Registration Dossier

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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.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

Based on the known mechanisms of fibre deposition, reproductive effects from inhalation exposure to mineral wool fibres appear to be unlikely such that the fibres do not reach reproductive organs. The bioavailability of MMVFs upon inhalation, oral or dermal exposure is expected to be low because of the physical dimensions of these elongated fibres and of the high biosolubility such that the fibres are dissolved in the lungs before entering into systemic circulation.

Furthermore, some glass wool fibres can contain diboron trioxide (with content up to 12%), which currently has a harmonised CLP classification of Repr. 1B for the effects of boron on fertility in several experimental animal species. Based on a risk assessment conducted by Jensen et al. (2009) the estimated worst-case daily intake of 0.16 mg boron from glass wool insulation fibres in an occupational setting is much lower than the tolerable daily intake levels set by regulatory authorities and agencies (starting at 9.6 mg/day). Therefore, inhalation exposure to glass wool fibres containing up to 12% of diboron trioxide is not expected to trigger reproductive effects in humans.

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:
other justification
Justification for data waiving:
other:
Justification for type of information:
The literature search and screening for data related to reproductive toxicity of fibres of scope resulted in 2 scientific references eligible for further screening. Both scientific references are human studies, one case report (Hinnen et al., 1997 ) and one epidemiological study using a cancer registry (Vasama-Neuvonen et al., 1999 ). Evaluation of both scientific references showed major deficiencies in the methodology which make the outcome of these studies not reliable (Klimisch rating: 3). The results of these studies have not been taken into account in this argumentation for the reasons detailed below.
In the Hinnen et al. (1997) study, the authors reported a patient with foreign body granuloma of the penis possibly due to occupational glass fibre exposure. However, this is a case report of one patient working in the fibre-reinforced plastic industry and showing a penile ulcer. This patient has an history of syphilis more than 20 years ago, but the biopsy performed indicated the presence of foreign bodies possibly consistent with glass fibres. The authors concluded that the granuloma may be linked to its occupational exposure to fibres. The link between this penile granuloma and the occupational exposure to glass fibres could not have been clearly identified during the study and the lack of other cases greatly decreases the robustness of the study. Anyway, this is not possible to extrapolate based on only one observation.
The study of Vasama-Neuvonen et al. (1999) investigated the relationship between ovarian cancer and occupational exposures to various substances including MMVFs in Finland. It has been reported in this study that women occupationally exposed to MMVFs has an elevated risk for ovarian cancer (standardised incidence ratio of 1.3; 95% confidence interval of 1.0-1.7). The cohort studied is composed of building workers, which are usually a majority of men, therefore the representability of the results regarding ovarian cancer may be questioned. In addition, it is mentioned that 100% of the building workers have been exposed to asbestos and 90% to the MMVF: it is not possible to distinguish the effect of asbestos from the one of MMVF on ovarian cancer incidence in this cohort. Indeed, the exact same number of cases has been reported with asbestos and MMVF confirming the absence of differentiation. This is a major deficiency as the hazard profile of these two substances is completely different. This study has been examined in 2001 by the IARC working group who also mentioned the limitations of this study.
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
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:
other:
Justification for type of information:
The full waiving argumentation is detailled in the document "Toxicity to reproduction_WoE" below.
The studies mentionned in the justification enclosed are detailed as weight of evidence in the other endpoints of the section 7.8.1 of the IUCLID dossier.
Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Type of information:
other: Scientific review
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline required
Principles of method if other than guideline:
The fibers chosen for this evaluation were MMVF11 (a glasswool), MMVF22 (a slagwool) with an average fiber diameter of approximately 1 pm and an average length of 15 to 25 pm. Fluid simulants used were modified Gamble's solutions. Sodium azide (0.5 mg/1) was added to both solutions as a biocidal agent. The extracellular fluid simulant was saturated with and kept under constant pressure of 5%C02/95%N2 to maintain pH 7.6 for the duration of the experiments. For the solution at pH 4, HCI was added in place of sodium bicarbonate and the level of sodium chloride adjusted to achieve the desired pH and maintain the same total cation concentration as that of the solution at pH 7.6. Experiments were performed in an in vitro flow-through system as described previously. In this system, weighed portions of each material are fixed within half-inch spacers between 0.2-pm polycarbonate membrane filters in modified air monitors which serve as the sample chambers. Fluid is pumped at a constant rate through individual polyethylene lines into the sample chambers where it is allowed to react with the fibers and the effluent is collected in individual bottles for each time increment. Aliquots of each solution are then removed for analysis. Nominal conditions used for this study were: 0.5 g fiber at a 10 ml/hr flow rate for 21 days and at a constant temperature of 37°C. Duplicate runs were made for each sample at each pH. Solutions were analyzed by inductively coupled plasma (ICP) to quantify the concentrations of the elements extracted from each fiber sample (in mg/L). The elements measured included both major and minor components of each fiber, as well as phosphorous which may be taken up from the fluid by some types of MMVF.
Justification for study design:
Please see paragraph above "Principles of method if other than guideline"
Dose descriptor:
other: not applicable
Effect level:
ca. 0 other: not applicable
Sex:
not specified
Basis for effect level:
other: not applicable
Remarks on result:
other: not applicable
Dose descriptor:
other: not applicable
Effect level:
ca. 0 other: not applicable
Sex:
not specified
Basis for effect level:
other: not applicable
Remarks on result:
other: not applicable
Reproductive effects observed:
not specified
Lowest effective dose / conc.:
0 other: not applicable
Treatment related:
not specified

For MMVF22, total dissolution rates were over 30 times greater at pH 4 than at pH 7.6.

Results in the table below (see field "any other information on results including tables") indicate that, as with total dissolution, compositional changes occurring in a particular fiber vary not only as a function of initial composition, but also with pH of the fluid. MMVF22, and to a lesser extents MMVF11, shows at least two significant changes: a progressive enrichment in both silica and alumina in the residual fiber, and loss by leaching of network-modifying alkali and alkaline earth cations. Leaching of network-modifying cations and concomitant enrichment in alumina, silica, and in some cases iron oxide was also found in fibers recovered from animal lungs from in vivo fiber durability studies on various MMVFs.

Table: Average fibre compositions after 21 -day exposure to synthetic physiological media (%wt of main components)

   MMVF22 original MMVF22 pH=4  MMVF22 pH=7.6 
 SiO2 38.4  58.3  44.5 
Al2O3  10.8  27.8  12.8 
Fe2O3  0.3  0.7  0.4 
Na2O  0.4  0.9  3.5 
K2O  1.2  0.4  0.1 
CaO  37.5  8.3  29.3 
MgO  9.9  1.8  7.9 
Total mass loss    61.9  16.2 
Conclusions:
The leaching of MMVF is congruent: the silica network and the alkali and alkaline earth ions are not released with the same rate. The Si-Al network dissolution is much slower.
Executive summary:

The leaching of MMVF is congruent: the silica network and the alkali and alkaline earth ions are not released with the same rate. The Si-Al network dissolution is much slower.

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Type of information:
other: Scientific review of the impact of REACH on glass
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Qualifier:
no guideline required
Principles of method if other than guideline:
No testing performed.
GLP compliance:
not specified
Justification for study design:
No testing performed.
Dose descriptor:
other: not applicable
Effect level:
ca. 0 other: not applicable
Sex:
not specified
Basis for effect level:
other: not applicable
Remarks on result:
other: not applicable
Dose descriptor:
other: not applicable
Effect level:
ca. 0 other: not applicable
Sex:
not specified
Basis for effect level:
other: not applicable
Remarks on result:
other: not applicable
Reproductive effects observed:
not specified
Lowest effective dose / conc.:
0 other: not applicable
Treatment related:
not specified

Glass is fundamentall non-crystalline solids characterised by a lack of translational order of their atomic structure. Glass is also characterized by the absence of any microstructure. It is an essentially isotropic material without any internal phase boundaries. From a thermodynamic point of view, glass is an undercooled frozen-in liquid.

From the REACH point of view, glass is an UVCB substance and not a mixture. The industrial glass is made of the following raw materials: sand (SiO2), feldspar (NaAlSi3O8), dolomite (CaMg(CO3)2), limestone (CaCO3), soda ash (Na2CO3) and some other oxides in small quantities.

The raw materials are simplified as pure substances featuring the man pahse of real raw material only. The resulting glass has an oxide omposition expressed in terms of SiO2, MgO.... which is a realistic representative of a typical container glass, but it should be kept in mind that glass present no internal phase boundaries. Some of the raw materials available may be classified as harmful.

But during the melting process, the raw materials lose their identities as individual substances and form a homogeneous melt. Their chemical properties are no longer reflected by the resulting glass.

The individual entities form building blocks (at the atomic scale) of a new non-cristalline matrix that chemically behaves in a way different from any of the raw materials. Chemically, the matrix as a whole behaves like a substance of its own.

Conclusions:
Glass under REACH is an UVCB substance. During the melting process, the raw materials lose their identities as individual substances and form a homogeneous melt. Their chemical properties are no longer reflected by the resulting glass.
It is exempted from registration under the entry 11 of the REACH annex V.
Executive summary:

Glass under REACH is an UVCB substance. During the melting process, the raw materials lose their identities as individual substances and form a homogeneous melt. Their chemical properties are no longer reflected by the resulting glass.

It is exempted from registration under the entry 11 of the REACH annex V.

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Type of information:
experimental study
Adequacy of study:
weight of evidence
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:
All measurements involved the constant flow of a fluid at a controlled rate through a mat of well characterised fibres at a temperature of 37 ± PC, as described in principle by e.g. Scholze and Conradt (1987), Potter and Mattson (1991), Mattson (1994), Christensene/a/. (1994), Thelohan etal. (1994).Bauer el al. (1994), Guldberg et al. (1995). Knudsen et al. (1996). Different F/A (flow-rate/initial surface area) were used for each fibre type. The simulated lung fluids were similar with respect to chemical composition and ionic strength to the modified Gamble's solutions used in the measurements of the dissolution rate at neutral pH (Zoitos el al. (1997)), but were modified to obtain a pH 4.5-5 by using different buffering systems or by adding hydrochloric acid. The fibre samples were characterised with respect to chemical composition and length-weighted fibre diameter distribution using either scanning electron microscopy (SEM) or optical microcopy (OM).(Christensen el al. (1993), Koenig et al.(1993)).
Weighed amounts of fibres were mounted in cells (filter cassettes), through which the liquid passed at a controlled flow rate. From the weighed amount of fibres, the measured flow-rate, and the initial specific surface area of the sample (calculated from the fibre diameter distribution and the density, or in some cases measured using gas adsorption techniquies (BET)), the F/A-ratio for each test was determined. In most cases a replicate of cells (2-3) were used for each test. The effluent was analysed for several of the fibre dissolving elements (Si, Ca, Mg Al, B, Fe) by means of atomic absorption spectrophotometry (AAS) or inductively coupled plasma atomic emission spectrometry (ICPAES). Based on the measurements the dissolution rates were calculated. A dissolution rate si for the network kSi was calculated based on the dissolution of Si. As leaching (incongruent dissolution) was observed at pH 4.5 for all fibres investigated here, an additional dissolution rate kk.jch was similarly calculated for the leaching elements, represented by Ca and Mg. Apart from Ca and Mg, Na, K, and B dissolve as leaching elements, while Fe, Ti and Al are neither allocated as leaching nor as belonging to the residual glass, although Al is known to leach at low pH (Elmer (1984)). The calculated dissolution rates were based on the dissolution during 25-30 days, or until either 95% of the leaching elements or 75% of the total fibre mass had dissolved, whichever happened first.
GLP compliance:
not specified
Justification for study design:
Please see paragraph above "Principles of method if other than guideline".
Dose descriptor:
other: not applicable
Effect level:
ca. 0 other: not applicable
Sex:
not specified
Basis for effect level:
other: not applicable
Remarks on result:
other: not applicable
Dose descriptor:
other: not applicable
Effect level:
ca. 0 other: not applicable
Sex:
not specified
Basis for effect level:
other: not applicable
Remarks on result:
other: not applicable
Reproductive effects observed:
not specified
Lowest effective dose / conc.:
0 other: not applicable
Treatment related:
not specified

For MMVF22, the dissolution rate at pH 4.5 of the alkali and alkaline earth ions is 4 times higher than the dissolution rate at pH 7.4 (459 ng/cm2h at pH=4.5, 119 ng/cm2h at pH=7.4).

For MMVF21, the dissolution rate at pH 4.5 of the alkali and alkaline earth ions is 3 times higher than the dissolution rate at pH 7.4 (72 ng/cm2h at pH=4.5, 23 ng/cm2h at pH=7.4).

Conclusions:
The leaching is more important at acidic pH than at neutral pH. In addition the leaching of alkali and alkaline earth ions is much more favorable that the leaching of the silica/alimina network. It means that the ionic species from alkali and alkaline earth elements will be released first and in a much higher concentration than those of Si and Al.
Executive summary:

The leaching is more important at acidic pH than at neutral pH. In addition the leaching of alkali and alkaline earth ions is much more favorable that the leaching of the silica/alimina network. It means that the ionic species from alkali and alkaline earth elements will be released first and in a much higher concentration than those of Si and Al.

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Type of information:
other: Study on glass fibres corrosion
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Qualifier:
no guideline required
Principles of method if other than guideline:
No testing performed for this endpoint.
Justification for study design:
No testing performed for this endpoint.
Dose descriptor:
other: not applicable
Effect level:
ca. 0 other: not applicable
Sex:
not specified
Basis for effect level:
other: not applicable
Remarks on result:
other: not applicable
Dose descriptor:
other: not applicable
Effect level:
ca. 0 other: not applicable
Sex:
not specified
Basis for effect level:
other: not applicable
Remarks on result:
other: not applicable
Reproductive effects observed:
not specified
Lowest effective dose / conc.:
0 other: not applicable
Treatment related:
not specified

Composition of MMVF10:

 Oxides  %wt
 SiO2 57.2 
SO3  0.12 
Fe2O3  0.07 
Al2O3  5.1 
CaO   7.5
MgO  4.1 
Na2O  15 
K2O  1.1 
B2O3  8.8 
F  0.8 
Conclusions:
Composition of MMVF10:
SiO2: 57.2 %wt
SO3: 0.12 %wt
Fe2O3: 0.07 %wt
Al2O3: 5.1 %wt
CaO: 7.5%wt
MgO: 4.1%wt
Na2O: 15%wt
K2O: 1.1%wt
B2O3: 8.8%wt
F: 0.8%wt
Executive summary:

Composition of MMVF10:

 Oxides %wt
 SiO2  57.2
SO3  0.12 
Fe2O3  0.07 
Al2O3  5.1 
CaO  7.5
 MgO 4.1 
Na2O  15 
K2O  1.1 
B2O3  8.8 
F  0.8 
Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
The study OECD 421, performed on an analogue substance (AES, Alkaline Earth Silicates, EC 610-130-5), has been evaluated and deemed robust for re-use in the argumentation.
However, we are still in discussion with the LR of the AES in order to get the right to use and sub-licence this study. Within the timeline imposed by ECHA to submit the updated MMVF LR dossier, it is not technically feasible to obtain such rights, pay the corresponding fees and then integrate the study within the dossier. You will find below proof of communication between the AES LR and MMVF LR represented by the consortium consultant SOCOTEC. The elements will be included in the dossier in the next update.
Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Type of information:
other: Scientific review
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline required
Principles of method if other than guideline:
Scientific review. No Guideline required.
GLP compliance:
no
Justification for study design:
Scientific review. No Guideline required.
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Dose descriptor:
other: Nort applicable
Effect level:
0 other: Not applicable
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Reproductive effects observed:
not specified

The chemistry of synthetic vitreous fibers determines their solubility, both in the aqueous systems described above and in the lung. Inhaled fibers that deposit in the lung are subjected to lung fluid. The lung’s epithelial layer is covered with extracellular lung fluid that contains a pulmonary surface-active material (lung surfactant) which allows one to breathe relatively effortlessly. The major physiologic function of surfactant is to lower surface tension and provide alveolar stability, but surfactant has other functions as well. Surfactant prevents alveolar flooding. A high surface tension would tend to draw fluid from the interstitium into the alveolar space. The result would be pulmonary edema and severely compromised gas exchange. Surfactant is also important for maintaining the patency and stabilization of small airways. Studies in narrow fluid-filled tubes have demonstrated the critical importance of low surface tension and the need for added surfactant to reduce opening pressures (Murray and Nadel, 2005, pp 302–303). Within the lung, the concentrations of carbon dioxide can be rapidly and precisely adjusted by the respiratory center to maintain a relatively constant neutral pH in the body. The pH of extracellular fluid in the lung is maintained at pH 7.4–7.5 (Effos and Wesson, 2005). This is in contrast to the pH within the phagolysosomes of macrophages which has been reported as acidic, pH 4.5–5 (Oberd¨orster 1991, 2000). In addition, Etherington et al. (1981) has shown that the microenvironment at the surface of activated macrophages is also acidic, with a pH < 5 found at the junction between attached macrophages and a nonporous glass surface (Etherington et al., 1981).

Conclusions:
Synthetic Vitreous Fibers (SVF) such as glasswool, stonewool and slagwool are unique in that they can dissolve relatively quickly in the lung. They are manufactured synthetically and have an amorphous or glassy structure. These amorphous materials are prepared by rapidly cooling selected molten oxides. The cooling reduces the mobility of the material’s molecules before they can pack into a more thermodynamically favorable crystalline state. In contrast to crystals (such as are found with asbestos), the structure of glass is devoid of a regular arrangement of atoms in a periodic lattice. The resulting amorphous structure makes SVFs considerably more susceptible to dissolution in the lung.
The potential for a fiber to produce a toxic effect in the lung has often been described in terms of the 3Ds that is dose, dimension and durability. The dose refers to the dose in the lung parenchyma of the longer fibers that the macrophage cannot fully engulf and remove; the dimension refers firstly to the diameter which will determine if the fiber can be inhaled into the deep lung (i.e., if the fiber is ‘respirable’); and secondly to the length which as mentioned determines whether the fiber can be engulfed and removed by the macrophage; and finally durability which determines how fast the fiber can dissolve and/or breakdown once deposited in the lung.
Executive summary:

Synthetic Vitreous Fibers (SVF) such as glasswool, stonewool and slagwool are unique in that they can dissolve relatively quickly in the lung. They are manufactured synthetically and have an amorphous or glassy structure. These amorphous materials are prepared by rapidly cooling selected molten oxides. The cooling reduces the mobility of the material’s molecules before they can pack into a more thermodynamically favorable crystalline state. In contrast to crystals (such as are found with asbestos), the structure of glass is devoid of a regular arrangement of atoms in a periodic lattice. The resulting amorphous structure makes SVFs considerably more susceptible to dissolution in the lung.

The potential for a fiber to produce a toxic effect in the lung has often been described in terms of the 3Ds that is dose, dimension and durability. The dose refers to the dose in the lung parenchyma of the longer fibers that the macrophage cannot fully engulf and remove; the dimension refers firstly to the diameter which will determine if the fiber can be inhaled into the deep lung (i.e., if the fiber is ‘respirable’); and secondly to the length which as mentioned determines whether the fiber can be engulfed and removed by the macrophage; and finally durability which determines how fast the fiber can dissolve and/or breakdown once deposited in the lung.

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Type of information:
other: Scientific opinion on dietary reference values for EU population
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Qualifier:
no guideline required
Principles of method if other than guideline:
No testing performed.
GLP compliance:
not specified
Justification for study design:
No testing performed.
Dose descriptor:
other: not applicable
Effect level:
ca. 0 other: not applicable
Sex:
not specified
Basis for effect level:
other: not applicable
Remarks on result:
other: not applicable
Dose descriptor:
other: not applicable
Effect level:
ca. 0 other: not applicable
Sex:
not specified
Basis for effect level:
other: not applicable
Remarks on result:
other: not applicable
Reproductive effects observed:
not specified
Lowest effective dose / conc.:
0 other: not applicable
Treatment related:
not specified

Chloride (Cl) is the predominant anion in intracellular fluid and one of the most important extracellular anions. It contributes to many body functions including the maintenance of osmotic and acid–base balance, muscular and nervous activity, and the movement of water and solutes between fluid compartments.

Conclusions:
Chloride (Cl) is the predominant anion in intracellular fluid and one of the most important extracellular anions. It contributes to many body functions including the maintenance of osmotic and acid–base balance, muscular and nervous activity, and the movement of water and solutes between fluid compartments.
Executive summary:

Chloride (Cl) is the predominant anion in intracellular fluid and one of the most important extracellular anions. It contributes to many body functions including the maintenance of osmotic and acid–base balance, muscular and nervous activity, and the movement of water and solutes between fluid compartments.

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Type of information:
other: Publication
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
no guideline followed
Principles of method if other than guideline:
Methods of Hersterberg et al. (1991)
GLP compliance:
not specified
Justification for study design:
Methods of Hersterberg et al. (1991)
Species:
rat
Strain:
Fischer 344
Sex:
not specified
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, NC.
- Age at study initiation: 6 weeks
- Housing: Polycarbonate cages
- Diet (e.g. ad libitum): Pelleted standard Kliba 343 rat maintenance diet
- Water (e.g. ad libitum): Filtered fresh water
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+-3 oC
- Humidity (%): 30-70%
- Air changes (per hr): 20 air changes/hr
- Photoperiod (hrs dark / hrs light): 12-hr light/dark
Route of administration:
inhalation
Type of inhalation exposure (if applicable):
nose only
Vehicle:
clean air
Remarks:
also filtered air
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Hazelton 2000 chamber
- Source and rate of air:
- System of generating particulates/aerosols:Research and Consulting Company, Geneva, fiber ae
rosol generation system.
- Temperature, humidity, pressure in air chamber: 22+-3 oC, 30-70%, -20mm H2O
- Air change rate: 20 air change/hr
- Method of particle size determination: WHO Monograph 4 (WHO, 1985)

TEST ATMOSPHERE
- Brief description of analytical method used:
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Aerosol samples were collected on Gelman membrane filters in the same location as the animal exposure port. Fiber mass concentrations were determined once during pretest, and at least four times per week during the 2 year exposure period. To assure the uniformity of exposure the fiber concentrations were monitored continuously using a RAS (GCA Corp.) light scattering monitor. Filter sampling was undertaken for each dose group. Samples were collected on Millipore filters, placed between glass slides, and clarified for counting.

Lung Burden Analysis
At necropsy the accessory lobe of the lung from each animal was removed and frozen. Diameter measurements and determination of the number of fibers recovered from the lungs were made at 5000X in a minimum of 20 fields or 200 fiber ends on either a JOEL T 300 SEM or a JOEL 840 SEM equipped with a Videoplan Image Analysis System according to the method outlined in WHO Monograph 4 for measuring airborne man-made mineral fibers (WHO, 1985) by scanning electron microscopy.
During preexposure trials and once every three months thereafter, MMVF note Q fibres' aerosols at each exposure concentration were captured on filters for determination of fiber length and diameter.
Duration of treatment / exposure:
24 months
Frequency of treatment:
6 hr/day, 5 days/week
Details on study schedule:
Post exposure period: Until approximately 20% survival in the control group (30 months).
Dose / conc.:
3 mg/m³ air (nominal)
Dose / conc.:
16 mg/m³ air (nominal)
Dose / conc.:
30 mg/m³ air (nominal)
No. of animals per sex per dose:
140 (only male rats were used)
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: To allow comparison with concurrent studies
- Rationale for animal assignment (if not random): Random
- Rationale for selecting satellite groups: No data
- Post-exposure recovery period in satellite groups: 6 months
- Section schedule rationale (if not random): Random
Positive control:
No
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
HISTOPATHOLOGY: NON-NEOPLASTIC
There was no evidence of treatment-related interstitial lung fibrosis or pleural fibrosis at any time point in the study. Exposure to the substance was associated with nonspecific inflammatory response (macrophage response) in the lungs that did not appear to progress after 6-12 months of exposure. These cellular changes are reversible and are similar to the effects observed after inhalation of an inert dust. No lung fibrosis was observed.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
Exposure resulted in no mesotheliomas and no statistically significant increase in lung tumor incidence when compared to that of negative control group.

BODY WEIGHT AND WEIGHT GAIN
There were no statistically significant body weight changes or excess mortality during the 2 years of exposure to the substance (data not shown).

The study showed that 24 months inhalation exposure to MMVF note Q fibres (up to 30 mg/m3) did not induce lung fibrosis, mesothelioma and lung tumours as compared to the control animals.
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Reproductive effects observed:
not specified

The only exposure related finding was a dose-dependent increase in mild (reversible) cellularity in the lungs that did not appear to progress after 6 months of exposure.

No effect on other organs/tissues, including reproductive organs, have been described in this 2-year chronic inhalation toxicity study of glass fibres in rats.

Conclusions:
During this study, a necropsy has been performed on targeted tissues. No effect on other organs/tissues, including reproductive organs, have been described in this 2-year chronic inhalation toxicity study of glass fibres in rats.
No treatment-related lung or pleural fibrosis was observed in the exposed animals. The only exposure related finding was a dose-dependent increase in mild cellularity in the lungs that did not appear to progress after 6 months of exposure. These cellular changes are reversible. There were no mesotheliomas observed and there was no biological or statistically significant increase in lung tumour incidence in the exposed groups when compared to that in the negative control group. Moreover, no treatment-related lesions were found in the nasal cavity, larynx, trachea, or upper airways.
Executive summary:

A carcinogenicity 2-year chronic inhalation toxicity study of glass fibres in rats (Hesterberg et al. 1993) has been performed.

During this study, a necropsy has been performed on targeted tissues. No effect on other organs/tissues, including reproductive organs, have been described in this 2-year chronic inhalation toxicity study of glass fibres in rats. No treatment-related lung or pleural fibrosis was observed in the exposed animals. The only exposure related finding was a dose-dependent increase in mild cellularity in the lungs that did not appear to progress after 6 months of exposure. These cellular changes are reversible. There were no mesotheliomas observed and there was no biological or statistically significant increase in lung tumour incidence in the exposed groups when compared to that in the negative control group. Moreover, no treatment-related lesions were found in the nasal cavity, larynx, trachea, or upper airways.

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Type of information:
other: Scientific review
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline required
Principles of method if other than guideline:
Scientific review. No Guideline required.
GLP compliance:
no
Justification for study design:
Scientific review. No Guideline required.
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Reproductive effects observed:
not specified
Conclusions:
It is shown that the calculated worst-case exposure scenario only corresponds to 10% of the average daily boron intakes through food and drinks of about 1.5 mg in adults. The inter-individual variations in boron intakes from foods, water and supplements will be much greater than the eventual, very worst-case, additional intake of boron from inhalation of glass wool fibres. The estimated boron intake from inhalation of glass wool fibres in occupational or residential settings—even at the very unrealistic, worst-case scenarios and non-compliance with occupational limit values—will be insignificant and without any health risks. Therefore, any proposal to label glass wool products with the risk phrases: ‘may impair fertility and may cause harm to the unborn child’, because of the boron content, is unreasonable and not supported by the present scientific knowledge.
Executive summary:

Background, aim and scope

Glass wools are man-made vitreous fibres, which consist principally of sodium, calcium and magnesium silicates, but may contain smaller amounts of other elements, including boron. The boron contents originate from the use of borates in the glass melting process as a glass former and a flux agent. During the production and application of glass wool insulation products, workers may legally be exposed to glass fibre up to the occupational limit value, commonly of 1 fibre/cm3 . However, in practice, the fibre exposure will be at least ten times lower. Boron is a non-metallic element widely distributed in nature, where it occurs as boric acid, borates and borosilicates. Humans are mainly exposed to boron via vegetarian food and drinking water, mineral supplements and various consumer products. Boron is an essential element for plant growth, but it may be essential for humans as intakes of trace amounts of the element seem to be useful for bone health and proper brain function; higher concentrations of boron, however, may be toxic.

Taking the values for a worst-case scenario (e.g. highest boron content of 12% in glass wool fibres, 100% retention and solubility of the fibres, a higher inhalation rate of 2 m3/h), it has been calculated that the worst-case daily boron intake in an occupational setting, assuming a 8-h work day, would be 0.16 mg boron, which is about 11-13% of the estimated average daily boron intake through diet of around 1.2-1.5 mg in adults. Furthermore, the combined daily intake (i.e. from inhalation of glass wool fibres and food consumption) of up to 1.7 mg boron per day is significantly lower than the current “Tolerable Upper Intake Level” (UL) of 10 mg boron/day for adults (weighing 60 kg) as recommended by the European Food Safety Authority (EFSA). This UL from EFSA was determined based on adverse effects from reproductive and multigenerational studies and also applies to pregnant and lactating women. It is worth mentioning that the UL of boron for adults from EFSA is lower than the respective tolerable intake levels/reference doses for adults (weighing 60 kg) as recommended by World Health Organisation (24 mg/day) and US EPA (12 mg/day) and similar to the safe upper level for daily consumption over a lifetime of 9.6 mg/day set by the UK Expert Group on Vitamins and Minerals. Altogether, it is unlikely that the inhalation exposure to glass wool fibres containing boron would result in internal dose of boron that would trigger reproductive effects in humans.

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Type of information:
other: Publication
Adequacy of study:
weight of evidence
Study period:
1998-2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
no guideline followed
Principles of method if other than guideline:
This study included one exposure level of the substance at 30 mg/m3 and a negative control group exposed to filtered air. The exposure duration was 6 hours/day, 5 days/week for 2 years with a subsequent postexposure period lasting approximately until 20% suvival in the control group.
GLP compliance:
yes
Limit test:
no
Justification for study design:
Not specified
Species:
rat
Strain:
Fischer 344
Details on species / strain selection:
Rats were selected for appropriate comparison of results from these studies with those from previous inhalation studies performed under similar conditions with other MMVFs. Male albino, specific-pathogen-free (SPF), Fischer 344 rats (Charles River Laboratories, Raleigh, NC) were used.
Sex:
male
Details on test animals or test system and environmental conditions:
- Source: Charles River Laboratory, Raleigh, NC
- Age at study initiation: 7-8 weeks at delivery
- Weight at study initiation: approx. 180g at delivery
- Fasting period before study: no data
- Housing: individually or in groups of two
- Diet (e.g. ad libitum):ad libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3°C
- Humidity (%): 30-70%
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation
Type of inhalation exposure (if applicable):
nose only
Remarks:
flow-past technique
Vehicle:
clean air
Remarks:
aso filtered air
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Flow-past exposure chamber. Animals were confined separately in restraint
tubes positioned radially at several levels of a vetical aerosol supplytube.
- Method of conditioning air: Electron charge neutralization with a Ni-63 line source.
- System of generating particulates/aerosols: The RCC fiber aerosol generation system.
- Temperature, humidity, pressure in air chamber and oxygen concetrations were all monitored.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Gravimetric concentration (mg/m3), WHO Fibers (fibers/cm3) and Fibers L>20μm (fibers/cm3) were monitored throughout the entire exposure period of two years.
Duration of treatment / exposure:
6 hours/day, 5 days/week for 2 years with a subsequent postexposure period lasting approximately until 20% survival in the control group.
Frequency of treatment:
6 hours/day, 5 days/week for 2 years
Details on study schedule:
Post exposure period
Until approximately 20% survival in the filtered air control group.
Dose / conc.:
30 mg/m³ air
Remarks:
gravimetric concentration
No. of animals per sex per dose:
107
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: The gravimetric concentration of 30 mg/m3 was selected to obtain a fiber concentration of at least 259 WHO fibers/cm3 throughout the exposure period and for being comparable to other studies.
Positive control:
No positive control group entered in the study.
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes: clinical signs, morbidity and mortality
- Time schedule: Daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: Once a week during the first 13 wk, then every 2 wk.

NECROPSY was performed on all animals
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
MMVF note Q fibres showed minimal collagen deposition, similar to what could be expected for any biologically inert dust at present exposure level. It is concluded that MMVF note Q fibres did not show a carcinogenic potential neither in the lungs nor in pleura.
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Reproductive effects observed:
not specified

Exposure Atmosphere and Fiber Characterization:

For both fibers, the reduction in diameter and length values from the stock to the aerosol fibers was small, indicating a minor influence of the aerosolization procedure on the fiber characteristics.

Lung Burden Analyses:

The number of long fibers per lung for MMVF21 increased until 18 mo of exposure and then decreased. For long HT fibers a steady-state lung burden was apparently reached by 3 to 6 mo exposure. The maximum lung burden achieved was considerably lower in the HT group than in both the 16-mg/m3 and the 30-mg/m3 MMVF21 groups.

Clinical Signs and Mortality:

In both studies, clinical signs were recorded in isolated animals but were not attributed to treatment with the test article. In addition, mortality in both studies was comparable to the unexposed controls.

Body Weights:

In the study with HT, body weight gains were comparable between the exposed and the air control groups, but the mean body weight in the control group sacrificed at 3 mo was slightly higher than in the exposed group. This might be related to some discomfort related to the initial administration of fibers.

In the study with MMVF21, in the high exposure group a marginal deficit in body weights was observed after approximately the first half year of exposure and remained until the end of exposure. In the medium exposure group the body weights were comparable to the control group.

Lung Weights and Lung-to-Body Weight Ratios:

At the 3-, 6-, 12-, and 18-mo sacrifices in the chronic studies, the mean lung weights in both the HT- and MMVF21-exposed groups showed statistically significant increases compared to the control values. This increase is considered to persist throughout the study including the 24-mo sacrifice. The lack of statistically supported difference at this time point is attributed to increased individual variation due to aging lesions.

Pathology:

The numbers of tumors in rats exposed to MMVFs were not statistically significantly above the levels found in their respective control groups; however, the incidence of nonneoplastic bronchoalveolar hyperplasia in the high-dosage MMVF21 group was statistically significantly increased compared to the concurrent control value.

Conclusions:
Neither MMVF21 nor HT showed any statistically significant increase in tumor rate after exposure.
The statistical analysis of the tumor data from the MMVF21 study and their significance has been further discussed by Rossiter and Chase (1995). In agreement with the increased biosolubility of the HT fiber, the pathology after 3, 6, 12, 18, and 24 mo of exposure showed minor histopathological changes with HT compared to both the MMVF21 high and medium dosage groups. This difference was especially pronounced using the morphometric fibrosis scoring. The HT showed minimal collagen deposition, similar to what would be expected for any biologically inert dust at this exposure level. For both fiber types, there was no evidence of carcinogenic activity in either the lungs or pleura. The significance of biopersistence was confirmed and shows that the introduction of fibers with higher biosolubility has increased the safety margins in manufacturing and use of fibrous insulation material.
The study showed that the MMVF note Q fibres possess neither fibrogenic nor carcinogenic potentials in the rat. No hispathological changes have been observed.MMVF note Q fibres are not carcinogenic in the rat and induced only minimal collagen deposition in the lungs.
Executive summary:

This is a comparable to guideline study with no deviations. Furthermore, it was published in a peerreviewed scientific journal and details on the test materials and experimental design are very well documented. The objective of the study was to assess potential pathogenic and/or oncogenic effects of chronic inhalation exposure to stone wool fibers in rats. 107 male Fischer 344 rats were exposed 6 h/day, 5 days/week for 2 years to MMVF note Q fibres at 30 mg/m3 by nose-only inhalation of a well-characterized test atmosphere. The study showed that the MMVF note Q fibres possess neither fibrogenic nor carcinogenic potentials in the rat.

No hispathological changes have been observed. MMVF note Q fibres are not carcinogenic in the rat and induced only minimal collagen deposition in the lungs.

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Type of information:
other: Publication
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline required
Principles of method if other than guideline:
Scientific publication: internal principle of method. No guideline required.
GLP compliance:
not specified
Justification for study design:
Scientific publication: internal principle of method. No guideline required.
Specific details on test material used for the study:
The experimental rockwool fiber was obtained from Paroc Oy Ab, Parainen, Finland. The glasswool fiber used in the studies was a commercial glasswool fiber. The fibers were collected from air as previously described (Luoto et al., 1992) and were otherwise similar to the commercial fibers, but prepared without a binder. The lenght of the fibers was decreased by grinding them with a mortar and pestle. the lenght of the ground fibers was measured by using a light microscope and grinding was prolonged until the lenght of the fibers was in the range of 10-20 µm. The ground fibers were allowed to age for 2 weeks before culturing to eliminate the effects of newly exposed fiber surface.
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Publication
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Publication
Dose descriptor:
other: Not applicable
Effect level:
0 other: Applicable
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Publication
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Reproductive effects observed:
not specified

The pulmonary effects of MMVF are a function of airbone fiber concentration, fiber diameter and lenght, and fiber composition and durability. The respirability of a fiber pirmarily depends on the aerodynamic diameter of the fiber, which is closely related to the actual fibre diameter an length. Moreover, for fibers of constant diameter, alveolar deposition decreases with increasing fiber length.

A single rat AM (alveolar macrophage) is able to phagocytize fibres preferentially less han 20µm long. Therefore, short fibers are likely to be phagocytized and subsequently dissolved mainly intracellularly. Longer fibers can be attacked by several AM and are therefore probably dissolved both intra and extra celllarly.

Extracellular pH is close to neutral but the intracellular pH within the phagolysosomes of teh AM is about 5.

Conclusions:
The pulmonary effects of MMVF are a function of airbone fiber concentration, fiber diameter and lenght, and fiber composition and durability. Fiber size influences the dissolution of fibers in vivo. The dissolution, as assessed by fiber dimensions, of short glass fibers is smaller than that of longer ones. However, the clearance of short glass fibers in rats seems to be effective. In contrast, long glasswool fibers may stimulate the rate of dissolution due to the additional pulmonary responses that are associated with the inability of macrophages to completely phagocytize long fibers.In the rockwool fibers, in turn, no changes between the dissolution of short and long fibers have been observed as assessed by the dimensions of the fibers.
In this study, there were clear-cut differences in the dissolution of short and long fibers, which suggests that the intracellular and extracellular dissolutions of MMVF are different. This, in turn, suggests that in vitro methods utilizing cells may be useful in identifying differences in fiber dissolution. Moreover, P388D1 macrophages are likely to reveal differences between fiber dissolution more readily than cultured rat AM.
Executive summary:

The pulmonary effects of MMVF are a function of airbone fiber concentration, fiber diameter and lenght, and fiber composition and durability. Fiber size influences the dissolution of fibers in vivo. The dissolution, as assessed by fiber dimensions, of short glass fibers is smaller than that of longer ones. However, the clearance of short glass fibers in rats seems to be effective. In contrast, long glasswool fibers may stimulate the rate of dissolution due to the additional pulmonary responses that are associated with the inability of macrophages to completely phagocytize long fibers.In the rockwool fibers, in turn, no changes between the dissolution of short and long fibers have been observed as assessed by the dimensions of the fibers.

In this study, there were clear-cut differences in the dissolution of short and long fibers, which suggests that the intracellular and extracellular dissolutions of MMVF are different. This, in turn, suggests that in vitro methods utilizing cells may be useful in identifying differences in fiber dissolution. Moreover, P388D1 macrophages are likely to reveal differences between fiber dissolution more readily than cultured rat AM.

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Type of information:
other: Publication
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline required
Principles of method if other than guideline:
Publication. No Guideline required.
GLP compliance:
not specified
Justification for study design:
Publication. No Guideline required.
Specific details on test material used for the study:
The rockwool and glasswool fibers used in the studies were commercial fibers. The fibers were collected from air as previously described (Luoto et al., 1992), and were prepared without a binder. For the studies of short fibers, and fibers were ground in a mortar with a pestle (Luoto et al., 1995b). The length of the ground fibers was measured by using a light microscope and the ground fibers were allowed to age for 2 weeks before their use to eliminate the effects of a fresh fiber surface. The fiber samples were sterilized by gamma radiation to eliminate possible microbiology contamination.
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Reproductive effects observed:
not specified
Conclusions:
The durability of fibers in the lungs is determined by their solubility and breakage into shorter particles, which can be eliminated from the lungs through phagocytosis by macrophages or via the lymphatic drainage system.

Alveolar macrophages (AM) are primary immunological cells which remove particles from the alveolar region of the lungs mainly by phagocytizing, but also by dissolving foreign bodies. Marcophages have been shown to dissolve metal oxides and MMVF. A single rat AM is able to phagocytize fibers less than 20 lm of length. Therefore, short fibers are likely to be phagocytized and dissolved intracellularly, whereas longer fibers can be attacked by several AM, and may therefore be dissolved both intracellularly and extracellularly (Bernstein et al., 1985; Morimoto et al., 1994; Luoto et al., 1995a). The intracellular pH inside the lysosomes is about 5, whereas the pH outside the cell is close to neutral (Nyberg et al., 1989; Heilmann et al., 1992). Thus, the dissolution of fibers depends on whether they are inside or outside of cells.

The harmful pulmonary effects of fibers depends on their dimensions, dose delivered to the target organ, their durability within biological fluids, surface morphology, and surface area. Soluble or fragmentable fibers are more readily removed or rendered innocuous by macrophage ingestion, protein coating and biological sequestration, mechanical clearance, or complete dissolution.
Executive summary:

The durability of fibers in the lungs is determined by their solubility and breakage into shorter particles, which can be eliminated from the lungs through phagocytosis by macrophages or via the lymphatic drainage system.

Alveolar macrophages (AM) are primary immunological cells which remove particles from the alveolar region of the lungs mainly by phagocytizing, but also by dissolving foreign bodies. Marcophages have been shown to dissolve metal oxides and MMVF. A single rat AM is able to phagocytize fibers less than 20 lm of length. Therefore, short fibers are likely to be phagocytized and dissolved intracellularly, whereas longer fibers can be attacked by several AM, and may therefore be dissolved both intracellularly and extracellularly (Bernstein et al., 1985; Morimoto et al., 1994; Luoto et al., 1995a). The intracellular pH inside the lysosomes is about 5, whereas the pH outside the cell is close to neutral (Nyberg et al., 1989; Heilmann et al., 1992). Thus, the dissolution of fibers depends on whether they are inside or outside of cells.

The harmful pulmonary effects of fibers depends on their dimensions, dose delivered to the target organ, their durability within biological fluids, surface morphology, and surface area. Soluble or fragmentable fibers are more readily removed or rendered innocuous by macrophage ingestion, protein coating and biological sequestration, mechanical clearance, or complete dissolution.

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Type of information:
other: Published Toxicology Data Network
Adequacy of study:
weight of evidence
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Qualifier:
no guideline required
Principles of method if other than guideline:
data from handbook or collection of data. No Guideline required.
GLP compliance:
no
Limit test:
no
Justification for study design:
data from handbook or collection of data. No Guideline required.
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Reproductive effects observed:
not specified
Conclusions:
There is no indication that aluminum is carcinogenic.
Executive summary:

Toxicity Summary:
Aluminum is a silvery-white, ductile and malleable metal. It is released to the environment both by natural processes and from anthropogenic sources. It is highly concentrated in soil-derived dusts from such activities as mining and agriculture, and in particulate matter from coal combustion. Aluminum occurs ubiquitously in the environment in the form of silicates, oxides and hydroxides, combined with other elements such as sodium and fluorine and as complexes with organic matter. It is not found as a free metal because of its reactivity. Aluminum metal has a wide variety of uses, including structural materials in construction, automobiles and aircraft, and the production of metal alloys. Aluminum compounds and materials also have a wide variety of uses, including production of glass, ceramics, rubber, wood preservatives, pharmaceuticals and waterproofing textiles. Natural aluminum minerals, especially bentonite and zeolite, are used in water purification, sugar refining, brewing and paper industries.

HUMAN EXPOSURE: Non-occupational human exposure to aluminum in the environment is primarily through ingestion of food and water. No acute pathogenic effects in the general population have been described after exposure to aluminum. Although human exposure to aluminum is widespread, in only a few cases has hypersensitivity been reported following exposure to some aluminum compounds after dermal application or parenteral administration. There is insufficient information to allow for classification of the cancer risk from human exposures to aluminum and its compounds. Aluminum and its compounds appear to be poorly absorbed in humans. The mechanism of gastrointestinal absorption of aluminum has not yet been fully elucidated. The highest levels of aluminum may be found in the lungs, where it may be present as inhaled insoluble particles. The urine is the most important route of aluminum excretion.

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

Effects on developmental toxicity

Description of key information

Based on the known mechanisms of fibre deposition, developmental effects from inhalation exposure to Note Q man-made vitreous fibres (MMVFs) appear to be unlikely such that the fibres do not reach reproductive organs. The bioavailability of MMVFs upon inhalation, oral or dermal exposure is expected to be low because of the physical dimensions of these elongated fibres and of the high biosolubility such that the fibres are dissolved in the lungs before entering into systemic circulation. In the intraperitoneal chronic carcinogenicity study of Note Q MMVFs, macroscopic postmortem examination was performed on the ovaries and uterus. No significant mineral wool fibres-related effects were mentioned in the study. It is predicted that maternal exposure to Note Q MMVFs does not result in the exposure of foetuses.

In addition, the US ATSDR published in 2004 its "Toxicological Profile for Synthetic Vitreous Fibers", which is a peer-reviewed report describing the toxicological and adverse health effects of synthetic vitreous fibres (including those fulfilling Note Q criteria). For developmental toxicity, the report concluded that there is no mechanistic basis to suspect that developmental effects may be of concern from exposure to synthetic vitreous fibres.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Justification for type of information:
The full waiving argumentation is detailled in the document "Developmental toxicity_WoE" below.
The studies mentionned in the justification enclosed are detailled as weight of evidence in the other endpoints of the section 7.8.2 of the IUCLID dossier.
Endpoint:
developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Justification for type of information:
The full waiving argumentation os detailled in the document "Develpmental toxicity_WoE" below.
The studies mentionned in the justification enclosed are detailled as weight of evidence in the other endpoints of the section 7.8.2 of the IUCLID dossier.
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
The study OECD 421, performed on an analogue substance (AES, Alkaline Earth Silicates, EC 610-130-5), has been evaluated and deemed robust for re-use in the argumentation.
However, we are still in discussion with the LR of the AES in order to get the right to use and sub-licence this study. Within the timeline imposed by ECHA to submit the updated MMVF LR dossier, it is not technically feasible to obtain such rights, pay the corresponding fees and then integrate the study within the dossier. You will find below proof of communication between the AES LR and MMVF LR represented by the consortium consultant SOCOTEC. The elements will be included in the dossier in the next update.
Endpoint:
developmental toxicity
Type of information:
other: Scientific review
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline required
Principles of method if other than guideline:
The fibers chosen for this evaluation were MMVF11 (a glasswool), MMVF22 (a slagwool) with an average fiber diameter of approximately 1 pm and an average length of 15 to 25 pm. Fluid simulant s used were modified Gamble's solutions. Sodium azide (0.5 mg/1) was added to both solutions as a biocidal agent. The extracellular fluid simulant was saturated with and kept under constant pressure of 5%C02/95%N2 to maintain pH 7.6 for the duration of the experiments. For the solution at pH 4, HCI was added in place of sodium bicarbonate and the level of sodium chloride adjusted to achieve the desired pH and maintain the same total cation concentration as that of the solution at pH 7.6. Experiments were performed in an in vitro flow-through system as described previously. In this system, weighed portions of each material are fixed within half-inch spacers between 0.2-pm polycarbonate membrane filters in modified air monitors which serve as the sample chambers. Fluid is pumped at a constant rate through individual polyethylene lines into the sample chambers where it is allowed to react with the fibers and the effluent is collected in individual bottles for each time increment. Aliquots of each solution are then removed for analysis. Nominal conditions used for this study were: 0.5 g fiber at a 10 ml/hr flow rate for 21 days and at a constant temperature of 37°C. Duplicate runs were made for each sample at each pH. Solutions were analyzed by inductively coupled plasma (ICP) to quantify the concentrations of the elements extracted from each fiber sample (in mg/L). The elements measured included both major and minor components of each fiber, as well as phosphorous which may be taken up from the fluid by some types of MMVF.
GLP compliance:
not specified
Species:
other: not applicable
Dose descriptor:
other: not applicable
Effect level:
ca. 0 other: not applicable
Basis for effect level:
other: not applicable
Remarks on result:
other: not applicable
Dose descriptor:
other: not applicable
Effect level:
ca. 0
Sex:
not specified
Basis for effect level:
other: not applicable
Remarks on result:
other: not applicable
Developmental effects observed:
not specified
Lowest effective dose / conc.:
0 other: not applicable
Treatment related:
not specified

For MMVF22, total dissolution rates were over 30 times greater at pH 4 than at pH 7.6.

Results in the table below (see field "any other information on results including tables") indicate that, as with total dissolution, compositional changes occurring in a particular fiber vary not only as a function

of initial composition, but also with pH of the fluid. MMVF22, and to a lesser extents MMVF11, shows at least two significant changes: a progressive enrichment in both silica and alumina in the residual

fiber, and loss by leaching of network-modifying alkali and alkaline earth cations. Leaching of network modifying cations and concomitant enrichment in alumina, silica, and in some cases iron oxide was also

found in fibers recovered from animal lungs from in vivo fiber durability studies on various MMVFs.

Table: Average fibre compositions after 21-day exposure to synthetic physiological media (%wt of main components)

   MMVF22 original MMVF22 pH=4 MMVF22 pH=7.6 
 SiO2 38.4  58.3  44.5 
Al2O3  10.8  27.8  12.8 
Fe2O3  0.3  0.7  0.4 
Na2O  0.4  0.9  3.5 
K2O  1.2  0.4  0.1 
CaO  37.5  8.3  29.3 
MgO  9.9  1.8  7.9 
Total mass loss    61.9  16.2 
Conclusions:
The leaching of MMVF is congruent: the silica network and the alkali and alkaline earth ions are not released with the same rate. The Si-Al network dissolution is much slower.
Executive summary:

The leaching of MMVF is congruent: the silica network and the alkali and alkaline earth ions are not released with the same rate. The Si-Al network dissolution is much slower.

Endpoint:
developmental toxicity
Type of information:
other: Scientific review
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline required
Principles of method if other than guideline:
Scientific review. No Guideline required.
GLP compliance:
not specified
Species:
rat
Strain:
not specified
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Based on:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Developmental effects observed:
not specified

The chemistry of synthetic vitreous fibers determines their solubility, both in the aqueous systems described above and in the lung. Inhaled fibers that deposit in the lung are subjected to lung fluid. The lung’s epithelial layer is covered with extracellular lung fluid that contains a pulmonary surfaceactive material (lung surfactant) which allows one to breathe relatively effortlessly. The major physiologic function of surfactant is to lower surface tension and provide alveolar stability, but surfactant has other functions as well. Surfactant prevents alveolar flooding. A high surface tension would tend to draw fluid from the interstitium into the alveolar space. The result would be pulmonary edema and severely compromised gas exchange. Surfactant is also important for maintaining the patency and stabilization of small airways. Studies in narrow fluid-filled tubes have demonstrated the critical importance of low surface tension and the need for added surfactant to reduce opening pressures (Murray and Nadel, 2005, pp 302–303). Within the lung, the concentrations of carbon dioxide can be rapidly and precisely adjusted by the respiratory center to maintain a relatively constant neutral pH in the body. The pH of extracellular fluid in the lung is maintained at pH 7.4–7.5 (Effos and Wesson, 2005). This is in contrast to the pH within the phagolysosomes of macrophages which has been reported as acidic, pH 4.5–5 (Oberd¨orster 1991, 2000). In addition, Etherington et al. (1981) has shown that the microenvironment

at the surface of activated macrophages is also acidic, with a pH < 5 found at the junction between attached macrophages and a nonporous glass surface (Etherington et al., 1981).

Conclusions:
Synthetic Vitreous Fibers (SVF) such as glasswool, stonewool and slagwool are unique in that they can dissolve relatively quickly in the lung. They are manufactured synthetically and have an amorphous or glassy structure. These amorphous materials are prepared by rapidly cooling selected molten oxides. The cooling reduces the mobility of the material’s molecules before they can pack into a more thermodynamically favorable crystalline state. In contrast to crystals (such as are found with asbestos), the structure of glass is devoid of a regular arrangement of atoms in a periodic lattice. The resulting amorphous structure makes SVFs considerably more susceptible to dissolution in the lung. The potential for a fiber to produce a toxic effect in the lung has often been described in terms of the 3Ds that is dose, dimension and durability. The dose refers to the dose in the lung parenchyma of the longer fibers that the macrophage cannot fully engulf and remove; the dimension refers firstly to the diameter which will determine if the fiber can be inhaled into the deep lung (i.e., if the fiber is ‘respirable’); and secondly to the length which as mentioned determines whether the fiber can be engulfed and removed by the macrophage; and finally durability which determines how fast the fiber can dissolve and/or breakdown once deposited in the lung.
Executive summary:

Synthetic Vitreous Fibers (SVF) such as glasswool, stonewool and slagwool are unique in that they can dissolve relatively quickly in the lung. They are manufactured synthetically and have an amorphous or glassy structure. These amorphous materials are prepared by rapidly cooling selected molten oxides. The cooling reduces the mobility of the material’s molecules before they can pack into a more thermodynamically favorable crystalline state. In contrast to crystals (such as are found with asbestos), the structure of glass is devoid of a regular arrangement of atoms in a periodic lattice. The resulting amorphous structure makes SVFs considerably more susceptible to dissolution in the lung.

The potential for a fiber to produce a toxic effect in the lung has often been described in terms of the 3Ds that is dose, dimension and durability. The dose refers to the dose in the lung parenchyma of the longer fibers that the macrophage cannot fully engulf and remove; the dimension refers firstly to the diameter which will determine if the fiber can be inhaled into the deep lung (i.e., if the fiber is ‘respirable’); and secondly to the length which as mentioned determines whether the fiber can be engulfed and removed by the macrophage; and finally durability which determines how fast the fiber can dissolve and/or breakdown once deposited in the lung.

Endpoint:
developmental toxicity
Type of information:
other: Scientific review of the impact of REACH on glass
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Qualifier:
no guideline required
Principles of method if other than guideline:
No testing performed.
GLP compliance:
not specified
Species:
other: not applicable
Dose descriptor:
other: not applicable
Effect level:
ca. 0 other: not applicable
Based on:
not specified
Basis for effect level:
other: not applicable
Remarks on result:
other: not applicable
Dose descriptor:
other: not applicable
Effect level:
ca. 0 other: not applicable
Sex:
not specified
Basis for effect level:
other: not applicable
Remarks on result:
other: not applicable
Developmental effects observed:
not specified
Lowest effective dose / conc.:
0 other: not applicable
Treatment related:
not specified

Glass is fundamentall non-crystalline solids characterised by a lack of translational order of their atomic structure. Glass is also characterized by the absence of any microstructure. It is an essentially isotropic material without any internal phase boundaries. From a thermodynamic point of view, glass is an undercooled frozen-in liquid. From the REACH point of view, glass is an UVCB substance and not a mixture. The industrial glass is made of the following raw materials: sand (SiO2), feldspar (NaAlSi3O8), dolomite (CaMg(CO3)2), limestone (CaCO3), soda ash (Na2CO3) and some other oxides in small quantities. The raw materials are simplified as pure substances featuring the man pahse of real raw material only. The resulting glass has an oxide omposition expressed in terms of SiO2, MgO.... which is a realistic representative of a typical container glass, but it should be kept in mind that glass present no internal phase boundaries. Some of the raw materials available may be classified as harmful. But during the melting process, the raw materials lose their identities as individual substances and form a homogeneous melt. Their chemical properties are no longer reflected by the resulting glass. The individual entities form building blocks (at the atomic scale) of a new non-cristalline matrix that chemically behaves in a way different from any of the raw materials. Chemically, the matrix as a whole behaves like a substance of its own.

Conclusions:
Glass under REACH is an UVCB substance. During the melting process, the raw materials lose their identities as individual substances and form a homogeneous melt. Their chemical properties are no longer reflected by the resulting glass.
It is exempted from registration under the entry 11 of the REACH annex V.
Executive summary:

Glass under REACH is an UVCB substance. During the melting process, the raw materials lose their identities as individual substances and form a homogeneous melt. Their chemical properties are no longer reflected by the resulting glass.

It is exempted from registration under the entry 11 of the REACH annex V.

Endpoint:
developmental toxicity
Type of information:
other: Scientific opinion on dietary reference values for EU population
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Qualifier:
no guideline required
Principles of method if other than guideline:
No testing performed.
GLP compliance:
not specified
Species:
other: not appplicable
Dose descriptor:
other: not applicable
Effect level:
ca. 0 other: not applicable
Basis for effect level:
other: not applicable
Remarks on result:
other: not applicable
Dose descriptor:
other: not applicable
Effect level:
ca. 0 other: not applicable
Sex:
not specified
Basis for effect level:
other: not applicable
Remarks on result:
other: not applicable
Developmental effects observed:
not specified
Lowest effective dose / conc.:
0 other: not applicable
Treatment related:
not specified

Chloride (Cl) is the predominant anion in intracellular fluid and one of the most important extracellular anions. It contributes to many body functions including the maintenance of osmotic and acid–base balance, muscular and nervous activity, and the movement of water and solutes between fluid compartments.

Conclusions:
Chloride (Cl) is the predominant anion in intracellular fluid and one of the most important extracellular anions. It contributes to many body functions including the maintenance of osmotic and acid–base balance, muscular and nervous activity, and the movement of water and solutes between fluid compartments.
Executive summary:

Chloride (Cl) is the predominant anion in intracellular fluid and one of the most important extracellular anions. It contributes to many body functions including the maintenance of osmotic and acid–base balance, muscular and nervous activity, and the movement of water and solutes between fluid compartments.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
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:
All measurements involved the constant flow of a fluid at a controlled rate through a mat of well characterised fibres at a temperature of 37 ± PC, as described in principle by e.g. Scholze and Conradt (1987), Potter and Mattson (1991), Mattson (1994), Christensene/a/. (1994), Thelohan etal. (1994).Bauer el al. (1994), Guldberg et al. (1995). Knudsen et al. (1996). Different F/A (flow-rate/initial surface area) were used for each fibre type. The simulated lung fluids were similar with respect to chemical composition and ionic strength to the modified Gamble's solutions used in the measurements of the dissolution rate at neutral pH (Zoitos el al. (1997)), but were modified to obtain a pH 4.5-5 by using different buffering systems or by adding hydrochloric acid. The fibre samples were characterised with respect to chemical composition and length-weighted fibre diameter distribution using either scanning electron microscopy (SEM) or optical microcopy (OM).(Christensen el al. (1993), Koenig et al.(1993)). Weighed amounts of fibres were mounted in cells (filter cassettes), through which the liquid passed at a controlled flow rate. From the weighed amount of fibres, the measured flow-rate, and the initial specific surface area of the sample (calculated from the fibre diameter distribution and the density, or in some cases measured using gas adsorption techniquies (BET)), the F/A-ratio for each test was determined. In most cases a replicate of cells (2-3) were used for each test. The effluent was analysed for several of the fibre dissolving elements (Si, Ca, Mg Al, B, Fe) by means of atomic absorption spectrophotometry (AAS) or inductively coupled plasma atomic emission spectrometry (ICPAES). Based on the measurements the dissolution rates were calculated. A dissolution rate si for the network kSi was calculated based on the dissolution of Si. As leaching (incongruent dissolution) was observed at pH 4.5 for all fibres investigated here, an additional dissolution rate kk.jch was similarly calculated for the leaching elements, represented by Ca and Mg. Apart from Ca and Mg, Na, K, and B dissolve as leaching elements, while Fe, Ti and Al are neither allocated as leaching nor as belonging to the residual glass, although Al is known to leach at low pH (Elmer (1984)). The calculated dissolution rates were based on the dissolution during 25-30 days, or until either 95% of the leaching elements or 75% of the total fibre mass had dissolved, whichever happened first.
GLP compliance:
not specified
Species:
other: not applicable
Dose descriptor:
other: not applicable
Effect level:
ca. 0 other: not applicable
Based on:
not specified
Basis for effect level:
other: not applicable
Remarks on result:
other: not applicable
Dose descriptor:
other: not applicable
Effect level:
ca. 0 other: not applicable
Sex:
not specified
Basis for effect level:
other: not applicable
Remarks on result:
other: not applicable
Developmental effects observed:
not specified
Lowest effective dose / conc.:
0 other:
Treatment related:
not specified

For MMVF22, the dissolution rate at pH 4.5 of the alkali and alkaline earth ions is 4 times higher than the dissolution rate at pH 7.4 (459 ng/cm2h at pH=4.5, 119 ng/cm2h at pH=7.4).

For MMVF21, the dissolution rate at pH 4.5 of the alkali and alkaline earth ions is 3 times higher than the dissolution rate at pH 7.4 (72 ng/cm2h at pH=4.5, 23 ng/cm2h at pH=7.4).

Conclusions:
The leaching is more important at acidic pH than at neutral pH. In addition the leaching of alkali and alkaline earth ions is much more favorable that the leaching of the silica/alimina network. It means that the ionic species from alkali and alkaline earth elements will be released first and in a much higher concentration than those of Si and Al.
Executive summary:

The leaching is more important at acidic pH than at neutral pH. In addition the leaching of alkali and alkaline earth ions is much more favorable that the leaching of the silica/alimina network. It means that the ionic species from alkali and alkaline earth elements will be released first and in a much higher concentration than those of Si and Al.

Endpoint:
developmental toxicity
Type of information:
other: Publication
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose for cross-reference:
reference to same study
Qualifier:
no guideline followed
Principles of method if other than guideline:
Methods of Hersterberg et al. (1991)
GLP compliance:
not specified
Species:
rat
Strain:
Fischer 344
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, NC.
- Age at study initiation: 6 weeks
- Housing: Polycarbonate cages
- Diet (e.g. ad libitum): Pelleted standard Kliba 343 rat maintenance diet
- Water (e.g. ad libitum): Filtered fresh water
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+-3 oC
- Humidity (%): 30-70%
- Air changes (per hr): 20 air changes/hr
- Photoperiod (hrs dark / hrs light): 12-hr light/dark
Route of administration:
inhalation
Type of inhalation exposure (if applicable):
nose only
Vehicle:
clean air
Remarks:
also filtered air
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Hazelton 2000 chamber
- Source and rate of air:
- System of generating particulates/aerosols:Research and Consulting Company, Geneva, fiber ae
rosol generation system.
- Temperature, humidity, pressure in air chamber: 22+-3 oC, 30-70%, -20mm H2O
- Air change rate: 20 air change/hr
- Method of particle size determination: WHO Monograph 4 (WHO, 1985)

TEST ATMOSPHERE
- Brief description of analytical method used:
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Aerosol samples were collected on Gelman membrane filters in the same location as the animal exposure port. Fiber mass concentrations were determined once during pretest, and at least four times per week during the 2 year exposure period. To assure the uniformity of exposure the fiber concentrations were monitored continuously using a RAS (GCA Corp.) light scattering monitor. Filter sampling was undertaken for each dose group. Samples were collected on Millipore filters, placed between glass slides, and clarified for counting.

Lung Burden Analysis
At necropsy the accessory lobe of the lung from each animal was removed and frozen. Diameter measurements and determination of the number of fibers recovered from the lungs were made at 5000X in a minimum of 20 fields or 200 fiber ends on either a JOEL T 300 SEM or a JOEL 840 SEM equipped with a Videoplan Image Analysis System according to the method outlined in WHO Monograph 4 for measuring airborne man-made mineral fibers (WHO, 1985) by scanning electron microscopy.
During preexposure trials and once every three months thereafter, MMVF note Q fibres' aerosols at each exposure concentration were captured on filters for determination of fiber length and diameter.
Duration of treatment / exposure:
24 months
Frequency of treatment:
6 hr/day, 5 days/week
Duration of test:
Post exposure period: Until approximately 20% survival in the control group (30 months).
Dose / conc.:
3 mg/m³ air (nominal)
Dose / conc.:
16 mg/m³ air (nominal)
Dose / conc.:
30 mg/m³ air (nominal)
No. of animals per sex per dose:
140 (only male rats were used)
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: To allow comparison with concurrent studies
- Rationale for animal assignment (if not random): Random
- Rationale for selecting satellite groups: No data
- Post-exposure recovery period in satellite groups: 6 months
- Section schedule rationale (if not random): Random
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Based on:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Developmental effects observed:
not specified

The only exposure related finding was a dose-dependent increase in mild (reversible) cellularity in the lungs that did not appear to progress after 6 months of exposure.

No effect on other organs/tissues, including reproductive organs, have been described in this 2-year chronic inhalation toxicity study of glass fibres in rats.

Conclusions:
During this study, a necropsy has been performed on targeted tissues. No effect on other organs/tissues, including reproductive organs, have been described in this 2-year chronic inhalation toxicity study of glass fibres in rats.
No treatment-related lung or pleural fibrosis was observed in the exposed animals. The only exposure related finding was a dose-dependent increase in mild cellularity in the lungs that did not appear to progress after 6 months of exposure. These cellular changes are reversible. There were no mesotheliomas observed and there was no biological or statistically significant increase in lung tumour incidence in the exposed groups when compared to that in the negative control group. Moreover, no treatment-related lesions were found in the nasal cavity, larynx, trachea, or upper airways.
Executive summary:

A carcinogenicity 2-year chronic inhalation toxicity study of glass fibres in rats (Hesterberg et al. 1993) has been performed.

During this study, a necropsy has been performed on targeted tissues. No effect on other organs/tissues, including reproductive organs, have been described in this 2-year chronic inhalation toxicity study of glass fibres in rats.No treatment-related lung or pleural fibrosis was observed in the exposed animals. The only exposure related finding was a dose-dependent increase in mild cellularity in the lungs that did not appear to progress after 6 months of exposure. These cellular changes are reversible. There were no mesotheliomas observed and there was no biological or statistically significant increase in lung tumour incidence in the exposed groups when compared to that in the negative control group. Moreover, no treatment-related lesions were found in the nasal cavity, larynx, trachea, or upper airways.

Endpoint:
developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Justification for type of information:
The literature search and screening for data related to reproductive toxicity of fibres of scope resulted in 2 scientific references eligible for further screening. Both scientific references are human studies, one case report (Hinnen et al., 1997 ) and one epidemiological study using a cancer registry (Vasama-Neuvonen et al., 1999 ). Evaluation of both scientific references showed major deficiencies in the methodology which make the outcome of these studies not reliable (Klimisch rating: 3). The results of these studies have not been taken into account in this argumentation for the reasons detailed below.
In the Hinnen et al. (1997) study, the authors reported a patient with foreign body granuloma of the penis possibly due to occupational glass fibre exposure. However, this is a case report of one patient working in the fibre-reinforced plastic industry and showing a penile ulcer. This patient has an history of syphilis more than 20 years ago, but the biopsy performed indicated the presence of foreign bodies possibly consistent with glass fibres. The authors concluded that the granuloma may be linked to its occupational exposure to fibres. The link between this penile granuloma and the occupational exposure to glass fibres could not have been clearly identified during the study and the lack of other cases greatly decreases the robustness of the study. Anyway, this is not possible to extrapolate based on only one observation.
The study of Vasama-Neuvonen et al. (1999) investigated the relationship between ovarian cancer and occupational exposures to various substances including MMVFs in Finland. It has been reported in this study that women occupationally exposed to MMVFs has an elevated risk for ovarian cancer (standardised incidence ratio of 1.3; 95% confidence interval of 1.0-1.7). The cohort studied is composed of building workers, which are usually a majority of men, therefore the representability of the results regarding ovarian cancer may be questioned. In addition, it is mentioned that 100% of the building workers have been exposed to asbestos and 90% to the MMVF: it is not possible to distinguish the effect of asbestos from the one of MMVF on ovarian cancer incidence in this cohort. Indeed, the exact same number of cases has been reported with asbestos and MMVF confirming the absence of differentiation. This is a major deficiency as the hazard profile of these two substances is completely different. This study has been examined in 2001 by the IARC working group who also mentioned the limitations of this study.
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Species:
rat
Endpoint:
developmental toxicity
Type of information:
other: Scientific review
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline required
Principles of method if other than guideline:
Scientific review. No Guideline required.
GLP compliance:
not specified
Species:
other: Not applicable
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Based on:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Developmental effects observed:
not specified
Conclusions:
It is shown that the calculated worst-case exposure scenario only corresponds to 10% of the average daily boron intakes through food and drinks of about 1.5 mg in adults. The inter-individual variations in boron intakes from foods, water and supplements will be much greater than the eventual, very worstcase, additional intake of boron from
inhalation of glass wool fibres. The estimated boron intake from inhalation of glass wool fibres in occupational or residential settings—even at the very unrealistic, worst-case scenarios and non-compliance with occupational limit values—will be insignificant and without any health risks. Therefore, any proposal to label glass wool products with the risk phrases: ‘may impair fertility and may cause harm to the unborn child’, because of the boron content, is unreasonable and not supported by the present scientific knowledge.
Executive summary:

Glass wools are man-made vitreous fibres, which consist principally of sodium, calcium and magnesium silicates, but may contain smaller amounts of other elements, including boron. The boron contents originate from the use of borates in the glass melting process as a glass former and a flux agent. During the production and application of glass wool insulation products, workers may legally be exposed to glass fibre up to the occupational limit value, commonly of 1 fibre/cm3 . However, in practice, the fibre exposure will be at least ten times lower. Boron is a non-metallic element widely distributed in nature, where it occurs as boric acid, borates and borosilicates. Humans are mainly exposed to boron via vegetarian food and drinking water, mineral supplements and various consumer products. Boron is an essential element for plant growth, but the essentiality for humans is not proven, although intakes of trace amounts of the element seem to be useful for bone health and proper brain function; higher concentrations of boron, however, may be toxic.

Taking the values for a worst-case scenario (e.g. highest boron content of 12% in glass wool fibres, 100% retention and solubility of the fibres, a higher inhalation rate of 2 m3/h), it has been calculated that the worst-case daily boron intake in an occupational setting, assuming a 8-h work day, would be 0.16 mg boron, which is about 11-13% of the estimated average daily boron intake through diet of around 1.2-1.5 mg in adults. Furthermore, the combined daily intake (i.e. from inhalation of glass wool fibres and food consumption) of up to 1.7 mg boron per day is significantly lower than the current “Tolerable Upper Intake Level” (UL) of 10 mg boron/day for adults (weighing 60 kg) as recommended by the European Food Safety Authority (EFSA). This UL from EFSA was determined based on adverse effects from reproductive and multigenerational studies and also applies to pregnant and lactating women. It is worth mentioning that the UL of boron for adults from EFSA is lower than the respective tolerable intake levels/ reference doses for adults (weighing 60 kg) as recommended by World Health Organisation (24 mg/day) and US EPA (12 mg/day) and similar to the safe upper level for daily consumption over a lifetime of 9.6 mg/day set by the UK Expert Group on Vitamins and Minerals. Altogether, it is unlikely that the inhalation exposure to glass wool fibres containing boron would result in internal dose of boron that would trigger reproductive effects in humans.

Endpoint:
developmental toxicity
Type of information:
other: Publication
Adequacy of study:
weight of evidence
Study period:
1998-2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
no guideline required
Principles of method if other than guideline:
This study included one exposure level of the substance at 30 mg/m3 and a negative control group exposed to filtered air. The exposure duration was 6 hours/day, 5 days/week for 2 years with a subsequent postexposure period lasting approximately until 20% suvival in the control group.
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Fischer 344
Details on test animals or test system and environmental conditions:
- Source: Charles River Laboratory, Raleigh, NC
- Age at study initiation: 7-8 weeks at delivery
- Weight at study initiation: approx. 180g at delivery
- Fasting period before study: no data
- Housing: individually or in groups of two
- Diet (e.g. ad libitum):ad libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period: no data
- Humidity (%): 30-70%
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation
Type of inhalation exposure (if applicable):
nose only
Vehicle:
clean air
Remarks:
also filtered air
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Flow-past exposure chamber. Animals were confined separately in restraint tubes positioned radially at several levels of a vetical aerosol supplytube.
- Method of conditioning air: Electron charge neutralization with a Ni-63 line source.
- System of generating particulates/aerosols: The RCC fiber aerosol generation system.
- Temperature, humidity, pressure in air chamber and oxygen concetrations were all monitored.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Gravimetric concentration (mg/m3), WHO Fibers (fibers/cm3) and Fibers L>20μm (fibers/cm3) were monitored throughout the entire exposure period of two years.
Duration of treatment / exposure:
6 hours/day, 5 days/week for 2 years with a subsequent postexposure period lasting approximately until 20% survival in the control group.
Frequency of treatment:
6 hours/day, 5 days/week for 2 years
Dose / conc.:
30 mg/m³ air
Remarks:
gravimetric concentration
No. of animals per sex per dose:
107 (only male)
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: The gravimetric concentration of 30 mg/m3 was selected to obtain a fiber concentration of at least 259 WHO fibers/cm3 throughout the exposure period and for being comparable to other studies.
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Based on:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Developmental effects observed:
not specified

Exposure Atmosphere and Fiber Characterization:

For both fibers, the reduction in diameter and length values from the stock to the aerosol fibers was small, indicating a minor influence of the aerosolization procedure on the fiber characteristics.

Lung Burden Analyses:

The number of long fibers per lung for MMVF21 increased until 18 mo of exposure and then decreased. For long HT fibers a steady-state lung burden was apparently reached by 3 to 6 mo exposure. The maximum lung burden achieved was considerably lower in the HT group than in both the 16-mg/m3 and the 30-mg/m3 MMVF21 groups.

Clinical Signs and Mortality:

In both studies, clinical signs were recorded in isolated animals but were not attributed to treatment with the test article. In addition, mortality in both studies was comparable to the unexposed controls.

Body Weights:

In the study with HT, body weight gains were comparable between the exposed and the air control groups, but the mean body weight in the control group sacrificed at 3 mo was slightly higher than in the exposed group. This might be related to some discomfort related to the initial administration of fibers. In the study with MMVF21, in the high exposure group a marginal deficit in body weights was observed after approximately the first half year of exposure and remained until the end of exposure. In the medium exposure group the body weights were comparable to the control group.

Lung Weights and Lung-to-Body Weight Ratios:

At the 3-, 6-, 12-, and 18-mo sacrifices in the chronic studies, the mean lung weights in both the HTand MMVF21-exposed groups showed statistically significant increases compared to the control values. This increase is considered to persist throughout the study including the 24-mo sacrifice. The lack of statistically supported difference at this time point is attributed to increased individual variation due to aging lesions.

Pathology:

The numbers of tumors in rats exposed to MMVFs were not statistically significantly above the levels found in their respective control groups; however, the incidence of nonneoplastic bronchoalveolar hyperplasia in the high-dosage MMVF21 group was statistically significantly increased compared to the concurrent control value.

Conclusions:
Neither MMVF21 nor HT showed any statistically significant increase in tumor rate after exposure. The statistical analysis of the tumor data from the MMVF21 study and their significance has been further discussed by Rossiter and Chase (1995). In agreement with the increased biosolubility of the HT fiber, the pathology after 3, 6, 12, 18, and 24 mo of exposure showed minor histopathological changes with HT compared to both the MMVF21 high and medium dosage groups. This difference was especially pronounced using the morphometric fibrosis scoring. The HT showed minimal collagen deposition, similar to what would be expected for any biologically inert dust at this exposure level. For both fiber types, there was no evidence of carcinogenic activity in either the lungs or pleura. The significance of biopersistence was confirmed and shows that the introduction of fibers with higher biosolubility has increased the safety margins in manufacturing and use of fibrous insulation material. The study showed that the MMVF note Q fibres possess neither fibrogenic nor carcinogenic potentials in the rat. No hispathological changes have been observed.MMVF note Q fibres are not carcinogenic in the rat and induced only minimal collagen deposition in the lungs.
Executive summary:

This is a comparable to guideline study with no deviations. Furthermore, it was published in a peerreviewed scientific journal and details on the test materials and experimental design are very well documented. The objective of the study was to assess potential pathogenic and/or oncogenic effects of chronic inhalation exposure to stone wool fibers in rats. 107 male Fischer 344 rats were exposed 6 h/day, 5 days/week for 2 years to MMVF note Q fibres at 30 mg/m3 by nose-only inhalation of a well-characterized test atmosphere. The study showed that the MMVF note Q fibres possess neither fibrogenic nor carcinogenic potentials in the rat.

No hispathological changes have been observed. MMVF note Q fibres are not carcinogenic in the rat and induced only minimal collagen deposition in the lungs.

Endpoint:
developmental toxicity
Type of information:
other: Study on glass ibres corrosion
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Qualifier:
no guideline required
Principles of method if other than guideline:
No testing performed for this endpoint.
GLP compliance:
not specified
Species:
other: not applicable
Dose descriptor:
other: not applicable
Effect level:
ca. 0 other: not applicable
Basis for effect level:
other: not applicable
Remarks on result:
other: not applicable
Dose descriptor:
other: not applicable
Effect level:
ca. 0 other: not applicable
Sex:
not specified
Basis for effect level:
other: not applicable
Remarks on result:
other: not applicable
Developmental effects observed:
not specified
Lowest effective dose / conc.:
0 other: not applicable
Treatment related:
not specified

Composition of MMVF10:

 Oxides %wt 
 SiO2 57.2 
SO3 0.12 
Fe2O3  0.07 
Al2O3  5.1 
CaO  7.5 
MgO  4.1 
Na2O  15 
K2O  1.1 
B2O3  8.8 
F   0.8
Conclusions:
Composition of MMVF10:
SiO2: 57.2 %wt
SO3: 0.12 %wt
Fe2O3: 0.07 %wt
Al2O3: 5.1 %wt
CaO: 7.5%wt
MgO: 4.1%wt
Na2O: 15%wt
K2O: 1.1%wt
B2O3: 8.8%wt
F: 0.8%wt
Executive summary:

Composition of MMVF10:

 Oxides  %wt
 SiO2 57.2 
SO3  0.12 
Fe2O3  0.07 
Al2O3  5.1 
CaO  7.5 
MgO  4.1 
Na2O  15 
K2O  1.1 
B2O3  8.8 
F  0.8 
Endpoint:
developmental toxicity
Type of information:
other: Publication
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline required
Principles of method if other than guideline:
Scientific publication: internal principle of method. No guideline required.
GLP compliance:
not specified
Specific details on test material used for the study:
The experimental rockwool fiber was obtained from Paroc Oy Ab, Parainen, Finland. The glasswool fiber used in the studies was a commercial glasswool fiber. The fibers were collected from air as previously described (Luoto et al., 1992) and were otherwise similar to the commercial fibers, but prepared without a binder. The lenght of the fibers was decreased by grinding them with a mortar and pestle. the lenght of the ground fibers was measured by using a light microscope and grinding was prolonged until the lenght of the fibers was in the range of 10-20 μm. The ground fibers were allowed to age for 2 weeks before culturing to eliminate the effects of newly exposed fiber surface.
Species:
other: Not applicable
Dose descriptor:
other: Not aaplicable
Effect level:
0 other: Not applicable
Based on:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Developmental effects observed:
not specified

The pulmonary effects of MMVF are a function of airbone fiber concentration, fiber diameter and lenght, and fiber composition and durability. The respirability of a fiber pirmarily depends on the aerodynamic

diameter of the fiber, which is closely related to the actual fibre diameter an length. Moreover, for fibers of constant diameter, alveolar deposition decreases with increasing fiber length.

A single rat AM (alveolar macrophage) is able to phagocytize fibres preferentially less han 20μm long. Therefore, short fibers are likely to be phagocytized and subsequently dissolved mainly intracellularly.

Longer fibers can be attacked by several AM and are therefore probably dissolved both intra and extra celllarly.

Extracellular pH is close to neutral but the intracellular pH within the phagolysosomes of teh AM is about 5.

Conclusions:
The pulmonary effects of MMVF are a function of airbone fiber concentration, fiber diameter and lenght, and fiber composition and durability. Fiber size influences the dissolution of fibers in vivo. The dissolution, as assessed by fiber dimensions, of short glass fibers is smaller than that of longer ones. However, the clearance of short glass fibers in rats seems to be effective. In contrast, long glasswool fibers may stimulate the rate of dissolution due to the additional pulmonary responses that are associated with the inability of macrophages to completely phagocytize long fibers.In the rockwool fibers, in turn, no changes between the dissolution of short and long fibers have been observed as assessed by the dimensions of the fibers.
In this study, there were clear-cut differences in the dissolution of short and long fibers, which suggests that the intracellular and extracellular dissolutions of MMVF are different. This, in turn, suggests that in vitro methods utilizing cells may be useful in identifying differences in fiber dissolution. Moreover, P388D1 macrophages are likely to reveal differences between fiber dissolution more readily than cultured rat AM.
Executive summary:

The pulmonary effects of MMVF are a function of airbone fiber concentration, fiber diameter and lenght, and fiber composition and durability. Fiber size influences the dissolution of fibers in vivo. The dissolution, as assessed by fiber dimensions, of short glass fibers is smaller than that of longer ones. However, the clearance of short glass fibers in rats seems to be effective. In contrast, long glasswool fibers may stimulate the rate of dissolution due to the additional pulmonary responses that are associated with the inability of macrophages to completely phagocytize long fibers.In the rockwool fibers, in turn, no changes between the dissolution of short and long fibers have been observed as assessed by the dimensions of the fibers.

In this study, there were clear-cut differences in the dissolution of short and long fibers, which suggests that the intracellular and extracellular dissolutions of MMVF are different. This, in turn, suggests that in vitro methods utilizing cells may be useful in identifying differences in fiber dissolution. Moreover, P388D1 macrophages are likely to reveal differences between fiber dissolution more readily than cultured rat AM.

Endpoint:
developmental toxicity
Type of information:
other: Publicatioin
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Qualifier:
no guideline required
Principles of method if other than guideline:
No Guideline required.
GLP compliance:
not specified
Specific details on test material used for the study:
The rockwool and glasswool fibers used in the studies were commercial fibers. The fibers were collected from air as previously described (Luoto et al., 1992), and were prepared without a binder. For the studies of short fibers, and fibers were ground in a mortar with a pestle (Luoto et al., 1995b). The length of the ground fibers was measured by using a light microscope and the ground fibers were allowed to age for 2 weeks before their use to eliminate the effects of a fresh fiber surface. The fiber samples were sterilized by gamma radiation to eliminate possible microbiology contamination.
Species:
other: Not applicable
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Based on:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Developmental effects observed:
not specified
Conclusions:
The durability of fibers in the lungs is determined by their solubility and breakage into shorter particles, which can be eliminated from the lungs through phagocytosis by macrophages or via the lymphatic drainage system.

Alveolar macrophages (AM) are primary immunological cells which remove particles from the alveolar region of the lungs mainly by phagocytizing, but also by dissolving foreign bodies. Marcophages have been shown to dissolve metal oxides and MMVF. A single rat AM is able to phagocytize fibers less than 20 lm of length. Therefore, short fibers are likely to be phagocytized and dissolved intracellularly, whereas longer fibers can be attacked by several AM, and may therefore be dissolved both intracellularly and extracellularly (Bernstein et al., 1985; Morimoto et al., 1994; Luoto et al., 1995a). The intracellular pH inside the lysosomes is about 5, whereas the pH outside the cell is close to neutral (Nyberg et al., 1989; Heilmann et al., 1992). Thus, the dissolution of fibers depends on whether they are inside or outside of cells.
The harmful pulmonary effects of fibers depends on their dimensions, dose delivered to the target organ, their durability within biological fluids, surface morphology, and surface area. Soluble or fragmentable fibers are more readily removed or rendered innocuous by macrophage ingestion, protein coating and biological sequestration, mechanical clearance, or complete dissolution.
Executive summary:

The durability of fibers in the lungs is determined by their solubility and breakage into shorter particles, which can be eliminated from the lungs through phagocytosis by macrophages or via the lymphatic drainage system.

Alveolar macrophages (AM) are primary immunological cells which remove particles from the alveolar region of the lungs mainly by phagocytizing, but also by dissolving foreign bodies. Marcophages have been shown to dissolve metal oxides and MMVF. A single rat AM is able to phagocytize fibers less than 20 lm of length. Therefore, short fibers are likely to be phagocytized and dissolved intracellularly, whereas longer fibers can be attacked by several AM, and may therefore be dissolved both intracellularly and extracellularly (Bernstein et al., 1985; Morimoto et al., 1994; Luoto et al., 1995a). The intracellular pH inside the lysosomes is about 5, whereas the pH outside the cell is close to neutral (Nyberg et al., 1989; Heilmann et al., 1992). Thus, the dissolution of fibers depends on whether they are inside or outside of cells.

The harmful pulmonary effects of fibers depends on their dimensions, dose delivered to the target organ, their durability within biological fluids, surface morphology, and surface area. Soluble or fragmentable fibers are more readily removed or rendered innocuous by macrophage ingestion, protein coating and biological sequestration, mechanical clearance, or complete dissolution.

Endpoint:
developmental toxicity
Type of information:
other: Published Toxicology Data Network
Adequacy of study:
weight of evidence
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Qualifier:
no guideline required
Principles of method if other than guideline:
data from handbook or collection of data. No Guideline required.
GLP compliance:
not specified
Species:
other: Not applicable
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Based on:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Dose descriptor:
other: Not applicable
Effect level:
0 other: Not applicable
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: Not applicable
Remarks on result:
other: Not applicable
Developmental effects observed:
not specified
Conclusions:
There is no indication that aluminum is carcinogenic.
Executive summary:

Toxicity Summary:

Aluminum is a silvery-white, ductile and malleable metal. It is released to the environment both by natural processes and from anthropogenic sources. It is highly concentrated in soil-derived dusts from such activities as mining and agriculture, and in particulate matter from coal combustion. Aluminum occurs ubiquitously in the environment in the form of silicates, oxides and hydroxides, combined with other elements such as sodium and fluorine and as complexes with organic matter. It is not found as a free metal because of its reactivity. Aluminum metal has a wide variety of uses, including structural materials in construction, automobiles and aircraft, and the production of metal alloys. Aluminum compounds and materials also have a wide variety of uses, including production of glass, ceramics, rubber, wood preservatives, pharmaceuticals and waterproofing textiles. Natural aluminum minerals, especially bentonite and zeolite, are used in water purification, sugar refining, brewing and paper industries.

HUMAN EXPOSURE: Non-occupational human exposure to aluminum in the environment is primarily through ingestion of food and water. No acute pathogenic effects in the general population have been described after exposure to aluminum. Although human exposure to aluminum is widespread, in only a few cases has hypersensitivity been reported following exposure to some aluminum compounds after dermal application or parenteral administration. There is insufficient information to allow for classification of the cancer risk from human exposures to aluminum and its compounds. Aluminum and its compounds appear to be poorly absorbed in humans. The mechanism of gastrointestinal absorption of aluminum has not yet been fully elucidated. The highest levels of aluminum may be found in the lungs, where it may be present as inhaled insoluble particles. The urine is the most important route of aluminum excretion.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

There is very limited information on the reproductive toxicity potential of mineral wool fibres. Two human studies were identified in the literature search and were both considered as not suitable evidence for classification.

In a case report from Hinnen et al. (1997, see IUCLID section 7.10.3 in study record “Target_Direct observations. Toxicity to Reproduction_sup_Hinnen_1997”), the authors reported a patient with foreign body granuloma of the penis possibly due to occupational glass fibre exposure. However, this is a case report of one patient working in the fibre-reinforced plastic industry and showing a penile ulcer. This patient has an history of syphilis more than 20 years ago, but the biopsy performed indicated the presence of foreign bodies possibly consistent with glass fibres. The authors concluded that the granuloma may be linked to its occupational exposure to fibres. The link between this penile granuloma and the occupational exposure to glass fibres could not have been clearly identified during the study and the lack of other cases greatly decreases the robustness of the study. Anyway, this is not possible to extrapolate based on only one observation.

In the second human study the relationship between ovarian cancer and occupational exposures to various substances including man-made vitreous fibers (MMVFs) in Finland was investigated by Vasama-Neuvonen et al. (1999, see IUCLID section 7.10.3 in study record “Target_Direct observations_Toxicity to Reproduction_sup_Vasama-Neuvonen_1999”). It has been reported in this study that women occupationally exposed to MMVFs has an elevated risk for ovarian cancer (standardised incidence ratio of 1.3; 95% confidence interval of 1.0-1.7). The cohort studied is composed of building workers, which are usually a majority of men, therefore the representability of the results regarding ovarian cancer may be questioned. In addition, it is mentioned that 100% of the building workers have been exposed to asbestos and 90% to the MMVF: it is not possible to distinguish the effect of asbestos from the one of MMVF on ovarian cancer incidence in this cohort. Indeed, the exact same number of cases has been reported with asbestos and MMVF confirming the absence of differentiation. This is a major deficiency as the hazard profile of these two substances is completely different. This study has been examined in 2001 by the IARC working group who also mentioned the limitations of this study.

 

Mineral wool fibres of scope (i.e. those fulfilling the Note Q criteria) are not expected to reach the reproductive organs in their fibrous forms due to the high fibre biosolubility, but it is possible that the dissolved chemical components of these fibres (e.g. aluminum and silicon oxides as well as alkali and alkaline earth oxides) could enter systemic circulation. Submitted data of the REACH registration dossiers for some of the individual key components of mineral wool fibres such as silicon dioxide, aluminum oxide, calcium oxide, zinc oxide and dipotassium oxide have shown no indication of reproductive toxicity. In addition, animal studies have shown that chronic ingestion of asbestos (more pathogenic fibre than mineral wool fibres but with similar chemical components) does not trigger reproductive toxicity and gestational exposure also does not negatively affect fertility (ATSDR, 2001).

Some glass wool fibres contain diboron trioxide (with content up to 12%), which currently has a harmonised CLP classification of Repr. 1B for the effects of boron on fertility in several experimental animal species. However, there have been only limited studies investigating the reproductive effects of boron in humans and a number of epidemiological studies have reported no fertility effects from inhalation exposure to boron (Duydu et al., 2018; Duydu et al., 2011; EPA, 2008; EVM, 2003; Robbins et al., 2010). Nevertheless, an estimation of a worst-case boron intake from glass wool fibres in occupational settings was performed in the paper by Jensen (2009, see IUCLID section 7.12 in study record “Target_sup_Jensen_2009_RA boron uptake). Taking the values for a worst-case scenario (e.g. highest boron content of 12% in glass wool fibres, 100% retention and solubility of the fibres, a higher inhalation rate of 2 m3/h), it was calculated that the worst-case daily boron intake in an occupational setting, assuming a 8-h work day, would be 0.16 mg boron, which is about ~11-13% of the estimated average daily boron intake through diet of ~1.2-1.5 mg in adults (IPCS, 1998; Jensen, 2009). Furthermore, the combined daily intake (i.e. from inhalation of glass wool fibres and food consumption) of up to 1.7 mg boron per day is significantly lower than the current “Tolerable Upper Intake Level” (UL) of 10 mg boron/day for adults (weighing 60 kg) as recommended by the European Food Safety Authority (EFSA) (Jensen, 2009). This UL from EFSA was determined based on adverse effects from reproductive and multigenerational studies and also applies to pregnant and lactating women (EFSA, 2006). It is worth mentioning that the UL of boron for adults from EFSA (10 mg/person/day) is either lower than the respective tolerable intake levels/reference doses for adults (weighing 60 kg) as established by the World Health Organisation (24 mg/day) and US EPA (12 mg/day) or is similar to the safe upper level for daily consumption over a lifetime of 9.6 mg/day set by the UK Expert Group on Vitamins and Minerals (EPA, 2008; EVM, 2003; IPCS, 1998). Altogether, it is unlikely that the inhalation exposure to glass wool fibres containing diboron trioxide would result in an internal dose of boron that would trigger reproductive effects in humans.

Furthermore, in the intraperitoneal chronic carcinogenicity study of Note Q MMVFs (see IUCLID section 7.7 in study record “Carcinogenicity_key_Grimm_2002”), macroscopic postmortem examination was performed on the ovaries and uterus. No significant mineral wool fibres-related effects were mentioned in the study. In addition, the US ATSDR published in 2004 its "Toxicological Profile for Synthetic Vitreous Fibers", which is a peer-reviewed report describing the toxicological and adverse health effects of synthetic vitreous fibres (including those fulfilling Note Q criteria). For reproductive toxicity, the report concluded that there is no mechanistic basis to suspect that reproductive effects may be of concern from exposure to synthetic vitreous fibres.

Collectively, it can be concluded that mineral wool fibres of scope without diboron trioxide do not warrant classification for reproductive toxicity. Considering the estimated worst-case daily intake of 0.16 mg boron from glass wool insulation fibres in an occupational setting is much lower than the tolerable daily intake levels set by regulatory authorities and agencies (starting at 9.6 mg/day), inhalation exposure to glass wool fibres containing up to 12% of diboron trioxide is not expected to trigger reproductive effects in humans.

Justification for classification or non-classification

Based on the known mechanisms of fibre deposition, reproductive or developmental effects from inhalation exposure to Note Q man-made vitreous fibres (MMVFs) appear to be unlikely such that these fibres are not expected to reach the reproductive organs. The bioavailability of Note Q MMVFs upon inhalation, oral or dermal exposure is expected to be low because of the physical dimensions of these elongated fibres and of the high biosolubility such that the fibres are dissolved in the lungs before entering into systemic circulation. It is predicted that maternal exposure to Note Q MMVFs does not result in the exposure of foetuses.

Taking this understanding, Note Q MMVFs do not warrant classification for reproductive toxicity.

Additional information