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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

The REACH regulation requires an evaluation of the reproductive and developmental toxicological properties of substances manufactured or imported at >1000 tpa. In the case of Synthetic Wollastonite no reproductive or developmental toxicology data are available from studies performed on the substance itself. However, there are data available from repeat dose toxicity studies carried out on the analogue substances kieselguhr soda ash flux-calcined and silicon dioxide, as well as data from developmental studies carried out on Silicic acid, calcium salt that may be read-across to Synthetic Wollastonite.


Read-Across Justification for developmental toxicity


Synthetic wollastonite is a UVCB substance, the main constituents of which are amorphous in nature. It also contains crystalline silica. The percentage of crystalline silica may range up to 1.5% (<=0.21% respirable). The analogues have been chosen for their similarity in structure and properties to Synthetic wollastonite. It is clear from a number of studies carried out on amorphous and crystalline silica and the analogue substance Silicic acid, calcium salt that results were consistent between the two substances and that there was no effect from the presence of the calcium ion. Moreover, it is well documented that these substances have a low potential for hazard to health and the environment. 


The toxicological properties of both forms are well described and may be used to predict the developmental effects of exposure to Synthetic wollastonite, and to support the available data for this substance.



In terms of the oral route a reliable 90-day oral toxicity study performed using kieselguhr soda ash flux-calcined is available [Wolfe 1992; IUCLID Section 7.5.1]. In this study rats were dosed with the substance at 1% (average of 698.3 mg/kg bw/day) and 5% (average of 3737.9 mg/kg bw/day). Histopathology revealed no effects on reproductive organs and did not produce any treatment-related effects in urine silica content. In a supporting 90-day oral study [Bertke 1963; IUCLID Section 7.5.1] silica analysis was performed on the liver, kidneys and spleen of rats fed diatomaceous earth at 5%. There was no significant increase in the percentage of residual silica in liver, kidneys and spleen of the test animals compared to control animals which received none of the test material. The data from these studies demonstrate that ingestion of silica does not affect the residual amounts which are found naturally in the body.
UNEP (2004) reports the outcomes of a number of studies on reproduction in the SIAR for synthetic amorphous silica and silicates. An early limited one-generation study on Wistar rats [Degussa 1963] gave no evidence of any adverse effects arising from long-term feeding of Aerosil (500 mg/kg bw/d) to both genders for a premating period of 4.5 months and continued up to 6 months [Degussa 1963]. Five pregnant test females and four pregnant untreated control females delivering 45 and 37 pups, respectively, were included in this test. The study had shortcomings with respect to the low number of pregnant animals used and the mating ratio of 1(m):5(f) which was too low according to current standards.
Within the scope of a comprehensive and valid testing programme, synthetic amorphous silica and silicates (non-amorphous silica and crystalline silica) were examined for embryotoxic and developmental effects during the gestation phase in various animals species, rat, mouse, rabbit and hamster, at oral doses up to 1600 mg/kg bw/d. There were no significant signs of maternal or embryotoxic/developmental toxic effects in any species tested. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the frequencies occurring spontaneously in the sham-treated controls (FDA 1972, FDA 1973a, FDA 1973b). The experimental data on intra-uterine development produced in four animal species across three types of synthetic amorphous silica and silicates suggest that there is no potential for adverse effects on embryonic/foetal development arising from exposure to these substances.
A dominant lethal assay conducted in rats did not produce significant adverse effects on reproductive performance parameters after exposure of male rats to either synthetic amorphous silica or calcium silicate after single or fivefold oral treatment at doses up to 5000 mg/kg bw/treatment [Litton Bionetics 1974].
The one-generation study conducted with a hydrophilic synthetic amorphous silica is not adequate to contribute reliable information for biostatistical reasons. However, numerous subchronic studies as well as a dominant lethal study with a calcium silicate failed to demonstrate any histopathological changes or deleterious effects in the reproductive organs of treated animals. Furthermore, given the inherent physico-chemical properties and ubiquitous nature of this class of compounds, the UNEP (2004) concluded that there is no structural alert to indicate a potential for reproductive and developmental toxicity.
These data support the findings in the 90-day study performed using kieselguhr soda ash flux-calcined and lead to the conclusion that no impairment of fertility/reproductive performance is expected from oral exposure to this substance.
For the inhalation route a 28-day toxicity study using kieselguhr soda ash flux-calcined at exposures up to 700 mg/m3 showed no effects on the reproductive organs of either sex [Schuler 2011; IUCLID Section 7.5.2]. In addition, in this study, the toxicity linked to the respirable crystalline silica was observed locally (i.e. lung) and no systemic changes were noted. It should be noted that this exposure is far in excess of the proposed DNEL of 0.05 mg/m3 for workers. No reproductive studies are available for amorphous or crystalline silica via the inhalation route [ECETOC, 2006]. However, it is considered that the available data for the oral route is also applicable for the inhalation route in terms of the effects of systemically-available silica on reproductive parameters. Further, it would be expected that the lower solubility of crystalline silica compared to amorphous silica would lead to reduced peak exposure, further mitigating the potential for effects. On this basis it is concluded that no impairment of fertility/reproductive performance is expected from inhalation exposure to this substance.
Further weight of evidence exists to demonstrate the lack of potential of crystalline and/or amorphous silica to cause toxicity to reproduction, and is described below.
Silica is essential for normal body function and is ingested orally via the consumption of foods containing silica naturally, as an additive, via dietary supplementation or drinking water. Silica can be found in whole grains (e. g. rice, oats, millet, wheat etc.), root vegetables (e. g. onions, beetroot, potatoes etc.), lettuce, horsetail, nettle, etc. The silica content of foods can vary widely but whole grasses and cereals, for example, may contain 3 – 6% of silica (Watson 2000). The FSA (2003) reports that beer contains 33 – 60 mg silica per kg of beer. Bamboo is said to be the highest of the edible plants in silica (around 1.5 – 2%) and has been eaten both as part of a daily diet and for medicinal purposes (various online sources) for thousands of years, with no evidence of toxicity.
Silicon dioxide (in its amorphous form) is an approved additive, listed as E551 (SCF 1991, JEFCA 2005) and authorized for use according to EC Directive 95/2/EC and its various amendments and adaptations. The maximum levels permitted are 10 or 30 g/kg (depending on the foodstuff), but is also allowed at up to a quantum satis concentration in other foodstuffs (EC Directive 95/2/EC). The physical differences between amorphous and crystalline silica should not affect reproductive toxicity, and therefore similar levels would also be applicable to crystalline silica, if its properties were more suitable to a food additive.
As a nutritional supplement, silica is sold in many commercially available products, with amounts typically up to 500 mg per capsule (FSA 2003). Silica supplements are said to promote the protection the function and structure of connective tissue, enhancement of the immune system, improvement of the elasticity of blood vessels, remineralisation of skeletal system, improvement of skin elasticity, stimulation of cell formation and metabolism (various online sources).
Silica is present in drinking water (De Zuane 1997, Watson 2000). Drinking water surveys in cities of the US reported a silica content of between 0 and 72 mg/L (median of 7.1 mg/L) (De Zuane 1997, p.133). There is no evidence of silica in drinking water constituting a health hazard, and no standards have been set (Watson 2000).
In relation to the ingestion of silicon dioxide from the sources mentioned above, silicon dioxide was assigned an ADI of “not limited” (JECFA 1974, p.16, p. 35), which the JEFCA (1974, p.10) described as an ADI without an explicit indication of the upper limit of intake, which is assigned to substances “…of very low toxicity, especially those that are food constituents or that may be considered as food or normal metabolites in man”. The term “not limited” has since been replaced by “not specified” which the JEFCA describes as applicable to a food substance of very low toxicity which “on the basis of the available data (chemical, biochemical, toxicological, and other), the total dietary intake of the substance arising from its use at the levels necessary to achieve the desired effect and from its acceptable background in food does not, in the opinion of the Committee, represent a hazard to health” (JEFCA 1976, p. 29). Furthermore, a study quoted in JEFCA (1970) (Klösterkotter 1956) which used “quartz water” (water in which silicic acid had been dissolved as a result of contact with quartz powder) given to rats over a prolonged period as the only source of liquid intake did not show any silica storage in tissues.
Therefore, based on the available data it is considered that both reproductive and developmental toxicity studies are scientifically unjustified and may be waived with no risk to either workers or the general population.
References:


De Zuane J (1997) Handbook of Drinking Water Quality. John Wiley and Sons
Degussa AG (1963) Ueber die chronische Toxizität von AEROSIL. Unpublished report, LPT, Degussa AG – US-IT-No. 63-0001-DKT
EC Directive 95/2/EC – European Parliament and Council Directive No. 95/2/EC of 20 February 1995 on Food Additives Other Than Colours and Sweeteners
ECETOC (2006) Synthetic Amorphous Silica (CAS No. 7631-86-9) JACC Report No. 51.
FDA (1972) Teratologic Evaluation of FDA 71-41 (Hydrated calcium silicate). Prep. For: FDA, U. S. Food and Drug Administration; NTIS, National Technical Information Service, U. S. Department of Commerce, USA, PB 221 801, 29 Dec. 1972
FDA (1973a) Teratologic Evaluation of FDA 71-48 (Syloid; silica aerogel). Prep. For: FDA, U. S. Food and Drug Administration; NTIS, National Technical Information Service, U. S. Department of Commerce, USA, PB-223 808
FDA (1973b) Teratologic Evaluation of FDA 71-45 (Sodium Silicoaluminate). Prep. For FDA, U. S. Food and Drug Administration; NTIS, National Technical Information Service, U. S. Department of Commerce, USA, PB 223-810 (01 May 1973)


FSA (2003) Safe Upper Levels for Vitamins and Minerals. Expert Group on Vitamins and Minerals, Food Standards Agency
IARC (1997) IARC Monographs On The Evaluation Of Carcinogenic Risks To Humans: Silica, Some Silicates, Coal Dust And Para-Aramid Fibrils. Vol 68. World Health Organisation, International Agency for Research on Cancer: Lyon, France
JEFCA (1974) Toxicological Evaluation of Certain Food Additives with a Review of General Principles and of Specifications, Seventeenth Report of the Joint FAO/WHO Expert Committee on Food Additives, World Health Organization Technical Report Series No. 539, FAO Nutrition Meetings Report Series 53, WHO: Geneva, Switzerland
JEFCA (1976) Evaluation of Certain Food Additives, Twentieth Report of the Joint FAO/WHO Expert Committee on Food Additives, World Health Organization Technical Report Series No. 599, FAO Nutrition Meetings Report Series No. 1, WHO: Geneva, Switzerland
JEFCA (2005) Endorsement and/or Revision of Maximum Levels for Food Additives and Processing Aids in Codex Standards. Codex Committee on Food Additives and contaminnats, 37th Session: he Hague, The Netherlands
SCF (1991) Reports of the Scientific Committee for Food, Twenty fifth series: First series of food additives of various technological functions. Scientific Committee for Food, commission of the European Communities, Luxemberg
UNEP (2004) Synthetic amorphous silica and silicates - SIDS Initial Assessment Report for SIAM 19. UNEP, Berlin, Germany
Watson RR (2000) Handbook of Nutrition in the Aged. CRC Press
WHO (2000) Concise International Chemical Assessment Document 24 – Crystalline Silica, Quartz, World Health Organization: Geneva, Switzerland

Link to relevant study records

Referenceopen allclose all

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because (i) the substance is of low toxicological activity (no evidence of toxicity seen in any of the tests available), (ii) it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure (e.g. plasma/blood concentrations below detection limit using a sensitive method and absence of the substance and of metabolites of the substance in urine, bile or exhaled air) and (iii) there is no or no significant human exposure
other:
Justification for type of information:
The REACH regulation requires an evaluation of the reproductive and developmental toxicological properties of substances manufactured or imported at >1000 tpa. In the case of Synthetic Wollastonite no reproductive or developmental toxicology data are available from studies performed on the substance itself. However, there are data available from repeat dose toxicity studies carried out on the analogue substances kieselguhr soda ash flux-calcined and silicon dioxide, as well as data from developmental studies carried out on Silicic acid, calcium salt that may be read-across to Synthetic Wollastonite.
In terms of the oral route a reliable 90-day oral toxicity study performed using kieselguhr soda ash flux-calcined is available [Wolfe 1992; IUCLID Section 7.5.1]. In this study rats were dosed with the substance at 1% (average of 698.3 mg/kg bw/day) and 5% (average of 3737.9 mg/kg bw/day). Histopathology revealed no effects on reproductive organs and did not produce any treatment-related effects in urine silica content. In a supporting 90-day oral study [Bertke 1963; IUCLID Section 7.5.1] silica analysis was performed on the liver, kidneys and spleen of rats fed diatomaceous earth at 5%. There was no significant increase in the percentage of residual silica in liver, kidneys and spleen of the test animals compared to control animals which received none of the test material. The data from these studies demonstrate that ingestion of silica does not affect the residual amounts which are found naturally in the body.
UNEP (2004) reports the outcomes of a number of studies on reproduction in the SIAR for synthetic amorphous silica and silicates. An early limited one-generation study on Wistar rats [Degussa 1963] gave no evidence of any adverse effects arising from long-term feeding of Aerosil (500 mg/kg bw/d) to both genders for a premating period of 4.5 months and continued up to 6 months [Degussa 1963]. Five pregnant test females and four pregnant untreated control females delivering 45 and 37 pups, respectively, were included in this test. The study had shortcomings with respect to the low number of pregnant animals used and the mating ratio of 1(m):5(f) which was too low according to current standards.
Within the scope of a comprehensive and valid testing programme, synthetic amorphous silica and silicates (non-amorphous silica and crystalline silica) were examined for embryotoxic and developmental effects during the gestation phase in various animals species, rat, mouse, rabbit and hamster, at oral doses up to 1600 mg/kg bw/d. There were no significant signs of maternal or embryotoxic/developmental toxic effects in any species tested. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the frequencies occurring spontaneously in the sham-treated controls (FDA 1972, FDA 1973a, FDA 1973b). The experimental data on intra-uterine development produced in four animal species across three types of synthetic amorphous silica and silicates suggest that there is no potential for adverse effects on embryonic/foetal development arising from exposure to these substances.
A dominant lethal assay conducted in rats did not produce significant adverse effects on reproductive performance parameters after exposure of male rats to either synthetic amorphous silica or calcium silicate after single or fivefold oral treatment at doses up to 5000 mg/kg bw/treatment [Litton Bionetics 1974].
The one-generation study conducted with a hydrophilic synthetic amorphous silica is not adequate to contribute reliable information for biostatistical reasons. However, numerous subchronic studies as well as a dominant lethal study with a calcium silicate failed to demonstrate any histopathological changes or deleterious effects in the reproductive organs of treated animals. Furthermore, given the inherent physico-chemical properties and ubiquitous nature of this class of compounds, the UNEP (2004) concluded that there is no structural alert to indicate a potential for reproductive and developmental toxicity.
These data support the findings in the 90-day study performed using kieselguhr soda ash flux-calcined and lead to the conclusion that no impairment of fertility/reproductive performance is expected from oral exposure to this substance.
For the inhalation route a 28-day toxicity study using kieselguhr soda ash flux-calcined at exposures up to 700 mg/m3 showed no effects on the reproductive organs of either sex [Schuler 2011; IUCLID Section 7.5.2]. In addition, in this study, the toxicity linked to the respirable crystalline silica was observed locally (i.e. lung) and no systemic changes were noted. It should be noted that this exposure is far in excess of the proposed DNEL of 0.05 mg/m3 for workers. No reproductive studies are available for amorphous or crystalline silica via the inhalation route [ECETOC, 2006]. However, it is considered that the available data for the oral route is also applicable for the inhalation route in terms of the effects of systemically-available silica on reproductive parameters. Further, it would be expected that the lower solubility of crystalline silica compared to amorphous silica would lead to reduced peak exposure, further mitigating the potential for effects. On this basis it is concluded that no impairment of fertility/reproductive performance is expected from inhalation exposure to this substance.
Further weight of evidence exists to demonstrate the lack of potential of crystalline and/or amorphous silica to cause toxicity to reproduction, and is described below.
Silica is essential for normal body function and is ingested orally via the consumption of foods containing silica naturally, as an additive, via dietary supplementation or drinking water. Silica can be found in whole grains (e. g. rice, oats, millet, wheat etc.), root vegetables (e. g. onions, beetroot, potatoes etc.), lettuce, horsetail, nettle, etc. The silica content of foods can vary widely but whole grasses and cereals, for example, may contain 3 – 6% of silica (Watson 2000). The FSA (2003) reports that beer contains 33 – 60 mg silica per kg of beer. Bamboo is said to be the highest of the edible plants in silica (around 1.5 – 2%) and has been eaten both as part of a daily diet and for medicinal purposes (various online sources) for thousands of years, with no evidence of toxicity.
Silicon dioxide (in its amorphous form) is an approved additive, listed as E551 (SCF 1991, JEFCA 2005) and authorized for use according to EC Directive 95/2/EC and its various amendments and adaptations. The maximum levels permitted are 10 or 30 g/kg (depending on the foodstuff), but is also allowed at up to a quantum satis concentration in other foodstuffs (EC Directive 95/2/EC). The physical differences between amorphous and crystalline silica should not affect reproductive toxicity, and therefore similar levels would also be applicable to crystalline silica, if its properties were more suitable to a food additive.
As a nutritional supplement, silica is sold in many commercially available products, with amounts typically up to 500 mg per capsule (FSA 2003). Silica supplements are said to promote the protection the function and structure of connective tissue, enhancement of the immune system, improvement of the elasticity of blood vessels, remineralisation of skeletal system, improvement of skin elasticity, stimulation of cell formation and metabolism (various online sources).
Silica is present in drinking water (De Zuane 1997, Watson 2000). Drinking water surveys in cities of the US reported a silica content of between 0 and 72 mg/L (median of 7.1 mg/L) (De Zuane 1997, p.133). There is no evidence of silica in drinking water constituting a health hazard, and no standards have been set (Watson 2000).
In relation to the ingestion of silicon dioxide from the sources mentioned above, silicon dioxide was assigned an ADI of “not limited” (JECFA 1974, p.16, p. 35), which the JEFCA (1974, p.10) described as an ADI without an explicit indication of the upper limit of intake, which is assigned to substances “…of very low toxicity, especially those that are food constituents or that may be considered as food or normal metabolites in man”. The term “not limited” has since been replaced by “not specified” which the JEFCA describes as applicable to a food substance of very low toxicity which “on the basis of the available data (chemical, biochemical, toxicological, and other), the total dietary intake of the substance arising from its use at the levels necessary to achieve the desired effect and from its acceptable background in food does not, in the opinion of the Committee, represent a hazard to health” (JEFCA 1976, p. 29). Furthermore, a study quoted in JEFCA (1970) (Klösterkotter 1956) which used “quartz water” (water in which silicic acid had been dissolved as a result of contact with quartz powder) given to rats over a prolonged period as the only source of liquid intake did not show any silica storage in tissues.
Therefore, based on the available data it is considered that both reproductive and developmental toxicity studies are scientifically unjustified and may be waived with no risk to either workers or the general population.
References:

De Zuane J (1997) Handbook of Drinking Water Quality. John Wiley and Sons
Degussa AG (1963) Ueber die chronische Toxizität von AEROSIL. Unpublished report, LPT, Degussa AG – US-IT-No. 63-0001-DKT
EC Directive 95/2/EC – European Parliament and Council Directive No. 95/2/EC of 20 February 1995 on Food Additives Other Than Colours and Sweeteners
ECETOC (2006) Synthetic Amorphous Silica (CAS No. 7631-86-9) JACC Report No. 51.
FDA (1972) Teratologic Evaluation of FDA 71-41 (Hydrated calcium silicate). Prep. For: FDA, U. S. Food and Drug Administration; NTIS, National Technical Information Service, U. S. Department of Commerce, USA, PB 221 801, 29 Dec. 1972
FDA (1973a) Teratologic Evaluation of FDA 71-48 (Syloid; silica aerogel). Prep. For: FDA, U. S. Food and Drug Administration; NTIS, National Technical Information Service, U. S. Department of Commerce, USA, PB-223 808
FDA (1973b) Teratologic Evaluation of FDA 71-45 (Sodium Silicoaluminate). Prep. For FDA, U. S. Food and Drug Administration; NTIS, National Technical Information Service, U. S. Department of Commerce, USA, PB 223-810 (01 May 1973)

FSA (2003) Safe Upper Levels for Vitamins and Minerals. Expert Group on Vitamins and Minerals, Food Standards Agency
IARC (1997) IARC Monographs On The Evaluation Of Carcinogenic Risks To Humans: Silica, Some Silicates, Coal Dust And Para-Aramid Fibrils. Vol 68. World Health Organisation, International Agency for Research on Cancer: Lyon, France
JEFCA (1974) Toxicological Evaluation of Certain Food Additives with a Review of General Principles and of Specifications, Seventeenth Report of the Joint FAO/WHO Expert Committee on Food Additives, World Health Organization Technical Report Series No. 539, FAO Nutrition Meetings Report Series 53, WHO: Geneva, Switzerland
JEFCA (1976) Evaluation of Certain Food Additives, Twentieth Report of the Joint FAO/WHO Expert Committee on Food Additives, World Health Organization Technical Report Series No. 599, FAO Nutrition Meetings Report Series No. 1, WHO: Geneva, Switzerland
JEFCA (2005) Endorsement and/or Revision of Maximum Levels for Food Additives and Processing Aids in Codex Standards. Codex Committee on Food Additives and contaminnats, 37th Session: he Hague, The Netherlands
SCF (1991) Reports of the Scientific Committee for Food, Twenty fifth series: First series of food additives of various technological functions. Scientific Committee for Food, commission of the European Communities, Luxemberg
UNEP (2004) Synthetic amorphous silica and silicates - SIDS Initial Assessment Report for SIAM 19. UNEP, Berlin, Germany
Watson RR (2000) Handbook of Nutrition in the Aged. CRC Press
WHO (2000) Concise International Chemical Assessment Document 24 – Crystalline Silica, Quartz, World Health Organization: Geneva, Switzerland
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because (i) the substance is of low toxicological activity (no evidence of toxicity seen in any of the tests available), (ii) it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure (e.g. plasma/blood concentrations below detection limit using a sensitive method and absence of the substance and of metabolites of the substance in urine, bile or exhaled air) and (iii) there is no or no significant human exposure
Justification for type of information:
The REACH regulation requires an evaluation of the reproductive and developmental toxicological properties of substances manufactured or imported at >1000 tpa. In the case of Synthetic Wollastonite no reproductive or developmental toxicology data are available from studies performed on the substance itself. However, there are data available from repeat dose toxicity studies carried out on the analogue substances kieselguhr soda ash flux-calcined and silicon dioxide, as well as data from developmental studies carried out on Silicic acid, calcium salt that may be read-across to Synthetic Wollastonite.
In terms of the oral route a reliable 90-day oral toxicity study performed using kieselguhr soda ash flux-calcined is available [Wolfe 1992; IUCLID Section 7.5.1]. In this study rats were dosed with the substance at 1% (average of 698.3 mg/kg bw/day) and 5% (average of 3737.9 mg/kg bw/day). Histopathology revealed no effects on reproductive organs and did not produce any treatment-related effects in urine silica content. In a supporting 90-day oral study [Bertke 1963; IUCLID Section 7.5.1] silica analysis was performed on the liver, kidneys and spleen of rats fed diatomaceous earth at 5%. There was no significant increase in the percentage of residual silica in liver, kidneys and spleen of the test animals compared to control animals which received none of the test material. The data from these studies demonstrate that ingestion of silica does not affect the residual amounts which are found naturally in the body.
UNEP (2004) reports the outcomes of a number of studies on reproduction in the SIAR for synthetic amorphous silica and silicates. An early limited one-generation study on Wistar rats [Degussa 1963] gave no evidence of any adverse effects arising from long-term feeding of Aerosil (500 mg/kg bw/d) to both genders for a premating period of 4.5 months and continued up to 6 months [Degussa 1963]. Five pregnant test females and four pregnant untreated control females delivering 45 and 37 pups, respectively, were included in this test. The study had shortcomings with respect to the low number of pregnant animals used and the mating ratio of 1(m):5(f) which was too low according to current standards.
Within the scope of a comprehensive and valid testing programme, synthetic amorphous silica and silicates (non-amorphous silica and crystalline silica) were examined for embryotoxic and developmental effects during the gestation phase in various animals species, rat, mouse, rabbit and hamster, at oral doses up to 1600 mg/kg bw/d. There were no significant signs of maternal or embryotoxic/developmental toxic effects in any species tested. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the frequencies occurring spontaneously in the sham-treated controls (FDA 1972, FDA 1973a, FDA 1973b). The experimental data on intra-uterine development produced in four animal species across three types of synthetic amorphous silica and silicates suggest that there is no potential for adverse effects on embryonic/foetal development arising from exposure to these substances.
A dominant lethal assay conducted in rats did not produce significant adverse effects on reproductive performance parameters after exposure of male rats to either synthetic amorphous silica or calcium silicate after single or fivefold oral treatment at doses up to 5000 mg/kg bw/treatment [Litton Bionetics 1974].
The one-generation study conducted with a hydrophilic synthetic amorphous silica is not adequate to contribute reliable information for biostatistical reasons. However, numerous subchronic studies as well as a dominant lethal study with a calcium silicate failed to demonstrate any histopathological changes or deleterious effects in the reproductive organs of treated animals. Furthermore, given the inherent physico-chemical properties and ubiquitous nature of this class of compounds, the UNEP (2004) concluded that there is no structural alert to indicate a potential for reproductive and developmental toxicity.
These data support the findings in the 90-day study performed using kieselguhr soda ash flux-calcined and lead to the conclusion that no impairment of fertility/reproductive performance is expected from oral exposure to this substance.
For the inhalation route a 28-day toxicity study using kieselguhr soda ash flux-calcined at exposures up to 700 mg/m3 showed no effects on the reproductive organs of either sex [Schuler 2011; IUCLID Section 7.5.2]. In addition, in this study, the toxicity linked to the respirable crystalline silica was observed locally (i.e. lung) and no systemic changes were noted. It should be noted that this exposure is far in excess of the proposed DNEL of 0.05 mg/m3 for workers. No reproductive studies are available for amorphous or crystalline silica via the inhalation route [ECETOC, 2006]. However, it is considered that the available data for the oral route is also applicable for the inhalation route in terms of the effects of systemically-available silica on reproductive parameters. Further, it would be expected that the lower solubility of crystalline silica compared to amorphous silica would lead to reduced peak exposure, further mitigating the potential for effects. On this basis it is concluded that no impairment of fertility/reproductive performance is expected from inhalation exposure to this substance.
Further weight of evidence exists to demonstrate the lack of potential of crystalline and/or amorphous silica to cause toxicity to reproduction, and is described below.
Silica is essential for normal body function and is ingested orally via the consumption of foods containing silica naturally, as an additive, via dietary supplementation or drinking water. Silica can be found in whole grains (e. g. rice, oats, millet, wheat etc.), root vegetables (e. g. onions, beetroot, potatoes etc.), lettuce, horsetail, nettle, etc. The silica content of foods can vary widely but whole grasses and cereals, for example, may contain 3 – 6% of silica (Watson 2000). The FSA (2003) reports that beer contains 33 – 60 mg silica per kg of beer. Bamboo is said to be the highest of the edible plants in silica (around 1.5 – 2%) and has been eaten both as part of a daily diet and for medicinal purposes (various online sources) for thousands of years, with no evidence of toxicity.
Silicon dioxide (in its amorphous form) is an approved additive, listed as E551 (SCF 1991, JEFCA 2005) and authorized for use according to EC Directive 95/2/EC and its various amendments and adaptations. The maximum levels permitted are 10 or 30 g/kg (depending on the foodstuff), but is also allowed at up to a quantum satis concentration in other foodstuffs (EC Directive 95/2/EC). The physical differences between amorphous and crystalline silica should not affect reproductive toxicity, and therefore similar levels would also be applicable to crystalline silica, if its properties were more suitable to a food additive.
As a nutritional supplement, silica is sold in many commercially available products, with amounts typically up to 500 mg per capsule (FSA 2003). Silica supplements are said to promote the protection the function and structure of connective tissue, enhancement of the immune system, improvement of the elasticity of blood vessels, remineralisation of skeletal system, improvement of skin elasticity, stimulation of cell formation and metabolism (various online sources).
Silica is present in drinking water (De Zuane 1997, Watson 2000). Drinking water surveys in cities of the US reported a silica content of between 0 and 72 mg/L (median of 7.1 mg/L) (De Zuane 1997, p.133). There is no evidence of silica in drinking water constituting a health hazard, and no standards have been set (Watson 2000).
In relation to the ingestion of silicon dioxide from the sources mentioned above, silicon dioxide was assigned an ADI of “not limited” (JECFA 1974, p.16, p. 35), which the JEFCA (1974, p.10) described as an ADI without an explicit indication of the upper limit of intake, which is assigned to substances “…of very low toxicity, especially those that are food constituents or that may be considered as food or normal metabolites in man”. The term “not limited” has since been replaced by “not specified” which the JEFCA describes as applicable to a food substance of very low toxicity which “on the basis of the available data (chemical, biochemical, toxicological, and other), the total dietary intake of the substance arising from its use at the levels necessary to achieve the desired effect and from its acceptable background in food does not, in the opinion of the Committee, represent a hazard to health” (JEFCA 1976, p. 29). Furthermore, a study quoted in JEFCA (1970) (Klösterkotter 1956) which used “quartz water” (water in which silicic acid had been dissolved as a result of contact with quartz powder) given to rats over a prolonged period as the only source of liquid intake did not show any silica storage in tissues.
Therefore, based on the available data it is considered that both reproductive and developmental toxicity studies are scientifically unjustified and may be waived with no risk to either workers or the general population.
References:

De Zuane J (1997) Handbook of Drinking Water Quality. John Wiley and Sons
Degussa AG (1963) Ueber die chronische Toxizität von AEROSIL. Unpublished report, LPT, Degussa AG – US-IT-No. 63-0001-DKT
EC Directive 95/2/EC – European Parliament and Council Directive No. 95/2/EC of 20 February 1995 on Food Additives Other Than Colours and Sweeteners
ECETOC (2006) Synthetic Amorphous Silica (CAS No. 7631-86-9) JACC Report No. 51.
FDA (1972) Teratologic Evaluation of FDA 71-41 (Hydrated calcium silicate). Prep. For: FDA, U. S. Food and Drug Administration; NTIS, National Technical Information Service, U. S. Department of Commerce, USA, PB 221 801, 29 Dec. 1972
FDA (1973a) Teratologic Evaluation of FDA 71-48 (Syloid; silica aerogel). Prep. For: FDA, U. S. Food and Drug Administration; NTIS, National Technical Information Service, U. S. Department of Commerce, USA, PB-223 808
FDA (1973b) Teratologic Evaluation of FDA 71-45 (Sodium Silicoaluminate). Prep. For FDA, U. S. Food and Drug Administration; NTIS, National Technical Information Service, U. S. Department of Commerce, USA, PB 223-810 (01 May 1973)

FSA (2003) Safe Upper Levels for Vitamins and Minerals. Expert Group on Vitamins and Minerals, Food Standards Agency
IARC (1997) IARC Monographs On The Evaluation Of Carcinogenic Risks To Humans: Silica, Some Silicates, Coal Dust And Para-Aramid Fibrils. Vol 68. World Health Organisation, International Agency for Research on Cancer: Lyon, France
JEFCA (1974) Toxicological Evaluation of Certain Food Additives with a Review of General Principles and of Specifications, Seventeenth Report of the Joint FAO/WHO Expert Committee on Food Additives, World Health Organization Technical Report Series No. 539, FAO Nutrition Meetings Report Series 53, WHO: Geneva, Switzerland
JEFCA (1976) Evaluation of Certain Food Additives, Twentieth Report of the Joint FAO/WHO Expert Committee on Food Additives, World Health Organization Technical Report Series No. 599, FAO Nutrition Meetings Report Series No. 1, WHO: Geneva, Switzerland
JEFCA (2005) Endorsement and/or Revision of Maximum Levels for Food Additives and Processing Aids in Codex Standards. Codex Committee on Food Additives and contaminnats, 37th Session: he Hague, The Netherlands
SCF (1991) Reports of the Scientific Committee for Food, Twenty fifth series: First series of food additives of various technological functions. Scientific Committee for Food, commission of the European Communities, Luxemberg
UNEP (2004) Synthetic amorphous silica and silicates - SIDS Initial Assessment Report for SIAM 19. UNEP, Berlin, Germany
Watson RR (2000) Handbook of Nutrition in the Aged. CRC Press
WHO (2000) Concise International Chemical Assessment Document 24 – Crystalline Silica, Quartz, World Health Organization: Geneva, Switzerland
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No data are available for Synthetic wollastonite. Data available for silica and other silicates indicate no effects on reproductive performance is expected for Synthetic wollastonite.

Effects on developmental toxicity

Description of key information

The administration of up to 1600 mg/kg (body weight)of the test material to pregnant hamsters for 5 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival.
The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occuring spontaneously in the sham-treated controls.

The administration of up to 1600 mg/kg (body weight) of the test material to pregnant mice for 10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival.
The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.



The administration of up to 1600 mg/kg (body weight) of the test material to pregnant rats for 10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival.
The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source:
- Age at study initiation:
- Weight at study initiation:
- Fasting period before study:
- Housing:
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum):
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light):

IN-LIFE DATES: From: To:
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: water suspension

VEHICLE
- Justification for use and choice of vehicle (if other than water): used as dispersant
- Concentration in vehicle: depending on the dose
- Amount of vehicle (if gavage): 1 mL suspension/kg bw (Tab. 1, p. 15)
[note: not conclusive, is supposed to read 10 mL/kg b.w., comp. corresponding report on NAS]

Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: no data
- Length of cohabitation: no data
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
Duration of treatment / exposure:
from day 6 to day 15 of gestation
Frequency of treatment:
1x/d
Duration of test:
Gestation day 20: sacrifice of all dams by Caesarian section
Remarks:
Doses / Concentrations:
0, 16, 74, 350 and 1600 mg/(kg*d) (as aqueous suspension)
Basis:

No. of animals per sex per dose:
20 - 22 pregnant female rats
Control animals:
yes, sham-exposed
other: positve control dosed with Aspirin (250 mg/kg bw)
Details on study design:
- Dose selection rationale: no data
- Other: Sham control is said to be dosed with corn oil, see Tab. 1, p. 15
(probably erroneous, contradicting corresponding report on NAS)
Maternal examinations:
BODY WEIGHT: Yes
- Time schedule for examinations: gestation day 0, 6, 11, 15, and 20 (Tab. 4, p. 19)


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes (not documented)
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: no data


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: in particular urogenital tract

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes (neonatal pup weight) [Appendix II, p. 21]
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
- Number of early resorptions: No data
- Number of late resorptions: No data
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: 1/3 per litter
- Skeletal examinations: Yes: 2/3 per litter
- Head examinations: yes
Statistics:
no data
Historical control data:
no data
Details on maternal toxic effects:
Maternal toxic effects:no effects
Key result
Dose descriptor:
NOAEL
Remarks:
(highest dose tested)
Effect level:
1 600 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Key result
Dose descriptor:
NOAEL
Remarks:
(highest dose tested)
Effect level:
1 600 mg/kg bw/day
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified

The administration of up to 1600 mg/kg (body weight) of the test material to pregnant rats for 

10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ
from the number occurring spontaneously in the sham-treated controls.

  

Conclusions:
The administration of up to 1600 mg/kg (body weight) of the test material to pregnant rats for 

10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ
from the number occurring spontaneously in the sham-treated controls.
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Justification for type of information:
The use of data derived for calcium oxosilanediolate are justified for read-across to synthetic wollastonite. Justification for read-across is warranted given the similarities in toxicity profile and physico-chemical properties for calcium oxosilanediolate and synthetic wollastonite.
Considering the available data:
The source substance show no concerns for the environment.
The source substance has low acute toxicity and low toxicity in repeated dose studies, is non-irritant (skin and eye), non-sensitizing, non-mutagenic to bacteria, non-cytogenic and has low toxicity for reproductive and developmental toxicity.
Please see RAAF attached in Section 13. for further details.
Reason / purpose for cross-reference:
read-across source
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source:
- Age at study initiation:
- Weight at study initiation:
- Fasting period before study:
- Housing:
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum):
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light):

IN-LIFE DATES: From: To:
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: water suspension

VEHICLE
- Justification for use and choice of vehicle (if other than water): used as dispersant
- Concentration in vehicle: depending on the dose
- Amount of vehicle (if gavage): 1 mL suspension/kg bw (Tab. 1, p. 15)
[note: not conclusive, is supposed to read 10 mL/kg b.w., comp. corresponding report on NAS]

Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: no data
- Length of cohabitation: no data
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
Duration of treatment / exposure:
from day 6 to day 15 of gestation
Frequency of treatment:
1x/d
Duration of test:
Gestation day 20: sacrifice of all dams by Caesarian section
Remarks:
Doses / Concentrations:
0, 16, 74, 350 and 1600 mg/(kg*d) (as aqueous suspension)
Basis:

No. of animals per sex per dose:
20 - 22 pregnant female rats
Control animals:
yes, sham-exposed
other: positve control dosed with Aspirin (250 mg/kg bw)
Details on study design:
- Dose selection rationale: no data
- Other: Sham control is said to be dosed with corn oil, see Tab. 1, p. 15
(probably erroneous, contradicting corresponding report on NAS)
Maternal examinations:
BODY WEIGHT: Yes
- Time schedule for examinations: gestation day 0, 6, 11, 15, and 20 (Tab. 4, p. 19)


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes (not documented)
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: no data


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: in particular urogenital tract

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes (neonatal pup weight) [Appendix II, p. 21]
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
- Number of early resorptions: No data
- Number of late resorptions: No data
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: 1/3 per litter
- Skeletal examinations: Yes: 2/3 per litter
- Head examinations: yes
Statistics:
no data
Historical control data:
no data
Details on maternal toxic effects:
Maternal toxic effects:no effects
Key result
Dose descriptor:
NOAEL
Remarks:
(highest dose tested)
Effect level:
1 600 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Key result
Dose descriptor:
NOAEL
Remarks:
(highest dose tested)
Effect level:
1 600 mg/kg bw/day
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified

The administration of up to 1600 mg/kg (body weight) of the test material to pregnant rats for 

10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ
from the number occurring spontaneously in the sham-treated controls.

  

Conclusions:
The administration of up to 1600 mg/kg (body weight) of the test material to pregnant rats for 

10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ
from the number occurring spontaneously in the sham-treated controls.
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
no
Limit test:
no
Species:
hamster, Syrian
Strain:
other: (outbred)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: no data
- Fasting period before study: no
- Housing: single
- Diet: ad libitum
- Water: ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Photoperiod (hrs dark / hrs light): no data
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: water suspension

VEHICLE
- Justification for use and choice of vehicle (if other than water): used as dispersant
- Concentration in vehicle: depending on the dose
- Amount of vehicle (if gavage): 1 mL suspension/kg bw (Tab. 1, p. 28)
[note: not conclusive, is supposed to read 10 mL/kg b.w., comp. corresponding report on NAS]
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: no data
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
from day 6 to day 10 of gestation
Frequency of treatment:
1x/d
Duration of test:
day 14: sacrifice of dams by Caesarian section
Remarks:
Doses / Concentrations:
0, 16.0, 74, 345 and 1600 mg/(kg bw*d)
Basis:

No. of animals per sex per dose:
19 - 22 pregnant hamsters
Control animals:
yes, sham-exposed
other: pos. control receiving Aspirin, 250 mg/(kg bw *d)
Details on study design:
- Other: Sham control is said to be dosed with corn oil, see Tab. 1, p. 28
(probably erroneous, contradicting corresponding report on NAS)
Maternal examinations:
BODY WEIGHT: Yes
- Time schedule for examinations: gestation day 0, 6, 8, 10, and 14


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: no data


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 14
- Organs examined: in particular urogenital tract

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: yes (neonatal pup weight) [Appendix II, p. 34]
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
- Number of early resorptions: No data
- Number of late resorptions: No data
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: 1/3 per litter
- Skeletal examinations: Yes: 2/3 per litter
- Head examinations: No data
Statistics:
no data
Historical control data:
no data
Details on maternal toxic effects:
Maternal toxic effects:no effects
Key result
Dose descriptor:
NOAEL
Remarks:
(highest dose tested)
Effect level:
1 600 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Key result
Dose descriptor:
NOAEL
Remarks:
(highest dose tested)
Effect level:
1 600 mg/kg bw/day
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified

The administration of up to 1600 mg/kg (body weight) of the test material to pregnant hamsters for 

5 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from
the number occuring spontaneously in the sham-treated controls.

Conclusions:
The administration of up to 1600 mg/kg (body weight) of the test material to pregnant hamsters for 

5 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from
the number occuring spontaneously in the sham-treated controls.
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Justification for type of information:
The use of data derived for calcium oxosilanediolate are justified for read-across to synthetic wollastonite. Justification for read-across is warranted given the similarities in toxicity profile and physico-chemical properties for calcium oxosilanediolate and synthetic wollastonite.
Considering the available data:
The source substance show no concerns for the environment.
The source substance has low acute toxicity and low toxicity in repeated dose studies, is non-irritant (skin and eye), non-sensitizing, non-mutagenic to bacteria, non-cytogenic and has low toxicity for reproductive and developmental toxicity.
Please see RAAF attached in Section 13. for further details.
Reason / purpose for cross-reference:
read-across source
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
no
Limit test:
no
Species:
hamster, Syrian
Strain:
other: (outbred)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: no data
- Fasting period before study: no
- Housing: single
- Diet: ad libitum
- Water: ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Photoperiod (hrs dark / hrs light): no data
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: water suspension

VEHICLE
- Justification for use and choice of vehicle (if other than water): used as dispersant
- Concentration in vehicle: depending on the dose
- Amount of vehicle (if gavage): 1 mL suspension/kg bw (Tab. 1, p. 28)
[note: not conclusive, is supposed to read 10 mL/kg b.w., comp. corresponding report on NAS]
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: no data
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
from day 6 to day 10 of gestation
Frequency of treatment:
1x/d
Duration of test:
day 14: sacrifice of dams by Caesarian section
Remarks:
Doses / Concentrations:
0, 16.0, 74, 345 and 1600 mg/(kg bw*d)
Basis:

No. of animals per sex per dose:
19 - 22 pregnant hamsters
Control animals:
yes, sham-exposed
other: pos. control receiving Aspirin, 250 mg/(kg bw *d)
Details on study design:
- Other: Sham control is said to be dosed with corn oil, see Tab. 1, p. 28
(probably erroneous, contradicting corresponding report on NAS)
Maternal examinations:
BODY WEIGHT: Yes
- Time schedule for examinations: gestation day 0, 6, 8, 10, and 14


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: no data


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 14
- Organs examined: in particular urogenital tract

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: yes (neonatal pup weight) [Appendix II, p. 34]
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
- Number of early resorptions: No data
- Number of late resorptions: No data
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: 1/3 per litter
- Skeletal examinations: Yes: 2/3 per litter
- Head examinations: No data
Statistics:
no data
Historical control data:
no data
Details on maternal toxic effects:
Maternal toxic effects:no effects
Key result
Dose descriptor:
NOAEL
Remarks:
(highest dose tested)
Effect level:
1 600 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Key result
Dose descriptor:
NOAEL
Remarks:
(highest dose tested)
Effect level:
1 600 mg/kg bw/day
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified

The administration of up to 1600 mg/kg (body weight) of the test material to pregnant hamsters for 

5 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from
the number occuring spontaneously in the sham-treated controls.

Conclusions:
The administration of up to 1600 mg/kg (body weight) of the test material to pregnant hamsters for 

5 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from
the number occuring spontaneously in the sham-treated controls.
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
no
Limit test:
no
Species:
mouse
Strain:
CD-1
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation:
- Weight at study initiation: no data
- Fasting period before study: no
- Housing: single
- Diet: ad libitum
- Water: ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Photoperiod (hrs dark / hrs light): no data
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: water suspension

VEHICLE
- Justification for use and choice of vehicle (if other than water): used as dispersant
- Concentration in vehicle: depending on the dose
- Amount of vehicle (if gavage): 1 mL suspension/kg bw (Tab. 1, p. 2)
[note: not conclusive, is supposed to read 10 mL/kg b.w., comp. corresponding report on NAS]
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: no data
- Length of cohabitation: no data
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
Duration of treatment / exposure:
from day 6 to day 15 of gestation
Frequency of treatment:
1x/d
Duration of test:
gestation day 17: sacrifice of all dams by Caesarian section
Remarks:
Doses / Concentrations:
0, 16, 74, 350 and 1600 mg/(kg*d) (as aqueous suspension)
Basis:

No. of animals per sex per dose:
20 - 23 pregnant dams
Control animals:
yes, sham-exposed
other: positive control dosed with Aspirin [150 mg/(kg bw*d)]
Details on study design:
- Other: Sham control is said to be dosed with corn oil, see Tab. 1, p. 2
(probably erroneous, contradicting corresponding report on NAS)
Maternal examinations:
BODY WEIGHT: Yes
- Time schedule for examinations: gestation day 0, 6, 11, 15, and 17 (Tab. 4, p. 6)


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes (not documented)
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 17
- Organs examined: in particular urogenital tract

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes (neonatal pup weight) [Appendix II, p. 8]
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
- Number of early resorptions: No data
- Number of late resorptions: No data
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: 1/3 per litter
- Skeletal examinations: Yes: 2/3 per litter
- Head examinations: yes
Statistics:
no data
Historical control data:
no data
Details on maternal toxic effects:
Maternal toxic effects:no effects
Key result
Dose descriptor:
NOAEL
Remarks:
(highest dose tested)
Effect level:
1 600 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Dose descriptor:
NOAEL
Remarks:
(highest dose tested)
Effect level:
1 600 mg/kg bw/day
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified

The administration of up to 1600 mg/kg (body weight) of the test material to pregnant mice for 

10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ
from the number occurring spontaneously in the sham-treated controls.

   

Conclusions:
The administration of up to 1600 mg/kg (body weight) of the test material to pregnant mice for 

10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ
from the number occurring spontaneously in the sham-treated controls.
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Justification for type of information:
The use of data derived for calcium oxosilanediolate are justified for read-across to synthetic wollastonite. Justification for read-across is warranted given the similarities in toxicity profile and physico-chemical properties for calcium oxosilanediolate and synthetic wollastonite.
Considering the available data:
The source substance show no concerns for the environment.
The source substance has low acute toxicity and low toxicity in repeated dose studies, is non-irritant (skin and eye), non-sensitizing, non-mutagenic to bacteria, non-cytogenic and has low toxicity for reproductive and developmental toxicity.
Please see RAAF attached in Section 13. for further details.
Reason / purpose for cross-reference:
read-across source
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
no
Limit test:
no
Species:
mouse
Strain:
CD-1
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation:
- Weight at study initiation: no data
- Fasting period before study: no
- Housing: single
- Diet: ad libitum
- Water: ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Photoperiod (hrs dark / hrs light): no data
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: water suspension

VEHICLE
- Justification for use and choice of vehicle (if other than water): used as dispersant
- Concentration in vehicle: depending on the dose
- Amount of vehicle (if gavage): 1 mL suspension/kg bw (Tab. 1, p. 2)
[note: not conclusive, is supposed to read 10 mL/kg b.w., comp. corresponding report on NAS]
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: no data
- Length of cohabitation: no data
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
Duration of treatment / exposure:
from day 6 to day 15 of gestation
Frequency of treatment:
1x/d
Duration of test:
gestation day 17: sacrifice of all dams by Caesarian section
Remarks:
Doses / Concentrations:
0, 16, 74, 350 and 1600 mg/(kg*d) (as aqueous suspension)
Basis:

No. of animals per sex per dose:
20 - 23 pregnant dams
Control animals:
yes, sham-exposed
other: positive control dosed with Aspirin [150 mg/(kg bw*d)]
Details on study design:
- Other: Sham control is said to be dosed with corn oil, see Tab. 1, p. 2
(probably erroneous, contradicting corresponding report on NAS)
Maternal examinations:
BODY WEIGHT: Yes
- Time schedule for examinations: gestation day 0, 6, 11, 15, and 17 (Tab. 4, p. 6)


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes (not documented)
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 17
- Organs examined: in particular urogenital tract

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes (neonatal pup weight) [Appendix II, p. 8]
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
- Number of early resorptions: No data
- Number of late resorptions: No data
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: 1/3 per litter
- Skeletal examinations: Yes: 2/3 per litter
- Head examinations: yes
Statistics:
no data
Historical control data:
no data
Details on maternal toxic effects:
Maternal toxic effects:no effects
Key result
Dose descriptor:
NOAEL
Remarks:
(highest dose tested)
Effect level:
1 600 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Dose descriptor:
NOAEL
Remarks:
(highest dose tested)
Effect level:
1 600 mg/kg bw/day
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified

The administration of up to 1600 mg/kg (body weight) of the test material to pregnant mice for 

10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ
from the number occurring spontaneously in the sham-treated controls.

   

Conclusions:
The administration of up to 1600 mg/kg (body weight) of the test material to pregnant mice for 

10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ
from the number occurring spontaneously in the sham-treated controls.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 600 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Three reliability 2 studies are available. The quality is considered to be good.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Additional information

As part of a larger comprehensive and valid testing programme, the embryotoxic and developmental toxic effects of the read-across material calcium silicate in rats, mice and hamsters were examined in studies performed using methods similar to OECD TG 414 [Food and Drug Research Laboratories (1972)].
In the rat study, groups of 20-22 pregnant Wistar rats were dosed by gavage with the substance at 0, 16, 74, 350 or 1600 mg/kg bw/day from day 6 to 15 of gestation. Dams were sacrificed on gestation day 20. No maternal toxic effects or embryotoxic/teratogenic effects were reported. There was no clearly discernible effect on nidation or on maternal or foetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls. The NOAEL in this study was 1600mg/kg bw/day, the highest dose tested.



In the mouse study, groups of 20-23 pregnant CD-1 mice were dosed by gavage with the substance at 0, 16, 74, 350 or 1600 mg/kg bw/day from day 6 to 15 of gestation. Dams were sacrificed on gestation day 17. No maternal toxic effects or embryotoxic/teratogenic effects were reported. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number
occurring spontaneously in the sham-treated controls. The NOAEL in this study was 1600mg/kg bw/day, the highest dose tested.



In the hamster study, groups of 19-22 pregnant Syrian hamsters were dosed by gavage with the substance at 0, 16, 74, 345 or 1600 mg/kg bw/day from day 6 to 10 of gestation. Dams were sacrificed on gestation day 14. No maternal toxic effects or embryotoxic/teratogenic effects were reported. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls. The NOAEL in this study was 1600mg/kg bw/day, the highest dose tested.



On the basis of read-across to these studies it is concluded that Synthetic wollastonite is not a developmental toxicant.

Justification for classification or non-classification

Available data for the read-across material calcium silicate, silica and other silicates indicate that classification for reproductive/developmental toxicity is not required.


On the basis of read-across it is concluded that classification for reproductive/developmental toxicity is not required for Synthetic wollastonite.


 

Additional information