Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
29.4 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
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
333.3 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
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

Acute toxicity

No acute toxicity data in humans are available. C10-13 chlorinated paraffins (40-70% chlorination) are of very low acute toxicity in laboratory animal studies, with some signs of systemic toxicity seen in rats and mice administered very high oral doses of 13 and 27 g/kg bw, respectively (NTP, 1986), but no signs of systemic toxicity in rats following 1 h exposure to vapours of 3.3 g/m3 and greater or with a 24-h dermal dose of 2.8 g/kg bw (Howard et al. 1975; ICI, 1971, 1974). Repeated dose toxicity studies (including reproductive toxicity studies), where available, provide no relevant (dose-response) information on acute toxicity. Based on the available data, SCCPs 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 for systemic effects will normally be sufficient to ensure that adverse effects do not occur. Consequently, no worker-DNELs for acute toxicity have been calculated.

Irritation/corrosivity

In well reported studies (Hoechst AG, 1986, 1983) conducted according to modern standards, C10-13 chlorinated paraffins (59 and 70% chlorination) have the potential to produce, at most, mild irritation when applied under a semi-occlusive dressing to the shaven skin of rabbits for 4 h. More pronounced irritation can occur following repeated exposure, and is probably due to a defatting action. Limited information in humans indicates that SCCPs do not cause skin irritation. There is no information from humans on the potential for SCCPs to cause eye irritation. However, C10-13 chlorinated paraffins (40 to 63% chlorination) produce only mild eye irritation in rabbits (Birtley et al. 1980; Hoechst AG, 1966; Howard et al. 1975; ICI, 1974; McElligott, 1966).The studies in laboratory animals and humans indicate that SCCPs are not corrosive to the skin and eyes. It is anticipated that SCCPs 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, SCCPs 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

A number of guinea pig maximisation tests, using diluted and undiluted C10-13 chlorinated paraffins (50 to 56% chlorination), have been performed. No consistent evidence of a skin sensitisation potential was reported in these tests, and no evidence was seen in limited human studies. Overall, the available data on SCCPs, and the generally unreactive nature of SCCPs (and data on MCCPs), 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, SCCPs 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.

Oral DNEL (repeated dose toxicity)

Not considered applicable for workers.

 

Inhalation DNEL (repeated dose toxicity)

Dose descriptor

There are no data available in humans or laboratory animals relating to repeated inhalation exposure. However, a number of reliable studies have investigated the repeated dose oral toxicity of C10-13 chlorinated paraffins (58 and 60% chlorination) in rodents and this has allowed the identification of a human relevant NOAEL of 100 mg/kg bw/day from a well-conducted 90-day dietary GLP study in rats administered a C10-12 chlorinated paraffin (58% chlorination), with kidney effects seen at a higher dose in this (IRDC, 1984a) and other studies.

Mode-of-action

C10-13 chlorinated paraffins are considered to have only threshold effects, as the weight-of-evidence indicates that SCCPs do not have genotoxic potential.

Modification of starting point

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals.

As no data on effects of repeated inhalation exposure to SCCPs 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 or is expected).

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 three14C-labelled C12 chlorinated paraffins (17, 56 or 69% chlorination) after a single oral gavage administration was investigated in pregnant and non-pregnant female mice (Darnerud et al. 1982). Significant absorption, possibly about 80 and 90% of the administered dose of the 69 and 58% chlorinated C12 paraffin, respectively, can occur within 12 h following single oral administration. There is no specific information for the inhalation route of exposure; however, given that the data indicate less than 0.01% absorption by the dermal route (Scott, 1985), and in view of the very high log Pow and the very low water solubility of SCCPs, it is reasonable to assume that inhalation absorption is also likely to be low. Although it is unlikely that absorption of SCCPs will be as high following inhalation exposure as following oral administration, a health precautionary approach is to assume similar absorption. Therefore, the starting point has not been corrected.

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, 100 mg/kg bw/day / 0.38 m3/kg bw/day = 263 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 100 mg/kg bw/day / 0.38 m3/kg bw x (6.7 m3/ 10 m3) = 176 mg/m3 (8-h exposure of workers, light activity).

ECHA/ECETOC AFs for workers – inhalation DNEL (repeated dose toxicity)

 

Uncertainty

AF

 Justification for 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 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; human health relevant NOAEL from well-conducted 90-day dietary study. Effects at the LOAEL of 625 mg/kg bw/day (slight reduction in body weight gain and kidney effects ) were 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.May want to increase this AF as no 1- or 2-gen studies.

Overall AF for worker

 

6

 

Worker (light activity) -DNEL (long-term for inhalation route-systemic) = 176 mg/m3/ 6 = 29.4 mg/m3

Dermal DNEL (repeated dose toxicity)

Dose descriptor

There are no data available in humans or laboratory animals relating to repeated dermal exposure which are suitable as the basis from which to calculate a dermal DNEL.However, a number of reliable studies have investigated the repeated dose oral toxicity of C10-13 chlorinated paraffins (58 and 60% chlorination) in rodents and this has allowed the identification of a human relevant NOAEL of 100 mg/kg bw/day from a well-conducted 90-day dietary GLP study in rats administered a C10-12 chlorinated paraffin (58% chlorination), with kidney effects seen at a higher dose in this (IRDC, 1984a) and other studies.

Mode-of-action

C10-13 chlorinated paraffins are considered to have only threshold effects, as the weight-of-evidence indicates that SCCPs do not have genotoxic potential.

Modification of starting point

In the absence of any data to the contrary, thesame bioavailability is assumed for humans and laboratory animals. As no relevant data on effects of repeated dermal exposure to SCCPs in humans or laboratory animals are available, route-to-route extrapolation to calculate a dermal DNEL 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 anin vitrostudy (Scott, 1985) less than 0.01% of Cereclor 56L (a C10-13 chlorinated paraffin; 56% chlorination) was absorbed through human epidermal membrane during 54 hours continuous skin contact, demonstrating extremely poor dermal absorption. However, a very conservative and health precautionary approach is to assume 1% dermal exposure in humans for risk characterization purposes. Therefore, it is appropriate to correct the starting point for differences in dermal (1%) and oral (80%) exposures, thus 100 mg/kg bw/day x 80 = 8 g/kg bw/day

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

ECHA/ECETOC AFs for workers – dermal DNEL (repeated dose toxicity)

 

Uncertainty

AF

Justification for 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

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; human health relevant NOAEL from well-conducted 90-day dietary study. Effects at the LOAEL of 625 mg/kg bw/day (slight reduction in body weight gain and kidney effects) were 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.May want to increase this AF as no 1- or 2-gen studies.

Overall AF for worker

 

24

 

Worker-DNEL (long-term for dermal route-systemic) = 8 g/kg bw/day / 24 = 333.3 mg/kg bw/day

Genotoxicity

No information is available on genotoxic effects in humans. Various C10-13 chlorinated paraffins (50-60% chlorination) have shown no evidence of mutagenic activity to bacteria (S. typhimurium and E. coli) in a number of Ames tests when tested at up to 5 mg/plate in the presence or absence of a mammalian liver activation system (S9). In a gene mutation (HPRT) study in Chinese hamster lung (V79) cells, a C10-13 chlorinated paraffin (56% chlorination) did not induce a significant, reproducible increase in mutant frequency at doses of up to 75 or 30 ug/mL with or without S9, respectively (Muller, 1987). No standard in vitro cytogenetic studies are available, but two well-conducted in vivo studies (Muller, 1989; IRDC, 1982) suggest that C10-13 chlorinated paraffins (58% chlorination) do not produce chromosome damage in somatic (bone marrow), and toxicokinetic study (Darnerud et al. 1982) has shown distribution of SCCPs to the bone marrow. In addition, a C10-13 chlorinated paraffins (58% chlorination) showed no evidence of germ cell mutagenicity in a dominant lethal assay in rats (IRDC, 1983). Overall, the data available on SCCPs (and MCCPs) and a consideration of the generally unreactive nature of these substances indicate that SCCPs (as a group) are not mutagenic and do not directly interact with DNA. Under EU CLP and DSD regulations, C10-13 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 to GLP 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 (but not at 625 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 SCCPs, specifically the lack of genotoxic activity and the kidney toxicity seen in repeated dose toxicity studies in rats (at 625 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. Therefore, given that SCCPs are not genotoxic, it is considered that there would be no risk of kidney tumour development associated with exposures lower than those required to produce chronic toxicity in this target organ. A NOAEL for kidney toxicity in male rats has been previously identified at 100 mg/kg bw/day in a 90-day dietary study. Therefore, the long-term worker-DNELs for systemic effects are considered protective of potential carcinogenic effects.

 

Reproductive toxicity (fertility impairment and developmental toxicity)

Fertility DNEL

No information is available on fertility effects in humans and there are no laboratory animal studies specifically investigating such effects. [A testing proposal for a two-generation study has been submitted for SCCPs.] However several repeated oral dose toxicity studies have assessed the reproductive organs of laboratory animals.In a GLP study (IRDC, 1981), male and female rats were administered a C10-12 chlorinated paraffin (58% chlorination) by oral gavage for 14 days at doses of 0, 30, 100, 300, 1000 or 3000 mg/kg bw/day and all surviving animals were killed and a complete post-mortem and tissue examination was performed. In top dose animals, a statistically significant decrease in absolute and relative ovary weights (35 to 48%, respectively) was seen compared to controls, and a slight decrease in testis weights, whereas no changes were seen in this reproductive organs at 1000 mg/kg bw/day and below. In good quality NTP studies, to GLP, no changes were seen in the seminal vesicles, prostate, testes, ovaries or uterus of rats and mice administered a C12 chlorinated paraffin (60% chlorination) at up to 5000 and 2000 mg/kg bw/day, respectively, for 13 weeks (NTP, 1986).Overall, therefore, a health precautionary approach is to use the NOAEL of 1000 mg/kg bw/day for the calculation of a fertility DNEL.

Inhalation DNEL (fertility)

Dose descriptor

There are no data available in humans or laboratory animals relating to fertility affects following repeated inhalation exposure. However, as explained above, a NOAEL of 1000 mg/kg bw/day has been seen in repeated dose toxicity studies for effects on the reproductive organs of rats following oral administration.

Mode-of-action

C10-13 chlorinated paraffins are considered to have only threshold effects, as the weight-of-evidence indicates that SCCPs do not have genotoxic potential.

Modification of starting point

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals. Route-to-route extrapolation to calculate a inhalation DNEL(fertility) from repeated dose oral toxicity studies was considered suitable (no high first-pass metabolism has been reported or is expected).

As explained previously, significant absorption, about 80% of the administered dose can occur within 12 h following single oral administration in mice (Darnerud et al. 1982). It is unlikely that absorption of SCCPs will be as high after inhalation exposure as following oral administration, but a health precautionary approach is to assume similar absorption. Therefore, the starting point has not been corrected.

The oral dose for the rat is converted to the corresponding air concentration, using a standard breathing volume for the rat, of 0.38 m3/kg bw for 8 h/day (exposure of workers). To account for the presumed light activity of workers, this value has been corrected for an increase in breathing volume, thus 1000 mg/kg bw/day / 0.38 m3/kg bw x (6.7 m3/ 10 m3) = 1763 mg/m3 (8-h exposure of workers, light activity).

ECHA/ECETOC AFs for workers – inhalation DNEL (fertility)

Uncertainty

AF

Justification for AF

Interspecies differences

1

 

 

1

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

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

3

ECHA/ECETOC AF for subacute (14-day) to chronic extrapolation. As a higher NOAEL was seen in reliable 90-day studies, this AF does not need to be increased further

Dose response and endpoint specific/severity issues

1

Default ECHA AF; NOAEL from well-conducted 14-day gavage study. Effects at the LOAEL of 3000 mg/kg bw/day (significant reduction in ovary weight) are considered to be secondary to other signs of toxicity (e.g. 20% decrease in body weight at this top dose), and indeed a NOAEL of 2000 mg/kg bw/day was seen in a reliable 90-day dietary study

Quality of whole database

3

ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high. However, a 2-gen study is proposed for SCCPs, therefore a additional AF seems appropriate

Overall AF for worker

 

27

 

Worker (light activity) -DNEL (fertility)long-term for inhalation route-systemic = 1763 mg/m3/ 27 = 65.3 mg/m3

Overall, therefore, as this inhalation DNEL(fertility) is higher than the inhalation DNEL for repeated dose effects (29.4 mg/m3), the long-term inhalation worker-DNEL for systemic effects is considered protective of fertility impairment in workers, and will be used in the risk characterisation.

Dermal DNEL (fertility)

Dose descriptor

There are no data available in humans or laboratory animals relating to fertility affects following repeated dermal exposure. However, as explained above, in repeated dose toxicity studies a conservative NOAEL of 1000 mg/kg bw/day for effects on the reproductive organs of rats following oral administration has been identified.

Mode-of-action

C10-13 chlorinated paraffins are considered to have only threshold effects, as the weight-of-evidence indicates that SCCPs do not have genotoxic potential.

Modification of starting point

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals.Route-to-route extrapolation to calculate a dermal DNEL (fertility) from repeated dose oral toxicity studies was considered suitable.

Less than 0.01% of Cereclor 56L was absorbed through human epidermal membrane during 54 hours continuous skin contact, demonstrating extremely poor dermal absorption (Scott, 1985). However, a very conservative and health precautionary approach is to assume 1% dermal exposure in humans for risk characterization purposes. Therefore, it is appropriate to correct the starting point for differences in dermal (1%) and oral (80%) exposures, thus 1000 mg/kg bw/day x 80 = 80 g/kg bw/day

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

ECHA/ECETOC AFs for workers – dermal DNEL (fertility)

 

Uncertainty

AF

Justification for 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

3

Default ECETOC AF for (healthy) worker

Differences in duration of exposure

3

ECHA/ECETOC AF for subacute (14-day) to chronic extrapolation. As a higher NOAEL was seen in reliable 90-day studies, this AF does not need to be increased further

Dose response and endpoint specific/severity issues

1

Default ECHA AF; NOAEL from well-conducted 14-day gavage study. Effects at the LOAEL of 3000 mg/kg bw/day (significant reduction in ovary weight) are considered to be secondary to other signs of toxicity (e.g. 20% decrease in body weight at this top dose), and indeed a NOAEL of 2000 mg/kg bw/day was seen in a reliable 90-day dietary study

Quality of whole database

3

ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high. However, a 2-gen study is proposed for SCCPs, therefore a additional AF seems appropriate

Overall AF for worker

 

108

 

Worker-DNEL (fertility)long-term for dermal route-systemic = 80 g/kg bw/day / 108 = 740 mg/kg bw/day

Overall, therefore, as this dermal DNEL(fertility) is higher than the dermal DNEL for repeated dose effects (333 mg/kg bw/day), the long-term dermal worker-DNEL for systemic effect is considered protective of fertility impairment in workers, and will be used in the risk characterisation.

Developmental

No information is available on developmental effects in humans. In a well-conducted GLP study (Spicer et al. 1982) [IRDC, 1982], similar to OECD Guideline 414, a C10-13 chlorinated paraffin (58% chlorination) produced developmental effects in rats at a dose which also caused severe maternal toxicity (2000 mg/kg bw/day), but no developmental effects were seen at lower doses (500 mg/kg bw/day and below). No developmental effects were observed in a study in rabbits at up to 100 mg/kg bw/day, although maternally toxic doses were not tested (Miller, 1983). Overall, therefore, a NOAEL of 500 mg/kg bw/day for developmental effects is established. As this is higher than the NOAEL for repeated dose effects (100 mg/kg bw/day), 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:
8.7 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
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
200 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
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.5 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
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

Acute toxicity

As explained in the worker DNEL section above, no acute hazard has been identified for SCCPs, therefore a DNEL for acute toxicity is unnecessary as the long-term systemic general population DNEL will be sufficient to ensure that adverse effects do not occur.

 

Irritation/corrosivity

As explained in the worker DNEL section above, based on the available data, SCCPs would not be classified as skin, eye or respiratory tract irritants. Consequently, no general population-DNELs for irritation/corrosivity have been calculated.

 

Sensitisation

As explained in the worker DNEL section above, based on the available data, SCCPs would not be classified as a skin or respiratory sensitiser and therefore, no general population-DNELs for skin or respiratory sensitisation have been calculated.

 

Oral DNEL (repeated dose toxicity)

Dose descriptor

As explained in the worker DNEL section above, no data is available on repeated dose oral toxicity effects in humans, but a number of reliable studies have investigated the repeated dose oral toxicity of SCCPs in rodents and this has allowed the identification of a human relevant NOAEL of 100 mg/kg bw/day from a well-conducted 90-day dietary GLP study in rats administered a C10-12 chlorinated paraffin (58% chlorination), with kidney effects seen at a higher dose in this (IRDC, 1984a) and other studies.

Mode-of-action

C10-13 chlorinated paraffins are considered to have only threshold effects, as the weight-of-evidence indicates that SCCPs do not have genotoxic potential.

Modification of starting point

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals. No modification of the starting point is necessary.

ECHA/ECETOC AFs for general population – oral DNEL (repeated dose toxicity)

Uncertainty

AF

 Justification for AF

Interspecies differences

4

 

 

1

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

Default ECETOC[1]AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences

Intraspecies differences

5

 

Default ECETOC[2]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; human health relevant NOAEL from well-conducted 90-day dietary study. Effects at the LOAEL of 625 mg/kg bw/day (slight reduction in body weight gain and kidney effects ) were 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.May want to increase this AF as no 1- or 2-gen studies.

Overall AF for general population

 

40

 

General population-DNEL (long-term for oral route-systemic)= 100 mg/kg bw/day / 40 = 2.5 mg/kg bw/day

Inhalation DNEL (repeated dose toxicity)

Dose descriptor

As explained in the worker DNEL section above, there are no data available in humans or laboratory animals relating to repeated inhalation exposure, however, a number of reliable studies have investigated the repeated dose oral toxicity of SCCPs in rodents and this has allowed the identification of a human relevant NOAEL of 100 mg/kg bw/day from a well-conducted 90-day dietary GLP study in rats administered a C10-12 chlorinated paraffin (58% chlorination), with kidney effects seen at a higher dose in this (IRDC, 1984a) and other studies.

Mode-of-action

C10-13 chlorinated paraffins are considered to have only threshold effects, as the weight-of-evidence indicates that SCCPs do not have genotoxic potential.

Modification of starting point

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals. Route-to-route extrapolation to calculate an inhalation DNEL from repeated dose oral toxicity studies was considered suitable (no high first-pass metabolism has been reported or is expected).

As explained previously, significant absorption, about 80% of the administered dose can occur within 12 h following single oral administration in mice (Darnerud et al. 1982). It is unlikely that absorption of SCCPs will be as high after inhalation exposure as following oral administration, but a health precautionary approach is to assume similar absorption. Therefore, the starting point has not been corrected.

General population exposure via the environment is assumed to be continuous (24 h/day, 7 d/wk). Only 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, 100 mg/kg bw/day / 1.15 m3/kg bw/day = 87 mg/m3(24-h exposure of the general population).

ECHA/ECETOC AFs for general population – inhalation DNEL (repeated dose toxicity)

Uncertainty

AF

 Justification for 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 ECETOC[1]AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences

Intraspecies differences

5

 

Default ECETOC[2]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; human health relevant NOAEL from well-conducted 90-day dietary study. Effects at the LOAEL of 625 mg/kg bw/day (slight reduction in body weight gain and kidney effects ) were 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.May want to increase this AF as no 1- or 2-gen studies.

Overall AF for worker

 

10

 

General population-DNEL (long-term for inhalation route-systemic)= 87 mg/m3/ 10 = 8.7 mg/m3

Dermal DNEL(repeated dose toxicity)

Dose descriptor

As explained in the worker DNEL section above, there are no data available in humans or laboratory animals relating to repeated dermal exposure which are suitable as the basis from which to calculate a dermal DNEL. However, a number of reliable studies have investigated the repeated dose oral toxicity of SCCPs in rodents and this has allowed the identification of a human relevant NOAEL of 100 mg/kg bw/day from a well-conducted 90-day dietary GLP study in rats administered a C10-12 chlorinated paraffin (58% chlorination), with kidney effects seen at a higher dose in this (IRDC, 1984a) and other studies.

Mode-of-action

C10-13 chlorinated paraffins are considered to have only threshold effects, as the weight-of-evidence indicates that SCCPs do not have genotoxic potential.

Modification of starting point

In the absence of any data to the contrary, thesame bioavailability is assumed for humans and laboratory animals.Route-to-route extrapolation to calculate a dermal DNEL from repeated dose oral toxicity studies was considered suitable.

Less than 0.01% of Cereclor 56L was absorbed through human epidermal membrane during 54 hours continuous skin contact, demonstrating extremely poor dermal absorption (Scott, 1985). However, a very conservative and health precautionary approach is to assume 1% dermal exposure in humans for risk characterization purposes. Therefore, it is appropriate to correct the starting point for differences in dermal (1%) and oral (80%) exposures, thus 100 mg/kg bw/day x 80 = 8 g/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 AFs for general population – dermal DNEL (repeated dose toxicity)

Uncertainty

AF

 Justification for 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; human health relevant NOAEL from well-conducted 90-day dietary study. Effects at the LOAEL of 625 mg/kg bw/day (slight reduction in body weight gain and kidney effects ) were 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.May want to increase this AF as no 1- or 2-gen studies.

Overall AF for worker

 

40

 


General population-DNEL (long-term for dermal route-systemic) = 8 g/kg bw/day / 40 = 200 mg/kg bw/day

Genotoxicity

As explained in the worker DNEL section above, the weight-of-evidence indicates that SCCPs do not have genotoxic potential, and would not be classified as mutagenic. Consequently, no general population-DMELs for genotoxicity have been calculated.

 

Carcinogenicity

As explained in the worker DNEL section above, increases in the incidence of liver, thyroid and kidney tumours have been observed in NTP rodent cancer bioassays. Clear modes-of-action have been 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, although the available evidence strongly suggests that the underlying mechanism would not be relevant to humans (although this cannot be ruled out). Given that SCCPs are not genotoxic, it is considered that there would be no risk of kidney tumour development associated with exposures lower than those required to produce chronic toxicity in this target organ. A NOAEL for kidney toxicity in male rats has been previously identified at 100 mg/kg bw/day in a 90-day dietary study. Therefore, the long-term worker-DNELs for systemic effects are considered protective of potential carcinogenic effects in the general population.

 

Reproductive toxicity (fertility impairment and developmental toxicity)

Fertility DNEL

No information is available on fertility effects in humans and there are no laboratory animal studies specifically investigating such effects. [A testing proposal for a two-generation study has been submitted for SCCPs.] However several repeated oral dose toxicity studies have assessed the reproductive organs of laboratory animals.In a GLP study (IRDC, 1981), male and female rats were administered a C10-12 chlorinated paraffin (58% chlorination) by oral gavage for 14 days at doses of 0, 30, 100, 300, 1000 or 3000 mg/kg bw/day and all surviving animals were killed and a complete post-mortem and tissue examination was performed. In top dose animals, a statistically significant decrease in absolute and relative ovary weights (35 to 48%, respectively) was seen compared to controls, and a slight decrease in testis weights, whereas no changes were seen in these reproductive organs at 1000 mg/kg bw/day and below. In good quality NTP studies, to GLP, no changes were seen in the seminal vesicles, prostate, testes, ovaries or uterus of rats and mice administered a C12 chlorinated paraffin (60% chlorination) at up to 5000 and 2000 mg/kg bw/day, respectively, for 13 weeks (NTP, 1986).Overall, therefore, a health precautionary approach is to use the NOAEL of 1000 mg/kg bw/day for the calculation of a fertility DNEL.

Oral DNEL (fertility)

Dose descriptor

As explained in the worker DNEL section above, there are no data available in humans or laboratory animals relating to fertility affects following repeated oral exposure. However, in repeated dose toxicity studies a NOAEL of 1000 mg/kg bw/day for effects on the reproductive organs of rats has been seen following oral administration.

Mode-of-action

C10-13 chlorinated paraffins are considered to have only threshold effects, as the weight-of-evidence indicates that SCCPs do not have genotoxic potential.

Modification of starting point

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals. No modification of the starting point is necessary.

ECHA/ECETOC AFs for general population – oral DNEL (fertility)

Uncertainty

AF

Justification for 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

3

ECHA/ECETOC AF for subacute (14-day) to chronic extrapolation. As a higher NOAEL was seen in reliable 90-day studies, this AF does not need to be increased further

Dose response and endpoint specific/severity issues

1

Default ECHA AF; NOAEL from well-conducted 14-day gavage study, with effects at the LOAEL of 3000 mg/kg bw/day (significant reduction in ovary weight) considered to be secondary to other signs of toxicity (e.g. 20% decrease in body weight at this top dose). Indeed a NOAEL of 2000 mg/kg bw/day was seen in a reliable 90-day dietary study

Quality of whole database

2

ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high. However, a 2-gen study is proposed for SCCPs, therefore a additional AF seems appropriate

Overall AF for general population

 

120

 

General population-DNEL (fertility) long-term for oral route-systemic = 1000 mg/kg bw/day / 120 = 8.33 mg/kg bw/day

As this oral DNEL (fertility) is higher than the oral DNEL for repeated dose effects (2.5 mg/kg bw/day), the long-term oral DNEL for systemic effects is considered protective of fertility impairment in the general population, and will be used in the risk characterisation.

Inhalation DNEL (fertility)

Dose descriptor

There are no data available in humans or laboratory animals relating to fertility affects following repeated inhalation exposure. However, in repeated dose toxicity studies a NOAEL of 1000 mg/kg bw/day for effects on the reproductive organs of rats has been seen following oral administration.

Mode-of-action

C10-13 chlorinated paraffins are considered to have only threshold effects, as the weight-of-evidence indicates that SCCPs do not have genotoxic potential.

Modification of starting point

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals.Route-to-route extrapolation to calculate a inhalation DNEL(fertility) from repeated dose oral toxicity studies was considered suitable (no high first-pass metabolism has been reported or is expected).

As explained previously, significant absorption, about 80% of the administered dose can occur within 12 h following single oral administration in mice (Darnerud et al. 1982). It is unlikely that absorption of SCCPs will be as high after inhalation exposure as following oral administration, but a health precautionary approach is to assume similar absorption. Therefore, the starting point has not been corrected.

General population exposure via the environment is assumed to be continuous (24 h/day, 7 d/wk). Only 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, 1000 mg/kg bw/day / 1.15 m3/kg bw/day = 870 mg/m3 (24-h exposure of the general population).

ECHA/ECETOC AFs for general population – inhalation DNEL (fertility)

Uncertainty

AF

Justification for AF

Interspecies differences

1

 

 

1

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

Default ECETOC[1]AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences

Intraspecies differences

5

 

Default ECETOC[2]AF for general population (including children and the elderly)

Differences in duration of exposure

3

ECHA/ECETOC AF for subacute (14-day) to chronic extrapolation. As a higher NOAEL was seen in reliable 90-day studies, this AF does not need to be increased further

Dose response and endpoint specific/severity issues

1

Default ECHA AF; NOAEL from well-conducted 14-day gavage study, with effects at the LOAEL of 3000 mg/kg bw/day (significant reduction in ovary weight) considered to be secondary to other signs of toxicity (e.g. 20% decrease in body weight at this top dose). Indeed a NOAEL of 2000 mg/kg bw/day was seen in a reliable 90-day dietary study

Quality of whole database

2

 

ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high. However, a 2-gen study is proposed for SCCPs, therefore a additional AF seems appropriate

Overall AF for worker

 

30

 

General population-DNEL (fertility)long-term for inhalation route-systemic= 870 mg/m3/ 30 = 19 mg/m3

As this inhalation DNEL(fertility) is higher than the inhalation DNEL for repeated dose effects (8.7 mg/m3), the long-term inhalation DNEL for systemic effects is considered protective of fertility impairment in the general population, and will be used in the risk characterisation.

Dermal DNEL (fertility)

Dose descriptor

There are no data available in humans or laboratory animals relating to fertility affects following repeated dermal exposure. However, as previously explained, in repeated dose toxicity studies a NOAEL of 1000 mg/kg bw/day for effects on the reproductive organs of rats has been seen following oral administration.

Mode-of-action

C10-13 chlorinated paraffins are considered to have only threshold effects, as the weight-of-evidence indicates that SCCPs do not have genotoxic potential.

Modification of starting point

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals. Route-to-route extrapolation to calculate a dermal DNEL (fertility) from repeated dose oral toxicity studies was considered suitable.

Less than 0.01% of Cereclor 56L was absorbed through human epidermal membrane during 54 hours continuous skin contact, demonstrating extremely poor dermal absorption (Scott, 1985). However, a very conservative and health precautionary approach is to assume 1% dermal exposure in humans for risk characterization purposes. Therefore, it is appropriate to correct the starting point for differences in dermal (1%) and oral (80%) exposures, thus 1000 mg/kg bw/day x 80 = 80 g/kg bw/day

ECHA/ECETOC AFs for general population – dermal DNEL (fertility)

Uncertainty

AF

Justification for AF

Interspecies differences

4

 

 

1

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

Default ECETOC[1]AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences

Intraspecies differences

5

 

Default ECETOC[2]AF for general population (including children and the elderly)

Differences in duration of exposure

3

ECHA/ECETOC AF for subacute (14-day) to chronic extrapolation. As a higher NOAEL was seen in reliable 90-day studies, this AF does not need to be increased further

Dose response and endpoint specific/severity issues

1

Default ECHA AF; NOAEL from well-conducted 14-day gavage study, with effects at the LOAEL of 3000 mg/kg bw/day (significant reduction in ovary weight) considered to be secondary to other signs of toxicity (e.g. 20% decrease in body weight at this top dose). Indeed a NOAEL of 2000 mg/kg bw/day was seen in a reliable 90-day dietary study

Quality of whole database

2

 

ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high. However, a 2-gen study is proposed for SCCPs, therefore a additional AF seems appropriate

Overall AF for worker

 

120

 

General population-DNEL (fertility)long-term for dermal route-systemic= 80 g/kg bw/day / 120 = 666.7 mg/kg bw/day

As this dermal DNEL (fertility) is higher than the dermal DNEL for repeated dose effects (200 mg/kg bw/day), the long-term dermal DNEL for systemic effects is considered protective of fertility impairment in the general population, and will be used in the risk characterisation.

Developmental

No information is available on developmental effects in humans. In a well-conducted GLP study (Spicer et al. 1982) [IRDC, 1982], similar to OECD Guideline 414, a C10-13 chlorinated paraffin (58% chlorination) produced developmental effects in rats at a dose which also caused severe maternal toxicity (2000 mg/kg bw/day), but no developmental effects were seen at lower doses (500 mg/kg bw/day and below). No developmental effects were observed in a study in rabbits at up to 100 mg/kg bw/day, although maternally toxic doses were not tested (Miller, 1983). Overall, therefore, a NOAEL of 500 mg/kg bw/day for developmental effects is established. As this is significantly higher than the NOAEL for repeated dose effects (100 mg/kg bw/day), the long-term general population-DNELs for systemic effects are considered protective of pregnant women and neonates, two potentially sensitive sub-populations.