Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
99.8 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
22.5
Modified dose descriptor starting point:
LOAEC

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.1 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
2
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
99.8 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
22.5
Dose descriptor starting point:
LOAEC

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 020 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

Based on the current data available regarding exposure, one main type of exposure occurs in case of cryolite: exposure to cryolite dust. Furthermore, in some scenarios (see table) processes occur under high temperatures which results in hydrogen fluoride exposure (partly as a result of cryolite use).

Scenarios in which processes occur under high temperatures which results in hydrogen fluoride exposure

ES2: Production and use of cryolite in the aluminium industry

Inside production cell:

Manufacture of cryolite

Cryolite as “medium” for aluminium production

ES4: Production of articles containing cryolite

ceramic frits, pigments, glazes and tiles production in ovens

Production of glassware (as opalizing agents)

ES5: End use of articles in industry

Use of cutting and grinding applications, e. g. the use of grinding wheels, cutting disks.

Welding, indoor, open processing

Welding, indoor, closed processing

ES6: Use as flux

Flux in metal industry for soldering, brazing and welding.

Casting production

ES7: End use of articles by professionals

Use of cutting and grinding applications, e. g. the use of grinding wheels, cutting disks, indoor

Welding, indoor, open processing

ES8: End use of articles by consumers

Use in cutting and grinding applications, e. g. the use of grinding wheels, cutting disks.

Welding, indoor, open processing

Firing of fireworks

 

Regarding selection of the critical DNELs, it is noted that according to the REACH regulation ‘DNELs’ already derived for the substance under consideration by the EU (see EU-RARs) or by the SCOEL should be considered.

 

In Annex I of REACH, section 0.5, it is explicitly mentioned that:

….. Where available and appropriate, an assessment carried out under Community legislation (e.g. risk assessments completed under Regulation (EEC) No 793/93) shall be taken into account in the development of, and reflected in, the chemical safety report. Deviations from such assessments shall be justified”.

 

In Appendix R.8-13 of the Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health it is noted that:

When an EU IOEL exists the registrant may, under conditions as described below, use the IOEL in place of developing a DNEL. A registrant is allowed to use an IOEL as a DNEL for the same exposure route and duration, unless new scientific information that he has obtained in fulfilling his obligations under REACH does not support the use of the IOEL for this purpose. This could be because the information obtained is more recent than the information that was used to support setting the IOEL at EU level and because it leads to another value being derived which requires different risk management measures (RMMs) and operational conditions (OCs)’.

 

Therefore, the EU RAR on cryolite, the SCOEL evaluation of hydrogen fluoride and the CSR of hydrogen fluoride were also considered.

Summary Tables of worker DNELs

 

Acute inhalation DNEL

Exposure pattern

Method

Exposure form

Critical effect

DNEL

Remarks

Acute inhalation

(DNEL for 15 minutes exposure)

REACH guidance

cryolite

alveolar congestion / haemorrhage

99.8 mg/m3

No acute DNEL was derived in the EU-RAR of cryolite.

SCOEL recommendation hydrogen fluoride / CSR of hydrogen fluoride

hydrogen fluoride

irritation

2.5 mg/m3

STEL of the SCOEL for hydrogen fluoride.Based upon the study of Largent and Columbus (1960), conducted in volunteers exposed for 6 h/d for 10-50d, a STEL (15 min) of 3 ppm (2.5 mg/m3) was proposed for hydrogen fluoride to limit peaks in exposure which could result in irritation.

 

For short term exposure to cryolite dust, a DNEL has been derived according to the REACH guidance. Assessment of short term exposure is not considered relevant, when 8 hour exposure levels remain under the chronic-DNEL. The short term DNEL for cryolite dust is very high (99.8 mg/m3, about 1000 times higher) relative to the chronic DNEL for cryolite dust.

The relationship between determinants of acute and full shift exposure distributions have been calculated (Kumagai and Matsunaga, 1994). In general, the 95thpercentile of 15 minute exposure data is about twice the 90thpercentile and 4 times the 75thpercentile of full shift data collected for the same situation. Even in a worst case situation when:

- the full shift measurement data reflects the 75thpercentile,

- there is a high variability within the short term data,

- the 99thpercentile of the short term value is required,

the factor by which to multiply the 8 hour value to get to the short term value is 40.

This is still much lower than 1000. This means that when 8 hour exposures remain under the chronic DNEL for cryolite dust, the 15 minute exposure levels will always be safe.

 

Remark:

Exposure to hydrogen fluoride may occur in some scenarios. The hydrogen fluoride exposure is in part a result of cryolite present. The acute DNEL for hydrogen fluoride is 2.5 mg/m3. For a quantitative risk characterisation for hydrogen fluoride it is referred to the CSR of hydrogen fluoride.

 

Long-term inhalation DNEL


Exposure pattern

Method

Exposure form

Critical effect

DNEL

Remarks

Long-term inhalation

(DNEL for 8 hours exposure)

REACH guidance

cryolite

local effects in the respiratory tract

17.6 µg/m3

-

EU-RAR of cryolite

cryolite

local effects in the respiratory tract

0.1 mg/m3

 

SCOEL recommendation hydrogen fluoride / CSR of hydrogen fluoride

hydrogen fluoride

skeletal fluorosis

1.5 mg/m3

8-hour TWA SCOEL for hydrogen fluoride of 1.5 mg/m3is proposed as DNEL in the CSR of hydrogen fluoride.

 

For exposure to cryolite dust, according to the REACH guidance a DNEL of 17.6 µg/m3is calculated while the EU-RAR of cryolite recommends 100 µg/m3as a DNEL. Both values are derived using the same key study. Regarding selection of the value to be used for the risk characterisation it is noted that according to the REACH regulation ‘DNELs’ already derived for the substance under consideration in an EU-RAR should be considered. In Annex I of REACH, section 0.5, it is explicitly mentioned that:

….. Where available and appropriate, an assessment carried out under Community legislation (e.g. risk assessments completed under Regulation (EEC) No 793/93) shall be taken into account in the development of, and reflected in, the chemical safety report. Deviations from such assessments shall be justified”.

Therefore, a DNEL of 0.1 mg/m3is recommended in this case.

 

Remark:

Exposure to hydrogen fluoride may occur in some scenarios. The hydrogen fluoride exposure is in part a result of cryolite present. The long-term inhalation DNEL for hydrogen fluoride is 1.5 mg/m3. For a quantitative risk characterisation for hydrogen fluoride it is referred to the CSR of hydrogen fluoride.

 

Long-term dermal DNEL

Exposure pattern

Method

Exposure form

Critical effect

DNEL

Remarks

Long-term dermal

(DNEL for daily exposure)

REACH guidance

cryolite

developmental toxic effects

1020 mg/kg bw/day

route-to-route extrapolation using oral data as starting point

CSR of hydrogen fluoride

hydrogen fluoride

skeletal fluorosis

not quantifiable due to lack of dermal absorption

 

 

Detailed presentation of derivation of worker DNELs

Acute – inhalation, systemic and local effects

Approach according to REACH guidance

Based on the available acute inhalation toxicity study in rats (Huntingdon Research Centre, 1993).

Description

Value

Remark

Step 1) Relevant dose-descriptor

LOAEC: 1330 mg/m3

No deaths occurred and no respiratory irritation was observed. Alveolar congestion/haemorrhage was recorded in all treatment groups, including 2/10 in the low dose group. Therefore, 1330 mg/m3is interpreted as a LOAEC.

Step 2) Modification of starting point

3√(13303x 16)

 

 

 

 

 

 

 

 

 

 

 

6.7/10

In the REACH guidance (R.8, Appendix R. 8-8), it is mentioned: ‘If a DNEL for acute toxicity needs to be established, this should be derived only for a specified fraction of the daily exposure duration (usually 15 minutes)’. The most appropriate approach is the modified Haber’s law (Cn* t = k). For extrapolation from longer to shorter durations a default value of n=3 should be used.

 

Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3).

Step 3) Assessment factors

 

 

Interspecies

2.5

For inhalation studies only a factor 2.5 is used, and no correction is made for differences in body size, because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animals and humans breathe at a rate depending on their caloric requirements.

Intraspecies

3

Using a reduced factor of 3 (instead of 5) is justified because the critical effect is a local effect that is hardly if at all, mainly determined by toxicodynamics and kinetics. Absorption, distribution, metabolism and elimination play no/a minor role.

Exposure duration

1

 

Dose response

3

Extrapolation from a LOAEC to NAEC

Quality of database

1

 

Step 4) Calculate DNEL

3√(13303x 16) x (6.7/10)/ (2.5 x 3 x 1 x 3 x 1) = 99.8 mg/m3

Long-term – inhalation, local effects

1. Approach according to REACH guidance

Based on 90 days inhalation toxicity study in rats (Huntington Life Sciences Ltd. (1997a))

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC: 0.21 mg/m3

Based on local respiratory effects in rats at higher concentrations

Step 2) Modification of starting point

6/8

 

 

 

6.7/10

Correction of exposure duration in study (6 hrs/day) to default worker exposure (8 hrs/day).

 

Correction for respiratory volume light activity for workers.

Step 3) Assessment factors

 

 

Interspecies

1

The local respiratory effects observed in the study are mainly irritating effects resulting in more severe responses; except the effects described as increased collagen in the alveolar duct walls. Regarding the irritating effects, it is known that rats are more sensitive to these effects compared to humans (Snipes, 1989, 1996; Nikula et al, 1997, 2001). Therefore the default interspecies factor of 2.5 can be reduced to 1.

For increased collagen in the alveolar duct walls there are no data to conclude a higher sensitivity for rats, on the contrary, humans may be more susceptible to these effects. Increased collagen in the alveolar duct walls was only observed at the highest test concentration in 2/20 animals (4.6 mg/m3) and not at 1.04 and 0.21 mg/m3. So the NOAEC for increased collagen in the alveolar duct walls is 1.04 mg/m3, for which a default factor of 2.5 should be applied. As this results in a higher concentration than the overall NOAEC of 0.21 mg/m3, the application of a reduced factor of 1 to the NOAEC of 0.21 mg/m3is considered sufficient to cover the occurrence of increased collagen in the alveolar duct walls as well.

Intraspecies

3

Using a reduced factor of 3 is justified because the critical effect is a direct local effect that is hardly if at all, mainly determined by toxicodynamics and kinetics. Absorption, distribution and elimination play no/a minor role.

Exposure duration

2

Extrapolation from sub-chronic to chronic exposure.

Dose response

1

 

Quality of database

1

 

Step 4) Calculate DNEL

(210 x 6/8 x 6.7/10) / (1 x 3 x 2 x 1 x 1) = 17.6 µg/m3

 

- Nikula KJ,KJ, Griffith WC, Mauderly JL (1997).Lung tissue responses and sites of particle retention differ between rats and cynomolgus monkeys exposed chronically to diesel exhaust and coal dust.Fundam Appl Toxicol.;37(1):37-53.

- Nikula KJ, Vallyathan V, Green FH, Hahn FF (2001).Influence of exposure concentration or dose on the distribution of particulate material in rat and human lungs.Environ Health Perspect.;109(4):311-8.

- Snipes MB (1989).Long-term retention and clearance of particles inhaled by mammalian species.Crit Rev Toxicol.;20(3):175-211.

- Snipes MB (1996). Current information on lung overload in nonrodent mammals: Contrast with rats. Inhal. Toxicol. 8:91-109.

2. Approach according to EU-RAR of cryolite

For prolonged inhalation exposure of workers to cryolite, data on possible health effects are available from different sources such as mining and processing of natural cryolite, production of synthetic cryolite and manufacturing of aluminium. There has been no indication for cryolite specific chronic respiratory effects in humans although specific examinations have been made (x-ray photography, pulmonary function tests, and questionnaires concerning incidences of acute pulmonary symptoms). Exposure in some cases has been rather high and long-lasting, causing severe skeletal fluorosis.

In a well-conducted 90-day inhalation study (Huntington Life Sciences Ltd. (1997a)) rats were exposed snout-only to particulate aerosols of cryolite in the concentration of 0, 0.21, 1.04, and 4.6 mg/m3. Alveolitis with interstitial thickening of alveolar duct walls and increased collagen in alveolar ducts occurred in the high dose group. At the intermediate dose of cryolite, a proportion of rats had interstitial thickening of the alveolar duct walls. At the low dose (0.21 mg/m3) no effect was observed.

For the risk assessment this NOAEC of 0.21 mg/m3is used as starting point concerning effects of cryolite after repeated inhalation exposure.

The human data give no indication for cryolite specific chronic respiratory effects. Therefore, the NOAEC gives a very precautious value for the evaluation of this endpoint. On that background it does not seem indicated to apply any additional assessment factors like inter- or intraspecies extrapolation or duration adjustment. On the other hand the NOAEC, based on a 90-day study, might make a duration factor of about 2 necessary, because a progression of effects in the lungs (thickening of alveolar ducts and increased collagen) cannot excluded; the critical exposure level calculates then to 0.1 mg/m3(0.21 mg/m3/ 2).

 

Long-term – dermal, systemic effects

Approach according to REACH guidance

No dermal repeated dose toxicity studies are available for cryolite. In the inhalation repeated dose toxicity studies no systemic effects were observed. Therefore a dermal long-term DNEL cannot be quantified using the inhalation route as starting point.

In the two-generation study (oral route) (Pharmaco LSR, Inc., 1994), effects on postnatal growth evidenced by significantly decreased pup body weights during lactation as well as pathologic gross findings in several organs of the pups resulted from dose levels without any significant parental toxicity. Because these effects occurred without any significant sign for parental toxicity it is considered to be indicative for a specific toxic potential of cryolite adverse to postnatal development. The respective NOAEL for these effects in this study was 42 mg cryolite/kg bw/day. This level will be used for derivation of the dermal DNEL.

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 42 mg/kg bw/day

Developmental toxic effects were observed at the dose level of 128 mg/kg bw/day and higher.

Step 2) Modification of starting point

85 / 0.07

 

Conversion into dermal NAEL (in mg/kg bw/day) assuming 85% oral absorption and 0.07% dermal absorption.

Step 3) Assessment factors

 

 

Interspecies

4 x 2.5

Default assessment factor for allometric scaling and remaining uncertainties as taken from the REACH guidance.

Intraspecies

5

Default assessment factor taken from REACH guidance.

Exposure duration

1

Not applicable

Dose response

1

 

Quality of database

1

 

Step 4) Calculate DNEL

(42 x 85 / 0.07) / 4 x 2.5 x 5 x 1 x 1 x 1 = 1020 mg/kg bw/day

 

No data are available concerning local effects after repeated dermal contact with cryolite. The acute skin tests did not show local irritating or sensitising properties. From epidemiological data no observations on skin reactions from workers have been reported. In summary local effects by prolonged skin contact are not expected.

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
74.5 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
45
Modified dose descriptor starting point:
LOAEC

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
25 µg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
2
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
74.5 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
45
Dose descriptor starting point:
LOAEC

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
510 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

Summary Table of general population DNELs

 

Acute inhalation DNEL

Exposure pattern

Method

Exposure form

Critical effect

DNEL

Remarks

Acute inhalation

(DNEL for 15 minutes exposure)

REACH guidance

cryolite

alveolar congestion / haemorrhage

74.5 mg/m3

-

CSR of hydrogen fluoride

hydrogen fluoride

irritation

1.25 mg/m3

The EU IOEL value of 2.5 mg/m3(3 ppm) was derived based on the results of the volunteer study of Largent & Columbus (1960) to limit peaks in exposure which could result in irritation. The application of an additional assessment factor of 2 (representing the potential for greater sensitivity of individuals within the general population and consistent with REACH guidance) to take into account potential additional intra-species variation in the exposed general population is considered to be appropriate.

 

For short term exposure to cryolite dust, a DNEL has been derived according to the REACH guidance. Assessment of short term exposure is not considered relevant, when 8 hour exposure levels remain under the chronic-DNEL. The short term DNEL for cryolite dust is very high (74.5 mg/m3, more than 1000 times higher) relative to the chronic DNEL for cryolite dust.

The relationship between determinants of acute and full shift exposure distributions have been calculated (Kumagai and Matsunaga, 1994). In general, the 95thpercentile of 15 minute exposure data is about twice the 90thpercentile and 4 times the 75thpercentile of full shift data collected for the same situation. Even in a worst case situation when:

- the full shift measurement data reflects the 75thpercentile,

- there is a high variability within the short term data,

- the 99thpercentile of the short term value is required,

the factor by which to multiply the 8 hour value to get to the short term value is 40.

This is still much lower than 1000. This means that when 8 hour exposures remain under the chronic DNEL for cryolite dust, the 15 minute exposure levels will always be safe.

 

Remark:

Exposure to hydrogen fluoride may occur in some scenarios. The hydrogen fluoride exposure is in part a result of cryolite present. The acute DNEL for hydrogen fluoride is 1.25 mg/m3. For a quantitative risk characterisation for hydrogen fluoride it is referred to the CSR of hydrogen fluoride.

 

Long-term inhalation DNEL

Exposure pattern

Method

Exposure form

Critical effect

DNEL

Remarks

Long-term inhalation

(DNEL for 24 hours exposure)

REACH guidance

cryolite

local effects in the respiratory tract

4.4 µg/m3

-

EU-RAR of cryolite

cryolite

local effects in the respiratory tract

25 µg/m3

Extrapolation from the worker EU-RAR approach

CSR of hydrogen fluoride

hydrogen fluoride

skeletal fluorosis

0.03 mg/m3

-

 

Conclusion:

For exposure to cryolite dust, according to the REACH guidance a DNEL of 4.4 µg/m3is calculated. Extrapolation of the worker EU-RAR approach results in a DNEL of 25 µg/m3. To be consistent with the worker DNEL, the DNEL of 25 µg/m3is selected for the risk characterisation.

 

Remark:

Exposure to hydrogen fluoride may occur in some scenarios. The hydrogen fluoride exposure is in part a result of cryolite present. The long-term inhalation DNEL for hydrogen fluoride is 0.03 mg/m3. For a quantitative risk characterisation for hydrogen fluoride it is referred to the CSR of hydrogen fluoride.

 

Long-term dermal DNEL

Exposure pattern

Method

Exposure form

Critical effect

DNEL

Remarks

Long-term dermal

(DNEL for daily exposure)

REACH guidance

cryolite

developmental toxic effects

510 mg/kg bw/day

route-to-route extrapolation using oral data as starting point

CSR of hydrogen fluoride

hydrogen fluoride

skeletal fluorosis

not quantifiable due to lack of dermal absorption

-

 

Detailed presentation of derivation of general population DNELs

Acute – inhalation, systemic and local effects

Approach according to REACH guidance

Based on the available acute inhalation toxicity study in rats (Huntingdon Research Centre, 1993)

Description

Value

Remark

Step 1) Relevant dose-descriptor

LOAEC: 1330 mg/m3

No deaths occurred and no respiratory irritation was observed. Alveolar congestion/haemorrhage was recorded in all treatment groups, including 2/10 in the low dose group. Therefore, 1,330 mg/m3is interpreted as a LOAEC

Step 2) Modification of starting point

3√(13303x 16)

In the REACH guidance (R.8, Appendix R. 8-8), it is mentioned: ‘If a DNEL for acute toxicity needs to be established, this should be derived only for a specified fraction of the daily exposure duration (usually 15 minutes)’. The most appropriate approach is the modified Haber’s law (Cn* t = k). For extrapolation from longer to shorter durations a default value of n=3 should be used.

Step 3) Assessment factors

 

 

Interspecies

2.5

For inhalation studies only a factor 2.5 is used, and no correction is made for differences in body size, because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animals and humans breathe at a rate depending on their caloric requirements.

Intraspecies

6

Using a reduced factor is justified because the critical effect is a direct local effect that is hardly if at all, mainly determined by toxicodynamics and kinetics. Absorption, distribution and elimination play no/a minor role.

Exposure duration

1

 

Dose response

3

Extrapolation from LOAEC to NAEC

Quality of database

1

 

Step 4) Calculate DNEL

3√(13303x 16) / (2.5 x 6 x 1 x 3 x 1) = 74.5 mg/m3

Long-term – inhalation, local effects

1. Approach according to REACH guidance

Based on 90 days inhalation toxicity study in rats (Huntington Life Sciences Ltd. (1997a))

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC: 0.21 mg/m3

Based on absence of local effects on the respiratory tract in rats (6 hrs/day, 6 days/week for 90 days

Step 2) Modification of starting point

6/24

Correction of exposure duration in study (6 hrs/day) to default population exposure (24 hrs/day).

Step 3) Assessment factors

 

 

Interspecies

1

The local respiratory effects observed in the study are mainly irritating effects resulting in more severe responses; except the effects described as increased collagen in the alveolar duct walls. Regarding the irritating effects, it is known that rats are more sensitive to these effects compared to humans (snipes, 1989, 1996; Nikula et al, 1997, 2001). Therefore the default interspecies factor of 2.5 can be reduced to 1.

For increased collagen in the alveolar duct walls there are no data to conclude a higher sensitivity for rats, on the contrary, humans may be more susceptible to these effects. Increased collagen in the alveolar duct walls was only observed at the highest test concentration in 2/20 animals (4.6 mg/m3) and not at 1.04 and 0.21 mg/m3. So the NOAEC for increased collagen in the alveolar duct walls is 1.04 mg/m3, for which a default factor of 2.5 should be applied. As this results in a higher concentration than the overall NOAEC of 0.21 mg/m3, the application of a reduced factor of 1 to the NOAEC of 0.21 mg/m3is considered sufficient to cover the occurrence of increased collagen in the alveolar duct walls as well.

Intraspecies

6

Using a reduced factor is justified because the critical effect is a direct local effect that is hardly if at all, mainly determined by toxicodynamics and kinetics. Absorption, distribution and elimination play no/a minor role.

Exposure duration

2

Extrapolation from sub-chronic to chronic exposure.

Dose response

1

 

Quality of database

1

 

Step 4) Calculate DNEL

(210 * 6/24) / (1 x 6 x 2 x 1 x 1) = 4.4 µg/m3

- Nikula KJ,KJ, Griffith WC, Mauderly JL (1997).Lung tissue responses and sites of particle retention differ between rats and cynomolgus monkeys exposed chronically to diesel exhaust and coal dust.Fundam Appl Toxicol.;37(1):37-53.

- Nikula KJ, Vallyathan V, Green FH, Hahn FF (2001).Influence of exposure concentration or dose on the distribution of particulate material in rat and human lungs.Environ Health Perspect.;109(4):311-8.

- Snipes MB (1989).Long-term retention and clearance of particles inhaled by mammalian species.Crit Rev Toxicol.;20(3):175-211.

- Snipes MB (1996). Current information on lung overload in nonrodent mammals: Contrast with rats. Inhal. Toxicol. 8:91-109.

2. Approach according to EU-RAR of cryolite

When extrapolation is performed from the worker approach, the following DNEL is calculated:

0.1 mg/m3 * 10/20 (a) * 5/10 (b) = 25 µg/m3

(a) modification based on differences in exposure duration and activity (10 m3 in 8 h for workers, 20 m3 in 24 h for the general population)

(b) correction for intraspecies differences: workers default factor: 5, general population default factor: 10

 

Long-term – dermal, systemic effects

Approach according to REACH guidance

No dermal repeated dose toxicity studies are available for cryolite. In the inhalation repeated dose toxicity studies no systemic effects were observed. Therefore a dermal long-term DNEL cannot be quantified using the inhalation route as starting point.

In the two-generation study (oral route) (Pharmaco LSR, Inc., 1994), effects on postnatal growth evidenced by significantly decreased pup body weights during lactation as well as pathologic gross findings in several organs of the pups resulted from dose levels without any significant parental toxicity. Because these effects occurred without any significant sign for parental toxicity it is considered to be indicative for a specific toxic potential of cryolite adverse to postnatal development. The respective NOAEL for these effects in this study was 42 mg cryolite/kg bw/day. This level will be used for derivation of the dermal DNEL.

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 42 mg/kg bw/day

Developmental toxic effects were observed at the dose level of 128 mg/kg bw/day and higher.

Step 2) Modification of starting point

85 / 0.07

 

Conversion into dermal NAEL (in mg/kg bw/day) assuming 85% oral absorption and 0.07% dermal absorption.

Step 3) Assessment factors

 

 

Interspecies

4 x 2.5

Default assessment factor for allometric scaling and remaining uncertainties as taken from the REACH guidance.

Intraspecies

10

Default assessment factor taken from REACH guidance.

Exposure duration

1

Not applicable

Dose response

1

 

Quality of database

1

 

Step 4) Calculate DNEL

(42 x 85 / 0.07) / 4 x 2.5 x 5 x 1 x 1 x 1 = 510 mg/kg bw/day

 

No data are available concerning local effects after repeated dermal contact with cryolite. The acute skin tests did not show local irritating or sensitising properties. From epidemiological data no observations on skin reactions from workers have been reported. In summary local effects by prolonged skin contact are not expected.