Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.7 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
6
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
47.9 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
24
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

Acute toxicity

No acute toxicity data in humans are available. In rats, C14-17 chlorinated paraffins (40-61% chlorination) are of low acute oral toxicity (Birtley, 1980; Chater, 1978; Kuhnert, 1986a,b). No acute inhalation or dermal exposure studies on MCCPs are available. However, based upon the low acute inhalation and dermal toxicity seen in laboratory animals exposed to C10-13 chlorinated paraffins (Howard et al. 1975; ICI, 1971, 1974) and supported by the low toxicity of C14-17 chlorinated paraffins via the oral route in rats, it is predicted that MCCPs are also likely to be of low acute inhalation and dermal toxicity. Repeated dose toxicity studies (including reproductive toxicity studies), where available, provide no relevant (dose-response) information on acute toxicity. Based on the available data, MCCPs would not be classified as acutely toxic under the EU CLP or DSD regulations.

 

DNELs for acute toxicity should be derived if an acute toxicity hazard, leading to classification and labelling (e.g. under EU CLP or DSD regulations), has been identified and there is a potential for high peak exposures (this is only usually relevant for inhalation exposures). As no acute hazard has been identified, then a DNEL for acute toxicity is unnecessary as the long-term DNEL will normally be sufficient to ensure that adverse effects do not occur. Consequently, no worker-DNELs for acute toxicity have been calculated.

 

 

Irritation/corrosivity

No irritation or corrosion data in humans are available. Following single application/instillation, C14-17 chlorinated paraffins (40-60% chlorination) are considered to be slight skin irritants in rabbits and rats (Chater, 1978; Kuhnert, 1986c,d; Moses, 1980) and slight eye irritants in rabbits (Birtley et al. 1980; Chater, 1978; Kuhnert, 1986e,f). No corrosion has been reported in laboratory animals. It is anticipated that MCCPs are unlikely to cause respiratory tract irritation. Acute and repeated dose toxicity studies, where available, provide no relevant (dose-response) information for irritant or corrosive effects. Based on the available data, MCCPs would not be classified as skin, eye or respiratory tract irritants under the EU CLP or DSD regulations. Consequently, no worker-DNELs for irritation/corrosivity have been calculated.

 

 

Sensitisation

No skin sensitisation data in humans are available. In three guinea pig maximisation tests, using diluted C14-17 chlorinated paraffins (40 or 45% chlorination), no evidence of a skin sensitisation potential was reported. Overall, the available data on MCCPs, and the generally unreactive nature of MCCPs (and data on SCCPs), indicate an absence of skin sensitisation potential. There are no data relating to respiratory sensitisation in humans or laboratory animals. However, the generally unreactive nature of this group of substances and the lack of skin sensitisation potential suggests that they do not possess the potential to cause respiratory sensitisation.

 

Based on the available data, MCCPs would not be classified as a skin or respiratory sensitiser under EU CLP or DSD regulations. Consequently, no worker-DNELs for skin or respiratory sensitisation have been calculated.

 

 

Repeated dose toxicity - oral DNEL

Not considered applicable for workers.

 

 

Repeated dose toxicity – inhalation DNEL

Dose descriptor

There are no data available in humans or laboratory animals relating to repeated inhalation exposure. However, as described below in more detail in the general population Discussion), a number of studies have investigated the repeated dose oral toxicity of C14-17 chlorinated paraffins (40% or 52% chlorination) in rodents and this has allowed the identification of a NOAEL of 23 mg/kg bw/day from a well-conducted 90-day dietary study in rats administered Cereclor S52 (Elcombe, 2005b), with kidney effects seen at a higher dose in this and other studies.

 

Mode-of-action

C14-17 chlorinated paraffins are considered to have only threshold effects.

 

Modification of starting point

The same bioavailability is assumed for humans and laboratory animals.

 

As no data on effects of repeated inhalation exposure to MCCPs in humans or laboratory animals are available, route-to-route extrapolation to calculate a DNEL for such effects from repeated dose oral toxicity studies was considered a suitable alternative (no high first-pass metabolism has been reported).

 

In the absence of route-specific information on absorption for both the starting route (oral) and end route (inhalation), a default factor of 2 should be used (which assumes 50% absorption for oral exposure, and 100% for inhalation). In this instance, the absorption, tissue distribution and elimination of a14C-labelled C14-17 chlorinated paraffin (52% chlorinated) after a single oral gavage administration at a dose level of 525 mg/kg bw was investigated in male rats (Elcombe, 2005a). Approximately 70% of the dose was recovered in the faeces and approximately 6% in the urine in the first 4 days after administration. This suggests that only about 30% of the orally administered dose was absorbed by day 4. Although there is no specific information for the inhalation route of exposure, given that the data indicate about 30% absorption by the oral route (Elcombe, 2005a) and less than 1% by the dermal route (Johnson, 2005), and in view of the very high log Pow and the very low water solubility of C14-17 chlorinated paraffins, it is reasonable to assume that inhalation absorption is also likely to be low (maximum of 50%). On this basis, it seems appropriate to assume 50% absoprtion for oral and inhalation exposure in both humans and laboratory animals, therefore there is no need to correct the starting point.

 

Workers are assumed to be exposed for 8 h/day.

 

Converting oral data to a corresponding air concentration in the rat is required. The oral dose for the rat is converted to this corresponding air concentration, using a standard breathing volume for the rat, of 0.38 m3/kg bw for 8 h/day (exposure of workers). Thus, 23 mg/kg bw/day / 0.38 m3/kg bw/8h = 60.5 mg/m3(8-h exposure of workers). To account for the presumed light activity of workers, this value has been corrected for an increase in breathing volume, thus 23 mg/kg bw/day / 0.38 m3/kg bw/8h x (6.7 m3/ 10 m3) = 40.6 mg/m3 (8-h exposure of workers, light activity).

 

ECHA/ECETOC assessment factors (AFs) for workers

Uncertainty

AF

Justification for assessment factor (AF)

Interspecies differences

1

 

 

1*

Default ECHA/ECETOC AF for rat for toxicokinetic differences in metabolic rate (allometric scaling); already considered in correcting starting point above

Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences

Intraspecies differences

3**

Default ECHA AF for (healthy) worker

Differences in duration of exposure

2

Default ECHA/ECETOC AF for subchronic (90-day) to chronic extrapolation

Dose response and endpoint specific/severity issues

1

Default ECHA AF; clear NOAEL from well-conducted 90-day dietary study. Effects at the LOAEL of 222 mg/kg bw/day are not considered severe

Quality of whole database

1

Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high

Overall AF for worker

 

6

 

 * In addition to the allometric scaling factor a further interspecies assessment factor of 2.5 (remaining difference) is proposed in REACH (Guidance R8, section R8.4.3.3), however no scientific basis for this is reported. In ECETOC Technical Report No 86 (ECETOC, 2003), a conclusion was reached that in the absence of a substance specific mode of action, allometric scaling based on metabolic rate is considered to provide an appropriate default assessment factor. No specific mode of action has been identified for the repeat-dose effects of MCCPs. As such, no interspecies AF is required for the inhalation route.

** A factor for workers of 5 has been suggested by the REACH guidance (8.4.3.1). However, based on several analyses of large data sets and in accordance with many workplace OEL setting practices, an intraspecies factor of 3 is considered appropriate for the worker population (ECETOC, 2003).

Worker (light activity)-DNEL (long-term for inhalation route-systemic) = 40 mg/m3/ 6 = 1.6 mg/m3

 

 

Repeated dose toxicity - dermal DNEL

Dose descriptor

There are no data available in humans or laboratory animals relating to repeated dermal exposure. However, as described in more detail below in the general population Discussion, a number of studies have investigated the repeated dose oral toxicity of C14-17 chlorinated paraffins (40% or 52% chlorination) in rodents and this has allowed the identification of a NOAEL of 23 mg/kg bw/day from a well-conducted 90-day dietary study in rats administered Cereclor S52 (Elcombe, 2005b), with kidney effects seen at a higher dose in this and other studies.

 

Mode-of-action

C14-17 chlorinated paraffins are considered to have only threshold effects.

 

Modification of starting point

The same bioavailability is assumed for humans and laboratory animals.

 

As no data on effects of repeated dermal exposure to MCCPs in humans or laboratory animals are available, route-to-route extrapolation to derive a DNEL for such effects from repeated dose oral toxicity studies was considered a suitable alternative.

 

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral-to-dermal extrapolation. Indeed, in a recent OECD-compliant in vitro study using human skin (Johnson, 2005) approximately 0.7% of Cereclor S52 was absorbed after 24 hours. The overall skin absorption determined by this study (0.7%) is likely to be an overestimate as the study was designed to measure skin penetration under the most conservative conditions. Therefore, it is appropriate to correct the starting point for differences in dermal (1%) and oral (50%) exposures, thus 23 mg/kg bw/day x 50 = 1150 mg/kg bw/day

 

Workers are assumed to be exposed for 8 h/day.

 

ECHA/ECETOC assessment factors (AFs) for workers

Uncertainty

AF

Justification for assessment factor (AF)

Interspecies differences

4

 

 

1*

Default ECETOC/ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling)

Default ECETOC AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences

Intraspecies differences

3*

Default ECETOC AF for (healthy) worker

Differences in duration of exposure

2

Default ECHA/ECETOC AF for subchronic (90-day) to chronic extrapolation

Dose response and endpoint specific/severity issues

1

Default ECHA AF; clear NOAEL from well-conducted 90-day dietary study. Effects at the LOAEL of 222 mg/kg bw/day are not considered severe

Quality of whole database

1

Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high

Overall AF for worker

 

24

 

 * In addition to the allometric scaling factor of 4 a further interspecies assessment factor of 2.5 (remaining difference) is proposed in REACH (Guidance R8, section R8.4.3.3), however no scientific basis for this is reported. In ECETOC Technical Report No 86 (ECETOC, 2003), a conclusion was reached that in the absence of a substance specific mode of action, allometric scaling based on metabolic rate is considered to provide an appropriate default assessment factor. No specific mode of action has been identified for the repeat- dose effects of MCCPs. As such, an assessment factor of 4 to take account of allometric scaling based on metabolic rate is considered to be appropriate for the dermal route.

** A factor for workers of 5 has been suggested by the REACH guidance (8.4.3.1). However, based on several analyses of large data sets and in accordance with many workplace OEL setting practices, an intraspecies factor of 3 is considered appropriate for the worker population (ECETOC, 2003).

Worker-DNEL (long-term for dermal route-systemic) = 1150 mg/kg bw/day / 24 = 47.9 mg/kg bw/day

 

 

Genotoxicity

No information is available on genotoxic effects in humans. C14-17 chlorinated paraffins (40-52% chlorination) consistently showed no evidence of mutagenic potential in four Ames bacterial tests. No in vitro cytogenetic or gene mutation studies in mammalian cells are available for MCCPs. However, for a C10-13 chlorinated paraffin (56% chlorinated) a negative result was obtained in a well-conducted in vitro gene mutation assay tested at up to cytotoxic concentrations in hamster cells; a similar negative result would, therefore, be anticipated for MCCPs. Three in vivo bone marrow studies in rodents demonstrate that C14-17 chlorinated paraffins are not clastogenic towards this target tissue, and an ADME study (Darnerud and Brandt, 1982) has shown distribution of MCCPs to the bone marrow. Negative results for in vivo genotoxicity tests in somatic and germ cells of rodents have been obtained for SCCPs. Overall, the available data on MCCPs (and SCCPs), and consideration of their generally unreactive nature, indicates that MCCPs are not mutagenic and do not directly interact with DNA. Under EU CLP and DSD regulations, C14-17 chlorinated paraffins would not be classified as mutagenic. Consequently, no worker-DN(M)ELs for genotoxicity have been calculated.

 

 

Carcinogenicity

No information on carcinogenic effects in humans are available. In long-term cancer bioassays (conducted as part of the US National Toxicology Program), significant increases in the incidences of liver (in males and females) and thyroid (in females only) tumours were seen in laboratory animals administered a C12 chlorinated paraffin (60% chlorinated) by gavage at 125 mg/kg bw/day and above (in mice) and 312 mg/kg bw/day and above (in rats), 5 d/wk for 2 yrs, and of kidney tumours in male rats at 312 mg/kg bw/day. Clear modes of action were indicated for the liver and thyroid tumours, and these tumours are considered to be of little or no relevance to human health. The underlying mechanism for the kidney tumours has not been fully elucidated. However, recent mechanistic evidence shows that alpha2u-binding is probably the primary mechanism for kidney tumour formation induced by this SCCP in male rats, and the available evidence strongly suggests that the underlying mechanism would not be relevant to humans. Taking into account all the other existing data on MCCPs, specifically the lack of genotoxic activity and the kidney toxicity seen in repeated dose toxicity studies in rats (at 222 mg/kg bw/day and above), it cannot be completely ruled out that this form of kidney toxicity might lead to cancer in male and female rats through a non-genotoxic mode of action, even though with the C12 chlorinated paraffin kidney tumours were seen in male rats only. Under the EU CLP and DSD regulations, MCCPs would not be classified for human carcinogenicity.

 

Therefore, the long-term worker-DNELs for systemic effects are considered protective of potential carcinogenic effects.

 

 

Reproductive toxicity (fertility impairment and developmental toxicity)

No information is available on fertility or developmental effects in humans. In two reliable one-generation reproduction studies, no effects on fertility were seen when male and female rats were administered Cereclor S52 in the diet at up to approximately 100 and 400 mg/kg bw/day (the highest tested doses) for 4 weeks prior to mating, and throughout mating and (in females only) gestation (and lactation). In two reliable teratology studies, no adverse effects on foetal development were seen when female rats or rabbits were administered Cereclor S52 by gavage during days 6-19 and 6-27 of gestation at up to approximately 5000 and 100 mg/kg bw/day (the highest tested doses), respectively. However, in other studies, NOAELs of 47 and 100 mg/kg bw/day (as maternal doses) have been identified for the adverse effects seen at higher doses on blood clotting seen in the offspring mediated via lactation and for the haemorrhaging potential in dams at parturition, respectively. These appear to be repeated dose toxicity effects.

Therefore, the long-term worker-DNELs for systemic effects are considered protective of pregnant women and neonates, two potentially sensitive sub-populations.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
28.75 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.58 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

Acute toxicity

No acute toxicity data in humans are available. In rats, C14-17 chlorinated paraffins (40-61% chlorination) are of low acute oral toxicity (Birtley, 1980; Chater, 1978; Kuhnert, 1986a,b). No acute inhalation or dermal exposure studies on MCCPs are available. However, based upon the low acute inhalation and dermal toxicity seen in laboratory animals exposed to C10-13 chlorinated paraffins (Howard et al. 1975; ICI, 1971, 1974) and supported by the low toxicity of C14-17 chlorinated paraffins via the oral route in rats, it is predicted that MCCPs are also likely to be of low acute inhalation and dermal toxicity. Repeated dose toxicity studies (including reproductive toxicity studies), where available, provide no relevant (dose-response) information on acute toxicity. Based on the available data, MCCPs would not be classified as acutely toxic under the EU CLP or DSD regulations.

 

DNELs for acute toxicity should be derived if an acute toxicity hazard, leading to classification and labelling (e.g. under EU CLP or DSD regulations), has been identified and there is a potential for high peak exposures (this is only usually relevant for inhalation exposures). As no acute hazard has been identified, then a DNEL for acute toxicity is unnecessary as the long-term DNEL will normally be sufficient to ensure that adverse effects do not occur. Consequently, no general population-DNELs for acute toxicity have been calculated.

 

 

Irritation/corrosivity

No irritation or corrosion data in humans are available. Following single application/instillation, C14-17 chlorinated paraffins (40-60% chlorination) are considered to be slight skin irritants in rabbits and rats (Chater, 1978; Kuhnert, 1986c,d; Moses, 1980) and slight eye irritants in rabbits (Birtley et al. 1980; Chater, 1978; Kuhnert, 1986e,f). No corrosion has been reported in laboratory animals. It is anticipated that MCCPs are unlikely to cause respiratory tract irritation. Acute and repeated dose toxicity studies, where available, provide no relevant (dose-response) information for irritant or corrosive effects. Based on the available data, MCCPs would not be classified as skin, eye or respiratory tract irritants under the EU CLP or DSD regulations. Consequently, no general population-DNELs for irritation/corrosivity have been calculated.

 

 

Sensitisation

No skin sensitisation data in humans are available. In three guinea pig maximisation tests, using diluted C14-17 chlorinated paraffins (40 or 45% chlorination), no evidence of a skin sensitisation potential was reported.Overall, the available data on MCCPs, and the generally unreactive nature of MCCPs (and data on SCCPs), indicate an absence of skin sensitisation potential. There are no data relating to respiratory sensitisation in humans or laboratory animals. However, the generally unreactive nature of this group of substances and the lack of skin sensitisation potential suggests that they do not possess the potential to cause respiratory sensitisation.

 

Based on the available data, MCCPs would not be classified as a skin or respiratory sensitiser under EU CLP or DSD regulations. Consequently, no general population-DNELs for skin or respiratory sensitisation have been calculated.

 

 

Repeated dose toxicity - oral DNEL

Dose descriptor

No data is available on repeated dose oral toxicity effects in humans. A number of studies have investigated the repeated dose oral toxicity of C14-17 chlorinated paraffins (40% or 52% chlorination) in rodents. These allow identification of a NOAEL of 23 mg/kg bw/day for kidney effects identified from a well-conducted 90-day dietary study (Elcombe, 2005b) in rats administered Cereclor S52, a C14-17 chlorinated paraffin (52% chlorinated). Increased kidney weights at 222 mg/kg bw/day (the highest tested dose in the Elcombe study) and mild ‘chronic nephritis’ and tubular pigmentation were seen at the highest tested dose of 625 mg/kg bw/day in another 90-day dietary study with Cereclor S52 (Spicer, 1984).

 

Mode-of-action

C14-17 chlorinated paraffins are considered to have only threshold effects.

 

Starting point

The same bioavailability is assumed for humans and laboratory animals. No modification of the starting point is necessary.

 

ECHA/ECETOC assessment factors (AFs) for general population

Uncertainty

AF

Justification for assessment factor (AF)

Interspecies differences

4

 

 

1*

Default ECHA/ECETOC AF for rat for toxicokinetic differences in metabolic rate (allometric scaling)

Default ECETOC AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences

Intraspecies differences

5**

 

Default ECETOC AF for general population (including children and the elderly)

Differences in duration of exposure

2

Default ECHA/ECETOC AF for subchronic (90-day) to chronic extrapolation

Dose response and endpoint specific/severity issues

1

Default ECHA AF; clear NOAEL from well-conducted 90-day dietary study. Effects at the LOAEL of 222 mg/kg bw/day are not considered severe

Quality of whole database

1

Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high

Overall AF for general population

 

40

 

 *In addition to the allometric scaling factor of 4 a further interspecies assessment factor of 2.5 (remaining difference) is proposed in REACH (Guidance R8, section R8.4.3.3, Table R.8-6), however no scientific basis for this is reported. In ECETOC Technical Report No 86 (ECETOC, 2003), a conclusion was reached that in the absence of a substance specific mode of action, allometric scaling based on metabolic rate is considered to provide an appropriate default assessment factor. No specific mode of action has been identified for the repeat-dose effects of MCCPs. As such, an assessment factor of 4 to take account of allometric scaling based on metabolic rate is considered to be appropriate for the oral route.

**A factor for the general population of 10 has been suggested by the REACH guidance (8.4.3.1). However, following a review of human data which included both sexes and a variety of disease states and ages, the use of the 95th percentile is considered sufficiently conservative to account for intraspecies variability within the general population and thus a default assessment factor of 5 is recommended for this population (ECETOC, 2003).

General population-DNEL (long-term for oral route-systemic) = 23 mg/kg bw/day / 40 = 0.58 mg/kg bw/day

 

 

Repeated dose toxicity – inhalation DNEL

Dose descriptor

There are no data available in humans or laboratory animals relating to repeated inhalation exposure. However, as described above, a number of studies have investigated the repeated dose oral toxicity of C14-17 chlorinated paraffins (40% or 52% chlorination) in rodents and this has allowed the identification of a NOAEL of 23 mg/kg bw/day from a well-conducted 90-day dietary study in rats administered Cereclor S52 (Elcombe, 2005b), with kidney effects seen at a higher dose in this and other studies.

 

Mode-of-action

C14-17 chlorinated paraffins are considered to have only threshold effects.

 

Modification of starting point

The same bioavailability is assumed for humans and laboratory animals.

 

As no data on effects of repeated inhalation exposure to MCCPs in humans or laboratory animals are available, route-to-route extrapolation to derive a DNEL for such effects from repeated dose oral toxicity studies was considered a suitable alternative (no high first-pass metabolism has been reported).

 

In the absence of route-specific information on absorption for both the starting route (oral) and end route (inhalation), a default factor of 2 should be used (which assumes 50% absorption for oral exposure, and 100% for inhalation). In this instance, the absorption, tissue distribution and elimination of a14C-labelled C14-17 chlorinated paraffin (52% chlorinated) after a single oral gavage administration at a dose level of 525 mg/kg bw was investigated in male rats (Elcombe, 2005a). Approximately 70% of the dose was recovered in the faeces and approximately 6% in the urine in the first 4 days after administration. This suggests that only about 30% of the orally administered dose was absorbed by day 4. Although there is no specific information for the inhalation route of exposure, given that the data indicate about 30% absorption by the oral route (Elcombe, 2005a) and less than 1% by the dermal route (Johnson, 2005), and in view of the very high log Pow and the very low water solubility of C14-17 chlorinated paraffins, it is reasonable to assume that inhalation absorption is also likely to be low (maximum of 50%). On this basis, it seems appropriate to assume 50% absoprtion for oral and inhalation exposure in both humans and laboratory animals, therefore there is no need to correct the starting point.

 

General population exposure via the environment is assumed to be continuous (24 h/day, 7 d/wk). Limited consumer exposure is expected.

 

Converting oral data to a corresponding air concentration in the rat is required. The oral dose for the rat is converted to this corresponding air concentration using a standard breathing volume for the rat of 1.15 m3/kg bw for 24 h/day. Thus, 23 mg/kg bw/day / 1.15 m3/kg bw/day = 20 mg/m3 (24-h exposure of the general population).

 

ECHA/ECETOC assessment factors (AFs) for general population

Uncertainty

AF

Justification for assessment factor (AF)

Interspecies differences

1

 

 

1*

Default ECHA/ECETOC AF for rat for toxicokinetic differences in metabolic rate (allometric scaling); already considered in modification of starting point

Default ECETOC AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences

Intraspecies differences

5**

 

Default ECETOC AF for general population (including children and the elderly)

Differences in duration of exposure

2

Default ECHA/ECETOC AF for subchronic (90-day) to chronic extrapolation

Dose response and endpoint specific/severity issues

1

Default ECHA AF; clear NOAEL from well-conducted 90-day dietary study. Effects at the LOAEL of 222 mg/kg bw/day are not considered severe

Quality of whole database

1

Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high

Overall AF for general population

 

10

 

*In addition to the allometric scaling factor a further interspecies assessment factor of 2.5 (remaining difference) is proposed in REACH (Guidance R8, section R8.4.3.3), however no scientific basis for this is reported. In ECETOC Technical Report No 86 (ECETOC, 2003), a conclusion was reached that in the absence of a substance specific mode of action, allometric scaling based on metabolic rate is considered to provide an appropriate default assessment factor. No specific mode of action has been identified for the repeat-dose effects of MCCPs. As such, no interspecies AF is required for the inhalation route.

**A factor for the general population of 10 has been suggested by the REACH guidance (8.4.3.1). However, following a review of human data which included both sexes and a variety of disease states and ages, the use of the 95th percentile is considered sufficiently conservative to account for intraspecies variability within the general population and thus a default assessment factor of 5 is recommended for this population (ECETOC, 2003).

General population-DNEL (long-term for inhalation route-systemic)= 20 mg/m3/ 10 = 2.0 mg/m3

 

 

Repeated dose toxicity - Dermal DNEL

Dose descriptor

There are no data available in humans or laboratory animals relating to repeated dermal exposure. However, as described above, a number of studies have investigated the repeated dose oral toxicity of C14-17 chlorinated paraffins (40% or 52% chlorination) in rodents and this has allowed the identification of a NOAEL of 23 mg/kg bw/day from a well-conducted 90-day dietary study in rats administered Cereclor S52 (Elcombe, 2005b), with kidney effects seen at a higher dose in this and other studies.

 

Mode-of-action

C14-17 chlorinated paraffins are considered to have only threshold effects.

 

Modification of starting point

The same bioavailability is assumed for humans and laboratory animals.

 

As no data on effects of repeated dermal exposure to MCCPs in humans or laboratory animals are available, route-to-route extrapolation to derive a DNEL for such effects from repeated dose oral toxicity studies was considered a suitable alternative.

 

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral-to-dermal extrapolation. Indeed, in a recent OECD-compliant in vitro study using human skin (Johnson, 2005) approximately 0.7% of Cereclor S52 was absorbed after 24 hours. The overall skin absorption determined by this study (0.7%) is likely to be an overestimate as the study was designed to measure skin penetration under the most conservative conditions. Therefore, it is appropriate to correct the starting point for differnces in dermal (1%) and oral (50%) exposures, thus 23 mg/kg bw/day x 50 = 1150 mg/kg bw/day.

 

General population exposure via the environment is assumed to be continuous (24 h/day, 7 d/wk). Limited consumer exposure is expected.

 

ECHA/ECETOC assessment factors (AFs) for general population

Uncertainty

AF

Justification for assessment factor (AF)

Interspecies differences

4

 

 

1*

Default ECHA/ECETOC AF for rat for toxicokinetic differences in metabolic rate (allometric scaling)

Default ECETOC AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences

Intraspecies differences

5**

 

Default ECETOC AF for general population (including children and the elderly)

Differences in duration of exposure

2

Default ECHA/ECETOC AF for subchronic (90-day) to chronic extrapolation

Dose response and endpoint specific/severity issues

1

Default ECHA AF; clear NOAEL from well-conducted 90-day dietary study. Effects at the LOAEL of 222 mg/kg bw/day are not considered severe

Quality of whole database

1

Default ECHA AF; the human health effects data are reliable and consistent

Overall AF for general population

 

40

 

 *In addition to the allometric scaling factor of 4 a further interspecies assessment factor of 2.5 (remaining difference) is proposed in REACH (Guidance R8, section R8.4.3.3), however no scientific basis for this is reported. In ECETOC Technical Report No 86 (ECETOC, 2003), a conclusion was reached that in the absence of a substance specific mode of action, allometric scaling based on metabolic rate is considered to provide an appropriate default assessment factor. No specific mode of action has been identified for the repeat-dose effects of MCCPs. As such, an assessment factor of 4 to take account of allometric scaling based on metabolic rate is considered to be appropriate for the dermal route.

**A factor for the general population of 10 has been suggested by the REACH guidance (8.4.3.1). However, following a review of human data which included both sexes and a variety of disease states and ages, the use of the 95th percentile is considered sufficiently conservative to account for intraspecies variability within the general population and thus a default assessment factor of 5 is recommended for this population (ECETOC, 2003).

General population-DNEL (long-term for dermal route-systemic) = 1150 mg/kg bw/day / 40 = 28.75 mg/kg bw/day

 

 

Genotoxicity

No information is available on genotoxic effects in humans. C14-17 chlorinated paraffins (40-52% chlorination) consistently showed no evidence of mutagenic potential in four Ames bacterial tests. No in vitro cytogenetic or gene mutation studies in mammalian cells are available for MCCPs. However, for a C10-13 chlorinated paraffin (56% chlorinated) a negative result was obtained in a well-conducted in vitro gene mutation assay tested at up to cytotoxic concentrations in hamster cells; a similar negative result would, therefore, be anticipated for MCCPs. Three in vivo bone marrow studies demonstrate that C14-17 chlorinated paraffins are not clastogenic towards this target tissue, and an ADME study (Darnerud and Brandt, 1982) has shown distribution of MCCPs to the bone marrow. Negative results for in vivo genotoxicity tests in somatic and germ cells have been obtained for SCCPs. Overall, the available data on MCCPs (and SCCPs), and consideration of their generally unreactive nature, indicates that MCCPs are not mutagenic and do not directly interact with DNA. Under EU CLP and DSD regulations, C14-17 chlorinated paraffins would not be classified as mutagenic. Consequently, no general population-DN(M)ELs for genotoxicity have been calculated.

 

 

Carcinogenicity

No information on carcinogenic effects in humans are available. In long-term cancer bioassays (conducted as part of the US National Toxicology Program), significant increases in the incidences of liver (in males and females) and thyroid (in females only) tumours were seen in laboratory animals administered a C12 chlorinated paraffin (60% chlorinated) by gavage at 125 mg/kg bw/day and above (in mice) and 312 mg/kg bw/day and above (in rats), 5 d/wk for 2 yrs, and of kidney tumours in male rats at 312 mg/kg bw/day. Clear modes of action were indicated for the liver and thyroid tumours, and these tumours are considered to be of little or no relevance to human health. The underlying mechanism for the kidney tumours has not been fully elucidated. However, recent mechanistic evidence shows that alpha2u-binding is probably the primary mechanism for kidney tumour formation induced by this SCCP in male rats, and the available evidence strongly suggests that the underlying mechanism would not be relevant to humans. Taking into account all the other existing data on MCCPs, specifically the lack of genotoxic activity and the kidney toxicity seen in repeated dose toxicity studies in rats (at 222 mg/kg bw/day and above), it cannot be completely ruled out that this form of kidney toxicity might lead to cancer in male and female rats through a non-genotoxic mode of action, even though with the C12 chlorinated paraffin kidney tumours were seen in male rats only. Under the EU CLP and DSD regulations, MCCPs would not be classified for human carcinogenicity.

 

Therefore, the long-term general population DNELs for systemic effects are considered protective of potential carcinogenic effects.

 

 

Reproductive toxicity (fertility impairment and developmental toxicity)

No information is available on fertility or developmental effects in humans. In two reliable one-generation reproduction studies, no effects on fertility were seen when male and female rats were administered Cereclor S52 in the diet at up to approximately 100 and 400 mg/kg bw/day (the highest tested doses) for 4 weeks prior to mating, and throughout mating and (in females only) gestation (and lactation). In two reliable teratology studies, no adverse effects on foetal development were seen when female rats or rabbits were administered Cereclor S52 by gavage during days 6-19 and 6-27 of gestation at up to approximately 5000 and 100 mg/kg bw/day (the highest tested doses), respectively. However, in other studies, NOAELs of 47 and 100 mg/kg bw/day (as maternal doses) have been identified for the adverse effects on blood clotting seen in the offspring mediated via lactation and for the haemorrhaging potential in dams at parturition, respectively. These appear to be repeated dose toxicity effects.

 

Therefore, the long-term general population DNELs for systemic effects are considered protective of pregnant women and neonates, two potentially sensitive sub-populations.