7a

264.6

271.5

268.9

254.7

2

255.7

252.5

264.7

262.1

243.3

4

264.8

262.2

271.9

270.7

254.7

8

283.3

279.8

282.5

286.3

266.5

15

305.8

300.5

306.1

310.2

282.2

Females

1

200.3

194.0

199.0

177.3

194.9

2

198.6

189.8

195.6

185.6

189.5

4

203.9

197.0

194.7

193.3

197.0

8

214.3

205.7

205.9

196.5

209.5

15

214.6

213.0

221.4

209.3

226.5

a Error undetermined

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The LC50 of Calcium carbonate (CAS: 471-34-1) obtained in this study was estimated to be greater than 3.0 mg/L air (chemically determined mean aerosol concentration). This was the highest technically achievable concentration and in accordance with Regulation (EC) No. 1272/2008 (EU CLP) the substance is not considered to be classified.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
6 040 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
yes
Remarks:
Purity and stability of test item missing. Weights of the animals during the observation period missing.
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
Purity and stability of test item missing. Weights of the animals during the observation period missing.
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Germany, External branch
- Weight at study initiation: 2.4 to 2.9 kg
- Housing: Individual cages
- Diet (ad libitum): Commercially available complete feed
- Water (ad libitum)
- Acclimation period: one week

ENVIRONMENTAL CONDITIONS
- Temperature: 21 +/- 2 °C
No further information on the test animals was given.
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Remarks:
The test item "Weisskalkteig" is most appropriately translated as "white lime paste". As such it is an aqeous paste-like preparation and does not require further moistening in order to ensure good skin contact.
Details on dermal exposure:
TEST SITE
- Area of exposure: On the day before the test sample was applied to the rabbits, the fur on their skin was sheared over an area of some 8 cm wide and 15 cm long. The test sample was applied evenly with a plastic spatula on an area of 100 cm^2 of shorn skin.
- Type of wrap if used: The treated skin area was covered with a gauze. The gauze was affixed using a "Peha-haft" dressing, so that the animal could not strip off the gauze.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The treated skin area was rinsed with water.
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): A quantity of 2.5 g/kg of body weight
No further infomration on dermal exposure was stated.
Duration of exposure:
24 hours
Doses:
2500 mg/kg
No. of animals per sex per dose:
5 males / 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days (including treatment day)
- Frequency of observations and weighing: The animals were clinically examined on a daily basis.
- Necropsy of survivors performed: Yes
On the last day of the observation phase, the rabbits were put down byintravenous injection of Pentobarbital (Nembutal R), and then immediately dissected in the Institute of Pathology, of the Hannover College of Veterinary Medicine.
- Other examinations performed: During the daily clinical observations, the general conditions were observed plus changes that occurred in the area of the fur and the treated skin, the eyes and the mucous membranes were registered and recorded.
No further information on the study design was stated.
Statistics:
No data
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 500 mg/kg bw
Mortality:
There were no indications of toxic effects from the test sample after dermal application.
Clinical signs:
other: Overall, redness, followed by scabbing, did occur in the area of the treated skin after the dressing was removed and the skin was cleaned. Slight redness after removal of the dressing was observed in one female rabbit. Moderate redness plus scabbing was o
Gross pathology:
Dissection of the rabbits yielded no particular results.
Other findings:
- Histopathology: The pathological-histological examination of the liver, kidneys, lung and skin yielded no particular results.
Interpretation of results:
GHS criteria not met
Conclusions:
The available data showed that the tested White lime paste caused no acute toxic effect after dermal application. However, thest did show skin irritating effects from the test sample.
According to the EC Regulation No. 1272/2008 and subsequent regulations, the test item is not classified.
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
06 January 2010 - 20 January 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories UK Limited, Bicester, Oxon, UK
- Age at study initiation: 8-12 weeks
- Weight at study initiation: at least 200 g
- Fasting period before study: No data
- Housing: The animals were housed in suspended solid floor polypropylene cages furnished with woodflakes. The animals were housed individually during the 24-hour exposure period and in groups of five, by sex, for the remainder of the study.
- Diet (e.g. ad libitum): Food (2014 Teklad Global Rodent diet) was available ad libitum.
- Water (e.g. ad libitum): Mains drinking water was available ad libitum.
- Acclimation period: At least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25 °C
- Humidity (%): 30-70%
- Air changes (per hr): at least fifteen changes per hour
- Photoperiod (hrs dark / hrs light): twelve hours continuous light (06:00 to 18:00) and twelve hours darkness
Type of coverage:
semiocclusive
Vehicle:
arachis oil
Details on dermal exposure:
TEST SITE
- Area of exposure: back and flanks of each animal
- % coverage: approximately 10% of the total body surface area
- Type of wrap if used: A piece of surgical gauze was placed over the treatment area and semi-occluded with a piece of self-adhesive bandage.


REMOVAL OF TEST SUBSTANCE
- Washing (if done): After the 24-hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with arachis oil BP to remove any residual test material.
- Time after start of exposure: 24 h


TEST MATERIAL
The appropriate amount of test material, moistened with arachis oil BP, was applied as evenly as possible to an area of shorn skin using a graduated syringe.
Duration of exposure:
24 h
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 animals/ sex/ dose
Control animals:
not specified
Details on study design:
The animals were observed for deaths or overt signs of toxicity 0.5, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days.

After removal of the dressings and subsequently once daily for fourteen days, the test sites were examined for evidence of primary irritation and scored according to the scale from Draize (1977).

Individual bodyweights were recorded prior to application of the test material on Day 0 and on Days 7 and 14.

At the end of the study the animals were killed by cervical dislocation. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths.
Clinical signs:
other: There were no signs of systemic toxicity or dermal irritation.
Gross pathology:
No abnormalities were noted at necropsy.

Table 1: Individual clinical observations and mortality data

Dose level (mg/kg)

Animal no. & sex

Effects noted after initiation of exposure (hours)

Effects noted after initiation of exposure (days)

0.5

1

2

4

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2000

Males

(1-1, 1-2, 1-3 & 1-4)

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Females

(2-1, 2-2, 2-3 & 2-4)

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0 = no signs of systemic toxicity

 

 

Table 2: Individual dermal reactions – Males

Dose level (mg/kg)

Animal no. & sex

Observation

Effects noted after initiation of exposure (days)

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2000

Males

(1-1, 1-2, 1-3 & 1-4)

Erythema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Oedema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0 = No reactions

 

 

Table 3: Individual dermal reactions – Females

Dose level (mg/kg)

Animal no. & sex

Observation

Effects noted after initiation of exposure (days)

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2000

Females

(2-1, 2-2, 2-3 & 2-4)

Erythema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Oedema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0 = No reactions

 

 

Table 4: Individual bodyweights and weekly bodyweight changes

Dose level (mg/kg)

Animal no. & sex

Bodyweight (g) at Day

Bodyweight change (g) during week

0

7

14

1

2

2000

1-0

Male

232

256

278

24

22

1-1

Male

235

255

270

20

15

1-2

Male

242

268

288

26

20

1-3

Male

224

246

270

22

24

1-4

Male

234

261

279

27

18

2-0

Female

220

228

239

8

11

2-1

Female

203

204

216

1

12

2-2

Female

211

216

218

5

2

2-3

Female

217

220

230

3

10

2-4

Female

212

213

220

1

7

 

 

Table 5: Individual necropsy findings

Dose level (mg/kg)

Animal no. & sex

Macroscopic observations

2000

Males

(1-1, 1-2, 1-3 & 1-4)

No abnormalities detected

Females

(2-1, 2-2, 2-3 & 2-4)

No abnormalities detected

 

 

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute dermal median lethal dose (LD50) of the test material in the Wistar strain rat was found to be greater than 2000 mg/kg bodyweight.
Endpoint:
acute toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Common mechanism of action.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Target: Lime (chemical), hydraulic [CAS 85117-09-5; See section 1.2 for information on purity.
Source: calcium dihydroxide [CAS 1305-62-0; EC 215-137-3] (no information on purity)

3. ANALOGUE APPROACH JUSTIFICATION
When administered to the skin for testing acute dermal toxicity properties (moistened with water, according to OEC TG 402), the main constituent of lime (chemical) hydraulic (target substance), calcium hydroxide dissociates into calcium- and hydroxyl ions in aqueous solutions, whereas calcium carbonate and silicate remain largely undissolved and are therefore of limited toxicological relevance. Calcium hydroxide (source substance) dissociates into Ca2+ and OH– ions. In view of the fact that both calcium hydroxide and lime (chemical) hydraulic result in the same “breakdown products” when administered in the appropriate test system, they can be considered as analogue substances.

4. DATA MATRIX
Source: No studies available
Target: LD50 (rabbit) > 2500 mg/kg bw

Reason / purpose for cross-reference:
read-across source
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 500 mg/kg bw
Based on:
test mat.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
2 500 mg/kg bw

Additional information

Acute oral toxicity:

No data are available for lime (chemical) hydraulic however a study is available for the read-across substance calcium dihydroxide. In a reliable GLP study performed to OECD TG 425 [Arcelin, 2007] calcium dihydroxide (purity=98.2%) was administered by gavage at 2,000 mg/kg bw to 5 female rats. The animals were examined for clinical signs and mortality for 14 days. There were no deaths during the study. Clinical signs were limited to slightly ruffled fur and hunched posture in four animals, whilst the fifth animal also showed slight sedation, deep respiration and rales. All clinical signs were reversed by the end of the study. There was a slight decrease in bodyweight of one animal but this was reversed by the end of the study. No macroscopic findings were observed at necropsy. The oral LD50 for rats was > 2000 mg/kg bw.

In a reliable GLP study performed to OECD TG 420 [Bradshaw 2008] calcium carbonate was administered by gavage at 2,000 mg/kg bw to 5 female rats (Sprague-Dawley). The animals were observed for clinical signs and mortality for 14 days. No mortalities were observed in the observation period and there were no clinical signs of systemic toxicity, adverse changes in bodyweight or macroscopic effects noted at necropsy. The oral LD50 for rats was > 2000 mg/kg bw.

On the basis of these studies it may be concluded that all grades of lime (chemical) hydraulic, including those with a calcium carbonate content of up to 40% are not acutely toxic via the oral route.

Acute inhalation toxicity:

No data are available for lime (chemical) hydraulic. However, data are available for the read-across substance Flue dust, Portland cement (EC 270-659-9). In a reliable GLP study performed to OECD TG 436 [TNO, 2010] three male and three female animals were exposed to a target limit concentration of 5 g/m3(6.04 g/m3measured) Flue dust, Portland cement for four hours. Animals were kept for an observation period of 15 days before sacrifice. Animals demonstrated a decreased breathing rate during exposure, which became more severe with time. One female was found dead after 3 hours of exposure. Clinical signs observed after exposure in surviving animals included breathing abnormalities, soiled eyes, nose and fur, blepharospasm, encrustations around the eyes, nose and mouth, dark eyes, and sluggishness. Female animals were slightly more affected than males. Generally, abnormalities were no longer seen after 5 to 6 days. Substantial body weight loss was observed during the first few days after exposure, which recovered in the second week of the 15-day recovery period. Macroscopic examination at necropsy revealed red discoloured lungs with several petechiae in the animal that died during exposure, and the animals’ nose seemed blocked. No treatment-related gross abnormalities were found in the surviving animals at the end of the recovery period. Physical obstruction of the nose may well have played a role in the observed respiratory abnormalities and mortality. Since rats are obligatory nose breathers, the relevance of this model for human exposure may be questioned for these effects. The 4-h LC50 in this study was > 6.04 g/m3air.

Based on the adopted Recommendation from the Scientific Committee on Occupational Exposure Limits (SCOEL) for Calcium oxide (CaO) and Calcium hydroxide (Ca(OH)2) the European Commission has established an IOELV of 4 mg/m³ respirable fraction (STEL) and 1 mg/m³ respirable fraction (8h-TWA) for both calcium dihydroxide and calcium oxide (Commission Directive (EU) 2017/164 of 31 January 2017) which is considered protective against long-term exposure to CaO and Ca(OH)2.

Two ethically approved human volunteer studies [Cain, 2004, 2008, section 7.10.1] also taken into account by SCOEL indicate chemosensory feel and local irritation of mucous membranes in the respiratory tract being the primary effect upon inhalation exposure of alkaline mineral materials (due to a pH shift).

A voluntary proposal for the classification of calcium hydroxide/calcium oxide is made as R37 / STOT SE 3 (H335 - May cause respiratory irritation), based on the findings of sensory irritation in humans.

In a reliable GLP study performed to OECD TG 403 [Schuler, 2010] calcium carbonate was administered by inhalation at a measured concentration of 3 mg/L air to 5 male and 5 female rats (Wistar) for 4 hours. The animals were observed for clinical signs and mortality for 14 days and on test day 15, all animals were sacrificed and necropsied. All animals survived the scheduled observation period. Ruffled fur was observed in all animals from the end of the exposure up to test day 4. Thereafter, all animals were free of clinical signs. Transient body weight loss was noted in most animals from test day 1 to test day 2 but normal body weight development was observed in general thereafter. No macroscopic findings were present at necropsy. The inhalation LC50 for rats was > 3 mg/L air. This was the highest technically achievable concentration.

The study on calcium carbonate demonstrates that it is not acutely toxic to rats up to the limit of the highest technically achievable concentration that could be tested. On this basis, calcium carbonate itself is not classified for acute inhalation toxicity. However, it may be assumed that grades of lime (chemical) hydraulic containing up to 40% calcium carbonate will still exhibit the chemosensory feel and local irritation of mucous membranes in the respiratory tract attributed to the presence of calcium dihydroxide, and hence the STOT SE 3 classification will be relevant equally for these grades.

Acute dermal toxicity:

No data are available for lime (chemical) hydraulic however a study is available for the read-across substance calcium dihydroxide.

In a reliable study performed to OECD TG 402 [Kietzmann, 1994] white lime paste (a mixture of calcium dihydroxide with water) was applied to the sheared skin of 5 male and 5 female rabbits (New Zealand White) under semi-occlusive conditions at a dose of 2500 mg/kg bw. After 24 hours, the treated area was washed with water. There were no deaths of clinical signs of systemic toxicity during the 14-day observation period. Irritation-related effects were seen, including redness and scabbing. No abnormalities were noted at necropsy. The LD50 was > 2500 mg/kg bw.

In a reliable GLP study performed to OECD TG 402 [Bradshaw 2010] calcium carbonate (nano) was applied as a paste in arachis oil to the skin of 5 male and 5 female rats (Wistar) at a dose of 2000 mg/kg bw and covered with a semi-occlusive dressing for 24 hours. After completion of the exposure period the skin was wiped with cotton wool moistened with arachis oil to remove any residual test material. There were no deaths or clinical signs of systemic toxicity during the 14 -day observation period. All animals showed expected bodyweight gains over the study period. No abnormalities were noted at necropsy. The LD50 was > 2000 mg/kg bw.

On the basis of these studies it may be concluded that all grades of lime (chemical) hydraulic, including those with a calcium carbonate content of up to 40% are not acutely toxic via the dermal route.

Justification for classification or non-classification

The available information indicates that lime (chemical) hydraulic is not acutely toxic or harmful. Therefore, classification of lime (chemical) hydraulic for acute toxicity is not warranted.